Q4 2023 Design Therapeutics Inc Earnings Call

March 19, 2024

[music].

Operator: Good afternoon, and welcome to Design’s Conference Call. At this time, all participants are on a listen only mode. There will be a question and answer session after the prepared remarks. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Dr. Sean Jeffries, Chief Operating Officer of Design Therapeutics. You may begin.

Okay.

Good afternoon, and welcome to designs conference call. At this time all participants are in a listen only mode. There'll be a question and answer session. After the prepared remarks. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Dr. Shawn Jeffries Chief operating officer of design Therapeutics, you may begin.

At this time all participants are in a listen only mode. There'll be a question and answer session. After the prepared remarks. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Dr. Shawn Jeffries Chief operating officer of design Therapeutics, you may begin.

There'll be a question and answer session. After the prepared remarks. Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Dr. Shawn Jeffries Chief operating officer of design Therapeutics, you may begin.

Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to Dr. Shawn Jeffries Chief operating officer of design Therapeutics, you may begin.

I would now like to turn the call over to Dr. Shawn Jeffries Chief operating officer of design Therapeutics, you may begin.

Welcome and thank you for joining us today. Earlier, we issued a press release outlining our fourth quarter and full year of 2023 financial results and updates across our portfolio of gene tax small molecule genomic medicine. The slides that will be using today during today's call will be available along with the recording of this call in the investors section of our website design, TX Dot com. I'm, Sean Jeffries, Chief operating officer of design and I'm joined today on the call by our chairman and CEO, Dr. Petite shop.

Earlier, we issued a press release outlining our fourth quarter and full year of 2023 financial results and updates across our portfolio of gene tax small molecule genomic medicine. The slides that will be using today during today's call will be available along with the recording of this call in the investors section of our website design, TX Dot com. I'm, Sean Jeffries, Chief operating officer of design and I'm joined today on the call by our chairman and CEO, Dr. Petite shop.

The slides that will be using today during today's call will be available along with the recording of this call in the investors section of our website design, TX Dot com. I'm, Sean Jeffries, Chief operating officer of design and I'm joined today on the call by our chairman and CEO, Dr. Petite shop.

I'm, Sean Jeffries, Chief operating officer of design and I'm joined today on the call by our chairman and CEO, Dr. Petite shop.

Sean Jeffries: During this call, we will use forward-looking statements to related to our current expectations and plans, including our program development plans, which are subject to risk and uncertainties. Actual results may differ materially due to various important factors, including those described in the risk factors section of our most recently filed Form 10-K. These statements represent our views as of this call and should not be relied upon as representing our views as of any date in the future. We take no obligation to publicly update any forward-looking statements. With that, I'd like to turn the call over to Dr. Shah.

Actual results may differ materially due to various important factors, including those described in the risk factors section of our most recently filed Form 10-K. These statements represent our views as of this call and should not be relied upon as representing our views as of any date in the future. Make no obligation to publicly update any forward looking statements with that I'd like to turn the call over to Dr. Shaw.

These statements represent our views as of this call and should not be relied upon as representing our views as of any date in the future. Make no obligation to publicly update any forward looking statements with that I'd like to turn the call over to Dr. Shaw.

Make no obligation to publicly update any forward looking statements with that I'd like to turn the call over to Dr. Shaw.

Pratik Shah: Thank you, Dr. Jeffries, and good afternoon, everyone. I'm excited to present Design Therapeutics’ First Significant Update for 2024. What makes this company unique and compelling is that we have discovered a new class of small molecules that are designed to dial up or dial down the expression of an individual gene in the genome. When you think about the role of individual genes and disease, there are many monogenic disorders where the single gene that causes the disease is well established. Our vision is to develop small molecules that can provide a restorative therapy and work with the patient's natural genome to help cells read the genes in a manner that restores cellular health despite the presence of the mutations. We are working on at least four major such disorders, Friedreich Ataxia, Fuchs Endothelial Corneal Dystrophy, Huntington’s Disease, and Myotonic Dystrophy. Each of the programs we are pursuing in these areas have the potential to be first in class or best in class.

I'm excited to present design therapeutics first significant update for 2024. What makes this company unique and compelling is that we have discovered a new class of small molecules that are designed to dial up or dialed down the expression of an individual gene in the genome. When you think about the role of individual genes and disease. There are many monogenic disorders, where the single gene that causes the disease is well established. Our vision is to develop small molecules that can provide a restorative therapy and work with the patients natural genome to help sell would you read the genes in a manner that. Restores cellular health despite the presence of the mutations. We are working on at least four major such disorders. Fix ataxia Fuchs endothelial corneal dystrophy, Huntington's disease and metallic dystrophy <unk>. Each of the programs we are pursuing in these areas have the potential to be first in class or best in class.

What makes this company unique and compelling is that we have discovered a new class of small molecules that are designed to dial up or dialed down the expression of an individual gene in the genome. When you think about the role of individual genes and disease. There are many monogenic disorders, where the single gene that causes the disease is well established. Our vision is to develop small molecules that can provide a restorative therapy and work with the patients natural genome to help sell would you read the genes in a manner that. Restores cellular health despite the presence of the mutations. We are working on at least four major such disorders. Fix ataxia Fuchs endothelial corneal dystrophy, Huntington's disease and metallic dystrophy <unk>. Each of the programs we are pursuing in these areas have the potential to be first in class or best in class.

When you think about the role of individual genes and disease. There are many monogenic disorders, where the single gene that causes the disease is well established. Our vision is to develop small molecules that can provide a restorative therapy and work with the patients natural genome to help sell would you read the genes in a manner that. Restores cellular health despite the presence of the mutations. We are working on at least four major such disorders. Fix ataxia Fuchs endothelial corneal dystrophy, Huntington's disease and metallic dystrophy <unk>. Each of the programs we are pursuing in these areas have the potential to be first in class or best in class.

Our vision is to develop small molecules that can provide a restorative therapy and work with the patients natural genome to help sell would you read the genes in a manner that. Restores cellular health despite the presence of the mutations. We are working on at least four major such disorders. Fix ataxia Fuchs endothelial corneal dystrophy, Huntington's disease and metallic dystrophy <unk>. Each of the programs we are pursuing in these areas have the potential to be first in class or best in class.

Restores cellular health despite the presence of the mutations. We are working on at least four major such disorders. Fix ataxia Fuchs endothelial corneal dystrophy, Huntington's disease and metallic dystrophy <unk>. Each of the programs we are pursuing in these areas have the potential to be first in class or best in class.

We are working on at least four major such disorders. Fix ataxia Fuchs endothelial corneal dystrophy, Huntington's disease and metallic dystrophy <unk>. Each of the programs we are pursuing in these areas have the potential to be first in class or best in class.

Fix ataxia Fuchs endothelial corneal dystrophy, Huntington's disease and metallic dystrophy <unk>. Each of the programs we are pursuing in these areas have the potential to be first in class or best in class.

Each of the programs we are pursuing in these areas have the potential to be first in class or best in class.

Pratik Shah: I'm Pratik Shah, I serve as the CEO. I was previously Chairman of Synthorx, which is now part of Sanofi as a result of $2.5 billion acquisition, and prior to that I was CEO of Auspex Pharmaceuticals, which was acquired for $3.5 billion. There we had discovered and developed AUSTEDO, which is now doing over $1 billion in annual revenue, and I'm joined by an accomplished and capable leadership team at Design, including Dr. Sean Jeffries, our Chief Operating Officer; and Dr. Jae Kim. Our Chief Medical Officer. Design's genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases. In addition, we have a five-year operating runway, which enables us to generate clinical proof of concept on up to four programs. Success in any one of these programs has the potential to generate enormous value for patients and shareholders.

The chairman of Centaur X, which is now part of Santa fee as a result of a $2 5 billion dollar acquisition and prior to that I was CEO of Auspex Pharmaceuticals, which was acquired for $3 $5 billion. There, we have discovered and developed a stereo which is now doing over $1 billion in annual revenue. I'm joined by an accomplished and capable leadership team of design <unk>. Including Dr. Sean Jeffries, our Chief operating officer, and Dr. Jay <unk>, our Chief Medical Officer. Designs genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases. In addition, we have a five year operating runway, which enables us to generate clinical proof of concept on up to four programs. And any one of these programs has the potential to generate enormous value for patients and shareholders.

There, we have discovered and developed a stereo which is now doing over $1 billion in annual revenue. I'm joined by an accomplished and capable leadership team of design <unk>. Including Dr. Sean Jeffries, our Chief operating officer, and Dr. Jay <unk>, our Chief Medical Officer. Designs genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases. In addition, we have a five year operating runway, which enables us to generate clinical proof of concept on up to four programs. And any one of these programs has the potential to generate enormous value for patients and shareholders.

I'm joined by an accomplished and capable leadership team of design <unk>. Including Dr. Sean Jeffries, our Chief operating officer, and Dr. Jay <unk>, our Chief Medical Officer. Designs genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases. In addition, we have a five year operating runway, which enables us to generate clinical proof of concept on up to four programs. And any one of these programs has the potential to generate enormous value for patients and shareholders.

Including Dr. Sean Jeffries, our Chief operating officer, and Dr. Jay <unk>, our Chief Medical Officer. Designs genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases. In addition, we have a five year operating runway, which enables us to generate clinical proof of concept on up to four programs. And any one of these programs has the potential to generate enormous value for patients and shareholders.

Designs genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases. In addition, we have a five year operating runway, which enables us to generate clinical proof of concept on up to four programs. And any one of these programs has the potential to generate enormous value for patients and shareholders.

In addition, we have a five year operating runway, which enables us to generate clinical proof of concept on up to four programs. And any one of these programs has the potential to generate enormous value for patients and shareholders.

And any one of these programs has the potential to generate enormous value for patients and shareholders.

Pratik Shah: Each of our programs is pursuing the treatment of monogenic diseases where the single gene root cause is known, and our therapeutic strategies to restore the normal gene expression state of this known single gene driver. Each of our programs has a first or best in class profile, which has highly differentiating features, and each of these are substantial market opportunities. Friedreich Ataxia or FA is a debilitating neuromuscular disorder with hypertrophic cardiomyopathy as the primary cause of death. It's caused by a GAA repeat mutation in the Frataxin gene, which is broadly expressed in the body. The goal of our genomic medicine is to increase levels of endogenous RITUXAN and address the monogenic cause of FA. We will address the background in greater detail later in the presentation.

Our therapeutic strategy is to restore the normal gene expression state of there's no one single gene driver. Each of our programs has a first or best in class profile, which has highly differentiating features in each of these are substantial market opportunities. Friedrichs attacks Euro phase a debilitating neuromuscular disorder. With hypertrophic cardiomyopathy as the primary cause of death. It's caused by a G. A repeat mutation in there for tax engine. Which is broadly expressed in the body. The goal of our genomic medicine is to increased levels of endogenous for Taxane and address the monogenic cause of FAA. We will address the background in greater detail later in the presentation.

Each of our programs has a first or best in class profile, which has highly differentiating features in each of these are substantial market opportunities. Friedrichs attacks Euro phase a debilitating neuromuscular disorder. With hypertrophic cardiomyopathy as the primary cause of death. It's caused by a G. A repeat mutation in there for tax engine. Which is broadly expressed in the body. The goal of our genomic medicine is to increased levels of endogenous for Taxane and address the monogenic cause of FAA. We will address the background in greater detail later in the presentation.

Friedrichs attacks Euro phase a debilitating neuromuscular disorder. With hypertrophic cardiomyopathy as the primary cause of death. It's caused by a G. A repeat mutation in there for tax engine. Which is broadly expressed in the body. The goal of our genomic medicine is to increased levels of endogenous for Taxane and address the monogenic cause of FAA. We will address the background in greater detail later in the presentation.

With hypertrophic cardiomyopathy as the primary cause of death. It's caused by a G. A repeat mutation in there for tax engine. Which is broadly expressed in the body. The goal of our genomic medicine is to increased levels of endogenous for Taxane and address the monogenic cause of FAA. We will address the background in greater detail later in the presentation.

It's caused by a G. A repeat mutation in there for tax engine. Which is broadly expressed in the body. The goal of our genomic medicine is to increased levels of endogenous for Taxane and address the monogenic cause of FAA. We will address the background in greater detail later in the presentation.

Which is broadly expressed in the body. The goal of our genomic medicine is to increased levels of endogenous for Taxane and address the monogenic cause of FAA. We will address the background in greater detail later in the presentation.

We will address the background in greater detail later in the presentation.

Pratik Shah: We had taken our lead molecule DT216 for Friedreich Ataxia into clinical trials in 2022 and ‘23, and confirmed that DT-216 can increase the level of frataxin RNA expression in patients with FA. We also learned about limitations to the prior formulation in human studies. Today, we would like to announce a new drug product using the same DT-216 drug substance as before. We refer to this new drug product as DT-216P2, which we believe has properties that resolve these prior barriers to progressing DT-216 further into development. The market opportunity for a systemic therapy that can restore endogenous Rituxan levels remains large and unaffected by progress by others in the field. The prior DT-216 drug product had a rapid elimination from plasma during a period called the alpha phase. And its exposure profile, and therefore, drug levels in the plasma were low after only a few hours. The orange curve shows the pharmacokinetics of the prior DT-216 drug product in non-human primates. In green is the PK of DT-216P2, which has a shorter alpha phase and a more rapid transition to the beta phase, and therefore a substantial increase in drug levels over a much longer period of time. Due to this increase in exposure, lower levels of administered drug are needed to achieve these desired profiles.

For friedrichs ataxia into clinical trials in. In 2022, and 'twenty, three and confirmed that <unk> can increase the level of for Taxane RNA expression in patients with SMA. We also learned. What limitations to the prior formulation in human studies. Today, we would like to announce a new drug product using the same <unk> drug substance as before. We refer to this new drug product as <unk> six <unk>. Which we believe has properties that resolve these prior barriers to progressing BTT one six further into development. The market opportunity for a systemic therapy that can restore endogenous for tax and levels remains large and unaffected by progress by others in the field. The prior <unk> drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma. We're low after only a few hours the orange curve shows the pharmacokinetics of the prior <unk> drug product in nonhuman primates. In Green. The PK of <unk>, 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

In 2022, and 'twenty, three and confirmed that <unk> can increase the level of for Taxane RNA expression in patients with SMA. We also learned. What limitations to the prior formulation in human studies. Today, we would like to announce a new drug product using the same <unk> drug substance as before. We refer to this new drug product as <unk> six <unk>. Which we believe has properties that resolve these prior barriers to progressing BTT one six further into development. The market opportunity for a systemic therapy that can restore endogenous for tax and levels remains large and unaffected by progress by others in the field. The prior <unk> drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma. We're low after only a few hours the orange curve shows the pharmacokinetics of the prior <unk> drug product in nonhuman primates. In Green. The PK of <unk>, 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

We also learned. What limitations to the prior formulation in human studies. Today, we would like to announce a new drug product using the same <unk> drug substance as before. We refer to this new drug product as <unk> six <unk>. Which we believe has properties that resolve these prior barriers to progressing BTT one six further into development. The market opportunity for a systemic therapy that can restore endogenous for tax and levels remains large and unaffected by progress by others in the field. The prior <unk> drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma. We're low after only a few hours the orange curve shows the pharmacokinetics of the prior <unk> drug product in nonhuman primates. In Green. The PK of <unk>, 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

What limitations to the prior formulation in human studies. Today, we would like to announce a new drug product using the same <unk> drug substance as before. We refer to this new drug product as <unk> six <unk>. Which we believe has properties that resolve these prior barriers to progressing BTT one six further into development. The market opportunity for a systemic therapy that can restore endogenous for tax and levels remains large and unaffected by progress by others in the field. The prior <unk> drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma. We're low after only a few hours the orange curve shows the pharmacokinetics of the prior <unk> drug product in nonhuman primates. In Green. The PK of <unk>, 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

Today, we would like to announce a new drug product using the same <unk> drug substance as before. We refer to this new drug product as <unk> six <unk>. Which we believe has properties that resolve these prior barriers to progressing BTT one six further into development. The market opportunity for a systemic therapy that can restore endogenous for tax and levels remains large and unaffected by progress by others in the field. The prior <unk> drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma. We're low after only a few hours the orange curve shows the pharmacokinetics of the prior <unk> drug product in nonhuman primates. In Green. The PK of <unk>, 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

We refer to this new drug product as <unk> six <unk>. Which we believe has properties that resolve these prior barriers to progressing BTT one six further into development. The market opportunity for a systemic therapy that can restore endogenous for tax and levels remains large and unaffected by progress by others in the field. The prior <unk> drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma. We're low after only a few hours the orange curve shows the pharmacokinetics of the prior <unk> drug product in nonhuman primates. In Green. The PK of <unk>, 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

Which we believe has properties that resolve these prior barriers to progressing BTT one six further into development. The market opportunity for a systemic therapy that can restore endogenous for tax and levels remains large and unaffected by progress by others in the field. The prior <unk> drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma. We're low after only a few hours the orange curve shows the pharmacokinetics of the prior <unk> drug product in nonhuman primates. In Green. The PK of <unk>, 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

The market opportunity for a systemic therapy that can restore endogenous for tax and levels remains large and unaffected by progress by others in the field. The prior <unk> drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma. We're low after only a few hours the orange curve shows the pharmacokinetics of the prior <unk> drug product in nonhuman primates. In Green. The PK of <unk>, 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

Pratik Shah: The prior DT-216 drug product had a rapid elimination from plasma during a period called the alpha phase. And its exposure profile, and therefore, drug levels in the plasma were low after only a few hours. The orange curve shows the pharmacokinetics of the prior DT-216 drug product in non-human primates. In green is the PK of DT-216P2, which has a shorter alpha phase and a more rapid transition to the beta phase, and therefore a substantial increase in drug levels over a much longer period of time. Due to this increase in exposure, lower levels of administered drug are needed to achieve these desired profiles.

The prior <unk> drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma. We're low after only a few hours the orange curve shows the pharmacokinetics of the prior <unk> drug product in nonhuman primates. In Green. The PK of <unk>, 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

We're low after only a few hours the orange curve shows the pharmacokinetics of the prior <unk> drug product in nonhuman primates. In Green. The PK of <unk>, 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

In Green. The PK of <unk>, 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

The PK of <unk>, 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

Over a much longer period of time. Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

Due to this increase in exposure lower levels of administered drug are needed to achieve these desired profiles.

Pratik Shah: In addition, a favorable injection site reaction profile has been seen with the new drug product in nonclinical studies. With this new advance, we are back on a path to continue further development of DT-216 for patients with FA. In the time since our last update, we have also advanced the GeneTAC platform and have refined our strategy and priorities for the programs. Our FECD program data have now been reviewed by the FDA resulting in an IND cleared to proceed. As a result, we plan to initiate Phase 1 development for DT-168 this year. We have also decided to conduct an observational study in patients with FECD prior to conducting an investigational drug treatment trial in patients.

With this new advance we are back on a path to continue further development of <unk> for patients with SMA. In the time since our last update we have also advanced the gene tack platform and have refined our strategy and priorities for the programs. Our <unk> program. Data have now been reviewed by the FDA, resulting in an IMD cleared to proceed. As a result, we plan to initiate phase one development for <unk> 106, eight this year. We have also decided to conduct an observational study in patients with FCC D. Prior to conducting an investigational drug treatment trial in patients.

In the time since our last update we have also advanced the gene tack platform and have refined our strategy and priorities for the programs. Our <unk> program. Data have now been reviewed by the FDA, resulting in an IMD cleared to proceed. As a result, we plan to initiate phase one development for <unk> 106, eight this year. We have also decided to conduct an observational study in patients with FCC D. Prior to conducting an investigational drug treatment trial in patients.

Our <unk> program. Data have now been reviewed by the FDA, resulting in an IMD cleared to proceed. As a result, we plan to initiate phase one development for <unk> 106, eight this year. We have also decided to conduct an observational study in patients with FCC D. Prior to conducting an investigational drug treatment trial in patients.

Data have now been reviewed by the FDA, resulting in an IMD cleared to proceed. As a result, we plan to initiate phase one development for <unk> 106, eight this year. We have also decided to conduct an observational study in patients with FCC D. Prior to conducting an investigational drug treatment trial in patients.

As a result, we plan to initiate phase one development for <unk> 106, eight this year. We have also decided to conduct an observational study in patients with FCC D. Prior to conducting an investigational drug treatment trial in patients.

We have also decided to conduct an observational study in patients with FCC D. Prior to conducting an investigational drug treatment trial in patients.

Pratik Shah: We are also announcing for the first time our Huntington's disease program, where we have identified small molecule candidates that exhibit allele selective reduction of Mutant Huntington expression considered an ideal, although elusive profile for molecules that could be reasonably advanced as systemically administered and widely distributing compounds. Similarly, we have identified compounds exhibiting allele selective inhibition of Mutant DMPK, which is the root cause of myotonic dystrophy with what we believe are best-in-class foci reduction and splicing restoration data.

Where we have identified small molecule candidates that exhibit allele selective reduction of mutant Huntington expression. Considered an ideal although elusive profile for molecules that could be reasonably advanced. Systemically administered and widely distributing compounds. Similarly, we have identified compounds exhibiting allele selective inhibition of <unk>, which is the root cause of my colleague dystrophy. With what we believe are best in class <unk> reduction and splicing restoration data.

Considered an ideal although elusive profile for molecules that could be reasonably advanced. Systemically administered and widely distributing compounds. Similarly, we have identified compounds exhibiting allele selective inhibition of <unk>, which is the root cause of my colleague dystrophy. With what we believe are best in class <unk> reduction and splicing restoration data.

Systemically administered and widely distributing compounds. Similarly, we have identified compounds exhibiting allele selective inhibition of <unk>, which is the root cause of my colleague dystrophy. With what we believe are best in class <unk> reduction and splicing restoration data.

Similarly, we have identified compounds exhibiting allele selective inhibition of <unk>, which is the root cause of my colleague dystrophy. With what we believe are best in class <unk> reduction and splicing restoration data.

With what we believe are best in class <unk> reduction and splicing restoration data.

Pratik Shah: We aim to advance both HD and DM1 programs to declare development candidates. Gene editing and gene therapy have understandably captured the imagination of humankind. Ever since, we learned that mutations in single genes cause disease, there has been a desire to edit the genome in some fashion to restore normal cellular health. Other approaches have also emerged that try to get at the root cause of monogenic diseases. However, if gene tech molecules work in patients, there would be little doubt that they represent the best option in genomic medicine. Since GeneTAC molecules when systemically administered, can distribute widely to a broad set of tissues in the target cells broadly to affect the desired outcome without altering a patient's natural genome.

Gene editing and gene therapy have understandably captured the imagination of humankind. Since we learned that mutations in single genes cause disease. There has been a desire to edit the genome in some fashion to restore normal cellular health. Other approaches have also emerged that try to get at the root cause of monogenic diseases. However. <unk> Tec molecules work in patients there would be little doubt that they represent the best option in genomic medicine since gene Tech molecules and systemically administered can distribute widely to a broad set of tissues in the target cells broadly to affect the desired outcome without <unk>. Turning a patient's natural genome.

Since we learned that mutations in single genes cause disease. There has been a desire to edit the genome in some fashion to restore normal cellular health. Other approaches have also emerged that try to get at the root cause of monogenic diseases. However. <unk> Tec molecules work in patients there would be little doubt that they represent the best option in genomic medicine since gene Tech molecules and systemically administered can distribute widely to a broad set of tissues in the target cells broadly to affect the desired outcome without <unk>. Turning a patient's natural genome.

Other approaches have also emerged that try to get at the root cause of monogenic diseases. However. <unk> Tec molecules work in patients there would be little doubt that they represent the best option in genomic medicine since gene Tech molecules and systemically administered can distribute widely to a broad set of tissues in the target cells broadly to affect the desired outcome without <unk>. Turning a patient's natural genome.

<unk> Tec molecules work in patients there would be little doubt that they represent the best option in genomic medicine since gene Tech molecules and systemically administered can distribute widely to a broad set of tissues in the target cells broadly to affect the desired outcome without <unk>. Turning a patient's natural genome.

Turning a patient's natural genome.

Pratik Shah: Furthermore, investments into new platform companies often suffer from frequent rounds of dilution due to the necessary high R&D burn rates that often require investors that time their investment decisions with great care. Design’s approach is more cost effective, making an investment decision for a longer horizon potentially quite attractive. The advantage of GeneTAC molecules become more apparent when you consider how much smaller these molecules are than those of competing modalities, which further explains the broad distribution properties.

Investments into new platform companies, often suffer from frequent rounds of dilution due to the necessary high R&D burn rates that often require investors the time their investment decisions with great care. And the approach is more cost effective <unk>. Making an investment decision for a longer horizon potentially quite attractive. The advantage of gene Tech molecules become more apparent when you consider how much smaller. These molecules are then those of competing modalities, which further explains the broad distribution properties.

And the approach is more cost effective <unk>. Making an investment decision for a longer horizon potentially quite attractive. The advantage of gene Tech molecules become more apparent when you consider how much smaller. These molecules are then those of competing modalities, which further explains the broad distribution properties.

Making an investment decision for a longer horizon potentially quite attractive. The advantage of gene Tech molecules become more apparent when you consider how much smaller. These molecules are then those of competing modalities, which further explains the broad distribution properties.

The advantage of gene Tech molecules become more apparent when you consider how much smaller. These molecules are then those of competing modalities, which further explains the broad distribution properties.

Pratik Shah: Also, by restoring endogenous gene expression, like in FA, the gene products are entirely normal and under normal physiologic control. The mechanism of action of these GeneTAC molecules, which drive these remarkable observations are shown in this animation that I'll walk you through. First, we start with FA. FA is caused by low levels of frataxin, which is a protein that's systemically expressed in the body. So if you look inside the cell and inside the nucleus, the frataxin gene has a GAA repeat expansion shown in red, which causes the RNA polymerase to slow down through this region and produce low levels of frataxin premium RNA, and therefore low levels of express translated protein. And that's what drives the dysfunction.

The gene products are entirely normal and under normal physiologic control. The mechanism of action of these gene Tech molecules, which drive these remarkable observations are shown in this animation that I'll walk you through. First we start with FAA. FAA has caused by low levels of for tax and which is a protein that systemically expressed in the body. So if you look inside the cell and inside the nucleus for taxing gene has a GAA repeat expansion shown in red which causes the RNA polymerase to slowdown through this region and produce low levels of pretax and pre <unk>. Barney and therefore low levels of express translated protein and Thats what drives that this function.

The mechanism of action of these gene Tech molecules, which drive these remarkable observations are shown in this animation that I'll walk you through. First we start with FAA. FAA has caused by low levels of for tax and which is a protein that systemically expressed in the body. So if you look inside the cell and inside the nucleus for taxing gene has a GAA repeat expansion shown in red which causes the RNA polymerase to slowdown through this region and produce low levels of pretax and pre <unk>. Barney and therefore low levels of express translated protein and Thats what drives that this function.

First we start with FAA. FAA has caused by low levels of for tax and which is a protein that systemically expressed in the body. So if you look inside the cell and inside the nucleus for taxing gene has a GAA repeat expansion shown in red which causes the RNA polymerase to slowdown through this region and produce low levels of pretax and pre <unk>. Barney and therefore low levels of express translated protein and Thats what drives that this function.

FAA has caused by low levels of for tax and which is a protein that systemically expressed in the body. So if you look inside the cell and inside the nucleus for taxing gene has a GAA repeat expansion shown in red which causes the RNA polymerase to slowdown through this region and produce low levels of pretax and pre <unk>. Barney and therefore low levels of express translated protein and Thats what drives that this function.

Barney and therefore low levels of express translated protein and Thats what drives that this function.

Pratik Shah: GeneTAC candidates are hetero bifunctional small molecules, where one end of the molecule has been designed to specifically recognize the GAA expanded repeats. When this compound is administered systemically, it distributes widely, gets into the cell, gets into the nucleus, and then recognizes the GAA repeat expansions by binding to the minor groove of intact double stranded DNA in the frataxin gene, and the other end of the molecule recruits a transcriptional elongation complex. The presence of these transcriptional elongation complexes enables the RNA - race to now rapidly read through the repeat region, and therefore produce normal levels of the frataxin pre mRNA, because the repeat expansion is in an intron, that portion of the RNA is just spliced out normally to produce normal levels of intact full length endogenous mRNA, which produces normal endogenous frataxin protein with all of its natural isoforms under the native regulatory control. This restores frataxin levels and therefore cellular health.

When this compound is administered systemically and distributes widely gets into the cell gets into the nucleus and then recognizes the GAA repeat expansions by binding to the minor groove of intact double stranded DNA in there for tax in gene and the other end of the molecule recruits a transcriptional E. <unk> complex. The presence of these transcriptional elongation complexes innate. <unk> enables the RNA polymerase. To now rapidly read through the repeat region. And therefore produce normal levels of deferred tax and pre mrna. Because the repeat expansion is in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length, endogenous marni, which produces normal endogenous for tax and protein with all of its natural acts of farms under the native regulatory control. This restores protection levels, and therefore health now.

<unk> complex. The presence of these transcriptional elongation complexes innate. <unk> enables the RNA polymerase. To now rapidly read through the repeat region. And therefore produce normal levels of deferred tax and pre mrna. Because the repeat expansion is in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length, endogenous marni, which produces normal endogenous for tax and protein with all of its natural acts of farms under the native regulatory control. This restores protection levels, and therefore health now.

The presence of these transcriptional elongation complexes innate. <unk> enables the RNA polymerase. To now rapidly read through the repeat region. And therefore produce normal levels of deferred tax and pre mrna. Because the repeat expansion is in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length, endogenous marni, which produces normal endogenous for tax and protein with all of its natural acts of farms under the native regulatory control. This restores protection levels, and therefore health now.

<unk> enables the RNA polymerase. To now rapidly read through the repeat region. And therefore produce normal levels of deferred tax and pre mrna. Because the repeat expansion is in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length, endogenous marni, which produces normal endogenous for tax and protein with all of its natural acts of farms under the native regulatory control. This restores protection levels, and therefore health now.

To now rapidly read through the repeat region. And therefore produce normal levels of deferred tax and pre mrna. Because the repeat expansion is in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length, endogenous marni, which produces normal endogenous for tax and protein with all of its natural acts of farms under the native regulatory control. This restores protection levels, and therefore health now.

And therefore produce normal levels of deferred tax and pre mrna. Because the repeat expansion is in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length, endogenous marni, which produces normal endogenous for tax and protein with all of its natural acts of farms under the native regulatory control. This restores protection levels, and therefore health now.

Because the repeat expansion is in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length, endogenous marni, which produces normal endogenous for tax and protein with all of its natural acts of farms under the native regulatory control. This restores protection levels, and therefore health now.

This restores protection levels, and therefore health now.

Pratik Shah: Now, for the other side of the platform, long repeat expansions in regions of genes are shown in red in the upper half. This is the case in diseases like Fuchs Endothelial Corneal Dystrophy and Myotonic Dystrophy. Repeat expansions in coding regions of genes are shown in the lower half in red, as is the case in Huntington’s Disease, and it only takes one allele to cause the disease. So patient has one wild type allele - [inaudible].

Long repeat expansions in non coding regions of genes are shown in red in the upper half. This is the case in diseases like Fuchs endothelial corneal dystrophy in monotonic dystrophy brief. <unk> repeat expansions in coding regions of genes are shown in the lower half in Red as is the case in Huntington's disease. And it only takes one allele to cause the disease. So patient has one wild type allele. As shown. The brand.

This is the case in diseases like Fuchs endothelial corneal dystrophy in monotonic dystrophy brief. <unk> repeat expansions in coding regions of genes are shown in the lower half in Red as is the case in Huntington's disease. And it only takes one allele to cause the disease. So patient has one wild type allele. As shown. The brand.

<unk> repeat expansions in coding regions of genes are shown in the lower half in Red as is the case in Huntington's disease. And it only takes one allele to cause the disease. So patient has one wild type allele. As shown. The brand.

And it only takes one allele to cause the disease. So patient has one wild type allele. As shown. The brand.

As shown. The brand.

The brand.

Healthy individuals carriers and patients.

We see the carriers have approximately half the level of their for tax season as indicated by the Black line, representing the group average.

Carriers do not have assay and have known disease burden.

Patients have a quarter to a fifth of normal protection levels on average.

Of course around every means of distribution and there may be individuals who are above or below the mean and different individuals might require different levels of restoration to get back into the normal zone, which is somewhere near carrier levels.

And that is the therapeutic goal, which is thought to be about a doubling.

Now most of the general population has less than 30 <unk> pizza in there for tax in gene, but someone with FAA has 400 or over 1000, and these repeats reduce the level of normal for Taxane.

And it turns out you can measure this reduction with a blood test.

As shown on the top right as a result of a PCR tests conducted on blood cells from patients you can see in the <unk>.

Gray bar on the graph that RNA levels are low in patient cells, when compared with pretax syndrome, and unaffected sibling, who has two normal copies of the for tax regime.

You can imagine our excitement when we were able to observe that when cells from patients are incubated with GTECH molecules. There's a restoration of for tax into normal levels in a dose dependent fashion.

And when sales from unaffected siblings are incubated with the compounds for Taxane levels remain unaltered. This is exactly what one would wish for naphtha.

A medicine that restores natural levels of the single gene product that causes all of these problems and that's what's so exciting about design as we have an opportunity to provide a restored of therapy of natural pretax set from the patients own jeans and to do it with a small molecule.

And we've seen that this effect is observed in a wide variety of cell types tested shown here is the result of treating terminally differentiated neurons taken from patient derived ips cells on.

On the left is an increase in for tax in RNA and on the right is an increase in pretax and protein which follows a few days later.

It has a long half life of several days.

<unk> 216 was taken into clinical trials in patients with FAA in 2022, and 23 with a prior formulation and the trial design is shown here.

We learned from the human studies that the duration of adequate levels of exposure of <unk> was much shorter than expected, while we knew that the drug was short lived and plasma <unk>.

<unk> study showed by muscle biopsy that it was also a short lived in tissue.

And what you observe in plasma is predictive of what is observed in tissue.

Tissue levels from human muscle biopsies were approximately only eight to 10 nanometer at day two.

And the drug was almost gone with levels at one animal or by day seven.

Well despite that.

There was a clear increase in for tax and expression observed in treated patients in a dose dependent fashion with one patients protection level going to clinically normal carrier levels as shown in the right.

However, the effect was transient because the drug exposure was transient so.

So we needed to develop a new drug product that could sustain this drug exposure.

While the drug was generally well tolerated and there were injection site thrombophlebitis events observed, which limited the frequency and levels of dosing with the prior product candidate.

Non clinical studies showed that these reactions were attributable to the formulation excipient in the drug product.

We have now conducted new non <unk> animal studies.

With <unk> 262, which lead us to believe that these issues have now been solved and we can progress to confirmatory GOP studies to get back into the clinic.

Furthermore, this new.

Drug product appear suitable for IV administration compatible.

Compatible with injections or infusions peripheral or central and also appear suitable for a subcutaneous route of administration.

As we showed in the beginning the new.

Drug product <unk> 262 has a much more sustained exposure profile as seen in the single dose IV PK curve from nonhuman primates.

You can see between day, one and day seven to levels are 10 to perhaps 100 fold higher than the prior drug product, even with a quarter to approximately a 10th of the referenced dose.

This is because of a shorter alpha phase and the elimination half life between the prior and new drug products are very similar.

This profile has been achieved by using a proprietary and novel excipient in the formulation.

<unk> hundred 62.

Also has a sustained exposure profile when administered by subcutaneous route of administration is shown on the right slide.

This profile has a blunted C Max and a sustained exposure with low peak to trough level fluctuations.

We have flexibility in both route of administration as well as frequency of dosing.

As seen here.

With both a daily or weekly subcutaneous injection in nonhuman primates.

Okay.

In the clinical trial, we observed that the tissue level as measured by muscle biopsy was in line with the plasma exposure.

And this is typical of a small molecule drug.

The new drug product also shows that the tissue levels as measured by muscle biopsy nonhuman primates is in line with plasma exposures, providing comfort that the extended profile seen in plasma.

We will provide the desired extended profile in tissues.

Repeat dose studies done in non GOP assessments have also been encouraging and the program will be proceeding to GOP studies, which are planned to be completed by the end of this year to support patient dosing in 2025.

Given the very different PK profile seen in preclinical studies. Our plan is now to conduct a phase one clinical trial in healthy volunteers.

So as to confirm the pharmacokinetics.

And also to confirm injection site tolerability.

This will also help us in choosing a dosing route and dosing frequency for longer term studies.

Subsequent trial will be in FA patients, which.

Which we plan to conduct to determine safety tolerability and the effective treatment of an endogenous for tax and levels.

Okay.

<unk> is now approved for the treatment of FAA and its update confirms that this is a large market opportunity.

Since Skycars does not affect protection levels. We believe this approval has no appreciable impact on the potential opportunity for <unk> to one six.

As we've discussed before Jean tack small molecules have several potential advantages over any other genomic medicine modalities.

Now in case, you see any literature reports of possible effects of other molecules on for tax and expression.

So here the gene tech molecules restore for Taxane in a more substantial way than anything else reported in the literature, which is not surprising given its direct and elegant mechanism of action.

Okay.

Fuchs endothelial corneal dystrophy or <unk> is a degenerative disease of the cornea that's been known for over 100 years.

The literature widely sites that this disease affects 4% of all adult Americans over the age of 40.

Only in the last decade, though hasnt been shown that approximately 70% 80% of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the Tcf for G.

Based on the current census, this works out to approximately four 6% to $5 3 million U S. S ACD patients.

There are no approved disease modifying prescription drugs for efficacy and treatment is restricted to things like hypertonic saline drops to try and dehydrate the cornea.

Eventually.

A small fraction of patients get a corneal transplant surgery, which they're about 18000 to 30000 cornea transplant surgeries done in the United States annually and Thats, a very small fraction and represented by the Red figure.

Most patients unfortunately quietly suffer from declining visual quality.

On the right is a photoshop image composed by a patient to communicate her loss of visual quality and late stage Fuchs.

The analogy is sometimes that of a foggy and rainy windshield, resulting in loss of low contrast, visual acuity.

Glare and contrast sensitivity.

And we have heard from a number of clinicians who see these patients.

If there was anything that slowed progression and was well tolerated they would treat everyone even patients who were pre symptomatic.

FEC these caused by dysfunction in the cells of the endothelial mono layer of the cornea and these cells have a role in maintaining a dehydrated stroma.

Keep the cornea free of extracellular matrix deposits.

The salad is slowly lost over time due to the disease.

And they are sick because of the Tcf for mutation, which is the CTG repeat expansion in the non coding region of the gene.

This inherited mutation can be detected by means of a blood test.

So how can we develop.

Therapy for this by.

By helping restore cellular health.

Two the endothelial layer.

This cell dysfunction arises from the single inherited mutant allele.

The preliminary reads the Lille and makes an RNA containing these repeats.

The RNA folds over on itself creates tangles.

And you can see them you can stain for them. These tangles sequester nbn splice proteins and cause mis splicing of a number of downstream genes, which then drive cellular dysfunction.

We have designed gene tax to buying them recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic Tcf form.

Arnie.

This slide shows the effectiveness of the gene Tech molecule.

I said that you could stand for these beautiful site, they're shown in the above panel in the Middle section is Dodge that light up with a fluorescently labeled probe.

The nucleus of endothelial cells taken directly from discarded cornea of patients who have undergone surgery.

On the lower panel, we observed that these folks side largely go away. When these patient corneal cells are treated with <unk> hundred six eight.

The compound has loan animal or potency as shown in the dose response curve on the right.

This slide shows the results of assay for Wild type Tcf for transcripts from patient cells as shown here.

Treatment has no effect on the wild type Tcf for expression.

This is an allele selective inhibition, which is highly desirable.

This slide looks at Mis splicing that occurs in a variety of downstream genes at baseline in light Green and we have a drug treatment.

As mutant <unk> CFO expressions dialed down.

And sequestered slicing proteins are released.

Downstream normal splicing is restored leading to a treatment of the cellular dysfunction.

Not only do we see an allele selective effect, which is the desired product profile.

We have also been able to formulate those to be suitably delivered as an eye drop.

All of the required non clinical safety studies have been conducted and reviewed by the FDA, resulting in a 90 that's been cleared.

We plan to initiate phase one development for <unk> hundred 68 in 2024.

Okay.

We now need to determine the impact of this type of treatment on the progression of this degenerative corneal disease and for that purpose, we need to gain experience with various possible endpoints and patient characteristics.

Therefore prior to jumping into an interventional trial in patients. We believe the correct strategy for clinical development is to first run an observational study with patients diagnosed fuchs, who have a genetically confirmed tcf for expansion mutation.

We have begun enrollment in such a trial and plan to recruit 200 patients during the year.

Planned to follow them for two years.

This will enable us to understand the patient characteristics.

And endpoints that allow us to measure the dysfunction and progression in these patients.

Once we have gathered sufficient data to measure disease progression and the performance of various endpoints. We will then focus on an intervention all treatment trial.

These endpoints include measures of visual quality anterior <unk> tomography.

And also microscopic visualization of the corneal endothelium.

We are revealing for the first time, our program for Huntington's disease as.

As you know HD is a devastating neurodegenerative disease caused by an exon ache repeat expansion in the Huntington gene.

A long standing objective in the field has been for there to be a selective inhibition of the mutant Huntington the lisle with a molecule that can distribute widely to the affected cells.

This has been a very elusive profile to achieve.

Here is data looking at the effect of one of our two candidate molecules on wild type and mutant Huntington RNA from treated patient fiberglass cells. The left panel shows data from our normal onset HD genotype in the right panel the effect on an early onset HD genotype.

Which contains a longer repeat expansion.

We observe an allele selective inhibition of mutant Huntington RNA.

The effect is even more pronounced in the early onset genotype. This is particularly encouraging because regardless of the genotype. It is known that the repeats undergo somatic expansion of various lengths and different neurons overtime.

This data suggests.

At the compound would have an even more profound impact on those cells, which have undergone a longer somatic expansion of their CAGR repeats.

This slide shows that the RNA effect shown earlier translated to the expected effect on mutant Huntington protein.

Above panel shows that a.

Huntington selective antibody is able to detect.

Protein disappearing with increasing concentrations of drug.

The Middle panel uses an antibody that detects both wild type and mutant Huntington and you can see unexpected reduction due to the protein being reduced.

Now the size of these proteins are hard to resolve and the normal onset genotype in the left panel gels.

Early onset Gino types, the mutant and wild type proteins are different enough in size.

So up as two bands on the middle panel on the right side.

Candidate to showing a similar allele selective inhibition.

And this is the protein inhibition data from candidate to also showing an effect as expected from the <unk> inhibition.

We expect to choose one of these compounds to move forward with as a development candidate once further testing is conducted.

Having seen these exciting profiles we are encouraged.

At the preliminary non <unk> tolerability of these molecules in both rodents and nonhuman primates.

We've conducted pharmacology assessments of these molecules and have selected a widely used Q1 75, DN Pharmacodynamic mouse model to SaaS PD.

We observe in this study and with systemic administration.

There is an over 50% reduction of mutant Huntington RNA and protein in the striatum.

Of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration.

We are very encouraged to see this in vivo confirmation of the activity seen in cell derived from patients.

If this pans out.

Jean Tech molecules hold the potential of selectively reducing mutant Huntington with a widespread distribution profile and systemic administration, regardless of the patient's HD genotype.

This would be a best in class profile.

Our next milestone for the program is to choose a development candidate.

We are also working on a program in monotonic dystrophy.

<unk> is caused by a CPG repeat and the DNP caging and the three prime untranslated region.

Much like the CCD story, <unk> form toxic for Si and downstream splicing dysfunction.

It would be highly desirable in a best in class profile to have a selective inhibitor of mutant <unk> PK for the treatment of monotonic dystrophy that would distribute broadly and all affected tissues and cell types.

This data shows that we have a gene tack molecule.

That reduce these toxic DM PK fore sight.

With loan animal or potency.

This is a splicing index from panel of misplaced genes.

With seven days of treatment from patient derived Meyer tubes, showing that the <unk> reduction does have beneficial downstream effect on cellular health.

The next milestone for this program is.

Is DC declaration.

In summary.

We have a promising new platform for genomic medicine that is meaningfully differentiated from other genomic medicine modalities.

We have four drug programs.

Each insignificant markets.

And with highly differentiated profiles.

First two of which are expected to be clinical stage next year.

We ended 2023 with approximately $281 million.

And this gives us a cash runway for the next five years.

Pending future R&D results in ongoing strategic review.

This cash runway, which support generating clinical proof of concept data in up to four programs.

We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors.

We are dedicated to moving these molecules forward.

And welcome you to participate in this journey.

And help us get to success.

This concludes our prepared remarks, and we'll now move to Q&A.

Operator.

Please open the line for questions.

Yeah.

As a reminder to ask a question. Please press star one one on your telephone and wait for your name to be announced so withdraw your question. Please star one again.

Please be advised that today's technical difficulty will be resolved for the archive purposes.

First question.

And that will come from the line of Joseph Schwartz with Leerink partners. Please go ahead.

<unk>.

Hi, Thanks, very much for the update I was wondering if you could.

Tell us more about the tissue distribution relative to the plasma distributions for DG 216 <unk>.

And all of the relevant tissue types for patients affected IFA and then have you gone back and back tested the ISR profile. So the original formulation of <unk> hundred six as well as the new one.

Thank you.

Thank you Joe for that question.

On the.

Exposure profile.

As a reminder, one of the major learnings from our prior clinical trial.

It was at the levels of drug required in tissue.

Or similar to the in vitro.

90.

So that eight to 10 nano will exposure that we saw in muscle in patients from the trial.

Is something that sets a target.

The prior drug product had this disconnect between the duration of plasma and tissue levels in animals, we did not observe any such disconnect in humans.

The new drug product <unk> 262 is well.

Well behaved in that even in animals. There is no longer a disconnect between plasma and tissue level. Then this is what you would expect with a small molecule drug.

So if you reference slide 22.

Muscle biopsies showed that tissue levels were predicted by plasma levels.

And.

That turns out to then also be true with our <unk> 262 were on the right you see that in nonhuman Primate studies the plasma levels are much higher.

And so are the tissue levels as shown by muscle biopsy from these in hps.

In addition, we have some additional confirmatory data.

In Iraq distribution study, which we can show you in.

Subsequent slide here.

That.

There is adequate levels of drug scene.

In a broad set of tissues against that target level of eight to 10 nanometer that we require to see a biological effect.

And so once you exceed a threshold required for biological effect, there's no access of pharmacology. So we feel that the the exciting results we've seen with the plasma PK to also set us up well for good tissue distribution.

On your other question about injection site reactions.

Non clinical studies show that the injection site reactions were attributable to the excipient in the prior clinical formulation.

And now the new non GOP studies that we've conducted with <unk> 262 <unk>.

Support the conclusion that this formulation has resolved the injection site issues and is suitable to progress into confirmatory.

<unk> studies.

And in fact in one arm of the study we've included daily injections.

Over four weeks, which gives us further confidence that the injection site.

Tolerability issues appear resolved.

Great. Thank you.

Thank you one moment for our next question.

And that will come from the line of Leo Ned Thomas <unk> with RBC capital markets. Your line is open.

Okay, Hi, everyone. This is <unk> on for Leo Thank you for taking our questions.

So just a couple from us.

Or are you thinking about designing your phase one for <unk>.

And then if you show for tax on expression increases in patient do you think.

But that might potentially open path forward for accelerated approval given some of the latest understanding of the biology and the FDA views on that and then should we also expect similar patient numbers to the original sat in that study. Thank you.

Okay.

Yes.

Okay.

Thanks for the question.

With regard to the phase one studies.

Because we see.

This remarkably different PK profile that hits all of the criteria that we were looking for.

Our approach here is to first conduct.

Phase one PK study in healthy volunteers.

And this is to confirm the encouraging PK profile of <unk> 206, two.

Once we.

Get data from that study, we then plan to conduct patient studies beginning in 2025.

With regard to your next question on.

F D a.

Sure.

And end points I would say that.

The unmet need here is high.

We don't.

Uh huh.

Have anything to add in terms of.

What the F D a.

May or may not require in the future we've had productive engagement with the FDA previously and we'll continue to engage with.

With the agency upon resumption.

Of clinical studies.

Okay. Thank you.

Thank you one moment our next question.

And that will come from the line of Laura Chico with Wedbush. Your line is open.

Your line is open.

Sorry about that thank you very much for taking the question.

I believe you were also working in parallel on some new method development with respect to for tax in this detection on a protein level I'm wondering if you can share any details kind of on where that methodologies stands at present, and maybe kind of timing to advance those efforts and then I have one quick follow up.

Thank you Laura.

We are.

Dedicated to continuing to work on.

Whatever improvements we can make in measurement of for tax and levels. We have robust assays that we've already used in prior clinical studies for measurement of for tax and RNA.

And we continue to make improvements on our ability to reliably measure for tax in protein and possible changes in pretax and protein and will provide updates on that progress as we as we progress through the clinic.

Okay. Thank you very much and then just quickly with respect to Q.

And then I missed maybe come out and your observational study, but I'm kind of curious.

With AMD.

Visual acuity measurements are pretty straightforward, but contrast that with something else like geographic atrophy, and it's a little bit more challenging.

<unk>.

Thank you for the question.

We are conducting an observational study in patients with Fuchs with a confirmed tcf for mutation to better understand both patient characteristics as well as the characteristics of.

The endpoints and disease progression.

And those.

Come in three different <unk>.

Broad buckets, one is a variety of measures of visual quality.

And there are numerous.

Reports in the literature of ways to measure the loss of visual quality and patients with Fuchs and we'll be getting direct experience with those types of measures.

Second is measures of edema or fluid buildup in the cornea because the endothelial cell layers.

The function is to dehydrate, the stroma and keep the cornea clear and there are ways in the clinic to measure this subclinical edema using using anterior <unk> tomography. For example, so we including those measures in the observational study.

And third.

As you've seen in the back of the eye and geographic atrophy.

There are analogous or a corresponding ways to directly visualize the corneal endothelium in patients.

Using specialized microscopy, and so it will be including those measures as well and that will give us.

A variety of tools to examine the.

Six of the patients and the disease progression.

Thanks very much.

Thank you I'm showing no further questions in the queue. At this time I would now like to turn the call back over to Mr. Petit for any closing remarks.

Well. Thank you everyone for joining us on today's call.

We look forward to updating you as we continue to make exciting progress and design.

Thank you all for participating. This concludes today's program you may now disconnect.

Okay.

[music].

Okay.

[music].

Chief operating officer of design Therapeutics, you may begin.

Sean Jeffries: Welcome and thank you for joining us today. Earlier, we issued a press release outlining our fourth quarter and full year 2023 financial results and updates across our portfolio of GeneTAC small molecule genomic medicines. The slides that we'll be using today during today's call will be available along with the recording of this call in the investor section of our website at designtx.com. I'm Sean Jeffries, Chief Operating Officer of Design, and I'm joined today on the call by our Chairman and CEO, Dr. Pratik Shah. During this call, we will use forward-looking statements to related to our current expectations and plans, including our program development plans, which are subject to risk and uncertainties. Actual results may differ materially due to various important factors, including those described in the risk factors section of our most recently filed Form 10-K. These statements represent our views as of this call and should not be relied upon as representing our views as of any date in the future. We take no obligation to publicly update any forward-looking statements. With that, I'd like to turn the call over to Dr. Shah.

Earlier, we issued a press release outlining our fourth quarter and full year 2023 financial results and updates across our portfolio of gene tack small molecule genomic medicines. The slides that will be using today during today's call will be available along with the recording of this call in the investors section of our website at design, TX Dot com. I'm, Sean Jeffries, Chief operating officer of design and I'm joined today on the call by our chairman and CEO Dr. <unk> Shah. During this call we will use forward looking statements related to our current expectations and plans, including our program development plans, which are subject to risks and uncertainties. Actual results may differ materially due to various important factors, including those described in the risk factors section of our most recently filed Form 10-K. These statements represent our views as of this call and should not be relied upon as representing our views as of any date in the future. Make no obligation to publicly update any forward looking statements with that I would like to turn the call over to Dr. Shaw.

The slides that will be using today during today's call will be available along with the recording of this call in the investors section of our website at design, TX Dot com. I'm, Sean Jeffries, Chief operating officer of design and I'm joined today on the call by our chairman and CEO Dr. <unk> Shah. During this call we will use forward looking statements related to our current expectations and plans, including our program development plans, which are subject to risks and uncertainties. Actual results may differ materially due to various important factors, including those described in the risk factors section of our most recently filed Form 10-K. These statements represent our views as of this call and should not be relied upon as representing our views as of any date in the future. Make no obligation to publicly update any forward looking statements with that I would like to turn the call over to Dr. Shaw.

I'm, Sean Jeffries, Chief operating officer of design and I'm joined today on the call by our chairman and CEO Dr. <unk> Shah. During this call we will use forward looking statements related to our current expectations and plans, including our program development plans, which are subject to risks and uncertainties. Actual results may differ materially due to various important factors, including those described in the risk factors section of our most recently filed Form 10-K. These statements represent our views as of this call and should not be relied upon as representing our views as of any date in the future. Make no obligation to publicly update any forward looking statements with that I would like to turn the call over to Dr. Shaw.

During this call we will use forward looking statements related to our current expectations and plans, including our program development plans, which are subject to risks and uncertainties. Actual results may differ materially due to various important factors, including those described in the risk factors section of our most recently filed Form 10-K. These statements represent our views as of this call and should not be relied upon as representing our views as of any date in the future. Make no obligation to publicly update any forward looking statements with that I would like to turn the call over to Dr. Shaw.

Make no obligation to publicly update any forward looking statements with that I would like to turn the call over to Dr. Shaw.

I'm excited to present design therapeutics first significant update for 2024. What makes this company unique and compelling is that we have discovered a new class of small molecules. But are designed to dial up or dial down the expression of an individual gene in the genome. When you think about the role of individual genes and disease. There are many monogenic disorders, where the single gene that causes the disease is well established. Our vision is to develop small molecules that can provide a restorative therapy and work with the patients natural genome to help sell the read the genes in a manner that restores cellular health. Despite the presence of the mutations. We are working on at least four major such disorders friedrichs. <unk> ataxia, Fuchs endothelial corneal dystrophy, Huntington's disease and Myasthenic dystrophy. Each of the programs we are pursuing in these areas. Have the potential to be first in class or best in class.

What makes this company unique and compelling is that we have discovered a new class of small molecules. But are designed to dial up or dial down the expression of an individual gene in the genome. When you think about the role of individual genes and disease. There are many monogenic disorders, where the single gene that causes the disease is well established. Our vision is to develop small molecules that can provide a restorative therapy and work with the patients natural genome to help sell the read the genes in a manner that restores cellular health. Despite the presence of the mutations. We are working on at least four major such disorders friedrichs. <unk> ataxia, Fuchs endothelial corneal dystrophy, Huntington's disease and Myasthenic dystrophy. Each of the programs we are pursuing in these areas. Have the potential to be first in class or best in class.

But are designed to dial up or dial down the expression of an individual gene in the genome. When you think about the role of individual genes and disease. There are many monogenic disorders, where the single gene that causes the disease is well established. Our vision is to develop small molecules that can provide a restorative therapy and work with the patients natural genome to help sell the read the genes in a manner that restores cellular health. Despite the presence of the mutations. We are working on at least four major such disorders friedrichs. <unk> ataxia, Fuchs endothelial corneal dystrophy, Huntington's disease and Myasthenic dystrophy. Each of the programs we are pursuing in these areas. Have the potential to be first in class or best in class.

When you think about the role of individual genes and disease. There are many monogenic disorders, where the single gene that causes the disease is well established. Our vision is to develop small molecules that can provide a restorative therapy and work with the patients natural genome to help sell the read the genes in a manner that restores cellular health. Despite the presence of the mutations. We are working on at least four major such disorders friedrichs. <unk> ataxia, Fuchs endothelial corneal dystrophy, Huntington's disease and Myasthenic dystrophy. Each of the programs we are pursuing in these areas. Have the potential to be first in class or best in class.

Our vision is to develop small molecules that can provide a restorative therapy and work with the patients natural genome to help sell the read the genes in a manner that restores cellular health. Despite the presence of the mutations. We are working on at least four major such disorders friedrichs. <unk> ataxia, Fuchs endothelial corneal dystrophy, Huntington's disease and Myasthenic dystrophy. Each of the programs we are pursuing in these areas. Have the potential to be first in class or best in class.

We are working on at least four major such disorders friedrichs. <unk> ataxia, Fuchs endothelial corneal dystrophy, Huntington's disease and Myasthenic dystrophy. Each of the programs we are pursuing in these areas. Have the potential to be first in class or best in class.

<unk> ataxia, Fuchs endothelial corneal dystrophy, Huntington's disease and Myasthenic dystrophy. Each of the programs we are pursuing in these areas. Have the potential to be first in class or best in class.

Each of the programs we are pursuing in these areas. Have the potential to be first in class or best in class.

Have the potential to be first in class or best in class.

I was previously chairman of Synthetics, which is now part of Santa fee as a result of a $2 $5 billion acquisition and prior to that I was CEO of Auspex Pharmaceuticals, which was acquired for $3 $5 billion. There, we had discovered and developed <unk>, which is now doing over $1 billion in annual revenue. And I'm joined by an accomplished and capable leadership team in design. Including Dr. Sean Jeffries, our Chief operating officer, and Dr. Jay <unk>, our Chief Medical Officer. Designs genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases in. In addition, we have a five year operating runway, which enables us to generate clinical proof of concept on up to four programs. Success in any one of these programs has the potential to generate enormous value for patients. And shareholders.

There, we had discovered and developed <unk>, which is now doing over $1 billion in annual revenue. And I'm joined by an accomplished and capable leadership team in design. Including Dr. Sean Jeffries, our Chief operating officer, and Dr. Jay <unk>, our Chief Medical Officer. Designs genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases in. In addition, we have a five year operating runway, which enables us to generate clinical proof of concept on up to four programs. Success in any one of these programs has the potential to generate enormous value for patients. And shareholders.

And I'm joined by an accomplished and capable leadership team in design. Including Dr. Sean Jeffries, our Chief operating officer, and Dr. Jay <unk>, our Chief Medical Officer. Designs genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases in. In addition, we have a five year operating runway, which enables us to generate clinical proof of concept on up to four programs. Success in any one of these programs has the potential to generate enormous value for patients. And shareholders.

Including Dr. Sean Jeffries, our Chief operating officer, and Dr. Jay <unk>, our Chief Medical Officer. Designs genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases in. In addition, we have a five year operating runway, which enables us to generate clinical proof of concept on up to four programs. Success in any one of these programs has the potential to generate enormous value for patients. And shareholders.

Designs genomic medicine platform has the potential to surpass competing modalities like gene editing and gene therapy for the treatment of these diseases in. In addition, we have a five year operating runway, which enables us to generate clinical proof of concept on up to four programs. Success in any one of these programs has the potential to generate enormous value for patients. And shareholders.

In addition, we have a five year operating runway, which enables us to generate clinical proof of concept on up to four programs. Success in any one of these programs has the potential to generate enormous value for patients. And shareholders.

Success in any one of these programs has the potential to generate enormous value for patients. And shareholders.

And shareholders.

<unk> therapeutic strategy is to restore the normal gene expression state of these known single gene driver <unk>. Each of our programs has a first or best in class profile, which has highly differentiating features in each of these are substantial market opportunities. Friedrichs ataxia phase a debilitating neuromuscular disorder. With hypertrophic cardiomyopathy as the primary cause of death. It's caused by a G. A repeat mutation in the <unk> tax engine, which is broadly expressed in the body. The goal of our genomic medicine is to increase levels of endogenous for taxing and address the monogenic cause of FAA. We will address the background in greater detail later in the presentation.

Each of our programs has a first or best in class profile, which has highly differentiating features in each of these are substantial market opportunities. Friedrichs ataxia phase a debilitating neuromuscular disorder. With hypertrophic cardiomyopathy as the primary cause of death. It's caused by a G. A repeat mutation in the <unk> tax engine, which is broadly expressed in the body. The goal of our genomic medicine is to increase levels of endogenous for taxing and address the monogenic cause of FAA. We will address the background in greater detail later in the presentation.

Friedrichs ataxia phase a debilitating neuromuscular disorder. With hypertrophic cardiomyopathy as the primary cause of death. It's caused by a G. A repeat mutation in the <unk> tax engine, which is broadly expressed in the body. The goal of our genomic medicine is to increase levels of endogenous for taxing and address the monogenic cause of FAA. We will address the background in greater detail later in the presentation.

With hypertrophic cardiomyopathy as the primary cause of death. It's caused by a G. A repeat mutation in the <unk> tax engine, which is broadly expressed in the body. The goal of our genomic medicine is to increase levels of endogenous for taxing and address the monogenic cause of FAA. We will address the background in greater detail later in the presentation.

It's caused by a G. A repeat mutation in the <unk> tax engine, which is broadly expressed in the body. The goal of our genomic medicine is to increase levels of endogenous for taxing and address the monogenic cause of FAA. We will address the background in greater detail later in the presentation.

We will address the background in greater detail later in the presentation.

Friedrichs ataxia into clinical trials. In 2022, and 'twenty, three and confirmed that <unk> can increase the level of for Taxane RNA expression in patients with fr. We also learned about limitations to the prior formulation in human studies.

In 2022, and 'twenty, three and confirmed that <unk> can increase the level of for Taxane RNA expression in patients with fr. We also learned about limitations to the prior formulation in human studies.

We also learned about limitations to the prior formulation in human studies.

Pratik Shah: The market opportunity for a systemic therapy that can restore endogenous Rituxan levels remains large and unaffected by progress by others in the field. The prior DT-216 drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile, and therefore, drug levels in the plasma were low after only a few hours. The orange curve shows the pharmacokinetics of the prior DT-216 drug product in non-human primates. In green is the PK of DT-216P2, which has a shorter alpha phase and a more rapid transition to the beta phase, and therefore a substantial increase in drug levels over a much longer period of time. Due to this increase in exposure, lower levels of administered drug are needed to achieve these desired profiles.

<unk> large and unaffected by progress by others in the field. The prior D. T 216 drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma. Low after only a few hours the orange curve shows the pharmacokinetics of the prior DT too unsafe struck product and nonhuman primates. And green. Is the P. K a D C 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. <unk> a much longer period of time. Due to this increase in exposure. Lower levels of administered drug are needed to achieve these desired profiles.

The prior D. T 216 drug product had a rapid elimination from plasma during a period called the alpha phase and its exposure profile and therefore drug levels in the plasma. Low after only a few hours the orange curve shows the pharmacokinetics of the prior DT too unsafe struck product and nonhuman primates. And green. Is the P. K a D C 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. <unk> a much longer period of time. Due to this increase in exposure. Lower levels of administered drug are needed to achieve these desired profiles.

Low after only a few hours the orange curve shows the pharmacokinetics of the prior DT too unsafe struck product and nonhuman primates. And green. Is the P. K a D C 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. <unk> a much longer period of time. Due to this increase in exposure. Lower levels of administered drug are needed to achieve these desired profiles.

And green. Is the P. K a D C 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. <unk> a much longer period of time. Due to this increase in exposure. Lower levels of administered drug are needed to achieve these desired profiles.

Is the P. K a D C 262, which has a shorter alpha phase and a more rapid transition to the beta phase and therefore, a substantial increase in drug levels. <unk> a much longer period of time. Due to this increase in exposure. Lower levels of administered drug are needed to achieve these desired profiles.

<unk> a much longer period of time. Due to this increase in exposure. Lower levels of administered drug are needed to achieve these desired profiles.

Due to this increase in exposure. Lower levels of administered drug are needed to achieve these desired profiles.

Lower levels of administered drug are needed to achieve these desired profiles.

Pratik Shah: In addition, a favorable injection site reaction profile has been seen with the new drug product in nonclinical studies. With this new advance, we are back on a path to continue further development of DT-216 for patients with FA. In the time, since our last update, we have also advanced the GeneTAC platform and have refined our strategy and priorities for the programs. Our FECD program data have now been reviewed by the FDA resulting in an IND cleared to proceed. As a result, we plan to initiate Phase I development for DT-168 this year. We have also decided to conduct an observational study in patients with FECD prior to conducting an investigational drug treatment trial in patients.

With this new advance we are back on a path to continue further development of D. C 2164 patients with SA.

With this new advance we are back on a path to continue further development of D. C 2164 patients with SA. In the time since our last update we have also advanced the gene tack platform and have refined our strategy and priorities for the programs. R F E C D program. Data have now been reviewed by the FDA, resulting in an Ivy cleared to proceed. As a result, we plan to initiate phase one development for D. T 168 this year. We have also decided to conduct an observational study in patients with F. E. C D. Prior to conducting an investigational drug treatment trial impatience.

of D. C 2164 patients with SA. In the time since our last update we have also advanced the gene tack platform and have refined our strategy and priorities for the programs. R F E C D program. Data have now been reviewed by the FDA, resulting in an Ivy cleared to proceed. As a result, we plan to initiate phase one development for D. T 168 this year. We have also decided to conduct an observational study in patients with F. E. C D. Prior to conducting an investigational drug treatment trial impatience.

In the time since our last update we have also advanced the gene tack platform and have refined our strategy and priorities for the programs. R F E C D program. Data have now been reviewed by the FDA, resulting in an Ivy cleared to proceed. As a result, we plan to initiate phase one development for D. T 168 this year. We have also decided to conduct an observational study in patients with F. E. C D. Prior to conducting an investigational drug treatment trial impatience.

R F E C D program. Data have now been reviewed by the FDA, resulting in an Ivy cleared to proceed. As a result, we plan to initiate phase one development for D. T 168 this year. We have also decided to conduct an observational study in patients with F. E. C D. Prior to conducting an investigational drug treatment trial impatience.

Data have now been reviewed by the FDA, resulting in an Ivy cleared to proceed. As a result, we plan to initiate phase one development for D. T 168 this year. We have also decided to conduct an observational study in patients with F. E. C D. Prior to conducting an investigational drug treatment trial impatience.

As a result, we plan to initiate phase one development for D. T 168 this year. We have also decided to conduct an observational study in patients with F. E. C D. Prior to conducting an investigational drug treatment trial impatience.

We have also decided to conduct an observational study in patients with F. E. C D. Prior to conducting an investigational drug treatment trial impatience.

Pratik Shah: We are also announcing for the first time our Huntington's disease program where we have identified small molecule candidates that exhibit allele selective reduction of Mutant Huntington expression considered an ideal, although elusive profile for molecules that could be reasonably advanced as systemically administered and widely distributing compounds. Similarly, we have identified compounds exhibiting allele selective inhibition of Mutant DMPK, which is the root cause of myotonic dystrophy with what we believe are best-in-class foci reduction and splicing restoration data.

Where we have identified small molecule candidates that exhibit allele selective reduction of mutant Huntington expression <unk>. Considered an ideal although elusive profile for molecules that could be reasonably advanced as systemically administered and widely distributing compounds. Similarly, we have identified compounds exhibiting a legal selective and ambition of mutant B M. P. K, which is the root cause of my tummy dystrophy. With what we believe our best in class foci reduction and splicing restoration data.

Considered an ideal although elusive profile for molecules that could be reasonably advanced as systemically administered and widely distributing compounds. Similarly, we have identified compounds exhibiting a legal selective and ambition of mutant B M. P. K, which is the root cause of my tummy dystrophy. With what we believe our best in class foci reduction and splicing restoration data.

Similarly, we have identified compounds exhibiting a legal selective and ambition of mutant B M. P. K, which is the root cause of my tummy dystrophy. With what we believe our best in class foci reduction and splicing restoration data.

With what we believe our best in class foci reduction and splicing restoration data.

Declared development candidates. Jean editing and gene therapy have understandably captured the imagination of humankind ever. Ever since we learned that mutations in single genes cause disease. There has been a desire to edit the genome in some fashion to restore normal cellular health. Other approaches have also emerged that try to get at the root cause of monogenic diseases. However. Jean Tech molecules work in patients there would be little doubt they represent the best option in genomic medicine since gene Tech molecules systemically administered can distribute widely to a broad set of tissues in the target cells broadly to effect the desired outcome without all. During a patient's natural genome.

Jean editing and gene therapy have understandably captured the imagination of humankind ever. Ever since we learned that mutations in single genes cause disease. There has been a desire to edit the genome in some fashion to restore normal cellular health. Other approaches have also emerged that try to get at the root cause of monogenic diseases. However. Jean Tech molecules work in patients there would be little doubt they represent the best option in genomic medicine since gene Tech molecules systemically administered can distribute widely to a broad set of tissues in the target cells broadly to effect the desired outcome without all. During a patient's natural genome.

Ever since we learned that mutations in single genes cause disease. There has been a desire to edit the genome in some fashion to restore normal cellular health. Other approaches have also emerged that try to get at the root cause of monogenic diseases. However. Jean Tech molecules work in patients there would be little doubt they represent the best option in genomic medicine since gene Tech molecules systemically administered can distribute widely to a broad set of tissues in the target cells broadly to effect the desired outcome without all. During a patient's natural genome.

Other approaches have also emerged that try to get at the root cause of monogenic diseases. However. Jean Tech molecules work in patients there would be little doubt they represent the best option in genomic medicine since gene Tech molecules systemically administered can distribute widely to a broad set of tissues in the target cells broadly to effect the desired outcome without all. During a patient's natural genome.

Jean Tech molecules work in patients there would be little doubt they represent the best option in genomic medicine since gene Tech molecules systemically administered can distribute widely to a broad set of tissues in the target cells broadly to effect the desired outcome without all. During a patient's natural genome.

During a patient's natural genome.

Investments into new platform companies, often suffer from frequent rounds of dilution due to the necessary high R&D burn rates that often require investors the time their investment decisions with great care <unk>. Designers approach is more cost effective making an investment decision for a longer horizon potentially quite attractive. The advantage of gene tech molecules become more apparent when you consider how much smaller these molecules are than those of competing modality. Which further explains the broad distribution properties.

Designers approach is more cost effective making an investment decision for a longer horizon potentially quite attractive. The advantage of gene tech molecules become more apparent when you consider how much smaller these molecules are than those of competing modality. Which further explains the broad distribution properties.

The advantage of gene tech molecules become more apparent when you consider how much smaller these molecules are than those of competing modality. Which further explains the broad distribution properties.

Which further explains the broad distribution properties.

Pratik Shah: Also, by restoring endogenous gene expression, like in FA, the gene products are entirely normal and under normal physiologic control. The mechanism of action of these GeneTAC molecules, which drive these remarkable observations are shown in this animation that I'll walk you through. First, we start with FA. FA is caused by low levels of frataxin, which is a protein that's systemically expressed in the body. So, if you look inside the cell and inside the nucleus, the frataxin gene has a GAA repeat expansion shown in red, which causes the RNA polymerase to slow down through this region and produce low levels of frataxin premium RNA, and therefore low levels of express translated protein. And that's what drives the dysfunction.

The gene products are entirely normal and under normal physiological control. The mechanism of action of these gene Tech molecules, which drive these remarkable observations are shown in this animation that I'll walk you through <unk>. First we start with <unk>. F. A a has caused by low levels of for tax and which is a protein that systemically expressed in the body. So if you look inside the cell on the inside of the nuclear the for taxing Jean has a G. A repeat expansion shown in red which causes the already preliminaries to slow down through this region and produce low levels of for tax and premium. <unk> and. And therefore low levels of express translated protein and that's what drives that this function.

The mechanism of action of these gene Tech molecules, which drive these remarkable observations are shown in this animation that I'll walk you through <unk>. First we start with <unk>. F. A a has caused by low levels of for tax and which is a protein that systemically expressed in the body. So if you look inside the cell on the inside of the nuclear the for taxing Jean has a G. A repeat expansion shown in red which causes the already preliminaries to slow down through this region and produce low levels of for tax and premium. <unk> and. And therefore low levels of express translated protein and that's what drives that this function.

First we start with <unk>. F. A a has caused by low levels of for tax and which is a protein that systemically expressed in the body. So if you look inside the cell on the inside of the nuclear the for taxing Jean has a G. A repeat expansion shown in red which causes the already preliminaries to slow down through this region and produce low levels of for tax and premium. <unk> and. And therefore low levels of express translated protein and that's what drives that this function.

F. A a has caused by low levels of for tax and which is a protein that systemically expressed in the body. So if you look inside the cell on the inside of the nuclear the for taxing Jean has a G. A repeat expansion shown in red which causes the already preliminaries to slow down through this region and produce low levels of for tax and premium. <unk> and. And therefore low levels of express translated protein and that's what drives that this function.

<unk> and. And therefore low levels of express translated protein and that's what drives that this function.

And therefore low levels of express translated protein and that's what drives that this function.

When this compound is administered systemically and distributes widely gets into the cell gets in in the nucleus and then recognizes the G. A a repeat expansions by binding to the minor groove of impact double stranded DNA in the for tax and Jean and the other end of the molecule recruits a transcription. <unk> elongation complex. Presence of these transcriptional elongation complexes. Enables the RNA prelim race. To now rapidly read through the repeat region. And therefore produce normal levels of the for tax and pre mrna. Because of the repeat expansion as in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length endogenous M Arnie, which produces normal endogenous for tax and protein with all of its natural isoforms under the native regulatory control. This restores protection levels, and therefore health

<unk> elongation complex. Presence of these transcriptional elongation complexes. Enables the RNA prelim race. To now rapidly read through the repeat region. And therefore produce normal levels of the for tax and pre mrna. Because of the repeat expansion as in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length endogenous M Arnie, which produces normal endogenous for tax and protein with all of its natural isoforms under the native regulatory control. This restores protection levels, and therefore health

Presence of these transcriptional elongation complexes. Enables the RNA prelim race. To now rapidly read through the repeat region. And therefore produce normal levels of the for tax and pre mrna. Because of the repeat expansion as in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length endogenous M Arnie, which produces normal endogenous for tax and protein with all of its natural isoforms under the native regulatory control. This restores protection levels, and therefore health

Enables the RNA prelim race. To now rapidly read through the repeat region. And therefore produce normal levels of the for tax and pre mrna. Because of the repeat expansion as in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length endogenous M Arnie, which produces normal endogenous for tax and protein with all of its natural isoforms under the native regulatory control. This restores protection levels, and therefore health

To now rapidly read through the repeat region. And therefore produce normal levels of the for tax and pre mrna. Because of the repeat expansion as in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length endogenous M Arnie, which produces normal endogenous for tax and protein with all of its natural isoforms under the native regulatory control. This restores protection levels, and therefore health

And therefore produce normal levels of the for tax and pre mrna. Because of the repeat expansion as in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length endogenous M Arnie, which produces normal endogenous for tax and protein with all of its natural isoforms under the native regulatory control. This restores protection levels, and therefore health

Because of the repeat expansion as in an intron that portion of the RNA is just spliced out normally to produce normal levels of impactful length endogenous M Arnie, which produces normal endogenous for tax and protein with all of its natural isoforms under the native regulatory control. This restores protection levels, and therefore health

This restores protection levels, and therefore health now for the other side of the platform.

This restores protection levels, and therefore health

Long repeat expansions in non coding regions of genes are shown in red in the upper half. This is the case and diseases like Fuchs endothelial corneal dystrophy in my Panic dystrophy. Repeat expansions in coding regions of genes are shown in the lower half and Red as is the case in Huntington's disease. Only takes one allele to cause the disease. So patient has one wild type allele shown in the strand without the red and a mutant allele shown in the strand with the Red expanded regions.

This is the case and diseases like Fuchs endothelial corneal dystrophy in my Panic dystrophy. Repeat expansions in coding regions of genes are shown in the lower half and Red as is the case in Huntington's disease. Only takes one allele to cause the disease. So patient has one wild type allele shown in the strand without the red and a mutant allele shown in the strand with the Red expanded regions.

Repeat expansions in coding regions of genes are shown in the lower half and Red as is the case in Huntington's disease. Only takes one allele to cause the disease. So patient has one wild type allele shown in the strand without the red and a mutant allele shown in the strand with the Red expanded regions.

Only takes one allele to cause the disease. So patient has one wild type allele shown in the strand without the red and a mutant allele shown in the strand with the Red expanded regions.

Pratik Shah: Now in the upper half, this mutant allele is transcribed by RNA polymerase to create RNA, which then folds over on itself causes tangles and sequesters MBNL proteins. This causes nuclear foci and - osteopathy and other cellular dysfunction. Now in the lower half, the RNA is transcribed and then translated by ribosomes to make toxic mutant proteins. These proteins cause toxic aggregates, as is the case in Mutant Huntington protein causing Huntington’s Disease. GeneTAC molecules selectively target these abnormal alleles at the repeat expansions shown in red, and they dial down transcription of toxic mutant gene products and thereby restore cellular health. The wild type alleles continue to function normally. This slide summarizes the mechanism of action that we've just reviewed in the animation.

In the upper half. This mutant allele is transcribed by army preliminaries to create RNA, which then folds over on itself causes tangles and sequesters MBNA proteins. Causes nuclear <unk> and slice office the another cellular dysfunction now in the lower half the <unk> transcribed and then translated by ribosomes to make toxic mutant proteins. These proteins cause toxic aggregates as is the case in Vietnam, Huntington protein, causing huntington's disease. Jean Tech molecules selectively target these abnormal <unk> at the repeat expansions shown in red and the dialed down transcription of toxic and gene products and thereby restore cellular health the wild type of deals continue to function normally. This slide summarizes the mechanism of action that we've just reviewed in the animation.

This mutant allele is transcribed by army preliminaries to create RNA, which then folds over on itself causes tangles and sequesters MBNA proteins. Causes nuclear <unk> and slice office the another cellular dysfunction now in the lower half the <unk> transcribed and then translated by ribosomes to make toxic mutant proteins. These proteins cause toxic aggregates as is the case in Vietnam, Huntington protein, causing huntington's disease. Jean Tech molecules selectively target these abnormal <unk> at the repeat expansions shown in red and the dialed down transcription of toxic and gene products and thereby restore cellular health the wild type of deals continue to function normally. This slide summarizes the mechanism of action that we've just reviewed in the animation.

Causes nuclear <unk> and slice office the another cellular dysfunction now in the lower half the <unk> transcribed and then translated by ribosomes to make toxic mutant proteins. These proteins cause toxic aggregates as is the case in Vietnam, Huntington protein, causing huntington's disease. Jean Tech molecules selectively target these abnormal <unk> at the repeat expansions shown in red and the dialed down transcription of toxic and gene products and thereby restore cellular health the wild type of deals continue to function normally. This slide summarizes the mechanism of action that we've just reviewed in the animation.

Jean Tech molecules selectively target these abnormal <unk> at the repeat expansions shown in red and the dialed down transcription of toxic and gene products and thereby restore cellular health the wild type of deals continue to function normally. This slide summarizes the mechanism of action that we've just reviewed in the animation.

This slide summarizes the mechanism of action that we've just reviewed in the animation.

Pratik Shah: And now for a deeper dive into our FA program. The root cause of FA lies in the single gene frataxin. It's the reduction in frataxin expression that causes the dysfunction, whether it's in the C&S, musculoskeletal tissues, cardiac hypertrophy, or metabolic problems that patients face. When we look at frataxin levels in [Audio Gap] healthy individuals, carriers and patients, we see that carriers have approximately half the level of their frataxin is indicated by the black line representing the group average, carriers do not have FA and have no disease burden. FA patients have a quarter to a fifth of normal frataxin levels on average. Of course, around every mean is a distribution, and there may be individuals who are above or below the mean and different individuals might require different levels of restoration to get back into the normal zone, which is somewhere near carrier levels. And that is the therapeutic goal, which is thought to be about a doubling.

The root cause of FAA lies in the single gene protection as the reduction reduction in for tax an expression that causes the dysfunction, whether it's in the CNS musculoskeletal tissues, cardiac hypertrophy or metabolic problems with patients face. When we look at for tax and levels. In healthy individuals carriers and patients we. We see that carriers have approximately half the level of their for tax N as indicated by the Black line, representing the group average <unk>. Carriers do not have <unk> and have no disease burden. Patients have a quarter to a fifth of normal for tax and levels on average. Of course around every mean as a distribution and there may be individuals who are above or below the mean and different individuals might require different levels of frustration to get back into normal stolen which is somewhere near carrier levels. That is the therapeutic goal, which is thought to be about a dumpling.

When we look at for tax and levels. In healthy individuals carriers and patients we. We see that carriers have approximately half the level of their for tax N as indicated by the Black line, representing the group average <unk>. Carriers do not have <unk> and have no disease burden. Patients have a quarter to a fifth of normal for tax and levels on average. Of course around every mean as a distribution and there may be individuals who are above or below the mean and different individuals might require different levels of frustration to get back into normal stolen which is somewhere near carrier levels. That is the therapeutic goal, which is thought to be about a dumpling.

In healthy individuals carriers and patients we. We see that carriers have approximately half the level of their for tax N as indicated by the Black line, representing the group average <unk>. Carriers do not have <unk> and have no disease burden. Patients have a quarter to a fifth of normal for tax and levels on average. Of course around every mean as a distribution and there may be individuals who are above or below the mean and different individuals might require different levels of frustration to get back into normal stolen which is somewhere near carrier levels. That is the therapeutic goal, which is thought to be about a dumpling.

We see that carriers have approximately half the level of their for tax N as indicated by the Black line, representing the group average <unk>. Carriers do not have <unk> and have no disease burden. Patients have a quarter to a fifth of normal for tax and levels on average. Of course around every mean as a distribution and there may be individuals who are above or below the mean and different individuals might require different levels of frustration to get back into normal stolen which is somewhere near carrier levels. That is the therapeutic goal, which is thought to be about a dumpling.

Carriers do not have <unk> and have no disease burden. Patients have a quarter to a fifth of normal for tax and levels on average. Of course around every mean as a distribution and there may be individuals who are above or below the mean and different individuals might require different levels of frustration to get back into normal stolen which is somewhere near carrier levels. That is the therapeutic goal, which is thought to be about a dumpling.

Patients have a quarter to a fifth of normal for tax and levels on average. Of course around every mean as a distribution and there may be individuals who are above or below the mean and different individuals might require different levels of frustration to get back into normal stolen which is somewhere near carrier levels. That is the therapeutic goal, which is thought to be about a dumpling.

Of course around every mean as a distribution and there may be individuals who are above or below the mean and different individuals might require different levels of frustration to get back into normal stolen which is somewhere near carrier levels. That is the therapeutic goal, which is thought to be about a dumpling.

That is the therapeutic goal, which is thought to be about a dumpling.

Pratik Shah: Now, most of the general population has less than 34 GA repeats in their frataxin gene, but someone with FA has 400 or over a 1,000 and these repeats reduce the level of normal frataxin, and it turns out you can measure this reduction with a blood test. What's shown on the top right is a result of a PCR test conducted on blood cells from patients. You can see in the gray bar on the graph that RNA levels are low in patient cells when compared with frataxin from an unaffected sibling who has two normal copies of the frataxin gene. You can imagine our excitement when we were able to observe that when cells from patients are incubated with GeneTAC molecules, there's a restoration of frataxin to normal levels in a dose dependent fashion. And when cells from unaffected siblings are incubated with the compounds, the frataxin levels remain unaltered. This is exactly what one would wish for an FA, a medicine that restores natural levels of the single gene product that causes all of these problems. And that's what's so exciting about Design, is we have an opportunity to provide a restorative therapy of natural frataxin from the patient's own genes and to do it with a small molecule.

And it turns out you can measure this reduction. With a blood test. What's shown on the top right as a result of a P. C. R tests conducted on blood cells from patients. Can see and gray bar on the graph that Arnie levels are low impatient sells when compared with protection from an unaffected siblings, who has two normal copies of the for tax regime. You can imagine our excitement when we were able to observe when cells from patients are incubated with gene Tech molecules, there's a restoration of for tax into normal levels and a dose dependent fashion. When cells from unaffected siblings are incubated with the compounds for tax and levels remain unaltered. This is exactly what one would wish for an essay. A medicine that restores natural levels of the single gene product that causes all of these problems and that's what's so exciting about design as we have an opportunity to provide a restored if therapy of natural protect sent from a patient's own jeans and to do it with a small molecule.

With a blood test. What's shown on the top right as a result of a P. C. R tests conducted on blood cells from patients. Can see and gray bar on the graph that Arnie levels are low impatient sells when compared with protection from an unaffected siblings, who has two normal copies of the for tax regime. You can imagine our excitement when we were able to observe when cells from patients are incubated with gene Tech molecules, there's a restoration of for tax into normal levels and a dose dependent fashion. When cells from unaffected siblings are incubated with the compounds for tax and levels remain unaltered. This is exactly what one would wish for an essay. A medicine that restores natural levels of the single gene product that causes all of these problems and that's what's so exciting about design as we have an opportunity to provide a restored if therapy of natural protect sent from a patient's own jeans and to do it with a small molecule.

What's shown on the top right as a result of a P. C. R tests conducted on blood cells from patients. Can see and gray bar on the graph that Arnie levels are low impatient sells when compared with protection from an unaffected siblings, who has two normal copies of the for tax regime. You can imagine our excitement when we were able to observe when cells from patients are incubated with gene Tech molecules, there's a restoration of for tax into normal levels and a dose dependent fashion. When cells from unaffected siblings are incubated with the compounds for tax and levels remain unaltered. This is exactly what one would wish for an essay. A medicine that restores natural levels of the single gene product that causes all of these problems and that's what's so exciting about design as we have an opportunity to provide a restored if therapy of natural protect sent from a patient's own jeans and to do it with a small molecule.

Can see and gray bar on the graph that Arnie levels are low impatient sells when compared with protection from an unaffected siblings, who has two normal copies of the for tax regime. You can imagine our excitement when we were able to observe when cells from patients are incubated with gene Tech molecules, there's a restoration of for tax into normal levels and a dose dependent fashion. When cells from unaffected siblings are incubated with the compounds for tax and levels remain unaltered. This is exactly what one would wish for an essay. A medicine that restores natural levels of the single gene product that causes all of these problems and that's what's so exciting about design as we have an opportunity to provide a restored if therapy of natural protect sent from a patient's own jeans and to do it with a small molecule.

You can imagine our excitement when we were able to observe when cells from patients are incubated with gene Tech molecules, there's a restoration of for tax into normal levels and a dose dependent fashion. When cells from unaffected siblings are incubated with the compounds for tax and levels remain unaltered. This is exactly what one would wish for an essay. A medicine that restores natural levels of the single gene product that causes all of these problems and that's what's so exciting about design as we have an opportunity to provide a restored if therapy of natural protect sent from a patient's own jeans and to do it with a small molecule.

When cells from unaffected siblings are incubated with the compounds for tax and levels remain unaltered. This is exactly what one would wish for an essay. A medicine that restores natural levels of the single gene product that causes all of these problems and that's what's so exciting about design as we have an opportunity to provide a restored if therapy of natural protect sent from a patient's own jeans and to do it with a small molecule.

A medicine that restores natural levels of the single gene product that causes all of these problems and that's what's so exciting about design as we have an opportunity to provide a restored if therapy of natural protect sent from a patient's own jeans and to do it with a small molecule.

Pratik Shah: Now, we've seen that this effect is observed in a wide variety of cell types tested shown here is the result of treating terminally differentiated neurons taken from patient derived IPS cells. On the left is an increase in frataxin RNA, and on the right is an increase in frataxin protein, which follows a few days later and has a long half-life of several days. DT-216 was taken into clinical trials in patients with FA in 2022 and ‘23 with a prior formulation and the trial design is shown here. We learned from the human studies that the duration of adequate levels of exposure of DT-216 was much shorter than expected. While we knew that the drug was short-lived in plasma. Human studies showed by muscle biopsy that it was also short-lived in tissue and that what you observe in plasma is predictive of what is observed in tissue. The tissue levels from human muscle biopsies were approximately only eight to 10 nanomolar at day two, and the drug was almost gone with levels of one nanomolar by day seven. Well, despite that, there was a clear increase in frataxin expression observed in treated patients in a dose dependent fashion with one patient frataxin level, going to clinically normal carrier levels as shown in the right. However, the effect was transient because the drug exposure was transient, so we needed to develop a new drug product that could sustain this drug exposure.

On the left is an increase in for tax and RNA and on the right is an increase in for tax and protein which follows a few days later and has a long half life of several days. DT 216 was taken into clinical trials in patients with FAA in 2022, and 23 with a prior formulation and the trial design is shown here. We learn from the human studies that the duration of adequate levels of exposure of DT 216 was much shorter than expected. While we knew that the drug was short lived in plasma. Human studies showed by muscle biopsy that it was also short lived in tissue. And that what you observe and plasma is predictive of what is observed in tissue <unk>. The tissue levels from human muscle biopsies, where approximately only eight to 10 Nanomolar at day too. The drug was almost gone with levels of one nanomolar by day seven. Well despite that. There was a clear increase in for tax and expression observed and treated patients and a dose dependent fashion. With one patient protection level going to clinically normal carrier levels are shown in the right. However, the effect was transient because the drug exposure was transient so. So we needed to develop a new drug product that could sustain this drug exposure.

DT 216 was taken into clinical trials in patients with FAA in 2022, and 23 with a prior formulation and the trial design is shown here. We learn from the human studies that the duration of adequate levels of exposure of DT 216 was much shorter than expected. While we knew that the drug was short lived in plasma. Human studies showed by muscle biopsy that it was also short lived in tissue. And that what you observe and plasma is predictive of what is observed in tissue <unk>. The tissue levels from human muscle biopsies, where approximately only eight to 10 Nanomolar at day too. The drug was almost gone with levels of one nanomolar by day seven. Well despite that. There was a clear increase in for tax and expression observed and treated patients and a dose dependent fashion. With one patient protection level going to clinically normal carrier levels are shown in the right. However, the effect was transient because the drug exposure was transient so. So we needed to develop a new drug product that could sustain this drug exposure.

Sean Jeffries: We learn from the human studies that the duration of adequate levels of exposure of DT 216 was much shorter than expected. While we knew that the drug was short lived in plasma. Human studies showed by muscle biopsy that it was also short lived in tissue. And that what you observe and plasma is predictive of what is observed in tissue <unk>. The tissue levels from human muscle biopsies, where approximately only eight to 10 Nanomolar at day too. The drug was almost gone with levels of one nanomolar by day seven. Well despite that. There was a clear increase in for tax and expression observed and treated patients and a dose dependent fashion. With one patient protection level going to clinically normal carrier levels are shown in the right. However, the effect was transient because the drug exposure was transient so. So we needed to develop a new drug product that could sustain this drug exposure.

Sean Jeffries: While we knew that the drug was short lived in plasma. Human studies showed by muscle biopsy that it was also short lived in tissue. And that what you observe and plasma is predictive of what is observed in tissue <unk>. The tissue levels from human muscle biopsies, where approximately only eight to 10 Nanomolar at day too. The drug was almost gone with levels of one nanomolar by day seven. Well despite that. There was a clear increase in for tax and expression observed and treated patients and a dose dependent fashion. With one patient protection level going to clinically normal carrier levels are shown in the right. However, the effect was transient because the drug exposure was transient so. So we needed to develop a new drug product that could sustain this drug exposure.

Sean Jeffries: Human studies showed by muscle biopsy that it was also short lived in tissue. And that what you observe and plasma is predictive of what is observed in tissue <unk>. The tissue levels from human muscle biopsies, where approximately only eight to 10 Nanomolar at day too. The drug was almost gone with levels of one nanomolar by day seven. Well despite that. There was a clear increase in for tax and expression observed and treated patients and a dose dependent fashion. With one patient protection level going to clinically normal carrier levels are shown in the right. However, the effect was transient because the drug exposure was transient so. So we needed to develop a new drug product that could sustain this drug exposure.

Speaker Change: And that what you observe and plasma is predictive of what is observed in tissue <unk>. The tissue levels from human muscle biopsies, where approximately only eight to 10 Nanomolar at day too. The drug was almost gone with levels of one nanomolar by day seven. Well despite that. There was a clear increase in for tax and expression observed and treated patients and a dose dependent fashion. With one patient protection level going to clinically normal carrier levels are shown in the right. However, the effect was transient because the drug exposure was transient so. So we needed to develop a new drug product that could sustain this drug exposure.

Speaker Change: The tissue levels from human muscle biopsies, where approximately only eight to 10 Nanomolar at day too. The drug was almost gone with levels of one nanomolar by day seven. Well despite that. There was a clear increase in for tax and expression observed and treated patients and a dose dependent fashion. With one patient protection level going to clinically normal carrier levels are shown in the right. However, the effect was transient because the drug exposure was transient so. So we needed to develop a new drug product that could sustain this drug exposure.

Speaker Change: The drug was almost gone with levels of one nanomolar by day seven. Well despite that. There was a clear increase in for tax and expression observed and treated patients and a dose dependent fashion. With one patient protection level going to clinically normal carrier levels are shown in the right. However, the effect was transient because the drug exposure was transient so. So we needed to develop a new drug product that could sustain this drug exposure.

Speaker Change: Well despite that. There was a clear increase in for tax and expression observed and treated patients and a dose dependent fashion. With one patient protection level going to clinically normal carrier levels are shown in the right. However, the effect was transient because the drug exposure was transient so. So we needed to develop a new drug product that could sustain this drug exposure.

Speaker Change: There was a clear increase in for tax and expression observed and treated patients and a dose dependent fashion. With one patient protection level going to clinically normal carrier levels are shown in the right. However, the effect was transient because the drug exposure was transient so. So we needed to develop a new drug product that could sustain this drug exposure.

Speaker Change: With one patient protection level going to clinically normal carrier levels are shown in the right. However, the effect was transient because the drug exposure was transient so. So we needed to develop a new drug product that could sustain this drug exposure.

Pratik Shah: However, the effect was transient because the drug exposure was transient so. So we needed to develop a new drug product that could sustain this drug exposure.

Pratik Shah: So we needed to develop a new drug product that could sustain this drug exposure.

Pratik Shah: While the drug was generally well tolerated, there were injection site thrombophlebitis events observed, which limited the frequency and levels of dosing with the prior product candidate. Nonclinical studies showed that these reactions were attributable to the formulation excipients in the drug product. We have now conducted new non GLP animal studies with DT-216P2, which lead us to believe that these issues have now been solved and we can progress to confirmatory GLP studies to get back into the clinic. Furthermore, this new drug product appears suitable for IV administration, compatible with injections or infusions, peripheral or central, and also appears suitable for a subcutaneous route of administration.

Pratik Shah: Non clinical studies show that these reactions were attributable to the formulation excipients in the drug product. We have now conducted new non G. L P animal studies. With D T 262, which lead us to believe that these issues have now been solved and we can progress to confirm it Tori GOP studies to get back into the clinic. Furthermore, this new. Drug product appear suitable for Ivy administration. Compatible with injections or infusions peripheral or central and also appear suitable for a subcutaneous route of administration.

We have now conducted new non G. L P animal studies. With D T 262, which lead us to believe that these issues have now been solved and we can progress to confirm it Tori GOP studies to get back into the clinic. Furthermore, this new. Drug product appear suitable for Ivy administration. Compatible with injections or infusions peripheral or central and also appear suitable for a subcutaneous route of administration.

Pratik Shah: With D T 262, which lead us to believe that these issues have now been solved and we can progress to confirm it Tori GOP studies to get back into the clinic. Furthermore, this new. Drug product appear suitable for Ivy administration. Compatible with injections or infusions peripheral or central and also appear suitable for a subcutaneous route of administration.

Pratik Shah: Furthermore, this new. Drug product appear suitable for Ivy administration. Compatible with injections or infusions peripheral or central and also appear suitable for a subcutaneous route of administration.

Pratik Shah: Drug product appear suitable for Ivy administration. Compatible with injections or infusions peripheral or central and also appear suitable for a subcutaneous route of administration.

Pratik Shah: Compatible with injections or infusions peripheral or central and also appear suitable for a subcutaneous route of administration.

Pratik Shah: As we showed in the beginning, the new drug product, DT-216P2 has a much more sustained exposure profile as seen in the single dose ID PK curve from non-human primates. You can see between day one and day seven, the levels are 10 to perhaps a hundred-fold higher than the prior drug product, even with a quarter to approximately a 10th of the reference dose. This is because of a shorter alpha phase and the elimination half-life between the prior and new drug products are very similar. This profile has been achieved by using a proprietary and novel excipient in the formulation. DT-216P2 also has a sustained exposure profile when administered by subcutaneous route of administration as shown on the right slide. This profile has a blunted CMAX and a sustained exposure with low peak to trough level fluctuations. We have flexibility in both root of administration as well as frequency of dosing as seen here with both a daily or weekly subcutaneous injection in non-human primates.

Pratik Shah: Drug products D. T 262 has a much more sustained exposure profile is seen in the single dose Ivy PK curve from nonhuman primates. You can see between day, one and a seven the levels are tend to perhaps 100 fold higher than the prior drug product, even with a quarter to approximately a 10th of the reference dose. This is because of a shorter alpha phase and the elimination half life between the prior a new drug products are very similar. This profile has been achieved by using a proprietary and novel Excipient. In the formulation. <unk> also has a sustained exposure profile when administered by subcutaneous route of administration is shown on the right slide. This profile has a blunted see Max kind of sustained exposure with low peak to trough level fluctuations. We have flexibility in both route of administration as well as frequency of dosing. Seeing here. With both a daily or weekly subcutaneous injection and nonhuman primates.

Pratik Shah: You can see between day, one and a seven the levels are tend to perhaps 100 fold higher than the prior drug product, even with a quarter to approximately a 10th of the reference dose. This is because of a shorter alpha phase and the elimination half life between the prior a new drug products are very similar. This profile has been achieved by using a proprietary and novel Excipient. In the formulation. <unk> also has a sustained exposure profile when administered by subcutaneous route of administration is shown on the right slide. This profile has a blunted see Max kind of sustained exposure with low peak to trough level fluctuations. We have flexibility in both route of administration as well as frequency of dosing. Seeing here. With both a daily or weekly subcutaneous injection and nonhuman primates.

This is because of a shorter alpha phase and the elimination half life between the prior a new drug products are very similar. This profile has been achieved by using a proprietary and novel Excipient. In the formulation. <unk> also has a sustained exposure profile when administered by subcutaneous route of administration is shown on the right slide. This profile has a blunted see Max kind of sustained exposure with low peak to trough level fluctuations. We have flexibility in both route of administration as well as frequency of dosing. Seeing here. With both a daily or weekly subcutaneous injection and nonhuman primates.

Pratik Shah: This profile has been achieved by using a proprietary and novel Excipient. In the formulation. <unk> also has a sustained exposure profile when administered by subcutaneous route of administration is shown on the right slide. This profile has a blunted see Max kind of sustained exposure with low peak to trough level fluctuations. We have flexibility in both route of administration as well as frequency of dosing. Seeing here. With both a daily or weekly subcutaneous injection and nonhuman primates.

In the formulation. <unk> also has a sustained exposure profile when administered by subcutaneous route of administration is shown on the right slide. This profile has a blunted see Max kind of sustained exposure with low peak to trough level fluctuations. We have flexibility in both route of administration as well as frequency of dosing. Seeing here. With both a daily or weekly subcutaneous injection and nonhuman primates.

Pratik Shah: <unk> also has a sustained exposure profile when administered by subcutaneous route of administration is shown on the right slide. This profile has a blunted see Max kind of sustained exposure with low peak to trough level fluctuations. We have flexibility in both route of administration as well as frequency of dosing. Seeing here. With both a daily or weekly subcutaneous injection and nonhuman primates.

Pratik Shah: This profile has a blunted see Max kind of sustained exposure with low peak to trough level fluctuations. We have flexibility in both route of administration as well as frequency of dosing. Seeing here. With both a daily or weekly subcutaneous injection and nonhuman primates.

Pratik Shah: We have flexibility in both route of administration as well as frequency of dosing. Seeing here. With both a daily or weekly subcutaneous injection and nonhuman primates.

Pratik Shah: Seeing here. With both a daily or weekly subcutaneous injection and nonhuman primates.

Pratik Shah: With both a daily or weekly subcutaneous injection and nonhuman primates.

Pratik Shah: In the clinical trial, we observed that the tissue level as measured by muscle biopsy was in line with the plasma exposure, and this is typical of a small molecule drug. The new drug product also shows that the tissue levels as measured by muscle biopsy in non-human primates is in line with plasma exposures, providing comfort that the extended profile seen in plasma will provide the desired extended profile in tissues. Repeat dose studies done in non GLP assessments have also been encouraging and the program will be proceeding to GLP studies, which are planned to be completed by the end of this year to support patient dosing in 2025. Given the very different PK profile seen in the preclinical studies, our plan is now to conduct a Phase I clinical trial in healthy volunteers so as to confirm the pharmacokinetics and also to confirm injection site tolerability. This will also help us in choosing a dosing root and dosing frequency for longer term studies. Subsequent trials will be in FA patients, which we plan to conduct to determine safety, tolerability, and the effect of treatment on endogenous frataxin levels.

Pratik Shah: And this is typical of a small molecule drug. The New York product also shows that the tissue levels as measured by muscle biopsy nonhuman primate is in line with plasma exposures, providing comfort that the extended profile scene in plasma. We'll provide the desired extended profile and tissues. Repeat those studies done in non G. L. P. Assessments have also been encouraging and the program will be proceeding to G. L. P studies, which are planned to be completed by the end of this year. Support patient dosing in 2025. Given the very different PK profile seen in the preclinical studies. Our plan is now to conduct a phase one clinical trial in healthy volunteers. So as to confirm the pharmacokinetics. And also to confirm injection site tolerability. This will also help us in choosing a duesing route and dosing frequency for longer term studies. Subsequent trials will be in F a patients which. Which we plan to conduct to determine safety tolerability and the effect of treatment and endogenous for tax and levels.

Pratik Shah: The New York product also shows that the tissue levels as measured by muscle biopsy nonhuman primate is in line with plasma exposures, providing comfort that the extended profile scene in plasma. We'll provide the desired extended profile and tissues. Repeat those studies done in non G. L. P. Assessments have also been encouraging and the program will be proceeding to G. L. P studies, which are planned to be completed by the end of this year. Support patient dosing in 2025. Given the very different PK profile seen in the preclinical studies. Our plan is now to conduct a phase one clinical trial in healthy volunteers. So as to confirm the pharmacokinetics. And also to confirm injection site tolerability. This will also help us in choosing a duesing route and dosing frequency for longer term studies. Subsequent trials will be in F a patients which. Which we plan to conduct to determine safety tolerability and the effect of treatment and endogenous for tax and levels.

Pratik Shah: We'll provide the desired extended profile and tissues. Repeat those studies done in non G. L. P. Assessments have also been encouraging and the program will be proceeding to G. L. P studies, which are planned to be completed by the end of this year. Support patient dosing in 2025. Given the very different PK profile seen in the preclinical studies. Our plan is now to conduct a phase one clinical trial in healthy volunteers. So as to confirm the pharmacokinetics. And also to confirm injection site tolerability. This will also help us in choosing a duesing route and dosing frequency for longer term studies. Subsequent trials will be in F a patients which. Which we plan to conduct to determine safety tolerability and the effect of treatment and endogenous for tax and levels.

Pratik Shah: Repeat those studies done in non G. L. P. Assessments have also been encouraging and the program will be proceeding to G. L. P studies, which are planned to be completed by the end of this year. Support patient dosing in 2025. Given the very different PK profile seen in the preclinical studies. Our plan is now to conduct a phase one clinical trial in healthy volunteers. So as to confirm the pharmacokinetics. And also to confirm injection site tolerability. This will also help us in choosing a duesing route and dosing frequency for longer term studies. Subsequent trials will be in F a patients which. Which we plan to conduct to determine safety tolerability and the effect of treatment and endogenous for tax and levels.

Pratik Shah: Support patient dosing in 2025. Given the very different PK profile seen in the preclinical studies. Our plan is now to conduct a phase one clinical trial in healthy volunteers. So as to confirm the pharmacokinetics. And also to confirm injection site tolerability. This will also help us in choosing a duesing route and dosing frequency for longer term studies. Subsequent trials will be in F a patients which. Which we plan to conduct to determine safety tolerability and the effect of treatment and endogenous for tax and levels.

Given the very different PK profile seen in the preclinical studies. Our plan is now to conduct a phase one clinical trial in healthy volunteers. So as to confirm the pharmacokinetics. And also to confirm injection site tolerability. This will also help us in choosing a duesing route and dosing frequency for longer term studies. Subsequent trials will be in F a patients which. Which we plan to conduct to determine safety tolerability and the effect of treatment and endogenous for tax and levels.

Pratik Shah: So as to confirm the pharmacokinetics. And also to confirm injection site tolerability. This will also help us in choosing a duesing route and dosing frequency for longer term studies. Subsequent trials will be in F a patients which. Which we plan to conduct to determine safety tolerability and the effect of treatment and endogenous for tax and levels.

Pratik Shah: And also to confirm injection site tolerability. This will also help us in choosing a duesing route and dosing frequency for longer term studies. Subsequent trials will be in F a patients which. Which we plan to conduct to determine safety tolerability and the effect of treatment and endogenous for tax and levels.

Pratik Shah: This will also help us in choosing a duesing route and dosing frequency for longer term studies. Subsequent trials will be in F a patients which. Which we plan to conduct to determine safety tolerability and the effect of treatment and endogenous for tax and levels.

Pratik Shah: Subsequent trials will be in F a patients which. Which we plan to conduct to determine safety tolerability and the effect of treatment and endogenous for tax and levels.

Which we plan to conduct to determine safety tolerability and the effect of treatment and endogenous for tax and levels.

Pratik Shah: SKYCLARYS is now approved for the treatment of FA and its update confirms that this is a large market opportunity. Since SKYCLARYS does not affect frataxin levels. We believe this approval has no appreciable impact on the potential opportunity for DT-216. As we've discussed before, GeneTAC small molecules have several potential advantages over any other genomic medicine modalities. Now, in case you see any literature reports of possible effects of other molecules on frataxin expression, we show here that GeneTAC molecules restore frataxin in a more substantial way than anything else reported in the literature, which is not surprising given its direct and elegant mechanism of action. Fuchs Endothelial Corneal Dystrophy, or FECD is a degenerative disease of the cornea that's been known for over a hundred years. The literature widely cites that this disease affects 4% of all adult Americans over the age of 40. Only in the last decade though, has it been shown that approximately 70% to 80% of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the TCF4 gene. Based on the current census, this works out to approximately 4.6 million to 5.3 million U.S. FECD patients. There are no approved disease modifying prescription drugs for FECD, and treatment is restricted to things like hypertonic saline drops to try and dehydrate the cornea.

Since Skye Clara's does not affect protection levels. We believe disapproval has no appreciable impact on the potential opportunity for D. T 216. As we've discussed before Jean Tech small molecules have several potential advantages over any other genomic medicine modalities. Now in case, you see any literature reports of possible effects of other molecules on for tax and expression. We show here that gene tech molecules restore for tax and in a more substantial way than anything else reported in the literature, which is not surprising given it's direct. <unk> mechanism of action. Fuchs endothelial corneal dystrophy RFE CD is a degenerative disease of the cornea that's been known for over 100 years. Extra widely sites that this disease effects, 4% of all adults Americans over the age of 40. Only in the last decade, though. Has it been shown that approximately 70 to 80 per cent of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the T C. A four G. Based on the current census, this works out to approximately. $4 six to 5.3 million U S. S E C D patients. There are no approved disease modifying prescription drugs for <unk> and. Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: As we've discussed before Jean Tech small molecules have several potential advantages over any other genomic medicine modalities. Now in case, you see any literature reports of possible effects of other molecules on for tax and expression. We show here that gene tech molecules restore for tax and in a more substantial way than anything else reported in the literature, which is not surprising given it's direct. <unk> mechanism of action. Fuchs endothelial corneal dystrophy RFE CD is a degenerative disease of the cornea that's been known for over 100 years. Extra widely sites that this disease effects, 4% of all adults Americans over the age of 40. Only in the last decade, though. Has it been shown that approximately 70 to 80 per cent of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the T C. A four G. Based on the current census, this works out to approximately. $4 six to 5.3 million U S. S E C D patients. There are no approved disease modifying prescription drugs for <unk> and. Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: Now in case, you see any literature reports of possible effects of other molecules on for tax and expression. We show here that gene tech molecules restore for tax and in a more substantial way than anything else reported in the literature, which is not surprising given it's direct. <unk> mechanism of action. Fuchs endothelial corneal dystrophy RFE CD is a degenerative disease of the cornea that's been known for over 100 years. Extra widely sites that this disease effects, 4% of all adults Americans over the age of 40. Only in the last decade, though. Has it been shown that approximately 70 to 80 per cent of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the T C. A four G. Based on the current census, this works out to approximately. $4 six to 5.3 million U S. S E C D patients. There are no approved disease modifying prescription drugs for <unk> and. Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: We show here that gene tech molecules restore for tax and in a more substantial way than anything else reported in the literature, which is not surprising given it's direct. <unk> mechanism of action. Fuchs endothelial corneal dystrophy RFE CD is a degenerative disease of the cornea that's been known for over 100 years. Extra widely sites that this disease effects, 4% of all adults Americans over the age of 40. Only in the last decade, though. Has it been shown that approximately 70 to 80 per cent of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the T C. A four G. Based on the current census, this works out to approximately. $4 six to 5.3 million U S. S E C D patients. There are no approved disease modifying prescription drugs for <unk> and. Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: <unk> mechanism of action. Fuchs endothelial corneal dystrophy RFE CD is a degenerative disease of the cornea that's been known for over 100 years. Extra widely sites that this disease effects, 4% of all adults Americans over the age of 40. Only in the last decade, though. Has it been shown that approximately 70 to 80 per cent of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the T C. A four G. Based on the current census, this works out to approximately. $4 six to 5.3 million U S. S E C D patients. There are no approved disease modifying prescription drugs for <unk> and. Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: Fuchs endothelial corneal dystrophy RFE CD is a degenerative disease of the cornea that's been known for over 100 years. Extra widely sites that this disease effects, 4% of all adults Americans over the age of 40. Only in the last decade, though. Has it been shown that approximately 70 to 80 per cent of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the T C. A four G. Based on the current census, this works out to approximately. $4 six to 5.3 million U S. S E C D patients. There are no approved disease modifying prescription drugs for <unk> and. Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: Extra widely sites that this disease effects, 4% of all adults Americans over the age of 40. Only in the last decade, though. Has it been shown that approximately 70 to 80 per cent of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the T C. A four G. Based on the current census, this works out to approximately. $4 six to 5.3 million U S. S E C D patients. There are no approved disease modifying prescription drugs for <unk> and. Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: Only in the last decade, though. Has it been shown that approximately 70 to 80 per cent of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the T C. A four G. Based on the current census, this works out to approximately. $4 six to 5.3 million U S. S E C D patients. There are no approved disease modifying prescription drugs for <unk> and. Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: Has it been shown that approximately 70 to 80 per cent of these adults get the condition due to inheriting a monogenic repeat CTG expansion in the T C. A four G. Based on the current census, this works out to approximately. $4 six to 5.3 million U S. S E C D patients. There are no approved disease modifying prescription drugs for <unk> and. Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: Based on the current census, this works out to approximately. $4 six to 5.3 million U S. S E C D patients. There are no approved disease modifying prescription drugs for <unk> and. Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: $4 six to 5.3 million U S. S E C D patients. There are no approved disease modifying prescription drugs for <unk> and. Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: There are no approved disease modifying prescription drugs for <unk> and. Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: Treatment is restricted to things like hypertonic ceiling drops to try and dehydrate the cornea.

Pratik Shah: Eventually, a small fraction of patients gets a corneal transplant surgery, which there are about 18,000 to 30,000 corneal transplant surgeries done in the United States annually, and that's a very small fraction and represented by the red figure. Most patients unfortunately quietly suffer from declining visual quality. On the right is a photoshop image composed by a patient to communicate her loss of visual quality in late stage Fuchs. The analogy is sometimes that of a foggy and rainy windshield resulting in loss of low contrast, visual acuity glare and contrast sensitivity. And we have heard from a number of clinicians who see these patients that if there was anything that slowed progression and was well tolerated, they would treat everyone, even patients who were presymptomatic.

A small fraction of patients get a corneal transplant surgery, which there about 18000 to 30000 corneal transplant surgery done in the United States annually and that's a very small fraction and represented by the Red figure. Most patients unfortunately. We suffer from declining visual quality. On the right is a photoshop image composed by a patient to communicate her loss of visual quality in late stage views. The analogy is sometimes out of a foggy and rainy windshield, resulting in loss of low contrast, visual acuity. Glare and contrast sensitivity. We have heard from a number of clinicians who see these patients. If there was anything that slowed progression that was well tolerated they would treat everyone even patients who were presymptomatic.

Pratik Shah: Most patients unfortunately. We suffer from declining visual quality. On the right is a photoshop image composed by a patient to communicate her loss of visual quality in late stage views. The analogy is sometimes out of a foggy and rainy windshield, resulting in loss of low contrast, visual acuity. Glare and contrast sensitivity. We have heard from a number of clinicians who see these patients. If there was anything that slowed progression that was well tolerated they would treat everyone even patients who were presymptomatic.

Pratik Shah: We suffer from declining visual quality. On the right is a photoshop image composed by a patient to communicate her loss of visual quality in late stage views. The analogy is sometimes out of a foggy and rainy windshield, resulting in loss of low contrast, visual acuity. Glare and contrast sensitivity. We have heard from a number of clinicians who see these patients. If there was anything that slowed progression that was well tolerated they would treat everyone even patients who were presymptomatic.

Pratik Shah: On the right is a photoshop image composed by a patient to communicate her loss of visual quality in late stage views. The analogy is sometimes out of a foggy and rainy windshield, resulting in loss of low contrast, visual acuity. Glare and contrast sensitivity. We have heard from a number of clinicians who see these patients. If there was anything that slowed progression that was well tolerated they would treat everyone even patients who were presymptomatic.

Pratik Shah: The analogy is sometimes out of a foggy and rainy windshield, resulting in loss of low contrast, visual acuity. Glare and contrast sensitivity. We have heard from a number of clinicians who see these patients. If there was anything that slowed progression that was well tolerated they would treat everyone even patients who were presymptomatic.

Pratik Shah: Glare and contrast sensitivity. We have heard from a number of clinicians who see these patients. If there was anything that slowed progression that was well tolerated they would treat everyone even patients who were presymptomatic.

We have heard from a number of clinicians who see these patients. If there was anything that slowed progression that was well tolerated they would treat everyone even patients who were presymptomatic.

Pratik Shah: If there was anything that slowed progression that was well tolerated they would treat everyone even patients who were presymptomatic.

Pratik Shah: FECD is caused by dysfunction in the cells of the endothelial, monolayer of the cornea, and these cells have a role in maintaining a dehydrated stroma and keep the cornea free of extracellular matrix deposits. These cells are slowly lost over time due to the disease, and they're sick because of the TCF4 mutation, which is the CTG repeat expansion in the non-coding region of the gene, this inherited mutation can be detected by means of a blood test. So, how can one develop a therapy for this? By helping restore cellular health to the endothelial layer and this cell dysfunction arises from this single inherited mutant allele. The polymerase reads the mutant allele and makes an RNA containing these repeats. The RNA folds over on itself, creates tangles, and you can see them. You can stain for them. These tangles sequester MBNL splice proteins and cause mis-splicing of a number of downstream genes, which then drive cellular dysfunction. We have designed GeneTAC to bind and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic TCF4 mutant RNA.

Pratik Shah: The salad is slowly lost over time due to the disease. And they are sick because of the P. C. A for mutation, which is the CTG repeat expansion in the non coding region of the gene. This inherited mutation can be detected by means of a blood test. So how can one develop a therapy for this by. By helping restore cellular health to the endothelial layer. And they sell dysfunction arises from the single inherited mute mobile. The preliminaries reads the mute the leal and makes an RNA containing these repeats. The RNA falls over on itself creates tangles and. And you can see them you can stand for them. These tangles sequester NBL splice proteins and cause misplacing, a a number of downstream genes, which then drive cellular dysfunction. We have designed gene tax the buying and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic T C. A for mutant RNA.

Pratik Shah: And they are sick because of the P. C. A for mutation, which is the CTG repeat expansion in the non coding region of the gene. This inherited mutation can be detected by means of a blood test. So how can one develop a therapy for this by. By helping restore cellular health to the endothelial layer. And they sell dysfunction arises from the single inherited mute mobile. The preliminaries reads the mute the leal and makes an RNA containing these repeats. The RNA falls over on itself creates tangles and. And you can see them you can stand for them. These tangles sequester NBL splice proteins and cause misplacing, a a number of downstream genes, which then drive cellular dysfunction. We have designed gene tax the buying and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic T C. A for mutant RNA.

Pratik Shah: This inherited mutation can be detected by means of a blood test. So how can one develop a therapy for this by. By helping restore cellular health to the endothelial layer. And they sell dysfunction arises from the single inherited mute mobile. The preliminaries reads the mute the leal and makes an RNA containing these repeats. The RNA falls over on itself creates tangles and. And you can see them you can stand for them. These tangles sequester NBL splice proteins and cause misplacing, a a number of downstream genes, which then drive cellular dysfunction. We have designed gene tax the buying and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic T C. A for mutant RNA.

Pratik Shah: So how can one develop a therapy for this by. By helping restore cellular health to the endothelial layer. And they sell dysfunction arises from the single inherited mute mobile. The preliminaries reads the mute the leal and makes an RNA containing these repeats. The RNA falls over on itself creates tangles and. And you can see them you can stand for them. These tangles sequester NBL splice proteins and cause misplacing, a a number of downstream genes, which then drive cellular dysfunction. We have designed gene tax the buying and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic T C. A for mutant RNA.

By helping restore cellular health to the endothelial layer. And they sell dysfunction arises from the single inherited mute mobile. The preliminaries reads the mute the leal and makes an RNA containing these repeats. The RNA falls over on itself creates tangles and. And you can see them you can stand for them. These tangles sequester NBL splice proteins and cause misplacing, a a number of downstream genes, which then drive cellular dysfunction. We have designed gene tax the buying and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic T C. A for mutant RNA.

Pratik Shah: And they sell dysfunction arises from the single inherited mute mobile. The preliminaries reads the mute the leal and makes an RNA containing these repeats. The RNA falls over on itself creates tangles and. And you can see them you can stand for them. These tangles sequester NBL splice proteins and cause misplacing, a a number of downstream genes, which then drive cellular dysfunction. We have designed gene tax the buying and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic T C. A for mutant RNA.

Pratik Shah: The preliminaries reads the mute the leal and makes an RNA containing these repeats. The RNA falls over on itself creates tangles and. And you can see them you can stand for them. These tangles sequester NBL splice proteins and cause misplacing, a a number of downstream genes, which then drive cellular dysfunction. We have designed gene tax the buying and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic T C. A for mutant RNA.

Pratik Shah: The RNA falls over on itself creates tangles and. And you can see them you can stand for them. These tangles sequester NBL splice proteins and cause misplacing, a a number of downstream genes, which then drive cellular dysfunction. We have designed gene tax the buying and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic T C. A for mutant RNA.

Pratik Shah: And you can see them you can stand for them. These tangles sequester NBL splice proteins and cause misplacing, a a number of downstream genes, which then drive cellular dysfunction. We have designed gene tax the buying and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic T C. A for mutant RNA.

Pratik Shah: We have designed gene tax the buying and recognize these long CTG repeat regions in the mutant allele and shut off production of the toxic T C. A for mutant RNA.

Pratik Shah: This slide shows the effectiveness of the GeneTAC molecule. Recall I said that you could stain for these mutant foci. They're shown in the above panel in the middle section as dots that light up with a fluorescently labeled probe inside the nucleus of endothelial cells taken directly from discarded cornea of patients who've undergone surgery. On the lower panel, we observed that these foci largely go away when these patient corneal cells are treated with DT-168. The compound has - potency as shown in the dose response curve on the right.

Pratik Shah: Recall I said that you could stand for these new info sign they're shown in the above paneling the middle section. That light up with a fluorescently label probe inside the nucleus of endothelial cells taken directly from discarded cornea of patients who have undergone surgery. On the lower panel, we observed that these foci largely go away. When these patient corneal cells are treated with the T 168. Compound has low nanomolar potency is shown in the dose response curve on the right.

Pratik Shah: That light up with a fluorescently label probe inside the nucleus of endothelial cells taken directly from discarded cornea of patients who have undergone surgery. On the lower panel, we observed that these foci largely go away. When these patient corneal cells are treated with the T 168. Compound has low nanomolar potency is shown in the dose response curve on the right.

On the lower panel, we observed that these foci largely go away. When these patient corneal cells are treated with the T 168. Compound has low nanomolar potency is shown in the dose response curve on the right.

Pratik Shah: Compound has low nanomolar potency is shown in the dose response curve on the right.

Pratik Shah: This slide shows the results of assay for wild type TCF4 transcripts from patient cells as shown here. Drug treatment has no effect on the wild type TCF4 expression. This is an allele selective inhibition, which is highly desirable. This slide looks at mis-splicing that occurs in a variety of downstream genes at baseline and light green, and with drug treatment as mutant TCF4 expression is dialed down and sequestered splicing proteins are released, downstream normal splicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desired product profile, we have also been able to formulate this to be suitably delivered as an eye drop. All the required nonclinical safety studies have been conducted and reviewed by the FDA resulting in an IND that's been cleared. We plan to initiate Phase I development for DT-168 in 2024.

Pratik Shah: Drug treatment has no effect on the wild type Tcf for expression. This is an allele selective inhibition, which is highly desirable. This slide looks at misplacing that occurs in a variety of <unk>. And we ended up treatment. And. <unk>. <unk>. And sequestered slicing proteins are released. Downstream normal slicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desire product profile. We have also been able to formulate those to be suitably delivered as in Eyedrop. All the required Nonclinical safety studies have been conducted in reviewed by the FDA, resulting in the 90 that's been cleared. We plan to initiate phase one development for D T 168 and 2024.

Pratik Shah: This is an allele selective inhibition, which is highly desirable. This slide looks at misplacing that occurs in a variety of <unk>. And we ended up treatment. And. <unk>. <unk>. And sequestered slicing proteins are released. Downstream normal slicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desire product profile. We have also been able to formulate those to be suitably delivered as in Eyedrop. All the required Nonclinical safety studies have been conducted in reviewed by the FDA, resulting in the 90 that's been cleared. We plan to initiate phase one development for D T 168 and 2024.

Pratik Shah: This slide looks at misplacing that occurs in a variety of <unk>. And we ended up treatment. And. <unk>. <unk>. And sequestered slicing proteins are released. Downstream normal slicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desire product profile. We have also been able to formulate those to be suitably delivered as in Eyedrop. All the required Nonclinical safety studies have been conducted in reviewed by the FDA, resulting in the 90 that's been cleared. We plan to initiate phase one development for D T 168 and 2024.

Pratik Shah: And we ended up treatment. And. <unk>. <unk>. And sequestered slicing proteins are released. Downstream normal slicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desire product profile. We have also been able to formulate those to be suitably delivered as in Eyedrop. All the required Nonclinical safety studies have been conducted in reviewed by the FDA, resulting in the 90 that's been cleared. We plan to initiate phase one development for D T 168 and 2024.

Pratik Shah: And. <unk>. <unk>. And sequestered slicing proteins are released. Downstream normal slicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desire product profile. We have also been able to formulate those to be suitably delivered as in Eyedrop. All the required Nonclinical safety studies have been conducted in reviewed by the FDA, resulting in the 90 that's been cleared. We plan to initiate phase one development for D T 168 and 2024.

Pratik Shah: <unk>. <unk>. And sequestered slicing proteins are released. Downstream normal slicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desire product profile. We have also been able to formulate those to be suitably delivered as in Eyedrop. All the required Nonclinical safety studies have been conducted in reviewed by the FDA, resulting in the 90 that's been cleared. We plan to initiate phase one development for D T 168 and 2024.

Pratik Shah: <unk>. And sequestered slicing proteins are released. Downstream normal slicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desire product profile. We have also been able to formulate those to be suitably delivered as in Eyedrop. All the required Nonclinical safety studies have been conducted in reviewed by the FDA, resulting in the 90 that's been cleared. We plan to initiate phase one development for D T 168 and 2024.

Pratik Shah: And sequestered slicing proteins are released. Downstream normal slicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desire product profile. We have also been able to formulate those to be suitably delivered as in Eyedrop. All the required Nonclinical safety studies have been conducted in reviewed by the FDA, resulting in the 90 that's been cleared. We plan to initiate phase one development for D T 168 and 2024.

Downstream normal slicing is restored leading to a treatment of the cellular dysfunction. Not only do we see an allele selective effect, which is the desire product profile. We have also been able to formulate those to be suitably delivered as in Eyedrop. All the required Nonclinical safety studies have been conducted in reviewed by the FDA, resulting in the 90 that's been cleared. We plan to initiate phase one development for D T 168 and 2024.

Pratik Shah: Not only do we see an allele selective effect, which is the desire product profile. We have also been able to formulate those to be suitably delivered as in Eyedrop. All the required Nonclinical safety studies have been conducted in reviewed by the FDA, resulting in the 90 that's been cleared. We plan to initiate phase one development for D T 168 and 2024.

Pratik Shah: We have also been able to formulate those to be suitably delivered as in Eyedrop. All the required Nonclinical safety studies have been conducted in reviewed by the FDA, resulting in the 90 that's been cleared. We plan to initiate phase one development for D T 168 and 2024.

All the required Nonclinical safety studies have been conducted in reviewed by the FDA, resulting in the 90 that's been cleared. We plan to initiate phase one development for D T 168 and 2024.

Pratik Shah: We plan to initiate phase one development for D T 168 and 2024.

Pratik Shah: We now need to determine the impact of this type of treatment on the progression of this degenerative corneal disease. And for that purpose, we need to gain experience with various possible endpoints and patient characteristics. Therefore, prior to jumping into an interventional trial in patients, we believe the correct strategy for clinical development is to first run an observational study with patients diagnosed with Fuchs, who have a genetically confirmed TCF4 expansion mutation. We have begun enrollment in such a trial and plan to recruit 200 patients during the year and plan to follow them for two years. This will enable us to understand the patient characteristics and endpoints that allow us to measure the dysfunction and progression in these patients. Once we have gathered sufficient data to measure disease progression and the performance of various endpoints, we will then focus on an interventional treatment trial.

Speaker Change: Therefore prior to jumping into an intervention all trial and patients. We believe the correct strategy for clinical development is to first run an observational study with patients diagnosed fuchs, who have a genetically confirm tcf for expansion mutation. We have begun enrollment in such a trial. Plan to recruit 200 patients during the year. And plan to follow them for two years. This will enable us to understand the patient characteristics and end points that allow us to measure the dysfunction and progression in these patients. Once we have gathered sufficient data to measure disease progression and the performance of various endpoints. We will then focus on an intervention all treatment trial.

Speaker Change: We have begun enrollment in such a trial. Plan to recruit 200 patients during the year. And plan to follow them for two years. This will enable us to understand the patient characteristics and end points that allow us to measure the dysfunction and progression in these patients. Once we have gathered sufficient data to measure disease progression and the performance of various endpoints. We will then focus on an intervention all treatment trial.

Plan to recruit 200 patients during the year. And plan to follow them for two years. This will enable us to understand the patient characteristics and end points that allow us to measure the dysfunction and progression in these patients. Once we have gathered sufficient data to measure disease progression and the performance of various endpoints. We will then focus on an intervention all treatment trial.

Speaker Change: And plan to follow them for two years. This will enable us to understand the patient characteristics and end points that allow us to measure the dysfunction and progression in these patients. Once we have gathered sufficient data to measure disease progression and the performance of various endpoints. We will then focus on an intervention all treatment trial.

Speaker Change: This will enable us to understand the patient characteristics and end points that allow us to measure the dysfunction and progression in these patients. Once we have gathered sufficient data to measure disease progression and the performance of various endpoints. We will then focus on an intervention all treatment trial.

Speaker Change: Once we have gathered sufficient data to measure disease progression and the performance of various endpoints. We will then focus on an intervention all treatment trial.

Pratik Shah: These endpoints include measures of visual quality, anterior eye tomography, and also microscopic visualization of the corneal endothelium. We are revealing for the first time our program for Huntington's disease. As you know, HD is a devastating neurodegenerative disease caused by an exonic repeat expansion in the Huntington gene. A longstanding objective in the field has been for there to be a selective inhibition of the mutant Huntington allele with a molecule that can distribute widely to the effect cells, and this has been a very elusive profile to achieve.

Interior I Kaumography and also microscopic visualization of the corneal endothelium. We are revealing for the first time our program for Huntington's disease. As you know H D is a devastating neurodegenerative disease caused by an ex sonic repeat expansion in the Huntington Jean. Longstanding objective in the field has been for there to be a selective inhibition of the mutant Huntington the wheel. With a molecule that can distribute widely to the effect itself. This has been a very elusive profile to achieve.

Speaker Change: We are revealing for the first time our program for Huntington's disease. As you know H D is a devastating neurodegenerative disease caused by an ex sonic repeat expansion in the Huntington Jean. Longstanding objective in the field has been for there to be a selective inhibition of the mutant Huntington the wheel. With a molecule that can distribute widely to the effect itself. This has been a very elusive profile to achieve.

Speaker Change: As you know H D is a devastating neurodegenerative disease caused by an ex sonic repeat expansion in the Huntington Jean. Longstanding objective in the field has been for there to be a selective inhibition of the mutant Huntington the wheel. With a molecule that can distribute widely to the effect itself. This has been a very elusive profile to achieve.

Speaker Change: Longstanding objective in the field has been for there to be a selective inhibition of the mutant Huntington the wheel. With a molecule that can distribute widely to the effect itself. This has been a very elusive profile to achieve.

Speaker Change: With a molecule that can distribute widely to the effect itself. This has been a very elusive profile to achieve.

Speaker Change: This has been a very elusive profile to achieve.

Pratik Shah: Here is data looking at the effect of one of our two candidate molecules on wild type and Mutant Huntington, RNA from treated patient fibroblast cells. The left panel shows data from a normal onset HD genotype and the right panel, the effect on an early onset HD genotype, which contains a longer repeat expansion. We observe an allele selective inhibition of Mutant Huntington RNA. The effect is even more pronounced in the early onset genotype. This is particularly encouraging because regardless of the genotype, it is known that the repeats undergo somatic expansion of various lengths in different neurons over time, and this data suggests that the compound would have an even more profound impact on those cells, which have undergone a longer somatic expansion of their CAG repeats.

Speaker Change: In the right panel the effect on an early onset HD genotype. Which contains a longer repeat expansion. We observe an allele selective and ambition of Newton Huntington RNA. The effect is even more pronounced in the early onset gym type this is particularly encouraging because regardless of the genotype. It is known that the repeats undergo somatic expansion of various lengths and different neurons over time. And this data suggests. At the compound would have an even more profound impact on those cells, which have undergone a longer somatic expansion of their CG repeats.

Speaker Change: Which contains a longer repeat expansion. We observe an allele selective and ambition of Newton Huntington RNA. The effect is even more pronounced in the early onset gym type this is particularly encouraging because regardless of the genotype. It is known that the repeats undergo somatic expansion of various lengths and different neurons over time. And this data suggests. At the compound would have an even more profound impact on those cells, which have undergone a longer somatic expansion of their CG repeats.

Speaker Change: We observe an allele selective and ambition of Newton Huntington RNA. The effect is even more pronounced in the early onset gym type this is particularly encouraging because regardless of the genotype. It is known that the repeats undergo somatic expansion of various lengths and different neurons over time. And this data suggests. At the compound would have an even more profound impact on those cells, which have undergone a longer somatic expansion of their CG repeats.

The effect is even more pronounced in the early onset gym type this is particularly encouraging because regardless of the genotype. It is known that the repeats undergo somatic expansion of various lengths and different neurons over time. And this data suggests. At the compound would have an even more profound impact on those cells, which have undergone a longer somatic expansion of their CG repeats.

Speaker Change: And this data suggests. At the compound would have an even more profound impact on those cells, which have undergone a longer somatic expansion of their CG repeats.

Speaker Change: At the compound would have an even more profound impact on those cells, which have undergone a longer somatic expansion of their CG repeats.

Pratik Shah: This slide shows that the RNA effect shown earlier, translated to the expected effect on mutant Huntington protein. The above panel shows that Mutant Huntington selective antibodies able to detect mutant protein disappearing with increasing concentrations of drug. The middle panel uses an antibody that detects both wild type and Mutant Huntington, and you can see an expected reduction due to the mutant protein being reduced. Now, the size of these proteins are hard to resolve in the normal onset genotype in the left panel gels, but in the early onset genotypes, the mutant and wild type proteins are different enough in size to actually show up as two bands on the middle panel on the right side.

Speaker Change: Above panel shows that a mutant. Huntington selective antibodies able to detect mutant protein. Disappearing with increasing concentrations of drug. Middle panel uses an antibody that detects both wildlife and Huntington. Can see unexpected reduction due to the mutant protein being reduced. The size of these proteins are hard to resolve in the normal onset genotype in the left panel gels, but. But in the early onset Juno types. And while that proteins are different enough in size to actually show up as two bands on the middle panel on the right side.

Speaker Change: Huntington selective antibodies able to detect mutant protein. Disappearing with increasing concentrations of drug. Middle panel uses an antibody that detects both wildlife and Huntington. Can see unexpected reduction due to the mutant protein being reduced. The size of these proteins are hard to resolve in the normal onset genotype in the left panel gels, but. But in the early onset Juno types. And while that proteins are different enough in size to actually show up as two bands on the middle panel on the right side.

Speaker Change: Disappearing with increasing concentrations of drug. Middle panel uses an antibody that detects both wildlife and Huntington. Can see unexpected reduction due to the mutant protein being reduced. The size of these proteins are hard to resolve in the normal onset genotype in the left panel gels, but. But in the early onset Juno types. And while that proteins are different enough in size to actually show up as two bands on the middle panel on the right side.

Speaker Change: Middle panel uses an antibody that detects both wildlife and Huntington. Can see unexpected reduction due to the mutant protein being reduced. The size of these proteins are hard to resolve in the normal onset genotype in the left panel gels, but. But in the early onset Juno types. And while that proteins are different enough in size to actually show up as two bands on the middle panel on the right side.

Speaker Change: Can see unexpected reduction due to the mutant protein being reduced. The size of these proteins are hard to resolve in the normal onset genotype in the left panel gels, but. But in the early onset Juno types. And while that proteins are different enough in size to actually show up as two bands on the middle panel on the right side.

Speaker Change: The size of these proteins are hard to resolve in the normal onset genotype in the left panel gels, but. But in the early onset Juno types. And while that proteins are different enough in size to actually show up as two bands on the middle panel on the right side.

Speaker Change: But in the early onset Juno types. And while that proteins are different enough in size to actually show up as two bands on the middle panel on the right side.

Speaker Change: And while that proteins are different enough in size to actually show up as two bands on the middle panel on the right side.

Pratik Shah: This is the RNA inhibition data from candidate two, showing a similar allele selective inhibition, and this is the protein inhibition data from candidate two. Also showing an effect as expected from the RNA inhibition. We expect to choose one of these compounds to move forward with as a development candidate once further testing is conducted. Having seen these exciting profiles, we are encouraged at the preliminary non-GLP tolerability of these molecules in both rodents and non-human primates. We've conducted pharmacology assessments of these molecules and have selected a widely used Q-175DN pharmacodynamic mouse model to SaaS PD. We observe in this study that with systemic administration, there is an over 50% reduction of Mutant Huntington RNA and protein in the striatum of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration.

Speaker Change: And this is the protein inhibition data from candidate to also showing an effect is expected from the army and ambition. We expect to choose one of these compounds to move forward with as a development candidate once further testing is conducted. Having seen these exciting profiles we are encouraged. At the preliminary non G. L. P. Tolerability of these molecules and both rodents. And nonhuman primates. We've conducted pharmacology assessments of these molecules and have selected a widely used Q1 75, Pharmacodynamic mouse model to assess PD. We observe in this study that with systemic administration. There is an over 50% reduction of Newton Huntington Ernie and protein. In the striatum. Of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration.

Speaker Change: We expect to choose one of these compounds to move forward with as a development candidate once further testing is conducted. Having seen these exciting profiles we are encouraged. At the preliminary non G. L. P. Tolerability of these molecules and both rodents. And nonhuman primates. We've conducted pharmacology assessments of these molecules and have selected a widely used Q1 75, Pharmacodynamic mouse model to assess PD. We observe in this study that with systemic administration. There is an over 50% reduction of Newton Huntington Ernie and protein. In the striatum. Of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration.

Speaker Change: Having seen these exciting profiles we are encouraged. At the preliminary non G. L. P. Tolerability of these molecules and both rodents. And nonhuman primates. We've conducted pharmacology assessments of these molecules and have selected a widely used Q1 75, Pharmacodynamic mouse model to assess PD. We observe in this study that with systemic administration. There is an over 50% reduction of Newton Huntington Ernie and protein. In the striatum. Of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration.

Speaker Change: At the preliminary non G. L. P. Tolerability of these molecules and both rodents. And nonhuman primates. We've conducted pharmacology assessments of these molecules and have selected a widely used Q1 75, Pharmacodynamic mouse model to assess PD. We observe in this study that with systemic administration. There is an over 50% reduction of Newton Huntington Ernie and protein. In the striatum. Of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration.

Speaker Change: And nonhuman primates. We've conducted pharmacology assessments of these molecules and have selected a widely used Q1 75, Pharmacodynamic mouse model to assess PD. We observe in this study that with systemic administration. There is an over 50% reduction of Newton Huntington Ernie and protein. In the striatum. Of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration.

Speaker Change: We've conducted pharmacology assessments of these molecules and have selected a widely used Q1 75, Pharmacodynamic mouse model to assess PD. We observe in this study that with systemic administration. There is an over 50% reduction of Newton Huntington Ernie and protein. In the striatum. Of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration.

Speaker Change: We observe in this study that with systemic administration. There is an over 50% reduction of Newton Huntington Ernie and protein. In the striatum. Of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration.

Speaker Change: There is an over 50% reduction of Newton Huntington Ernie and protein. In the striatum. Of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration.

In the striatum. Of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration.

Speaker Change: Of mice, which supports the idea that this compound is able to get into the brain and get into the cells and have the intended effect with systemic administration.

Pratik Shah: We are very encouraged to see this in vivo confirmation of the activity seen in cells derived from patients. If this pans out, HD GeneTAC molecules hold the potential of selectively reducing mutant Huntington with a widespread distribution profile and systemic administration regardless of the patient's HD genotype. This would be a best-in-class profile. Our next milestone for the program is to choose a development candidate. We are also working on a program in myotonic dystrophy. DM1 is caused by a CTG repeat in the DMPK gene in the three prime untranslated region. Much like the FECD story mutant DMPK RNA form toxic foci and downstream splicing dysfunction. It would be highly desirable and a best-in-class profile to have a selective inhibitor of mutant DMPK for the treatment of myotonic dystrophy that would distribute broadly in all affected tissues and cell types. This data shows that we have a GeneTAC molecule that reduce these toxic DMPK foci with low nanomolar potency. This is a splicing index from panel of splice genes with seven days of treatment from patient derived myotubes, showing that the DM1 foci reduction does have beneficial downstream effect on cellular health. The next milestone for this program is DC declaration.

Speaker Change: If this pans out. HD gene tech molecules hold the potential of selectively reducing mutant Huntington with a widespread distribution profile and systemic administration, regardless of the patient's HD genotype. This would be a best in class profile. Our next milestone for the program is to choose a development candidate. We're also working on a program and monotonic dystrophy. T M. One is caused by a CPG repeat in the D. M. P. K G and the three prime on translated region. Much like the F. C C D story, <unk> form toxic foci and downstream splicing dysfunction. It would be highly desirable and a best in class profile to have a selective inhibitor of mutant DMT K for the treatment of monotonic dystrophy that would distribute broadly and all effective tissues and cell types. This data shows that we have a gene tack molecule. That reduce these toxic DNP K for site. With low Nanomolar potency. This is a spicing index from panel of misplaced jeans. With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

Speaker Change: HD gene tech molecules hold the potential of selectively reducing mutant Huntington with a widespread distribution profile and systemic administration, regardless of the patient's HD genotype. This would be a best in class profile. Our next milestone for the program is to choose a development candidate. We're also working on a program and monotonic dystrophy. T M. One is caused by a CPG repeat in the D. M. P. K G and the three prime on translated region. Much like the F. C C D story, <unk> form toxic foci and downstream splicing dysfunction. It would be highly desirable and a best in class profile to have a selective inhibitor of mutant DMT K for the treatment of monotonic dystrophy that would distribute broadly and all effective tissues and cell types. This data shows that we have a gene tack molecule. That reduce these toxic DNP K for site. With low Nanomolar potency. This is a spicing index from panel of misplaced jeans. With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

Speaker Change: This would be a best in class profile. Our next milestone for the program is to choose a development candidate. We're also working on a program and monotonic dystrophy. T M. One is caused by a CPG repeat in the D. M. P. K G and the three prime on translated region. Much like the F. C C D story, <unk> form toxic foci and downstream splicing dysfunction. It would be highly desirable and a best in class profile to have a selective inhibitor of mutant DMT K for the treatment of monotonic dystrophy that would distribute broadly and all effective tissues and cell types. This data shows that we have a gene tack molecule. That reduce these toxic DNP K for site. With low Nanomolar potency. This is a spicing index from panel of misplaced jeans. With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

Our next milestone for the program is to choose a development candidate. We're also working on a program and monotonic dystrophy. T M. One is caused by a CPG repeat in the D. M. P. K G and the three prime on translated region. Much like the F. C C D story, <unk> form toxic foci and downstream splicing dysfunction. It would be highly desirable and a best in class profile to have a selective inhibitor of mutant DMT K for the treatment of monotonic dystrophy that would distribute broadly and all effective tissues and cell types. This data shows that we have a gene tack molecule. That reduce these toxic DNP K for site. With low Nanomolar potency. This is a spicing index from panel of misplaced jeans. With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

Speaker Change: We're also working on a program and monotonic dystrophy. T M. One is caused by a CPG repeat in the D. M. P. K G and the three prime on translated region. Much like the F. C C D story, <unk> form toxic foci and downstream splicing dysfunction. It would be highly desirable and a best in class profile to have a selective inhibitor of mutant DMT K for the treatment of monotonic dystrophy that would distribute broadly and all effective tissues and cell types. This data shows that we have a gene tack molecule. That reduce these toxic DNP K for site. With low Nanomolar potency. This is a spicing index from panel of misplaced jeans. With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

T M. One is caused by a CPG repeat in the D. M. P. K G and the three prime on translated region. Much like the F. C C D story, <unk> form toxic foci and downstream splicing dysfunction. It would be highly desirable and a best in class profile to have a selective inhibitor of mutant DMT K for the treatment of monotonic dystrophy that would distribute broadly and all effective tissues and cell types. This data shows that we have a gene tack molecule. That reduce these toxic DNP K for site. With low Nanomolar potency. This is a spicing index from panel of misplaced jeans. With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

Speaker Change: Much like the F. C C D story, <unk> form toxic foci and downstream splicing dysfunction. It would be highly desirable and a best in class profile to have a selective inhibitor of mutant DMT K for the treatment of monotonic dystrophy that would distribute broadly and all effective tissues and cell types. This data shows that we have a gene tack molecule. That reduce these toxic DNP K for site. With low Nanomolar potency. This is a spicing index from panel of misplaced jeans. With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

Speaker Change: It would be highly desirable and a best in class profile to have a selective inhibitor of mutant DMT K for the treatment of monotonic dystrophy that would distribute broadly and all effective tissues and cell types. This data shows that we have a gene tack molecule. That reduce these toxic DNP K for site. With low Nanomolar potency. This is a spicing index from panel of misplaced jeans. With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

Speaker Change: This data shows that we have a gene tack molecule. That reduce these toxic DNP K for site. With low Nanomolar potency. This is a spicing index from panel of misplaced jeans. With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

Speaker Change: That reduce these toxic DNP K for site. With low Nanomolar potency. This is a spicing index from panel of misplaced jeans. With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

Speaker Change: With low Nanomolar potency. This is a spicing index from panel of misplaced jeans. With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

Speaker Change: This is a spicing index from panel of misplaced jeans. With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

With seven days of treatment from patient derived Maya tubes, showing that the D. M. One <unk> reduction does have beneficial downstream effect on southern or health. The next milestone for this program is. Is D C declaration.

Speaker Change: The next milestone for this program is. Is D C declaration.

Is D C declaration.

Pratik Shah: In summary, we have a promising new platform for genomic medicine that is meaningfully differentiated from other genomic medicine modalities. We have four drug programs, each in significant markets and with highly differentiated profiles, the first two of which are expected to be clinical stage next year. We ended 2023 with approximately $281 million, and this gives us a cash runway for the next five years. Pending future R&D results and ongoing strategic review, this cash runway would support generating clinical proof of concept data in up to four programs. We believe each of these programs has the potential to transform the treatment of these debilitating conditions. And success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward and welcome you to participate in this journey and help us get to success. This concludes our prepared remarks and we'll now move to Q&A. Operator, please open the line for questions.

Speaker Change: We have a promising new platform for genomic medicine that is meaningfully differentiated from other genomic medicine modalities. We have four drug programs. Each insignificant markets. And with highly differentiated profiles. First two of which are expected to be clinical stage next year. We ended 2023 with approximately $281 million. And this gives us a cash one way for the next five years. Pending future R&D results and ongoing strategic review. This cash runway with support generating clinical proof of concept data and up to four programs. We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward. And welcome you to participate in this journey. And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: We have four drug programs. Each insignificant markets. And with highly differentiated profiles. First two of which are expected to be clinical stage next year. We ended 2023 with approximately $281 million. And this gives us a cash one way for the next five years. Pending future R&D results and ongoing strategic review. This cash runway with support generating clinical proof of concept data and up to four programs. We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward. And welcome you to participate in this journey. And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: Each insignificant markets. And with highly differentiated profiles. First two of which are expected to be clinical stage next year. We ended 2023 with approximately $281 million. And this gives us a cash one way for the next five years. Pending future R&D results and ongoing strategic review. This cash runway with support generating clinical proof of concept data and up to four programs. We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward. And welcome you to participate in this journey. And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: And with highly differentiated profiles. First two of which are expected to be clinical stage next year. We ended 2023 with approximately $281 million. And this gives us a cash one way for the next five years. Pending future R&D results and ongoing strategic review. This cash runway with support generating clinical proof of concept data and up to four programs. We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward. And welcome you to participate in this journey. And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

First two of which are expected to be clinical stage next year. We ended 2023 with approximately $281 million. And this gives us a cash one way for the next five years. Pending future R&D results and ongoing strategic review. This cash runway with support generating clinical proof of concept data and up to four programs. We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward. And welcome you to participate in this journey. And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: We ended 2023 with approximately $281 million. And this gives us a cash one way for the next five years. Pending future R&D results and ongoing strategic review. This cash runway with support generating clinical proof of concept data and up to four programs. We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward. And welcome you to participate in this journey. And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: And this gives us a cash one way for the next five years. Pending future R&D results and ongoing strategic review. This cash runway with support generating clinical proof of concept data and up to four programs. We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward. And welcome you to participate in this journey. And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: Pending future R&D results and ongoing strategic review. This cash runway with support generating clinical proof of concept data and up to four programs. We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward. And welcome you to participate in this journey. And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: This cash runway with support generating clinical proof of concept data and up to four programs. We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward. And welcome you to participate in this journey. And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: We believe each of these programs has the potential to transform the treatment of these debilitating conditions and success in any one of these would create significant value for investors. We are dedicated to moving these molecules forward. And welcome you to participate in this journey. And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: We are dedicated to moving these molecules forward. And welcome you to participate in this journey. And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: And welcome you to participate in this journey. And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: And help us get to success. This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

This concludes our prepared remarks. We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: We will now move to Q&A. Operator, please open the line for questions.

Speaker Change: Operator, please open the line for questions.

Operator: As a reminder, to ask a question, please press start 11 on your telephone and wait for your name to be announced. To withdraw your question, press star 11 again. Please be advised that today's technical difficulty will be resolved for the archive purposes. One moment five first question. That will come from the line of Joseph Schwartz with Leerink Partners. Please go ahead.

Speaker Change: Please be advised that today technical technical team will be resolved for the archive type with that one moment five first question.

Speaker Change: And that will come from the line of Joseph Schwartz Leering pie.

Joseph Schwartz: Go ahead.

Joseph Schwartz: Hi, thanks very much for the update. I was wondering if you could tell us more about the tissue distribution relative to the plasma distribution for DT-216P2 in all of the relevant tissue types for patients affected by FA? And then, have you gone back and back tested the ISR profile for the original formulation of DT-216, as well as the new one. Thank you.

Joseph Schwartz: Tell us more about the tissue distribution relative to the plasma distribution for D. G 216 P. Two. All of the relevant tissue types of our patients are affected by fr. And then. Got back and back tested the ISR profile for the original formulation of D. G 216, as well as the the new one.

Joseph Schwartz: All of the relevant tissue types of our patients are affected by fr. And then. Got back and back tested the ISR profile for the original formulation of D. G 216, as well as the the new one.

Joseph Schwartz: And then. Got back and back tested the ISR profile for the original formulation of D. G 216, as well as the the new one.

Joseph Schwartz: Got back and back tested the ISR profile for the original formulation of D. G 216, as well as the the new one.

Speaker Change: Thank you.

Sean Jeffries: Thank you, Joe, for that question. On the exposure profile. As a reminder, one of the major learnings from our prior clinical trial was that the levels of drug required in tissue are similar to the in vitro EC90. So, that eight to 10 animal exposure that we saw in muscle in patients from the trial is something that sets a target. The prior drug product had this disconnect between the duration of plasma and tissue levels in animals. We did not observe any such disconnect in humans and the new drug product DT-216P2 is well behaved in that even in animals there's no longer a disconnect between plasma and tissue levels. And this is what you would expect with a small molecule drug. So, if you reference slide 22, muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with our DT-216P2, where on the right you see that in non-human primate studies, the plasma levels are much higher and so are the tissue levels as shown by muscle biopsy from these NHPs. In addition, we have some additional confirmatory data in a rat distribution study, which we can show you in the subsequent slide here, that there's adequate levels of drugs seen in a broad set of tissues against that target level of eight to 10 animals that we require to see a biological effect.

Speaker Change: On the. Exposure profile as a reminder, one of the major learnings from our prior clinical trial. Was it the levels of drug required in tissue. Are similar to the in vitro AC 90. So that's eight to 10 animal exposure that we saw in muscle in patients from the trial. Is something that sets a target. The prior drug product had this disconnect between the duration of plasma and tissue levels and animals, we did not observe any such disconnect in humans. And the new drug product <unk> is well. Well behaved and that even an animal's there's no longer a disconnect between plasma and tissue level. Then this is what you would expect with a small molecule drug. So if you reference slide 22. Muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with R. D. T 262, we're on the right you see that in nonhuman Primate studies, the plasma levels are much higher. And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: Exposure profile as a reminder, one of the major learnings from our prior clinical trial. Was it the levels of drug required in tissue. Are similar to the in vitro AC 90. So that's eight to 10 animal exposure that we saw in muscle in patients from the trial. Is something that sets a target. The prior drug product had this disconnect between the duration of plasma and tissue levels and animals, we did not observe any such disconnect in humans. And the new drug product <unk> is well. Well behaved and that even an animal's there's no longer a disconnect between plasma and tissue level. Then this is what you would expect with a small molecule drug. So if you reference slide 22. Muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with R. D. T 262, we're on the right you see that in nonhuman Primate studies, the plasma levels are much higher. And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: Was it the levels of drug required in tissue. Are similar to the in vitro AC 90. So that's eight to 10 animal exposure that we saw in muscle in patients from the trial. Is something that sets a target. The prior drug product had this disconnect between the duration of plasma and tissue levels and animals, we did not observe any such disconnect in humans. And the new drug product <unk> is well. Well behaved and that even an animal's there's no longer a disconnect between plasma and tissue level. Then this is what you would expect with a small molecule drug. So if you reference slide 22. Muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with R. D. T 262, we're on the right you see that in nonhuman Primate studies, the plasma levels are much higher. And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Are similar to the in vitro AC 90. So that's eight to 10 animal exposure that we saw in muscle in patients from the trial. Is something that sets a target. The prior drug product had this disconnect between the duration of plasma and tissue levels and animals, we did not observe any such disconnect in humans. And the new drug product <unk> is well. Well behaved and that even an animal's there's no longer a disconnect between plasma and tissue level. Then this is what you would expect with a small molecule drug. So if you reference slide 22. Muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with R. D. T 262, we're on the right you see that in nonhuman Primate studies, the plasma levels are much higher. And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: So that's eight to 10 animal exposure that we saw in muscle in patients from the trial. Is something that sets a target. The prior drug product had this disconnect between the duration of plasma and tissue levels and animals, we did not observe any such disconnect in humans. And the new drug product <unk> is well. Well behaved and that even an animal's there's no longer a disconnect between plasma and tissue level. Then this is what you would expect with a small molecule drug. So if you reference slide 22. Muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with R. D. T 262, we're on the right you see that in nonhuman Primate studies, the plasma levels are much higher. And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Is something that sets a target. The prior drug product had this disconnect between the duration of plasma and tissue levels and animals, we did not observe any such disconnect in humans. And the new drug product <unk> is well. Well behaved and that even an animal's there's no longer a disconnect between plasma and tissue level. Then this is what you would expect with a small molecule drug. So if you reference slide 22. Muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with R. D. T 262, we're on the right you see that in nonhuman Primate studies, the plasma levels are much higher. And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: The prior drug product had this disconnect between the duration of plasma and tissue levels and animals, we did not observe any such disconnect in humans. And the new drug product <unk> is well. Well behaved and that even an animal's there's no longer a disconnect between plasma and tissue level. Then this is what you would expect with a small molecule drug. So if you reference slide 22. Muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with R. D. T 262, we're on the right you see that in nonhuman Primate studies, the plasma levels are much higher. And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: And the new drug product <unk> is well. Well behaved and that even an animal's there's no longer a disconnect between plasma and tissue level. Then this is what you would expect with a small molecule drug. So if you reference slide 22. Muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with R. D. T 262, we're on the right you see that in nonhuman Primate studies, the plasma levels are much higher. And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: Well behaved and that even an animal's there's no longer a disconnect between plasma and tissue level. Then this is what you would expect with a small molecule drug. So if you reference slide 22. Muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with R. D. T 262, we're on the right you see that in nonhuman Primate studies, the plasma levels are much higher. And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: So if you reference slide 22. Muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with R. D. T 262, we're on the right you see that in nonhuman Primate studies, the plasma levels are much higher. And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: Muscle biopsies showed the tissue levels were predicted by plasma levels. And that turns out to then also be true with R. D. T 262, we're on the right you see that in nonhuman Primate studies, the plasma levels are much higher. And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: And that turns out to then also be true with R. D. T 262, we're on the right you see that in nonhuman Primate studies, the plasma levels are much higher. And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: And so are the tissue level as is shown by muscle biopsy from these NH fees. In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

In addition, we have some additional confirmatory data and a rat distribution study, which we can show you and and the subsequent slide here. That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: That. There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: There is adequate levels of drug scene. Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Speaker Change: Then a broad set of tissues against that target level of eight to 10, an animal that we require to see a biological effect.

Sean Jeffries: And so, once you exceed the threshold required for biological effect, there's no excessive pharmacology. So, we feel that the exciting results we've seen with the plasma PK do also set us up well for good tissue distribution. On your other question about injection site reactions, non-clinical studies show that the injection site reactions were attributable to the excipients in the prior clinical formulation. And now the new non-GLP studies that we've conducted with DT-216P2 support the conclusion that this formulation has resolved the injection site issues and is suitable to progress into confirmatory GLP studies. And in fact, in one arm of the study, we've included daily injections over four weeks, which gives us further confidence that the injection site tolerability issues appear resolved.

Speaker Change: So we feel that the <unk> the exciting results, we've seen with the plasma T. K two also set us up well for good tissue distribution. On your other question about injection site reactions. Non clinical studies show that the injection site reactions were attributable to the excipients in the prior clinical formulation. And now the new non GOP studies that we've conducted with D 262. Support the conclusion that this formulation is resolve the injection site issues and is suitable to progress into confirmatory. G L P studies. And in fact in one arm of the study we've included daily injections. Over four weeks, which gives us further confidence that the injection site. <unk> tolerability issues appear resolved.

Speaker Change: On your other question about injection site reactions. Non clinical studies show that the injection site reactions were attributable to the excipients in the prior clinical formulation. And now the new non GOP studies that we've conducted with D 262. Support the conclusion that this formulation is resolve the injection site issues and is suitable to progress into confirmatory. G L P studies. And in fact in one arm of the study we've included daily injections. Over four weeks, which gives us further confidence that the injection site. <unk> tolerability issues appear resolved.

Speaker Change: Non clinical studies show that the injection site reactions were attributable to the excipients in the prior clinical formulation. And now the new non GOP studies that we've conducted with D 262. Support the conclusion that this formulation is resolve the injection site issues and is suitable to progress into confirmatory. G L P studies. And in fact in one arm of the study we've included daily injections. Over four weeks, which gives us further confidence that the injection site. <unk> tolerability issues appear resolved.

And now the new non GOP studies that we've conducted with D 262. Support the conclusion that this formulation is resolve the injection site issues and is suitable to progress into confirmatory. G L P studies. And in fact in one arm of the study we've included daily injections. Over four weeks, which gives us further confidence that the injection site. <unk> tolerability issues appear resolved.

Speaker Change: Support the conclusion that this formulation is resolve the injection site issues and is suitable to progress into confirmatory. G L P studies. And in fact in one arm of the study we've included daily injections. Over four weeks, which gives us further confidence that the injection site. <unk> tolerability issues appear resolved.

Speaker Change: G L P studies. And in fact in one arm of the study we've included daily injections. Over four weeks, which gives us further confidence that the injection site. <unk> tolerability issues appear resolved.

And in fact in one arm of the study we've included daily injections. Over four weeks, which gives us further confidence that the injection site. <unk> tolerability issues appear resolved.

Speaker Change: Over four weeks, which gives us further confidence that the injection site. <unk> tolerability issues appear resolved.

Speaker Change: <unk> tolerability issues appear resolved.

Joseph Schwartz: Great. Thank you.

Operator: Thank you. One moment for our next question. And that will come from the line of Leonid Timashev with RBC Capital Markets. Your line is open.

Speaker Change: And that will come from the line <unk>. <unk> R. B C capital markets. Your line is open.

<unk> R. B C capital markets. Your line is open.

Leonid Timashev: Hey, everyone. This is Nevin on for Leo. Thank you for taking our questions. Just a couple from us. How are you thinking about designing your Phase I for DT-216P3. And then, if you show for tax and expression increases in patients, do you think that that might potentially open a path forward for accelerated approval given some of the latest understanding of the biology and the FDA's views on that? And then, should we also expect similar patient numbers to the original SAT in that study? Thank you.

So just a couple of from US how old are you thinking about designing your phase 142, and sex P. Two and then if you show for tax on expression increases and patience to think. That that might potentially open a path forward for accelerated approval given some of the latest understanding of biology. He is on that and then should we also expect similar patient numbers to the original sat in that study. Thank you. [noise], Okay [noise].

Speaker Change: That that might potentially open a path forward for accelerated approval given some of the latest understanding of biology. He is on that and then should we also expect similar patient numbers to the original sat in that study. Thank you. [noise], Okay [noise].

Speaker Change: He is on that and then should we also expect similar patient numbers to the original sat in that study. Thank you. [noise], Okay [noise].

Speaker Change: [noise], Okay [noise].

Pratik Shah: Thank you for the question. With regard to the Phase I studies, because we see this remarkably different PK profile that hits all of the criteria that we were looking for. Our approach here is to first conduct a Phase I PK study in healthy volunteers. And this is to confirm the encouraging PK profile of DT-216P2. Once we get data from that study, we then plan to conduct patient studies beginning in 2025. With regard to your next question on FDA and endpoints, I would say that the unmet need here is high. We don't have anything to add in terms of what the FDA may or may not require in the future. We've had productive engagement with the FDA previously and we'll continue to engage with the agency upon resumption of clinical studies.

Speaker Change: With regard to the Uhm phase one studies. Because we see this remarkably. Different PK profile. It hits all of the criteria that we were looking for. Approach here is to first can docked. Phase one PK study in healthy volunteers. And this is to confirm the encouraging PK profile of D. G 216 P. Two. Once we. Get data from that study, we then plan to conduct patient studies beginning in 2025. With regards to your next question on. F D a. And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: Because we see this remarkably. Different PK profile. It hits all of the criteria that we were looking for. Approach here is to first can docked. Phase one PK study in healthy volunteers. And this is to confirm the encouraging PK profile of D. G 216 P. Two. Once we. Get data from that study, we then plan to conduct patient studies beginning in 2025. With regards to your next question on. F D a. And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Different PK profile. It hits all of the criteria that we were looking for. Approach here is to first can docked. Phase one PK study in healthy volunteers. And this is to confirm the encouraging PK profile of D. G 216 P. Two. Once we. Get data from that study, we then plan to conduct patient studies beginning in 2025. With regards to your next question on. F D a. And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: It hits all of the criteria that we were looking for. Approach here is to first can docked. Phase one PK study in healthy volunteers. And this is to confirm the encouraging PK profile of D. G 216 P. Two. Once we. Get data from that study, we then plan to conduct patient studies beginning in 2025. With regards to your next question on. F D a. And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: Approach here is to first can docked. Phase one PK study in healthy volunteers. And this is to confirm the encouraging PK profile of D. G 216 P. Two. Once we. Get data from that study, we then plan to conduct patient studies beginning in 2025. With regards to your next question on. F D a. And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: Phase one PK study in healthy volunteers. And this is to confirm the encouraging PK profile of D. G 216 P. Two. Once we. Get data from that study, we then plan to conduct patient studies beginning in 2025. With regards to your next question on. F D a. And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

And this is to confirm the encouraging PK profile of D. G 216 P. Two. Once we. Get data from that study, we then plan to conduct patient studies beginning in 2025. With regards to your next question on. F D a. And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: Once we. Get data from that study, we then plan to conduct patient studies beginning in 2025. With regards to your next question on. F D a. And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: Get data from that study, we then plan to conduct patient studies beginning in 2025. With regards to your next question on. F D a. And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: With regards to your next question on. F D a. And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: F D a. And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

F D a. And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: And and points I would say that. The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: The unmet need here is high. We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: We don't. Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: Have anything to add in terms of what the F D. A. May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: May or may not require in the future we've had productive engagement with the F. D. A previously and will continue to engage with the agency upon resumption of. Clinical studies.

Speaker Change: Clinical studies.

Leonid Timashev: Okay. Thank you.

Operator: Thank you. One moment for our next question. And that will come from the line of Laura Chico with Wedbush. Your line os open. - Laura, your line is open.

Lurid Chico: And that will come from the line of a lurid Chico with Wedbush. Your line is out then. Alright your line is open.

Speaker Change: Alright your line is open.

Laura Chico: Sorry about that. Thank you very much for taking the question. I believe you were also working in parallel on some new method development with respect to frataxin and detection on a protein level. I'm wondering if you can share any details, kind of on where that methodology stands at present, and maybe kind of timing to advance those efforts. And then I have one quick follow up.

Speaker Change: I believe you are also working in parallel on some new method development with respect to for tax and just <unk> on a protein level I'm wondering if you can share any details kind of unaware that methodology stands at present, and maybe kind of timing to advance those efforts and then I have one quick follow up.

Pratik Shah: Thank you, Laura. We are dedicated to continuing to work on whatever improvements we can make in measurement of frataxin levels. We have robust assays that we've already used in prior clinical studies for measurement of frataxin RNA, and we continue to make improvements on our ability to reliably measure frataxin protein and possible changes in frataxin protein. And we will provide updates on that progress as we progress to the clinic.

Speaker Change: We are. Indicated to continuing to work on. Whatever improvements we can make in measurement for tax and levels. We have robust assays that we've already used in prior clinical studies for measurement of protects an RNA. And we continue to make improvements on our ability to reliably measure for tax and protein and possible changes and for tax and protein and will provide updates on that progress as we as we progress to the clinic.

Speaker Change: Indicated to continuing to work on. Whatever improvements we can make in measurement for tax and levels. We have robust assays that we've already used in prior clinical studies for measurement of protects an RNA. And we continue to make improvements on our ability to reliably measure for tax and protein and possible changes and for tax and protein and will provide updates on that progress as we as we progress to the clinic.

Speaker Change: Whatever improvements we can make in measurement for tax and levels. We have robust assays that we've already used in prior clinical studies for measurement of protects an RNA. And we continue to make improvements on our ability to reliably measure for tax and protein and possible changes and for tax and protein and will provide updates on that progress as we as we progress to the clinic.

Speaker Change: And we continue to make improvements on our ability to reliably measure for tax and protein and possible changes and for tax and protein and will provide updates on that progress as we as we progress to the clinic.

Laura Chico: Okay. Thank you very much. And then just quickly with respect to Fuchs, and this may come out in your observational study, but I'm kind of curious with AMD visual acuity measurements are pretty straightforward, but contrast that with something else like geographic atrophy and it's a little bit more challenging to characterize progression or loss of vision. So, I'm curious where does Fuchs kind of shake out in that spectrum and any ideas in terms of kind of measurements that you think might be most promising? Thank you.

Speaker Change: Mmm Misnamed come out and you're observational study, but I'm kind of curious with a M D. Visual acuity measurements are pretty straight forward, but <unk> with something else like geographic atrophy, and it's a little bit more challenging. You characterize progression or loss of vision. So I'm curious, where it is fuchs kind of shake out in that spectrum and any ideas in terms of kind of measurements that you think might be most promising thank you.

Speaker Change: Visual acuity measurements are pretty straight forward, but <unk> with something else like geographic atrophy, and it's a little bit more challenging. You characterize progression or loss of vision. So I'm curious, where it is fuchs kind of shake out in that spectrum and any ideas in terms of kind of measurements that you think might be most promising thank you.

Speaker Change: You characterize progression or loss of vision. So I'm curious, where it is fuchs kind of shake out in that spectrum and any ideas in terms of kind of measurements that you think might be most promising thank you.

Pratik Shah: Thank you for the question. We're conducting an observational study in patients with Fuchs, with a confirmed TCF4 mutation to better understand both patient characteristics as well as the characteristics of the endpoints and disease progression. And those come in three different broad buckets. One is a variety of measures of visual quality, and there are numerous reports in the literature of ways to measure the loss of visual quality in patients with Fuchs. And we'll be getting direct experience with those types of measures.

Speaker Change: Yeah, we're conducting an observational study in patients with Fuchs with a confirm tcf for mutation to better understand both patient characteristics as well as the characteristics of the end points and disease progression. And those. Come in three different. Broad buckets, one is a variety of measures of visual quality. And there are numerous reports. Reports in the literature of ways to measure the loss of visual quality in patients with Fuchs and we'll be getting direct experience with those types of measures.

Speaker Change: And those. Come in three different. Broad buckets, one is a variety of measures of visual quality. And there are numerous reports. Reports in the literature of ways to measure the loss of visual quality in patients with Fuchs and we'll be getting direct experience with those types of measures.

Speaker Change: Come in three different. Broad buckets, one is a variety of measures of visual quality. And there are numerous reports. Reports in the literature of ways to measure the loss of visual quality in patients with Fuchs and we'll be getting direct experience with those types of measures.

Speaker Change: Broad buckets, one is a variety of measures of visual quality. And there are numerous reports. Reports in the literature of ways to measure the loss of visual quality in patients with Fuchs and we'll be getting direct experience with those types of measures.

Speaker Change: And there are numerous reports. Reports in the literature of ways to measure the loss of visual quality in patients with Fuchs and we'll be getting direct experience with those types of measures.

Speaker Change: Reports in the literature of ways to measure the loss of visual quality in patients with Fuchs and we'll be getting direct experience with those types of measures.

Pratik Shah: Second is measures of edema or fluid buildup in the cornea, because the endothelial cell layers' function is to dehydrate the stroma and keep the cornea clear. And there are ways in the clinic to measure this subclinical edema using anterior eye tomography, for example. We including those measures in the observational study. And third, as you've seen in the back of the eye in geographic atrophy, there are analogous or corresponding ways to directly visualize the corneal endothelium in patients using specialized microscopy. And so, we'll be including those measures as well. And that will give us a variety of tools to examine the characteristics of the patients and the disease progression.

Speaker Change: Is to dehydrate, the strong mind keep the cornea clear and there are ways in the clinic to measure this subclinical edema using using interior I tomography for example, so be including those measures and the observational study. Third. You know as you've seen in the back of the eye and geographic atrophy. There are analogous to a corresponding ways to directly visualized corneal endothelium in patients. Using specialized microscopy, and so it will be including those measures as well and that will give us a variety of tools to examine. <unk> for the patience and the disease progression.

Speaker Change: Third. You know as you've seen in the back of the eye and geographic atrophy. There are analogous to a corresponding ways to directly visualized corneal endothelium in patients. Using specialized microscopy, and so it will be including those measures as well and that will give us a variety of tools to examine. <unk> for the patience and the disease progression.

Speaker Change: You know as you've seen in the back of the eye and geographic atrophy. There are analogous to a corresponding ways to directly visualized corneal endothelium in patients. Using specialized microscopy, and so it will be including those measures as well and that will give us a variety of tools to examine. <unk> for the patience and the disease progression.

Speaker Change: There are analogous to a corresponding ways to directly visualized corneal endothelium in patients. Using specialized microscopy, and so it will be including those measures as well and that will give us a variety of tools to examine. <unk> for the patience and the disease progression.

Speaker Change: Using specialized microscopy, and so it will be including those measures as well and that will give us a variety of tools to examine. <unk> for the patience and the disease progression.

Speaker Change: <unk> for the patience and the disease progression.

Laura Chico: Thanks very much.

Operator: Thank you. I'm showing no further questions in the queue at this time. I would now like to turn the call back over to Mr. Pratik Shah for any closing remarks.

Pratik Shah: Well, thank you everyone for joining us on today's call. We look forward to updating you as we continue to make exciting progress at Design.

We look forward to updating you as we continue to make exciting progress at design.

Operator: Thank you all for participating. This concludes today's program. You may now disconnect.

Good afternoon, and welcome to designs conference call.

Q4 2023 Design Therapeutics Inc Earnings Call

Request a DemoDemo

DSGN

Design Therapeutics

Earnings