Q4 2023 PepGen Inc Earnings Call
Operator: Good afternoon, and welcome to PEPGEN's fourth quarter and full year 2023 earnings call to discuss its financial results and recent corporate development. At this time, all participants are on a listen only. To ask a question during the session, or to ask a question at that time, please press star followed by 11 on your touchtone phone.
Good afternoon, and welcome to Pep Jens fourth quarter and full year 2023 earnings call to discuss its financial results and recent corporate developments at this time all participants are in a listen only mode. Following the managers' prepared remarks, we will hold a question and answer session.
To ask a question.
During this session.
Ask the question at that time. Please press star followed by one one on your Touchtone phone as a reminder, this call is being recorded today Thursday March six 2024, I would now like to turn the conference call over to Mick O'brien.
Operator: As a reminder, this call is being recorded today, Thursday, March 6, 2024. I would now like to turn the conference call over to Emiko Bryant, Chief of Staff of PEPGEN. Emiko, please go ahead.
A staff of Pechin Amigo. Please go ahead.
Emiko Bryant: Thank you, operator. Good afternoon, everyone. And thank you for joining today's call. Earlier today, we released our financial results for the fourth quarter and full year 2023 and provided an update on recent corporate developments. The press release and our 10-K filed with the SEC this afternoon outlining our financial results are both available on our website at pepgens.com.
Okay.
Thank you operator, good afternoon, everyone and thank you for joining today's call earlier today, we released our financial results for the fourth quarter and full year 2023, and provided an update on recent corporate development.
This release and our 10-K filed with the SEC. This afternoon outlining our financial results are both available on our website.
Emiko Bryant: Joining me on the call today are James MacArthur, Ph. D., President and Chief Executive Officer, Dr. Michelle Mellion, Senior Vice President, Head of Clinical Development, and Noel Donnelly, Chief Financial Officer. As a reminder, we will be making forward-looking statements regarding our financial outlook in addition to regulatory and product development plans and research activities. These statements are subject to risks and uncertainties that may cause actual results to materially differ from those forecast
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Joining me on the call today are James Macarthur Ph D, President and Chief Executive Officer, Dr. Michelle million Senior Vice President head of clinical development, and Noel Donnelly Chief Financial Officer.
As a reminder, we will be making forward looking statements regarding our financial outlook.
Addition to regulatory and product development plans and research activities. These statements are subject to risks and uncertainties that may cause actual results to materially differ.
Emiko Bryant: A description of these risks can be found in our most recent 10K on file with the SEC. PEPGEN does not undertake any obligation to publicly update its forward-looking statements as a result of new information, future events, or changes in its expectations. I will now turn the call over to our CEO, James McArthur. Thank you, Amiko, and good afternoon, everyone.
A description of these risks can be found in our most recent 10-K on file with the SEC.
<unk> does not undertake any obligation to publicly update its forward looking statements as a result of new information future events or changes in its expectations.
I will now turn the call over to our CEO James Mcarthur.
Thank you tamika and good afternoon, everyone.
James G. McArthur: PEPGEN made meaningful progress over the course of 2023, including the initiation of our first inpatient clinical trials evaluating programs derived from PEPGEN's Enhanced Delivery Oligonucleotide, or EDO, cell-penetrating peptide platform in two neuromuscular diseases with high unmet medical need. Our lead clinical program, PGN-EDO51, or EDO51, is designed for the treatment of patients with Duch As a reminder, an estimated 13% of people with DMD, or approximately 4,200 individuals in the U.S. and EU, have a mutation amenable to an Exon 51 skipping approach. Our second clinical program, PGEN-EDO-DM1 or EDO-DM1, is designed for the treatment of myotonic dystrophy type 1 or DM1. We estimate that DM1 affects more than 100,000 people in the U.S. and Europe for whom there is currently no approved disease-modifying treatment.
Captured make meaningful progress over the course of 2023, including the initiation of our first in patient clinical trials evaluating programs to write for Pep Gen enhance delivery oligonucleotide or E. D. L cell penetrating peptide platform and two neuromuscular diseases with high unmet medical need.
Our lead clinical program P. G. M E D O 51, or <unk> 51 is designed for the treatment of patients with Duchenne muscular dystrophy also known as DMD, whose diseases are amenable to an exon 51 skipping approach.
As a reminder, an estimated 13% of people with D. M. D are approximately 4200 individuals in the U S and EU have a mutation amenable to an exon 51 skipping approach.
Our second clinical program PGN <unk> <unk>, one or <unk> is designed for the treatment of my Atonic dystrophy type one or <unk>.
We estimate the D M. One affects more than 100000 people in the U S and Europe for whom there are currently no approved disease modifying treatments.
James G. McArthur: Here at PEPGEN, developing potentially transformative medicines is the foundation of our mission and long-term vision for building the company. We believe that both our DMD and DM1 programs have the potential to be disease-modifying and meaningfully improve outcomes for patients. Our team is committed to advancing these important programs through the clinic with a sense of urgency to get them to the people living with these diseases as quickly as possible. We believe our recent stock offering puts us in a strong financial position for our team to execute on this commitment.
Europe pechin developing potentially transformative medicines is the foundation of our mission and long term vision for building. The company, we believe that our D. M D and DM one programs have the potential to be disease, modifying and meaningfully improve outcomes for patients.
Our team is committed to advancing these important programs through the clinic with a sense of urgency to get them to the people living with these diseases as quickly as possible.
We believe our recent stock offering puts us in a strong financial position for our team to execute on this commitment.
James G. McArthur: The net proceeds from this offering, together with our existing cash and cash equivalents, extend our projected cash runway into 2026. Turning to the latest updates and highlights from our clinical programs, we are pleased to announce we have completed enrollment for Cohort 1 and Connect 1 EDO51, evaluating the five MIG per TIG dose in DMD patients in our first phase two clinical trial. Following the review of the safety data of the 5 mg per kg dose cohort by our Data Safety Monitoring Board and assuming an acceptable emerging safety profile, we plan to escalate to the second cohort at 10 mg per kg of EDO51. The same process will take place prior to advancing to Cohort 3.
Net proceeds from this offering together with our existing cash and cash equivalents extend our projected cash runway into 2026.
Turning to the latest updates and highlights from our clinical program. We are pleased to announce we have completed enrollment for cohort one and connect 151 evaluating the five Meg per kg dose in DMD patients in our first phase two clinical trial.
Following the review of the safety data of the five Meg per kg dose cohort by our data safety monitoring board and assuming an acceptable emerging safety profile, we plan to escalate to the second cohort at 10 Meg per kg of <unk> 51.
The same process will take place prior to advancing to cohorts right.
James G. McArthur: In parallel, earlier this week we announced we received clearance from the MHRA in the UK to initiate Connect2 EDO51, our phase 2 study of EDO51 in people with DMD and medical indications for an exon 51 skipping serum. We currently expect to be initiating dosing in cohort one, evaluating the five make per kick dose level in patients in the UK in the third quarter of 2024. Following ConnectOne's preliminary data readout for the five MIG-PRKT cohorts, we expect to open trial sites for Connect2 in other geographies, including the U.S., subject to regulatory authorization. We anticipate reporting preliminary data for the Connect1 5MGPRK cohort in mid-2024, including safety, exon skipping, and dystrophin production, based upon externally available data and using our own clinical and non-clinical work for internal PEPGEN expects treatment with EDO51 in DMD patients to produce high levels of dystrophin protein.
In parallel earlier this week, we announced we received clearance from the MH and the U K to initiate connect to <unk> 51, our phase two study of <unk> 51 in people with DMD amenable to an exon 51 skipping therapy with.
We currently expect to be initiating dosing in cohort one evaluating the five make per kg dose level in patients in the U K in the third quarter of 2024.
Following connect one preliminary data readout for the five Meg per kg cohort, we expect to open trial sites for connect to in other geographies, including the U S subject to regulatory authorizations.
We anticipate reporting preliminary data for the connect one five make protect cohort in mid 2024, including safety.
I'm skipping and dystrophin production.
Based upon externally available data and using our own clinical and non clinical work for internal modeling assumptions Pep Gen expects treatment with <unk> 51 in DMD patients to produce high levels of dystrophin protein.
James G. McArthur: At the 5 mg per kg dose level, we expect to see greater than 1% of normal levels of dystrophin protein above background levels in the CONNECT1 EDO51 trial as measured by Western Blot analysis following 4 repeat doses of EDO51 in DMD patients. For our 10-microcig dose cohort, if EDO51 were to achieve dystrophin levels of greater than 7%, this would be the highest level of dystrophin production achieved by a DMD exome skipping therapy to date. Our modeling projections for this dose level suggest the possibility that we could potentially achieve greater than nine percent of normal levels of dystrophin protein.
At the five make protect dose level, we expect to see greater than 1% abnormal levels of dystrophin protein above background levels in the connect one idiot 51 trial as measured by Western Blot analysis following for repeat doses of <unk> 51 in DMD patients.
Before I can make per kg dose cohort at <unk> 51 word we achieved dystrophin levels of greater than 7%. This would be the highest level of dystrophin production achieved by a DMD exon skipping therapy to date.
Our modeling projections for this guest levels suggest the possibility that we could potentially achieve greater than 9% of normal levels of dystrophin protein.
James G. McArthur: The combined safety and dystrophin expression data package from Connect 1 and Connect 2 is designed to support a potential path towards accelerated approval, assuming alignment with regulatory authority. Turning to our DM1 development program, we were pleased the clinical hold on EDO-DM1 was lifted by the FDA in October 2023. Following discussions with regulatory authorities, we are advancing our EDO-DM1 therapy at the same dose level, starting at five mg per kg, across all countries, including the U.S., in the Phase I Freedom DM1 clinical trial for people living with DM1. Just last month, EDO DM-1 was granted fast-track designation by FDA. This designation is designed to facilitate the development and expedite the review of potential therapies designed to treat serious diseases and conditions with clear unmet medical needs. Importantly, fast track designation allows for early and more frequent communication with the FDA, which can potentially lead to earlier drug approval and access for patients.
The combined safety and dystrophin expression data package from connect one and connect to is designed to support a potential path towards accelerated approval, assuming alignment with regulatory authorities.
Turning to our <unk> development program, we were pleased the clinical hold on <unk> was lifted by the FDA in October 2023.
Following discussions with regulatory authorities, we are advancing our <unk> one therapy at the same dose levels, starting at five make working across all countries, including the U S. In the phase one freedom DM, one clinical trial for people living with <unk>.
Just last month <unk> was granted fast track designation by FDA.
This designation is designed to facilitate the development and expedite the review of potential therapies designed to treat serious diseases and conditions with clear unmet medical needs.
Importantly, fast track designation allows for early and more frequent communication with the FDA, which can potentially lead to earlier drug approval and access for patients.
James G. McArthur: In December 2023, PEPGEN announced the first patient was dosed in the Phase 1 Freedom DM1 single ascending dose clinical trial, and we expect to report preliminary data, including safety, splicing correction, and functional outcome measures from at least five McPrickig dose core hits in the second half of 2024. We expect both the 5 McPrickig dose and the 10 McPrickig dose evaluated in the Freedom DM1 clinical study to be pharmacologically active and believe that the 10 McPrickig dose could exhibit meaningful splicing correction and myotonia correction. In addition to our Freedom DM1 trial, we expect to open our Freedom 2 DM1 placebo-controlled multiple sending dose clinical trial in DM1 patients in the second half of 2024. An important differentiator of rPGN-EDO-DM1 is that it is designed to selectively target the pathogenic DMPK RNA with the COG repeat expansion rather than degrading both the normal as well as the pathogenic DMPK RNA.
In December 2023, Pep Jin announced the first patient was dosed in the phase one freedom D. M. One single ascending dose clinical trial, and we expect to report preliminary data, including safety spicing correction and functional outcome measures from at least five Meg per kg dose cohort in the <unk>.
Half of 2024.
We expect both the five <unk> per kg dose and can make protect us evaluated in the freedom DM one clinical study to be pharmacologically active and believe that 10 Meg per kg dose could exhibit meaningful splicing correction and myotonia correction.
In addition to our freedom do you have one trial, we expect to open our freedom to DM, one placebo controlled multiple ascending dose clinical trial in DM one patients in the second half of 2024.
An important differentiator of our PGN <unk> <unk> is that it is designed to selectively target the pathogenic Emt K Arnie with <unk> repeat expansion rather than integrating both than normal as well as pathogenic <unk> RNA <unk>.
As a result of the selectivity and based on our preclinical data. We believe that <unk> has the potential to achieve superior correction of splicing events at a well tolerated dose levels, which could lead to improved functional outcomes for patients.
James G. McArthur: As a result of this selectivity and based on our preclinical data, we believe that EDO DM1 has the potential to achieve superior correction of splicing events at well-tolerated dose levels, which could lead to improved functional outcomes for patients. In addition to our clinical programs, our research team continues to advance and evaluate our preclinical candidates in key areas of focus for neuromuscular and neurologic disorders. PGN-EDO53 is our lead preclinical program designed to skip exon 53 of the dystrophin transcript, a therapeutic target for approximately 8% of patients with DMD. We previously reported superior exon skipping in repeat-dose studies in non-human primates, and our team is commencing IND and CTA-enabling studies in 2024.
In addition to our clinical programs. Our research team continues to advance and evaluate our preclinical candidates in key areas of focus for neuromuscular and neurologic disorders.
PGN <unk> 53 is our lead preclinical program designed to skip exon 53 of the dystrophin transcript of therapeutic targets for approximately 8% of patients with DMD.
We previously reported superior exon skipping in repeat dose studies in non human primates, and our team is commencing Indy and Cta, enabling studies in 2024.
We look forward to providing more details as we progress.
I will now turn the call over to Dr. Michelle Melia <unk> head of clinical development to provide an in depth review of the trial designs of the ongoing clinical trials in DMD and D. M. One that I just mentioned Michele.
James G. McArthur: We look forward to providing more details as we progress. I will now turn the call over to Dr. Michelle Mellion, PEPGEN's Head of Clinical Development, to provide an in-depth review of the trial designs of the ongoing clinical trials in DMD and DM1 that I just mentioned.
Thank you James.
Starting with our clinical trials in D. M. D. Connect one is a phase 213 week open label multiple ascending dose clinical trial that is enrolling both ambulatory and non ambulatory boys and young men living with DMD amenable to an exon 51 skipping.
Dr. Michelle Mellion: Thank you, Jane. Starting with our clinical trials in DMD, Connect One is a phase two, 13-week, open-label, multiple ascending-dose clinical trial that is enrolling both ambulatory and non-ambulatory boys and young men living with DMD amenable to an Exxon 51 skipping approach. Each of the DMD patients must be at least 8 years of age to enroll and will have a muscle biopsy pre-dose and on week 13. The dosing of EDO51 will occur once every four weeks for 12 weeks. We will evaluate safety data from three subjects in the 5 Mg per kg dose cohort with DSM-B before progressing to the 10 Mg per kg dose cohort. We will evaluate further dose escalations based upon the evaluation of safety data from prior dose cohorts.
Each of the DMD patients must be at least eight years of age to enroll and we will provide and muscle biopsy pre dose and on week 13.
The dosing of Eto 51 will occur once every four weeks for 12 weeks.
We will evaluate safety data from three subjects in the seismic per kg dose cohort with the D. S. M B before progressing to the 10 Meg per kg dose cohort.
We will evaluate further dose escalation based upon the evaluation of safety data from prior dose cohorts.
Connect to is a multinational phase 226 week double blind placebo controlled multiple ascending dose clinical trial that will enroll both ambulatory and non ambulatory boys and young men living with DMD amenable to an exon 51 skipping.
Dr. Michelle Mellion: Connect 2 is a multinational phase 2, 26-week, double-blind, placebo-controlled, multiple ascending dose clinical trial that will enroll both ambulatory and non-ambulatory boys and young men living with DMD who are amenable to an Exxon 51 skipping therapy who are at least six years old. Participants will provide a muscle biopsy at baseline and then at week 25. EDO 51 will be administered every four weeks for six months.
<unk> therapy, who are at least six years old.
Participants will provide a muscle biopsy at baseline and then at week 25.
E D O 51 will be administered every four weeks for six months.
The D S M B well review the data before we proceed to the next dose cohort.
In February we received authorization from the M. HRA for our Cta to initiate connect to in the UK and are planning to open the study in the EU and the U S. Later this year following regulatory clearance.
Dr. Michelle Mellion: The DSMB will review the data before we proceed to the next dose cohort. In February, we received authorization from the MHRA for our CTA to initiate Connect2 in the UK and are planning to open the study in the EU and the U.S. later this year following regulatory clearance. Turning to our EDO-DM1 development plan, we are pleased to have dosed the first patient in our FREEDOM-DM1 Global Phase I Single Ascending Dose Randomized Double-Blind Placebo-Controlled Trial of EDO-DM1 in DM1 patients in December, 2023. Freedom DM1 will enroll a total of 24 DM1 patients, randomized three to one in favor of drug versus placebo, evaluating The subjects will have a muscle biopsy at baseline followed by a single infusion of EDO-DM1, with muscle biopsies taken again at day 28 and week 16.
Turning to our E D O D. M. One development plan. We are pleased to have dosed. The first patient in our freedom D. M. One global phase one single ascending dose randomized double blind placebo controlled trial of E. D. O D M. One in D. M. One patients in December <unk>.
23.
Freedom D M. One will enroll a total of 24 D. M. One patients randomized three to one in favor of drug versus placebo evaluating 510 and up to 20 Megs per keg with dose escalation. Following review of safety data from prior dose cohorts.
The subjects will provide a muscle biopsy at baseline followed by a single infusion of E. D. O D M. One with muscle biopsies taken again at day 28 and week 16.
Our freedom T. M. One study will inform our planned multinational phase two trial M. D. M. One a multiple ascending dose clinical trial that is designed to support potential regulatory approvals subject to alignment with regulatory authorities.
Dr. Michelle Mellion: Our FREEDOM DM-1 study will inform our planned multinational Phase 2 trial of DM-1, a multiple ascending dose clinical trial that is designed to support potential regulatory approvals subject to alignment with regulatory authorities. We anticipate opening the Phase 2 trial of EDO-DM1 in the second half of 2024 following discussions with regulatory authorities. With that review of PETSEN's clinical development plans, I will now hand the line to Noel Donley, our Chief Financial Officer, to review our latest financial results.
We anticipate opening the phase two trial of E. D O D M. One in the second half of 2024 following discussions with the regulators.
With that review of Pet sounds clinical development plans I will now hand, the line to know Dan Lee, Our Chief Financial Officer to review our latest financial results.
Al.
Thank you Michelle My comments will reflect the high level financial results of our fourth quarter and full year 2023 periods.
Noel P. Donnelly: Thank you, Michelle. My comments will reflect the high-level financial results of our fourth quarter and full year 2023 period. More details are provided in this afternoon's financial results press release and in the corresponding SEC filing. As of December 31st, 2023, PEPFEN held $110.4 million in cash and cash equivalents, compared to $181.8 million on December 31, 2022.
More details are provided in this afternoon's financial results press release, and then the corresponding SEC filing.
As of December 31, 2023.
Jen held $110 $4 million in cash and cash equivalents compared to 181 8 million on December 31 2022.
As James mentioned previously on February nine 2020 for Pep Gen successfully completed an underwritten stock offering of seven point.
Five 3 million common shares for gross proceeds of approximately $80 million.
Noel P. Donnelly: As James mentioned previously, on February 9, 2024, PEPGEN successfully completed an underwritten stock offering of 7.53 million common shares for gross proceeds of approximately $80 million. Based on our current operating plans, PEPGEN's current cash and cash equivalents, including the proceeds of the offering, are expected to fund operations into 2026. Our net loss for the fourth quarter of 2023 was $19.5 million; our net loss for the full year 2023 was $78.6
Based on our current operating plans Pep Gen current cash and cash equivalents, including the proceeds of the offering are expected to fund operations into 2020.
Net loss for the fourth quarter of 2023 was $19 5 million or net loss for the full year 2023 was $78 6 million.
Research and development expenses for the three months ended December 31, 2023 were $16 $3 million for the full year 2023 research and development expenses were $68 1 million.
Noel P. Donnelly: Research and development expenses for the three months ended December 31, 2023 were $16.3 million. For the full year 2023, research and development expenses were $68.1 million. The increase in research and development expenses in the fourth quarter of 2023 compared to the fourth quarter of 2022 was primarily attributable to costs associated with the advancement of the company's PGN EDO 51 and PGN EDO DM1 programs, including preclinical, clinical, and manufacturing costs related to our ongoing and future clinical trials. General and administrative expenses were $4.5 million for the three months ended December 31st, 2023. General and administrative expenses for the full year 2023 were $16.6 million. The increase in general and administrative expenses was primarily due to an increase in personnel-related costs.
The increase in research and development expenses in the fourth quarter.
Of 2023 compared to the fourth quarter of 2022 was primarily attributable to costs associated with the advancement of the Companys PGN <unk>, <unk> 51, and PGN <unk> <unk>, one programs, including preclinical clinical and manufacturing.
Costs related to our ongoing and future clinical trials.
General and administrative expenses were $4 5 million for the three months ended December 31 2023.
General and administrative expenses for the full year 2023 were 16 $6 million.
The increase in general and administrative expenses was primarily due to an increase in personnel related cost.
Finally as of February 29, 2024 have Gen had approximately 32 4 million shares outstanding and with that I will turn the call back to James.
Thank you.
I am very proud of our team's ability to advance multiple clinical programs in 2023 and look forward to continuing the successful operational execution over the course of 2024 and beyond.
This year is an important time for <unk> as we will have multiple upcoming clinical data readouts from our ongoing clinical trials in DMD and <unk> patients, making the first in patient clinical data from our proprietary <unk> platform.
James G. McArthur: Finally, as of February 29, 2024, PetGen had approximately 32.4 million shares outstanding. And with that, I'll turn the call back to James. Thank you, Noel. I'm very proud of our team's ability to advance multiple clinical programs in 2023 and look forward to continuing this successful operational execution over the course of 2024 and beyond. This year is an important time for PEPGEN as we will have multiple upcoming clinical data readouts from our ongoing clinical trials in DMD and DM1 patients, making the first inpatient clinical data from our proprietary EDO platform. To quickly review our anticipated data announcements for the year, in the middle of 2024, we expect to report preliminary data from the 5-microcig dose cohort in Connect1 EDO51, the Multiple Sending Dose Trial invoice We plan to provide safety, Exon 51 skipping, and disk from production data.
To quickly review, our anticipated data announcements for the year in the middle of 2024, we expect to report preliminary data from the five <unk> per kg dose cohort and connect one <unk> 51, a multiple ascending dose trial in boys with DMD.
We plan to provide safety exon 51, skipping and dystrophin production data.
For the multinational freedom DM, one phase one trial of <unk> in patients with <unk>, we anticipate reporting preliminary safety splicing correction and functional outcome measures from at least the five Meg per kg dose cohort in the second half of 2024.
With that I will open the call for questions operator.
And thank you.
As a reminder to ask a question. Please press star one on your telephone and wait for your name to be announced to withdraw. Your question. Please press star one again and we please ask that you limit yourself to one question and one follow up again, just limit yourself to one question one follow up and one moment for our first question.
James G. McArthur: For the Multinational Freedom DM-1 Phase 1 trial of EDO DM-1 in patients with DM-1, we anticipate reporting preliminary safety, splicing correction, and functional outcome measures from at least the 5 Mg per kg dose cohort in the second half of 2024. With that, I will open the call for questions. Operator.
And our first question comes from Joseph Schwartz from Leerink Partners. Your line is now open.
Hi, everyone. This is Jamie on for Joe.
Just wondering if you could talk a little bit more about the mechanism of <unk> one.
Operator: And thank you. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again.
And if you expect the blocking approach to result in.
For more specific profile and how that might read through.
So I think direction any implications for safety.
Yes.
Thank you Jay.
Operator: And we please ask that you limit yourself to one question and one follow-up. Again, just limit yourself to one question and one follow-up. And one moment for our first question. And our first question comes from Joseph Schwartz from Larynx Partners. Your line is now open. Hi, everyone. This is Jenny on behalf of Joe.
Our mechanism. Unlike other approaches which are seeking to degrade both the pathogenic DMT K as well as the non pathogenic TNK is targeting <unk> and we've been able to demonstrate in cell based models that we can liberate.
One as well as reduced the number of topics both sides of it.
So as well as dramatically correct this slightly impatient and.
James G. McArthur: I was just wondering if you could talk a little bit more about the mechanism of PDM, EDO, and DM1, and if you expect a blocking approach to result in a more specific profile and how that might read through to splicing correction and any implications for safety. Thank you. Thank you, Jay. Our mechanism, unlike other approaches which seek to degrade both the pathogenic DMPK as well as the non-pathogenic DMPK, targets the C-U-G repeat, and we've been able to demonstrate in cell-based models that we can liberate MVNL1 as well as reduce the number of toxic foci and nuclei of patient cells, as well as dramatically correct the splicing in patient cells.
In a mouse models were also similarly able to correct slicing and importantly, correct, both the electrophysiology as well as the observer myotonia in the mouse model.
This is a very profound response and we're able to do this at dose levels, which we were able to demonstrate achievable with our <unk> 51.
In healthy volunteers, which employs the same medium.
And conjugation chemistry to the P&L.
As such we believe that we are specifically targeting the top issues that drive this disease and coupling it to our video platform technology, which has been demonstrated to produce.
The highest level of exon 51, skipping following a single dose in humans as well as a robust delivery in nonhuman primates and mice, coupled with excellent exon skipping.
James G. McArthur: And in mouse models, we're also similarly able to correct splicing and, importantly, correct both the electrophysiologic as well as the observable myotonia in the mouse model. This is a very profound response, and we're able to do this at dose levels which we were able to demonstrate achievable with our EDO51 technology in Healthy Volunteers, which employs the same EDO peptide and conjugation chemistry as the As such, we believe that we are specifically targeting the toxic species that drive this disease and coupling it to our video platform technology, which has been demonstrated to produce the highest level of exon 51 skipping following a single dose in humans, as well as robust delivery in non-human primates and mice, coupled with excellent exon skipping.
As such we believe that at doses that we say, we can achieve robust levels of slicing correction that will allow us to demonstrate correction myotonia improvement strength.
Although it has not been demonstrated that Atwood sufficiency is a larger challenge in this disease by industry.
We believe that we will be able to avoid this by targeting the.
R&D species.
The fundamentals of this disease.
And thank you.
Okay.
And one moment our next question.
And our next question comes from Paul Matteis from Stifel. Your line is now open.
Hey, this is James on for Paul Thanks for taking our question.
I just had one as it relates to the upcoming readout.
As it relates to dystrophin specific one there's been some discussions recently about.
Different cuts of dystrophin, including an adjusted figure that accounts for muscle fat content and.
James G. McArthur: As such, we believe that at doses of resacral or taurate, we can achieve robust levels of splicing correction that will allow us to demonstrate correction of myotonia and improvement in strength. Although it has not been demonstrated that haploid insufficiency is a toxicologic challenge in this disease by indiscriminately knocking down DMPK, we believe that we will be able to avoid this by targeting the RNA species that is pathogenic and drives the fundamentals.
You mentioned for your study at five mix per kg youre looking for greater than 1% Dystrophin and then.
For 10, Megs, hoping to get above 9% I guess one are these.
Unadjusted dystrophin measures and then too.
Just how much above 1% district, when do we need to see initial initial readout to have confidence that we can get to 9% plus at the next dose. Thanks so much.
Operator: And thank you. And one moment for our next question. And our next question comes from Paul Matisse from CIFL. Your line is now open. Hey, this is James on behalf of Paul.
Great I. Appreciate the question. So you are correct that we are planning on reporting dystrophin levels above background.
Reason why that's important is an individual entered the study with two 5% endogenous levels of dystrophin and one can only elevated by eight 3% is really a net of 3% gain in history. So we are looking to see at least a 1% gain over background in terms of dystrophin levels.
Operator: Thanks for taking our question. I just had one as it relates to the upcoming readout. You know, just as it relates to dystrophin specifically, there's been, you know, some discussions recently about, you know, different cuts of dystrophin, including an adjusted figure that accounts for, you know, muscle fat content. And, you know, you mentioned for your study at, you know, five mg per kg, you're looking for greater than 1% dystrophin. And then, you know, for 10 mg per kg, you know, hoping to get above 9%. I guess one are these, you know, unadjusted dystrophin measures, and then two, just how much above 1% dystrophin do we need to see in the initial readout to, you know, have confidence that we can get to 9% plus at the next dose. Thanks so much.
Okay.
But we have the possibility to see higher levels still the reason why this 1% would give us confidence that it can.
In any case, we have produced 9% or better levels of dystrophin.
In patients is that when we look at.
Non human Primate studies, we've observed that a single dose at a low level of 20 Meg per kg produces approximately 2% dystrophin, but following four monthly doses of <unk> 51, and non human Primate. This has increased almost 35% of exon skipping and I apologize I missed.
James G. McArthur: Great, I appreciate the question. So you're correct that we're planning on reporting dystrophin levels above background. The reason why this is important is that an individual enters the study with 0.5% endogenous levels of dystrophin, and one can only increase it by 0.3%. It's really a net 0.3% gain of dystrophin. So we're looking to see at least a 1% gain over background in terms of dystrophin levels at the 5.8% to K dose level, but we have the possibility to go higher still. The reason why this 1% would give us confidence that at 10 mix per gig, we could produce 9% or better levels of dystrophin in patients is that when we looked at our non-human primate studies, we observed that a single dose at a low level of 20 mix per gig produces approximately 2% of dystrophin.
It's 2% exon skipping going to 35% exon skipping.
Obviously higher levels of exon skipping over to these higher levels of dystrophin production.
Give us a good sense that going from low single digit levels, we have the potential to see much higher levels.
Exon skipping and dystrophin production. This is also supported as I mentioned in the call by our modeling work based on both.
Primary.
Work itself.
In a mouse model non human primates and of course that we have.
In healthy volunteers.
Thanks, so much.
And thank you.
And one moment our next question.
And our next question comes from <unk> Ahmed from Bank of America. Your line is now open.
Great. Thanks, so much for taking my questions just two quick ones on DMD.
James G. McArthur: But following four monthly doses of EDO51 in non-human primates, this has increased to almost 35% exon skipping, and I apologize; I misspoke; it was 2% exon skipping going to 35% exon skipping. Obviously, higher levels of exon skipping will produce higher levels of dystrophin production, but it gives us a good sense that going from low single-digit levels, we have the potential to see much higher This is also supported, as I mentioned in the call, by our modeling work based on both primary work in cells, in the mouse model, non-human primates, and, of course, the work we have done in healthy volunteers. Thanks so much.
For the 10 Meg per kg cohort have you already started the process of identifying patients for that and based on on your timeline for when to expect the seismic.
Do you think would be a reasonable expectation.
To expect data from the 10, Meg cohort this year as well.
Thank you Susie.
So we see a lot of enthusiasm from our clinical investigators for the Kinect one clinical study and we anticipate seeing robust recruitment of this study.
Pension we've already recruited the cohort one.
And we anticipate reporting out of that asset.
Mid this year.
As soon as we have an update for you in terms of recruitment will give more guidance in terms of the timing of the 10-K.
Operator: And thank you. And one moment for our next question. And our next question comes from Tazeem Ahmed from Bank of America. Your line is now open.
Data readout, but we anticipate being able to report out in a timely fashion.
Operator: Great, thanks so much for taking my questions. Just two quick ones on DMD. For the 10 MIG per K cohort, have you already started the process of identifying patients for that? And based on your timeline for when to expect the 5 MIG data, do you think it would be a reasonable expectation to expect data from the 10 MIG cohort this year as well? Thank you.
So the enthusiasm we're seeing for both patients as well as investigators in the study.
And thank you.
One moment our next question.
And our next question comes from Laura Chico from Wedbush. Your line is now open.
Hey, good afternoon, guys. Thanks, very much for taking the questions I have two for you so with respect to connect one data.
James G. McArthur: So we've seen a lot of enthusiasm from our clinical investigators for the Connect One clinical study, and we anticipate seeing robust recruitment for this study. You know, as I mentioned, we've already recruited a cohort, one five-day cohort, and we anticipate reporting out that data set by mid-year this year. As soon as we have an update for you in terms of recruitment, we will give more guidance in terms of the timing of the 10-maker K data readout, but we anticipate being able to report that out in a timely fashion based on the enthusiasm we're seeing from both patients as well as investigators in this study. And thank you. One moment, our next question. And our next question comes from Laura Chico from Wedbush. Your line is now open.
It seems I'm wondering if you could spend a moment discussing a little bit more about the preliminary kinetics and the pace of exon skipping that youre staying with initial doses I think in the nonhuman.
If im not mistaken there was kind of a maximal or effect or a plateauing, which occurred over time I'm curious if you kind of anticipate seeing that in the patient samples I guess, what's the expectation that the magnitude of skipping can increase over time and then I have a quick follow up for you.
Terrific I appreciate the question Laura you are correct. When we look at our non human primate data for both our 51 as well as our 53 program governance.
Operator: Hey, good afternoon guys. Thanks very much for taking the questions. I have two for you. So with respect to Connect1 data, James, I'm wondering if you could spend a moment discussing a little bit more about the preliminary kinetics and the pace of exon skipping that you're seeing with initial doses. I think in the non-human primates, if I'm not mistaken, there was kind of a maximal effect or a plateauing, which occurred over time.
Some of the greatest increase that we've seen in terms of exon skipping is occurring from those blended to a smaller level of those two to three and a smaller increase sales.
As for and it does appear we are reaching these very high levels of exon skipping by Dennis or there may not be incrementally that much more.
One can achieve.
Where do we do anticipate seeing.
Better than 7% and very likely above 9% dystrophin production.
James G. McArthur: I'm curious if you kind of anticipate seeing that in the patient samples. I mean, what's the expectation that the magnitude of skipping can increase over time? And then I have a quick follow-up for you. Terrific. I appreciate the question, Laura. You're correct.
Our level of exon skipping and the modeling work that we've done based on extrapolation, we've done from prior work of other companies, where we compare our single dose exon skipping in humans to their single dose exon skipping in humans and lastly, based on the very extensive non human primate model.
James G. McArthur: When we look at our non-human primate data for both R51 as well as the R53 program, we go and observe that some of the greatest increase that we've seen in terms of exon skipping is occurring from dose one to dose two, a smaller level from dose two to dose three, and a smaller increase still from dose three to dose four. And it does appear that we are reaching these very high levels of exon skipping by dose four, and there may not be that much more that one can achieve incrementally. As such, we do anticipate seeing better than 7% and, very likely, above 9% differences in production based on the level of exon skipping and the modeling work that we've done. Based on the extrapolation we've done from prior work of other companies where we compare our single-dose exon skipping in humans to their single-dose exon skipping in humans.
The work we've done looking at both single and multiple doses so as such.
Do I expect a very robust levels of exxon's following.
Following four doses.
This will be reflective of what we're able to achieve we believe long term.
Okay. That's helpful. And then maybe one quick question on Jan one and I'll hop back in the queue here.
With respect to kind of the magnitude of slicing correction that you're looking for I'm wondering if you can kind of share any more color around what you think would be a meaningful level and if you could just remind us with respect to freedom. One what's the extent of functional assessments that we will be getting in the second half update thanks very much.
Okay.
First speak to the splicing correction work can.
We've done a preclinical data that I'll hand, it over to the shelf.
So the outcome measures that will be looking at it freedom while.
James G. McArthur: And then lastly, based on the very extensive non-human primate modeling work we've done, looking at both single and multiple doses, we do expect to see very robust levels of exon skipping following four doses. And this will be reflective of what we're able to achieve, we believe, in the long-term. Okay, that's helpful. And then maybe one quick question on DM1, and I'll hop back in the queue here. With respect to kind of the magnitude of the slice and correction that you're looking for, I'm wondering if you could kind of share any more color around what you think would be a meaningful level.
So in terms of the preclinical work that we have conducted we have observed that with higher and higher levels of licensing correction in a mouse model, which is rapid and engineered animal model. We can go to the higher and higher levels of myotonia correction, both from the standpoint of the dragging behind them.
This model as well as measurement by electrophysiology.
We're looking at 30, 40% spike in correction at that level in the mouse model are beginning to see robust levels of a correction myotonia and as we approach 60% at higher levels by some correction. We can begin to approach 70, 80% correction of the myotonia. So we.
James G. McArthur: And if you could just remind us, with respect to Freedom 1, what the extent of the functional assessments that we will be getting in the second half update? Thanks very much.
Do believe it's important to be able to demonstrate better than 25 plus percent slightly correction to see really robust changes in terms of the physiology of the pathology of this disease.
Dr. Michelle Mellion: Let me first speak to the splicing correction work that we've done pre-clinically, and then I'll hand it over to Michelle Melly to speak to the outcome measures that we'll be looking at at Freedom Watch. So in terms of the preclinical work that we have conducted, we have observed that with higher and higher levels of splicing correction in the mouse model, which is an engineered animal model, we can go and see higher and higher levels of myotonia correction, both from the standpoint of the dragging behind limbs, which can be observed in this model as well as measurement by electrophysiology. As such, if we're looking at 30, 40% splicing correction at that level in the mouse model, we're beginning to see robust levels of correction for myotonia.
With that I'll turn it over to Michelle to speak to the outcome and we'll be looking at a three to one.
So we have freedom line, our clinical outcome measures.
<unk> included a fall assortments.
Symptoms related to DIY and this assessment includes the Lehigh oscillations in this asset class and I believe most are now.
Familiar with as well as strength assessment.
Several different muscle.
Rex and other functional outcome measures such as the 10 meter walk test.
On the top and these will be done at different endpoints.
Pipelines during the study to assess the impact of planting correction on these investments.
Dr. Michelle Mellion: And as we approach 60% and higher levels of splicing correction, we can begin to approach 70, 80% correction of the myotonia. So we do believe it's important to be able to demonstrate better than, you know, 25 plus percent splicing correction to see really robust results in terms of the physiology and the pathology of this. With that, I'll turn it over to Michelle to speak to the outcome measures that we'll be looking at in 3 to 1. So in Freedom 1, our clinical outcome measures include a full assessment of symptoms related to DM1. And this assessment includes the VHOT, which is an assessment of myotonia that I believe most people are now familiar with, as well as strength assessments of several different muscles, including grip, and other functional outcome measures, such as the 10-meter walk test and the TUB.
And I just want to add to what Michel said as was mentioned earlier the freedom one clinical studies a single ascending dose click.
Clinical study and we expect both based on our work with the work of others that following a single dose we can reasonably expect to see.
Robust slice a correction as well as changes in terms of monetizing some of the other assessments that Michelle action that we will be looking at may take multiple doses.
Start seeing meaningful change there, but we've got a very good test from the data that we'll be presenting this year on the power of the <unk> molecule to go and really change the technology.
Yes.
Thanks, very much and I appreciate it.
And thank you.
And if he would like to ask a question that is star. One again, if you would like to ask a question that is star one one and one moment our next question.
And our next question comes from Ananda goes from H C. Wainwright and company. Your line is now open.
James G. McArthur: And these will be done at different endpoints or at time points during the study to assess the impact of splicing correction on these assessments. And I just want to add to what Michelle said. As was mentioned earlier, the Freedom 1 clinical study is a single ascending dose clinical study. And we expect, both based on our work as well as the work of others, that following a single dose, we can reasonably expect to see both robust splicing correction as well as changes in terms of myotonia. However, some of the other assessments that Michelle mentioned that we will be looking at may take multiple doses before we start seeing meaningful change there. But we will get a very good sense from the data that we'll be presenting this year on the power of the EDODM1 molecule to go and really change the pathology. Thanks very much, James. I appreciate it. And thank you. And if you would like to ask a question, that is star 11. Again, if you would like to ask a question, that is star 11.
Hi, James Thanks for the opportunity I have two questions. One on DMD that is with respect to the recent <unk> identified one data.
What does the data tell you about your program.
Confirming the platform.
Yeah.
And the idea of 51.
And then I have one follow up question on the on the.
Jim One program.
Thanks, Matt I appreciate the question.
So we have done a cross trial comparison of the ability of <unk> 51 to mediate exon 51 skipping in humans. Following a single dose and there we were able to observe six fold higher levels of exon 51, skipping compared to a single dose of the $50 51 wall.
At 20, Megs per K R 20, Meg per kg 50, 51 was relatively well tolerated at techniques for K, Ethiopia, Iran demonstrates.
Demonstrated following a single dose of humans only.
Only grade one reversible transient adverse events, so very very well tolerated product.
We anticipate as we extrapolate forward that we couldnt be producing six fold higher levels of exon skipping actually disrepair than what was observed in both the three months momentum A&D six month momentum be clinical status with 50 51 and this.
Operator: And one moment for our next question, and our next question comes from Ananda Ghosh from H.C. Wainwright and Company. Your line is now open.
James G. McArthur: Hi James, thanks for the opportunity. I had two questions, one on DMD and that is with respect to the recent SRP 5051 data. What does that data tell you about your program, you know, concerning the platform and the IDO 51?
<unk> supports our contention that we have the potential to produce greater than 90% dystrophin levels in patients following forecast and so we remain very confident both based on the.
James G. McArthur: And then I have one follow-up question on the DM1 program. Thank you, and I appreciate the question. So we have done a cross-trial comparison of the ability of EDO51 to mediate exon 51 skipping in humans following a single dose, and there we were able to observe six-fold higher levels of exon 51 skipping compared to a single dose of the 50-51 molecule at 20 mg per kg. Now at 20 mg per kg, 50-51 was relatively well tolerated, and at 10 mg per kg, EDO51 So it is a very, very well-tolerated drug.
Extrapolation in a cross trial comparison to that clinical data the work that we've done in animal models in nonhuman primates and the overall modeling work is incorporated.
Non human primate and human data with EUR 51.
He will be able to see better than 9% dystrophin.
Patients.
If we could even achieved 7% ex dystrophin production with an exon skipping approach specifically the highest level of dystrophin produced by any exon skipping drug and projected to be produced by the exon skipping drug and so we would be feel that to be a huge success, but we believe based on all the work.
We have the potential to be greater than not this later than 9% dystrophin.
James G. McArthur: We anticipate, as we extrapolate forward, that we could be producing six-fold higher levels of exon skipping and potentially dystrophin than what was observed in both the three-month Momentum A and the six-month Momentum B clinical studies with 50-51, and this is what supports our contention that we have the potential to produce greater than 9 percent dystrophin levels in patients. And so we remain very confident, both based on the extrapolation and the cross-trial comparison to that clinical data, the work that we've done in animal modeling and non-human priming, and the overall modeling work that has incorporated both mouse, non-human primates, and human data with DDO51, that indeed, we'll be able to see better than 9% dystrophin in patients. If we could even achieve 7% dystrophin production with an exon skipping approach, this would be the highest level of dystrophin produced by any exon skipping drug and projected to be produced by any exon skipping drug.
Yes.
Got it thanks.
With respect to the game Jim One program there has been a debate in terms of what kind of primary endpoint.
The companies might see.
One programs had bonds.
And so there has been lot of discussions around the V heart. So what is what is your peak about.
It includes view one primary endpoint.
Sure.
In the <unk>, one program and Mike.
A follow up question to that is is there a is there a correlation between the pricing correction.
And the very hot.
Measurements.
Perhaps I can start off and then I'll ask Michel <unk> to add to my thoughts.
These conversations with regulators are ongoing as we cannot speak to what would be the approval endpoints.
James G. McArthur: And so we would feel that would be a huge success, but we believe, based on all the work we've done, we have the potential to produce greater than 9% dystrophin in patients. Got it. Thanks. And, you know, with respect to the DM1 program, there has been a debate in terms of, you know, what kind of primary endpoint the companies might see as the DM1 programs advance.
Our freedom to and beyond clinical studies.
What we can say is that we believe the slight thing isn't important mechanistic underpinning of the <unk> program.
With greater levels of slightly correction, we have in animal models seeing greater levels of myotonia correct.
As such we would expect to see with greater levels of slicing correction in patients, we would see greater levels of myotonia correction and longer term correction of many of the movement related.
James G. McArthur: And so, there has been a lot of discussions around the VHOD. So, what is your take on the agency's view on the primary endpoint in the DM1 program? And my, you know, a follow-up question to that is, is there a correlation between the splicing correction and the VHOD assay measurement? Perhaps I could start off, and then I'll ask Michelle Millian to add to my thoughts. So these conversations with regulators are ongoing, and so we cannot speak to what would be the approval endpoints from our Freedom II and beyond clinical studies. What we can say is that we believe that splicing is an important mechanistic underpinning of the EODM1 program, and with greater levels of splicing correction, we have seen in animal models greater levels of myotonia correction.
Apologies of this disease.
It is our anticipation that all of these will go into ultimately what would become an approvable endpoint.
Let me allow Michelle perhaps.
Add to that.
Yes, that's right James I believe that we will learn from our freedom DIONE study because our single ascending dose study about the potential impact on several of these intermediate endpoints such as the heart and potentially at later time points.
And our strength and it is likely that looking at the totality of these endpoints taken together the hot strength, Greg and maybe selected functional endpoints such as the heavier walked half we'll be able to assess the full impact of pricing correction over multiple doses in a future study on these endpoints to incur.
Greasing the potential.
James G. McArthur: And as such, we would expect that with greater levels of splicing correction in patients, we would see greater levels of myotonia correction and longer-term correction of many of the movement-related pathologies of this disease. So it is our anticipation that all of these will go into ultimately what would become an approvable endpoint. But let me allow Michelle to perhaps add to that.
The type of impact on the disease that our therapy will have for this population.
Alright, thanks very much much appreciate it.
Thank you.
Thank you.
And I am showing no further questions I would now like to turn the call back over to James Mcarthur for closing remarks.
Thank you operator, and thank you everybody for participating in today's call. If you have any questions or follow up items. Please do reach out to me or know we look forward to connecting with all of you soon at upcoming Investor conferences.
James G. McArthur: Yeah, that's great, James. I believe that we will learn from our FREEDOM-DM1 study, which is our single ascending dose study, about the potential impact on several of these intermediate endpoints, such as VHOT, and potentially at later time points, GRIP, and STRENGTH. And it is likely that, looking at the totality of these endpoints taken together, the VHOT, STRENGTH, GRIP, and maybe selected functional endpoints, such as the 10-meter walk test, will be able to assess the full impact of splicing correction over multiple doses in a future study on these endpoints to appreciate the potential impact on the disease that our therapies will have for this population.
Have a great.
This concludes today's conference call. Thank you participating you may now disconnect.
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Dr. Michelle Mellion: Sorry. Thanks very much. Much appreciated. Thank you. And I am showing no further questions.
Operator: I would now like to turn the call back over to James MacArthur for closing remarks. Thank you, Operator, and thank you, everybody, for participating in today's call. If you have any questions or follow-up items, please do reach out to me or Noel. We look forward to connecting with all of you soon at upcoming investor conferences. Have a great evening. Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect. Go to Beadaholique.com for all of your beading supply needs! Welcome everyone, this is Blurr. Let's do something a bit different. Let's try that again. There we go. Okay, how do we make ourselves feel? Let's try something different.
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