Q4 2020 PTC Therapeutics Inc Earnings Call

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Unknown Executive: [inaudible] Ladies and gentlemen, thank you for standing by, and welcome to the PTC 4th Quarter 2020 Financial Results Conference Call. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone. If you require any further assistance, please press star 0.

[music].

Kylie O'Keefe: I would now like to hand the conference over to your speaker today, Kylie O'Keefe, Head of Investor Relations. Please go ahead. Good afternoon, and thank you for joining us to discuss the PTC Therapeutics fourth quarter and year-end 2020 corporate updates and financial results. Joining me on today's call is our Chief Executive Officer, Stuart Peltz, our Chief Financial Officer, Emily Hill, our Chief Development Officer, Matthew Klein, and our Chief Business Officer, Eric Pauwels.

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Kylie O'Keefe: Before we start, let me remind you that today's call will include forward-looking statements based on current expectations. Please take a moment to review the slide posted on our Investor Relations website in conjunction with the call, which contains our forward-looking statements. Our actual results could materially differ from these forward-looking statements, as any and all such risks can materially and adversely affect our business and results of operations. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent annual report, Form 10-K, filed with the Securities and Exchange Commission, as well as the company's other SEC filings.

Ladies and gentlemen, thank you for standing by and welcome to the PTC fourth quarter, 'twenty and 'twenty financial results Conference call. At this time all participants are in a listen only mode. After the speaker's presentation. There will be a question and answer session. That's a good question day in this session you will need to press star one on your telephone if you acquired any further.

Assistance, Please press star and Yeah, I would now like to hand, the competency and speaker today, Kylie O'keefe head of Investor Relations. Please go ahead ma'am.

Kylie O'Keefe: We will disclose certain non-GAAP information during this call. Information regarding our use of GAAP and non-GAAP financial measures and a reconciliation of GAAP to non-GAAP is available in today's earnings release. With that said, let me now pass the call over to our CEO, Sue.

Good afternoon, and thank you for joining us to discuss the PTC therapeutics fourth quarter and year end 2020, corporate update and financial results.

Stuart Peltz: Thanks, Kylie. And thanks for joining us today. In 2020, we have made significant progress in moving our pipeline forward to bring new therapies to patients on all fronts from research and development through commercial. Despite the COVID-19 pandemic, we initiated five clinical trials, including two registration-directed trials with fatiguing. Let me begin with the Duchenne Muscular Dystrophy Franchise. We continue to see strong global...

Joining me on today's call and Zhao Chief Executive Officer, Stuart Peltz Chief.

Chief Financial Officer, Emily Hill.

Our Chief Development Officer, Matthew Klein, and our Chief business Officer, Eric Pals.

Before we start let me remind you that today's call will include forward looking statements based on current expectations.

Please take a moment to review the slides posted on our Investor Relations website in conjunction with the call which contains our forward looking statements.

Actual results could materially differ from these forward looking statements as any and such risks can materially and adversely affect our business and results of operation.

Stuart Peltz: Our DMD franchise sales in 2020 were approximately $331 million. Specifically, in the U.S., the annual revenue of the Plaza totaled $139 million, which is a 38% APH from last year. The annual revenue for TransLineman totaled $192 million and was driven by geographic expansion.

For a detailed description of applicable risks and uncertainties. We encourage you to review the company's most recent annual report form 10-K filed with the Securities and Exchange Commission as well as the company's other SEC filings.

We will disclose certain non-GAAP information during this call information regarding our use of GAAP and non-GAAP financial measures and a reconciliation of GAAP and non-GAAP is available in today's earnings release.

Stuart Peltz: and Label Modification. For example... TransLiner received marketing authorization in Russia in the fourth quarter. We have also continued to drive additional geographic expansion in Central and Eastern Europe and in Latin America. Even during the turmoil caused by the COVID-19 pandemic, we secured a Brazilian group purchase order for TransLino, and Eric will go into these details shortly. As a reminder, we also recently reported the results of the 045 Disturbance Study. We plan to discuss these results along the trend line of totality of evidence, including existing clinical and real-world data, with the FDA.

With that let me now pass the call over to out the day.

Thanks for Kylie and.

Thanks for joining us today.

And 2020, we have made significant progress and moving our pipeline forward and bring new therapies for patients on all fronts from research and development for commercial.

Despite the COVID-19 pandemic, we initiated five.

Clinical trial, including two registration directed trial with particular mill.

Let me begin with the Duchenne muscular dystrophy.

We continue to see strong global growth and geographic expansion.

DMD franchise sales in 2021 were approximately 331 million.

Stuart Peltz: Our goal has always been...

Stuart Peltz: Transliner to U.S. patients who have long been waiting for this therapy as quickly as possible. Moving to our splicing platform, the approval of the RISD in 2020 was an important milestone for our partners ROSE and the FLA Foundation. RISD is a groundbreaking treatment which has a benefit for all.

Specifically and the U S. The annual revenue from Plaza totaled $139 million.

Which is a 38% increase from last year.

Annual revenue for transplant and the total of $192 million and was driven by geographic expansion, new pension and Labour modification.

For example.

And as long and received marketing authorization and Russell and the fourth quarter.

We have also continued to drive additional geographic expansion and central and Eastern Europe and in Latin America.

Stuart Peltz: As a consequence of the benefits of ERISI, it has continued to show a strong uptake, and RISD will become the treatment of choice in the U.S. in 2021. With the near-term expected European approval followed by the Japanese approval of RISD, we should see continued significant growth this year. Another accomplishment of 2020 with regard to RISD

Even during the turmoil caused by the COVID-19 for example.

We secured a resilient group purchase order for Translarna and Eric will go into these details shortly.

And a reminder.

We also recently reported the results from the old for five just to start and.

Unknown Executive: The Royalty Monetization Deal, which puts $650 million dollars on our backs.

We plan to discuss these results along with Prince London, totality rabbit, including existing clinical and real world data with the FDA.

Unknown Executive: Okay. Okay.

Unknown Executive: The structure of the deal allows PTC to receive approximately 60% of the royalty revenue and reverts to 100% once our royalty monetization partner receives $1.3 billion. Our next most advanced molecule from the validated splicing platform is PTC518 for the treatment of Huntington's disease. As a reminder, PTC 518 is an orally bioavailable small molecule that crosses the blood-brain barrier and reaches all regions of the brain. Preclinical results demonstrated a dose-dependent reduction in the HTT mRNA and protein in cells of the striatum, cortex, and cerebellum in the BEC-HD mouse model. This is critically important as hunting disease is a whole brain disease.

Our goal has always been to.

Britain translated to U S patients.

And have long been waiting for this therapy as quickly as possible.

Moving to our splicing platform and the approval of a risky.

2020 was an important milestone for PTC.

Our partners Roche and the SMA policies.

He is a ground breaking free which is a benefit for all lessened and patients with particular benefits of durability and broad tissue distribution.

And as a consequence of the benefits of a risky business.

Continued to show a strong uptake and Roche and.

Rune will become the treatment of choice and the U S and 2021.

With the near term expected European approval, followed by the Japanese approval of risky.

Unknown Executive: HTT reduction is clearly titrated both based on PTC 518 levels, and so the degree of HTT lowering can be tightly controlled. In addition to the whole-brain distribution... PTC 518 achieves uniform exposure and HTT lowering in all tissues analyzed, showing a near one-to-one ratio between CNS and blood. This is important because it shows the exposure and effect within the brain are analogous to what we see in the

And your significant growth this year.

And remember accomplishment of 'twenty and 'twenty with regards to a risky.

Royalty monetization deal, which put 600 or $15 million.

The structure of the deal allows PTC to receive approximately 60% of the royalty revenue and reverts to a 100% once our royalty monetization partner and let's see.

And one $3 billion.

Unknown Executive: PTC 518 is currently in a single and multiple ascending dose phase one trial in healthy volunteers. We will be measuring both HTT mRNA and protein levels in cells within the blood. This slide quickly demonstrates drug activity that results in HTT lowering. This will allow us to select the dose with the desired level of activity.

Our net most advanced molecule from the validated splicing platform.

PTC five one day for the treatment of Huntington's.

As a reminder, PTC 518 is an orally bio available small molecule that crosses the blood brain barrier and reaches all regions of the brain.

Preclinical results, demonstrating a dose dependent reduction and the <unk>.

<unk> mrna and protein and cells of the striatum cortex, and cerebellum and the back HD Mouse model. This is critically important and Huntington's disease is a whole brain disease.

Unknown Executive: This same approach was successfully used in the RISDA plan program, where proof-of-concept was demonstrated in the Healthy Volunteer Study. We expect the same trajectory in the Huntington's Disease Program. We are very excited about this program and look forward to the results that are expected in the first half of 2021.

H T T reduction is clearly titrate and both based on PTC part one day.

So the degree of HCP, lower and lower it can be tightly control.

In addition to the whole brain distributions PTC $5 80 per cheap uniform exposure and the H T T lowering and all tissues and alike.

Unknown Executive: The second and final stage of the Fight 19 Registrational Trial for COVID-19 has commenced. As a reminder, PTC 299 is an oral small molecule with a dual mechanism of action that demonstrates both antiviral and anti-inflammatory effects. PTC 299 inhibits SARS-CoV-2 viral replication and calms the cytokine storm. PTC 299 functions by targeting a cellular enzyme, dihydroorotate dehydrogenase, or DHODA. The advantage of targeting the cellular enzyme instead of a viral protein is that it's less likely to elicit drug resistance.

So in the near one to one ratio between CMS and block.

This is important because it shows the exposure and effect within the brain just analogous to what we see in the blood flow.

PTC five one day is currently in a single and multiple ascending dose phase one trial in healthy volunteers.

We will be measuring both H T T mrna and protein level.

And sales within the block, allowing us.

To quickly demonstrate drug activity that results from H T T mobile arena.

This will allow us to select the dose with the desired levels of activity.

Same approach with successfully.

And the risk the planned program, where a proof of concept was demonstrated in the healthy volunteer study.

Unknown Executive: Though there have been great strides made in the development of vaccines, the lack of effective COVID-19 treatments has significantly hampered our ability to resume normal life, and therefore, the continued focus on developing treatments is key. Now, let me turn to our BioE platform. We have initiated two registration-directed trials with vitiquinone, one in mitochondrial epilepsy and one in fetal attack, and we are rolling patients in both studies. The global prevalence of mitochondrial epilepsy is estimated at 20,000 patients.

We expect the sales trajectory and the Huntington's disease program. We are very excited about this program and look forward to the results that are expected and the first half of 'twenty, one and you want.

Now turning to our Barology platform, the second and final stage of the 519 Registrational trials for COVID-19 has come back.

As a reminder.

PTC through nine months, given all small molecule with a dual mechanism of action that demonstrate both anti viral and your time.

Unknown Executive: And the global prevalence of FA is approximately 25,000. Let me now touch on our gene therapy platform. Our initial focus is to launch our first gene therapy for patients with AADC deficiency, which is expected to occur in Europe during the second half of 2021. The BLA submission is also on track for the second quarter of this year. As a reminder, PTC-AADC is a transformative gene therapy that has the potential to produce meaningful changes in the AADC-deficient patient.

Inventory effects.

PTC, two 9 million inhibit Sars COVID-19, two viral replication and calm the cytokine storm.

PTC to 99, one to arguably a cellular enzyme hydro orchard dehydrogenase or D. H O T H.

The advantage of targeting the cellular and instead of a viral protein is that it's less likely to illicit drug resistance.

And there have been great strides made and the development my screen and the lack of effect of COVID-19 treatment and so.

Significantly hampered our ability to resume normal life and therefore for continued focus on developing treatments is key.

Now, let me turn for our bio E platform.

Unknown Executive: PTC-AADC has robust clinical data that demonstrates durability of effects for up to 10 years post-treatment, a crucial consideration in a single-dose gene therapy. Now, let me discuss our plans for PTC 923. As a reminder, there is an estimated global prevalence of 58,000 CKU patients.

We have initiated two registration directed trials with particular note, one and mitochondrial epilepsy and wanted to attack and.

And our rolling patients in both studies for.

And the global prevalence of mitochondrial epilepsy and estimated at 20000 patients.

And the global prevalence.

Unknown Executive: We are excited about the potential of PTC 923 as a clinically differentiated therapy to address this high-end medical need. We will start the registration process.

Approximately 25000 patients.

Let me now touch on our gene therapy platform. Our initial focus is to.

The launch of our first gene therapy for patients with ADC deficiency, which is expected to occur in Europe. During the second half of 'twenty and 'twenty one.

Matt: PTC 923 for treating PKU called Affinity mid this year. Last year, we achieved many important milestones. We anticipate an exciting year in 2021 that will continue to create substantial value for all our states. I'll now turn the call over to Matt for key updates on our clinical program.

For BLA submission is also on track for the second quarter of this year and.

As a reminder.

PTC agency and here's a transformative gene therapy that has the potential to produce meaningful changes and the AGC deficient patients PTC.

PTC has robust clinical data that demonstrate durability of effect roughly 10 years Post street.

Matt: Thanks, Stu. I want to build on Stu's comments on our development team's achievements in 2020. We have worked hard at PTC to navigate the many challenges of the past year and are excited to continue to deliver on planned development milestones across our multiple platforms. I would like to start with our BioEats platform. This platform focuses on diseases of oxidative stress by targeting a special class of enzymes called oxidoreductases. Oxidoreductases are a family of enzymes that perform important electron transfer reactions and are known to have important biological functions.

Crucial consideration and a single dose gene therapy.

Now, let me discuss our plans for PTC, 19th three as a reminder.

And there was an estimated global prevalent for 58000 PKU patients and the vast majority is not well addressed by current there and therefore, we are excited about the potential of PTC and 92, three and the clinically differentiated therapy to address this high unmet medical need.

We will start a registrational trial evaluating and PTC not Q3 for truly PKU called the affinity mid this year.

Last year, we achieved many important milestones.

We anticipate and exciting year and 2021 that will continue to create substantial value for all our stakeholders I'll now turn the call over to Matt for key updates on our clinical program.

Matt: The Tiquinone, the first compound being developed from the BioE platform, targets the oxidoreductase-15 lipoxygenase, which is a key regulator of inflammation and oxidative stress pathways and has been implicated in a number of CNS diseases. As Stu mentioned, we have initiated two vatiquinone registrational trials in mitochondrial epilepsy and Friedrich's attack. As a reminder, the Tiquanon has extensive safety features.

Matt.

Thanks, Dave and I want to build on and Stew's comments on our development team's achievements in 2020.

And we have worked hard at PTC to navigate and many challenges and the past year and are excited to continue to deliver on planned development milestones across our multiple platforms.

I'd like to start with our bio <unk>.

This platform focuses on the needs of oxidative stress by targeting a special class of enzymes called oxidoreductase oxidoreductase, as our family of enzymes that perform and important electron transfer reactions and are known to have important biological function.

Matt: Particularly in pediatric patients with the longest duration of exposure being over 10 years. For the first indication of mitochondrial epilepsy, previous clinical studies demonstrated that tiquinone had a positive effect on seizures and seizure-related morbidity across multiple mitochondrial disease subtypes. These results give us confidence that tiquinone has the potential to show clinically differentiated improvement for mitochondrial epilepsy patients. The ongoing Mitochondrial Epilepsy Trial, the MITEI trial, is a randomized placebo-controlled study enrolling 60 children at centers worldwide. The primary endpoint of the study is reduction in observed motor seizures, with secondary endpoints capturing other aspects of seizure activity and seizure-related morbidity.

Particularly now and the first compound being developed for the bio E platform targets, the oxygen and Dr. T 15 lipoxygenase.

And I pathogen is the key regularly from Inc.

Formation and hot for data stress pathways and has been implicated and a number of CNS diseases.

You mentioned, we have initiated two particularly non registrational trials and mitochondrial epilepsy and free joke ataxia as a reminder, particularly non has extensive safety data, particularly.

And pediatric patients with the longest duration of exposure being over 10 years.

For the first indication mitochondrial epilepsy previous clinical studies demonstrated particularly now and had a positive effect on seizures and seizure related morbidity and across multiple mitochondrial disease subtypes.

Matt: Enrollment is underway, and data is expected in the third quarter of next year. We are very excited to bring this therapy to children with mitochondrial disease. The second ticrinone registrational trial is in Friedrich ataxia, which is a rare inherited progressive neuromuscular disease that affects the nervous system and heart. In a previous Phase 2 trial, Tiquinone treatment demonstrated significant improvements in disease severity compared to a matched natural history cohort over 24 months.

These results give us confidence that particularly now and has the potential to show clinically differentiated improved from minus conjugal epilepsy patients.

Ongoing mitochondrial epilepsy trial for 90 trial.

And as a randomized placebo controlled study enrolling 60 children at centers worldwide.

The primary endpoints for the study and some reduction and observed motor seizures with secondary endpoints, capturing other aspects of seizure activity and seizure related morbidity and enrolled.

Enrollment is underway and data are expected and the third quarter of next year.

And we're very excited to bring this therapy to children with mitochondrial disease.

Matt: These results support that tiquinone can deliver a meaningful effect in Friedrich ataxia patients. The Phase 3 FA Trial, MOVE-FA, is a 72-week, randomized, placebo-controlled study. The primary endpoint of the trial is change from baseline in the Modified Friedrich-Cataxier Rating Scale, or MFARs. The key secondary endpoint is the change from baseline in activities of daily living as assessed by the FA-

The second particular, non Registrational trial isn't Friedrich and taxi, which is a rare inherited progressive neuromuscular disease that affects the nervous system and heart.

And a previous phase two trial, particularly non treatment demonstrated a significant improvement and disease severity compared to matched natural history cohort over 24 months.

These results support that particularly non can deliver a meaningful effect to free joke ataxia and patients.

The phase III trial move that day, it's a 72 week randomized placebo controlled study and <unk>.

Primary endpoint for the trial is change from baseline and the modified <unk> ataxia rating scale and cars. The key secondary endpoint is the change from baseline and activities of daily living as assessed by the FAA ADL scale.

Matt: This endpoint strategy was developed in consultation with regulatory authorities in the U.S. and EU. We began trial enrollment in the fourth quarter of last year, and we anticipate results in 2020. Now, let me turn to our PTC 518 Clinic Tumor Disease Program. PTC 518 is an orally bioavailable small molecule developed from our splicing platform that was designed specifically to treat Huntington's disease.

This endpoint strategy was developed in consultation with regulatory authorities in the U S and E U.

Began trial enrollment and fourth quarter of last year, and we anticipate results in 2023.

Now, let me turn to our PTC $5 eight and Disney's approach.

PTC five one is an orally bio available small molecule developed from our splicing platform that was designed specifically to treat Huntington disease given.

Matt: Given the need to effectively target every region of the brain, the molecule is designed to cross the blood-brain barrier and avoid efflux, a significant advantage for treating neurodegenerative disorders. The Phase 1 Healthy Volunteer Trial is underway and includes both single ascending and multiple ascending dose registrations. As a reminder, this Healthy Volunteer Trial is designed to not only capture key safety and pharmacology data typical of a Phase I study but also establish proof-of-splicing mechanisms and guide dose selection for future studies.

Given the need to effectively target every region of the brain. The molecule is designed to cross the blood brain barrier and avoid equinox, a significant advantage for treating <unk> disease.

And the phase one healthy volunteer trial is underway and includes both single ascending and multiple ascending dose regimens. As a reminder, this healthy volunteer trial is designed to not fully captured key safety and pharmacology data typically the phase one study, but to also establish proof of splicing mechanism and guide dose selection.

For future studies.

The study includes five dosing cohorts, each with pick back and two placebo subjects.

Matt: The SED study includes five dosing cohorts, each with six active and two placebo. The MAD study is expected to have three to five cohorts, each with six active and two placebo. In the phase one study, we are monitoring drug concentrations in both the CSF and blood and will be measuring levels of HTT mRNA and protein in the cells of the blood. This ability to gain key proof-of-splicing mechanism data is similar to what we were able to accomplish in the RISD Plan Phase 1 Healthy Volunteer Study.

Study and expecting to have three to five cohorts each with six active and placebo subjects in.

And the phase one study, we are monitoring drug concentration and both the CSF and blood and we'll be measuring levels of http mrna and protein and the sales of the blood.

This ability to gain key proof of splicing mechanism data is similar to what we were able to accomplish and there is a planned phase one healthy volunteer studies.

The data from the PTC 508, F&B and there may be studies are expected and the first half of this year.

Matt: Data from the PTC 518 SAD and MAD studies are expected in the first half of this year. Now turning to our gene therapy platform, we remain on schedule for the CHMP opinion on the PTC AADC MAM and for the BLA submission to the FDA in the second quarter of this year. In addition, we are continuing to progress our FA gene therapy program and expect first-in-human dosing before year-end. Turning to our PPC-299-FITE-19 clinical trial, we recently announced that enrollment in the first stage of the study was completed. As planned, the DSMB reviewed the interim safety data and unanimously recommended continuing with the second stage of the study.

Now turning to our gene therapy platform, we remain on schedule for the <unk> and key opinion on the PTC ADC MH and for the BLA submission to the FDA and the second quarter of this year.

In addition, we are continuing to progress our <unk> gene therapy program and expect first in human dosing before year end.

Turning to our PTC to 99 519 clinical trial, we recently announced that enrollment of the first stage and the study was complete.

As planned the day SMB and review the interim safety data and unanimously recommended continuing with the second stage and expense.

We have already initiated enrollment in the second stage and data are expected in the second half for 2021.

Eric Pauwels: We have already initiated enrollment in the second stage, and data are expected in the second half of 2021. In 2021, we look forward to advancing additional programs to modify. We are on schedule to initiate the Affinity Phase III trial for PTC923 in patients with PKU in mid-2021, with data expected by the end of 2022. As Stu mentioned, despite existing therapies, PKU remains a high unmet medical need. To summarize, we look forward to building on the successful execution of our clinical development programs in 2021 and sharing important updates when these programs become available. I'll now turn the call over to Eric to provide more detail on our commercial. Thanks Matt.

And 2021, and we look forward to advancing additional programs from our pipeline.

We are on schedule to initiate the affinity phase III trial for PTC 93, and patients with PKU and mid 2021 with data expected by the end of 2022.

As Stuart mentioned, despite existing therapies PKU remains a high unmet medical need.

To summarize we look forward to building on the successful execution of our clinical development programs and 2021 and sharing important updates from these programs one of Vail.

I'll now turn the call to Eric to provide more detail on our commercial business.

Yeah.

Thanks, Matt.

We're very excited with the progress of our late stage clinical pipeline, which is poised to potentially deliver multiple innovative neurology therapies that we can leverage with our global commercial footprint and existing expertise and rare diseases.

Eric Pauwels: We are very excited with the progress of our late-stage clinical pipeline, which is poised to potentially deliver multiple innovative neurology therapies that we can leverage with our global commercial footprint and existing expertise in rare diseases. As Stu highlighted, the DMV franchise had strong growth in 2020, with both Inflaza and Translarna generating significant revenue. Despite the challenges of the pandemic, we continue to see year-over-year growth in the DMD franchise. For TransLorna, the only treatment for non-sense mutation D&D patients ages 2 and older, we saw revenues of $192 million in 2020.

As Stuart highlighted the DMD franchise had strong growth in 2020 with both in Florida and trends Lauder generating significant revenue.

Despite the challenges of the pandemic, we continue to see year over year growth of the DMD franchise.

For trend, Florida.

Only treatment for nonsense mutation DMD patients ages, two and older. We saw revenues of $192 million in 2020.

The growth was due to the ongoing expansion of the patient stays high.

Eric Pauwels: The growth was due to the ongoing expansion of the patient-based, High Compliance, as well as recent label updates allowing broader access and continued geographic expansion. With the recent approval of Tranquana in Russia in Q4 2020, we are excited to bring this therapy to non-sense mutation DMD patients and expand the use of TransLana globally, which is now available in over 50 countries. In Latin America, we continue to see good progress. As a reminder, last October, we entered into a purchase agreement with Brazil's Ministry of Health to supply Translana for both new and existing patients. This order was important given the governmental administrative delays in Brazil, which was hit exceptionally hard by the pandemic.

Hi compliance.

Recent label update allow us broader access and continued geographic expansion.

With the recent approval of Translarna in Russia, and Q4 2020.

We are excited to bring this therapy to nonsense mutation DMD patients and.

And expand the use of transplanted globally, which is now available and over 50 countries.

In Latin America, we continued to see good progress as a reminder, last October we entered into a purchase agreement with Brazil's Ministry of health to supply trends water for both new and existing patients.

This order was important given the governmental administrative delays in Brazil.

Separately hard by the pandemic.

The agreement specified to shipments.

Eric Pauwels: The agreement specified to ship, We are excited to announce that both shipments were received by Brazil's Ministry of Health last year, including the last shipment in Q4 2020 to ensure continuity of the growing base of Brazilian nonsense mutation DMD patients. We continue to see further growth coming from new patients in the region and expect the next Brazilian order in the second half of this year. Now moving on to Implaza, which is the first and only corticosteroid approved for all DMD patients ages 2 and older.

We were excited to announce that both shipments were received by Brazil's Ministry of health last year and.

Including the last shipment in Q4 2020 to ensure continuity of the growing base of Brazilian nonsense mutation DMD patients.

We continue to see further growth coming from new patients and the region and expect the next Brazil order and the second half of this year.

Now moving onto <unk>, which is the first and only corticosteroid approved for all DMD patients ages, two and older.

We saw revenues of $139 million, and 2020, which is a 38% year over year growth.

Eric Pauwels: We saw revenues of $139 million in 2020, which is a 38% year-over-year growth, driven primarily from New Patient Starts. A reduction in bridge and PAP free of charge programs, and increased compliance and lower treatment discontinuation. Importantly, we continue to see This is a strong new prescription growth into 2021, supported by publications of Emplaza's real-world clinical benefit over prednisone, which is now driving patients to seek switching treatment from their health care provider.

Driven primarily from new patient starts.

Reduction and bridge and Pap free of charge programs.

And increase in compliance and lower treatment discontinuation.

Importantly, we continue to see strong new prescription growth into 2021 supported by publications of and Plaza its real world clinical benefit over prednisone, which is now driving patients to seek switching treatment from.

From their health care providers.

We expect the DMD global franchise growth to continue in 2021 with geographic expansion for Trans Martin.

Eric Pauwels: We expect the DMD global franchise growth to continue in 2021 with geographic expansion for Transmarna and new patients for both in PLAZA and TRANSLARM. Based on this, our revenue guidance for the DMD franchise for 2021 is $355 million to $375 million.

And new patients for both and Plaza and transform.

Based on this our revenue guidance for the DMD franchise for 2021 is $355 billion to $375 million.

Eric Pauwels: Now, switching to TxETI and Way Libre, we continue discussions with CMED for pricing of TxETI in Brazil. During this process, we continue to provide medical education, genetic testing, and patient program support as needed. For both TxEDI and WeLibro, we continue to engage in patient finding in Latin America with ongoing success in these programs. We also continue to engage in early access programs in the region as we await a decision on the way LIVRA and visa filing in Brazil, which is expected in Q3 2021. Now, moving on to AAVC.

Yeah.

Now switching to tech studying weighted and growth we continue discussions with seabed for pricing uptake steady in Brazil. During this process. We will continue to provide medical education genetic testing and patient program support as needed.

For both tech steady and weighted Libra, we continue to engage in patient finding more and Latin America with ongoing success and these programs.

We also continue to engage and early access programs and the region as we await a decision on the way Libre and visa filing and Brazil, which is expected in Q3 2021.

Now moving onto a day.

Eric Pauwels: PTC Therapeutics Inc

PTC a D. C is a transformative gene therapy that has the potential to produce meaningful changes and ADC patients.

Eric Pauwels: AADC is a transformative gene therapy that has the potential to produce meaningful changes in AADC patients. As a reminder, AADC deficiency is a highly morbid and fatal pediatric neurological disorder. There are currently no approved disease-modifying therapies available. In clinical trials, PTC AADC gene therapy demonstrated significant and durable neurological and neuromuscular improvement shown to continue for up to 10 years after treatment. PTC is currently preparing for our first gene therapy launch for patients with AADC deficiency.

As a reminder, ADC deficiency is a highly morbid and fatal pediatric neurological disorder.

There are currently no approved disease modifying therapies available.

And clinical trials PTC ADC gene therapy demonstrated significant and durable neurological and neuromuscular improvement shown to continue for up to 10 years after treatment.

PTC is currently preparing for our first gene therapy launch for patients with ADC deficiency, which is expected to occur in Europe. During the second half of 2021.

Eric Pauwels: This is expected to occur in Europe during the second half of 2021. As part of these efforts, identification and preparation of expert pediatric neurological centers of excellence are underway throughout the U.S., Europe, and Latin America. Patient finding activities are also accelerating, with over 60 screening programs in over 20 countries to identify 300 patients by the time of launch. I continue to take pride in our global customer-facing teams as they ensure continuity of access to PTC products for rare disease patients in need.

As part of these efforts identification and preparation of expert pediatric neurological centers of excellence is underway throughout the U S Europe and Latin America.

Patient finding activities are also accelerating with over 60 screening programs and over 20 countries to identify 300 patients by the time of launch.

I continue to take pride in our global customer facing teams as they ensure continuity of access to PTC products for rare disease patients in need.

We continue to expand our commercial expertise with the upcoming launch for ADC deficiency, and neurology and build on our success and translating groundbreaking science to transform the lives of rare disease patients worldwide.

Eric Pauwels: We continue to expand our commercial expertise with the upcoming launch for AADC deficiency in neurology and build on our success in translating groundbreaking science to transform the lives of rare disease patients worldwide. Now, I'll turn the call over to Emily for a financial update.

Now, let me turn the call over to Emily for a financial update.

Thanks, Eric and 2020, PTC saw strong continued revenue growth and progress across multiple platforms of our pipeline.

Emily Luisa Hill: Thanks, Eric. In 2020, PTC saw strong continued revenue growth and progress across multiple platforms. We are executing on a number of fronts to deliver on many potentially value-creating milestones this year. The press release issued earlier this afternoon summarizes the details of our fourth quarter and year-end 2020 financial results. I will take a few minutes now to review these financial results and our 2021 guidance. Please refer to the press release for additional details. Starting with our top-line results, we reported $380.8 million in total revenue for the full year 2020, compared to $307 million for the full year 2019. This increase was driven primarily by three factors.

We are executing on a number of France to deliver on many potentially value creating milestones this year.

The press in the press release issued earlier this afternoon summarizes the details of our fourth quarter and year end 2020 financial results.

I will take a few minutes now to review the financial results and our 2021 guidance. Please.

Please refer to the press release for additional details.

Starting with our top line results, we reported $388 million and total revenue for the full year 2020, compared to 307 million for the full year 2019. This.

This increase was driven primarily by three factors and <unk>.

Plaza growth due to both new patient starts and high compliance trends, Lauren and driven by broader access geographic expansion and label updates as well as that resonate and driven by royalties and milestones associated with the U S approval and launch.

Emily Luisa Hill: MFLAZA growth due to both new patient starts and high compliance, TransLarna growth due to broader access, geographic expansion, and label updates, as well as EVRISD growth due to royalties and milestones associated with the U.S. approval and launch. However, revenue growth was due primarily to our global DMD franchise. TransLarna Net Product Revenues were $191.9 million for the year, compared to $190 million for the full year of 2019. Forum Plaza reported net product revenues of approximately $139 million for the full year of 2020, which compares to $101 million from the prior year.

Revenue growth was due primarily to our global DMD franchise.

Chancellor and on net product revenues were $191 9 million for the year compared to $190 million for the full year 2019.

For Plaza, we reported net product revenues of approximately $139 million for the full year 2020, which compares to 101 million from the prior year, Mr represents a 38% and year over year for us.

Emily Luisa Hill: This represents a 38% year-over-year growth. The total DMD franchise net product revenue was $331 million for 2020. Our 2021 DMD Franchise Revenue Guidance is between $355 and $375 million, and this guidance does not reflect any other anticipated revenue contribution.

Total DMD franchise net product revenue was $331 million for 2020.

Our 2021, DMD franchise revenue guidance of between 355 and $375 million and this guidance does not reflect any other anticipated revenue contribution.

The royalty purchase agreement with RPI has allowed PTC to diversify its market risk of having a future royalty stream currently tied to one product by transforming its potential future cash flows into a $615 million cash asset.

Emily Luisa Hill: The Royalty Purchase Agreement with RPI has allowed PTC to diversify its market risk of having a future royalty stream currently tied to one product by transforming its potential future cash flows into a $650 million cash asset. This has created real value for PTC's financial position, as the cash is being invested to support PTC's research and development platforms and patient care initiatives. Additionally, by retaining the majority interest in the future royalties due from Rose.

This has created real value for PTC financial position as the cash is being invested to support PTC as research and development platforms and patient care initiatives.

Additionally, by retaining the majority interest in the future royalty due from Roche tapping the potential paths RPI at one 3 billion to retain future upsides and the rights to receive the remaining potential regulatory and sales milestone.

Emily Luisa Hill: Tapping the potential payout to RPI of $1.3 billion to retain future upside and the rights to receive the remaining potential regulatory and sales milestones, PTC has retained its ability to receive consistent cash flows in future periods.

PTC has retained its ability to receive consistent cash flows and future periods.

We recognized $42 6 million and collaboration revenue in 2020 and increase of $26 9 million from the prior year the.

Emily Luisa Hill: We recognized $42.6 million in collaboration revenue in 2020, an increase of $26.9 million from the prior year. The increase is primarily related to three regulatory milestones that were triggered from Roche in 2020. We also recognized $4.8 million in royalty revenue in 2020 due to the FDA approvals of RISD in August, as we are entitled to royalties on worldwide annual net sales. Non-GAAP R&D expenses were $438.9 million for the full year 2020, excluding $38.7 million in non-cash, stock-based compensation expenses.

The increase was primarily related to three regulatory milestones that were triggered from Roche and 2020.

We also recognized $4 8 million and royalty revenue and 2020 due to the FDA approval of Brinci and August because we are entitled to royalties on worldwide annual net sales.

Non-GAAP R&D expenses for $438 9 million for the full year 2020, excluding $38 7 million and noncash stock based compensation expense.

Emily Luisa Hill: Compared to $236.6 million for the full year 2019, excluding $20.8 million in non-cash stock-based compensation expenses. This increase in R&D expenditures reflects costs associated with advancing the gene therapy, splicing, and BioE platform as well as increased investment in research programs and the advancement of the clinical pipeline.

Impaired to $236 6 million for the full year 2019, excluding $20 8 million and noncash stock based compensation expense.

The increase in R&D expenditures reflects costs associated with advancing the gene therapy splicing and <unk> platforms.

Increased investment and research programs and the advancement of our clinical pipeline.

Additionally, the increase in R&D expenses includes onetime charges of $53 6 million related to the acquisition of sensor pharmaceuticals.

Emily Luisa Hill: Additionally, the increase in R&D expenses includes one-time charges of $53.6 million related to the acquisition of Sensa Pharmaceuticals and $41.4 million related to the MassBio agreement for commercial manufacturing of our lead gene therapy program in AADC deficiencies. Non-GAAP SG&A expenses were $213.6 million for the full year 2020, excluding $31.6 million in non-cash stock-based compensation, compared to $181.2 million for the full year 2019, We anticipate non-GAAP R&D and SG&A expenses for the full year 2021 to be between $725 and $755 million, excluding approximately $100 million in estimated non-cash, stock-based compensation expense. Cash, cash equivalents, and marketable securities totaled $1.1 billion as of December 31, 2020, compared to $686.6 million as of December 31, 2019.

And $41 4 million related to the mass bio agreement for commercial manufacturing of our lead gene therapy program and ADC deficiency.

Non-GAAP SG&A expenses for $213 6 million for the full year 2020, excluding $31 6 million and noncash stock based compensation expense.

Compared to $181 2 million for the full year 2019, excluding $21 3 million and noncash stock based compensation expense.

We anticipate non-GAAP R&D and SG&A expenses for the full year 2021 to be between 725 and $755 million, excluding approximately $100 million and estimated noncash stock based compensation expense.

Cash cash equivalents and marketable securities totaled $1 1 billion as of December 31, 2020.

Compared to $686 6 million as of December 31, 2019.

I'll now hand, the call over to the operator to start our question and answer session.

Unknown Executive: I'll now hand the call over to the operator to start our question and answer session. Operator. Thank you. As a reminder, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Eric Joseph with J.P. Morgan. Your line is now open.

Operator.

Thank you as a reminder to ask a question you will need to press star one on your telephone.

For the dry your question press the pound key please standby, while we compile the Q&A roster.

Our first question comes from Eric Joseph with Jpmorgan. Your line is now open.

Yes, good evening, thanks for taking my questions.

Eric William Joseph: Good evening. Thanks for taking my questions. Just a couple from me.

Just a couple from me first with PTC PTC ADC, assuming positive phe HMT decision.

Unknown Executive: First, with PTC ADC, assuming a positive CHMP decision. Perhaps you could just sort of walk us through the initial launch strategy in Europe. And of the 200 patients that you're anticipating to identify at launch, what countries, excuse me, I guess, how should we be thinking about this?

Perhaps you could just sort of walk us through the initial launch strategy in Europe.

And of the 200 patients that anticipating two identified and watch what countries excuse me.

And I guess, how should we be thinking about that.

Yeah.

Yes.

Unknown Executive: You know, they're about their regional distribution, what proportion are in Europe? and then, And then also, I guess, in just thinking about the risk and just thinking about the age.

Good.

Hello.

The regional distribution.

A proportion or in Europe.

And.

And then.

And then also I guess and just thinking about the risks and Nicole.

And just thinking about the Asia EBIT for patient.

Unknown Executive: The Universal Case Population

Population here as well.

Unknown Executive: Please talk a little bit about the risk-benefit profile as it varies by age. Um, challenges with putemic stereotactic delivery in older juveniles compared to what's been sort of described today in infants. Thanks.

Talk a little bit with the rest of the risk benefit profile as it varies by age is there any.

Challenges with.

For your teammates and stereotactic delivery and all the Google now compared to what's been sort of described today and.

Thanks.

Yeah, Thanks, Eric and.

Unknown Executive: Yes, thanks, Eric. And thanks for the call. Maybe I'll start and then I'll turn it over to Eric, who can talk to you more about the commercial planning.

And.

Thanks for the.

Call, maybe I'll start and then I'll Oh.

Ill turn it over to Eric talk to more about the for.

And commercial planning and so I thought I'd start off per se just to remind everyone.

Unknown Executive: So I thought I'd start just by saying, just to remind everyone that the AADC treatment that we have for gene therapy, actually, we think is really a transformative gene therapy that really can make very meaningful differences in the lives of patients with AADC deficiencies. And that is, it just reminds us of an ultra or highly more of Fetal Pediatric Disorder. And, you know, much like when you think about SMA in the severe form of these patients,

And that the agency treatments.

The other.

And that we have for gene therapy actually and we think it's really a transformative gene therapy.

And that really can.

Very meaningful.

Differences and the lives of patients with any consistency.

Efficiencies and that is.

Just a reminder for ultra orphan highly more for them.

Pedro pediatric disorder and.

Much like when you think about SMA.

And the severe form of the patients.

Yes.

Really our developmental and arrested and are unable to hold their head up rollover, Sam and <unk>.

Unknown Executive: They really are developmentally arrested and aren't able to hold their heads up, roll over, sit, stand, and move, and they can die within a few years of life. There's really no approved therapies, and nothing really for disease-modifying therapies that's available for them. And I think in the clinical trials, we showed that it was really transformative... We saw some really remarkable changes in these patients where patients that were developmentally arrested like this all improved, and we had patients that went from not being able to move to being capable of rolling, sitting, standing, and walking.

And they are there.

And can value from them to yourself why there's really no.

Approved.

Therapies, and nothing really for disease modifying therapy, and that's available for them and I think and the clinical trials.

And we showed that there was really transformative.

Changes in these patients where patients are problems that were developed mentally and arrest is like this.

And they all improved and we have patients that went from not being able to move to be capable of.

Rolling and sitting there being unlocked and so we saw substantial progression.

Unknown Executive: So we saw substantial progression as a consequence of this, with really highly transformative results. Clinical data for five years. Five years showing improvement, up to 10 years from which we continue to follow them, and we saw this in all pediatric age groups that we measured, including older children and adolescents. So we saw a very nice benefit as a consequence. We didn't see anything from the standpoint of surgeries, but challenges related as a consequence to the surgeries.

As a consequence of this so really highly.

Transformative resolve clinics.

Clinical data for five years.

Five five years showing improvement after 10 years.

We continue to follow them and when we saw this and all pediatric age groups that we met and sort of including older children and adolescents.

And we saw very nice benefit and as a consequence over.

We didn't see any really.

And then from the standpoint, and the surgery and so.

Challenges related.

For the surgeries.

Unknown Executive: So we think it's a highly valuable product, we believe because we think it's one of the best packages. [inaudible] is really powerful. And so what we've been working on in terms of the launch is obviously getting ready to identify, get ready and identify patients, get centers of excellence. And so, Eric, why don't you talk through a bit about the potential launch and what we're doing to launch that.

That constitutes a highly valuable product we believe so.

We think that's one of the best practices.

Clinical packages because their ability.

And the ability to see a biomarker.

Changes in.

Dopamine levels to continue to see.

And so I think thats actually was really.

Yes.

Is really powerful and so what we've been working on in terms of the losses, obviously are getting ready to identify and getting ready and tender.

And patients getting centers of excellence and so.

Eric once you've talked through a bit about.

A bit about the potential launch and what we're doing from watching that.

Yeah sure Eric Thanks for the question there.

Eric Pauwels: Yeah, sure. Eric, thanks for the question there. You know, first of all, most importantly, we have a number of key activities that Stu outlined in preparing that regional rollout. So those included an increase in disease education programs that drive genetic testing. We now have 60 screening programs in over 20 countries, the vast majority in Europe, as well as LATAM in other central and eastern Europe and other places where we know there will be access and reimbursement for gene therapy products and ultra-rare disease products.

First of all.

And most importantly, we have a number of key activities that Steve outlined and preparing debt regional Rollouts does included.

And increase in disease educational programs, who were driving genetic testing. We now have 60 screening programs now and over 20 countries, the vast majority and Europe as well as Latam.

And other Central Park, Central and Eastern Europe, and other places, where we know there will be access and reimbursement for gene therapy products and ultra rare disease products.

And we've done a number of things in terms of global country, and specific webinars and virtual symposia and so the level of preparation and the marketplace has been extremely I would say aggressive in terms of how and where we're preparing and in terms of our patient finding activities and education.

Eric Pauwels: We've done a number of things in terms of global country and specific webinars and virtual symposiums. So the level of preparation in the marketplace has been extremely, I would say, aggressive in terms of how and where we're preparing in terms of our patient finding activities and education. And as Stu mentioned, one of the key areas as well is making sure that those sites, those centers of excellence, are prepared to not only treat patients but also follow them. And we've been doing that in many key areas.

And as Stu mentioned, what are the key areas as well is making sure that those sites the centers of excellence are prepared.

To not only the tree.

And the patients, but also follow them and we've been doing that in many of the key areas. The regional rollout is going to be specific as you would expect with first commercial launches in Germany, but we will immediately.

Eric Pauwels: The regional rollout is going to be specific, as you would expect, with the first commercial launches in Germany. But we will immediately roll out a number of early access programs and take full advantage of the mechanisms by which Europeans, as well as Latin American, and other areas of the world, will have once the final opinion and approval come from Europe. So we would anticipate Germany, of course, and then early access programs in countries like France, Italy, Spain, Northern Europe, Scandinavia, and others.

Roll out a number of early access programs and taking full advantage of the mechanisms by which European as well as Latin American and other.

Areas of the World will have once the final opinion and approval comes from Europe. So we would anticipate Germany of course, and then and then early access programs and countries like France, Italy, Spain and.

And Europe, and Scandinavia, and others, and we will take full advantage of early access programs and Latin America as well based on the European approval for <unk>.

Eric Pauwels: And we'll take full advantage of early access programs in Latin America as well, based on European approval. We're very confident at this point. And most importantly, I would say I'm excited that we've seen an acceleration of patient finding since we implemented a large number of these programs, and we're anticipating to have 300 patients addressable at the time of launch. And these will be in countries where we have access to and reimbursement for gene therapy.

Very confident at this point and were Inc.

Most importantly, I would say.

Excited that the we've seen an acceleration of patient finding since we've implemented a large number of these programs and we anticipating to have 300 patients addressable at the time of launch.

And these will be in countries, where we have access and reimbursement to gene therapy.

Great that's helpful I'll hop back and carefully.

Thank you. Our next question comes from Gena Wang with Barclays. Your line is now open.

Eric Pauwels: Great, that's helpful. I'll hop back in here, thanks.

I guess Stuart this is David on for Gena. Thank.

Thank you for taking my questions I have a few questions around the net for the operating.

Unknown Executive: Thank you. Our next question comes from Gina Wang with Barclays. Your line is now open. Hi, how are you guys doing? This is David. I'm from GINA.

I'll get into disease program and PTC for 18.

The first question, there and just around the.

The dose so can you discuss what dose levels for testing in healthy volunteers and whats the half life and dosing frequency.

Unknown Attendee: Thank you for taking my questions. I have a few questions around the unit for the

Sure.

Unknown Executive: Ambulance Disease Program, PTC 518

Yeah. So.

Thanks.

Unknown Executive: The first question is around the dose, so can you discuss what dose levels you're testing in healthy volunteers and what's the half-life and dosing frequency?

Thanks for that and just to remind everybody.

But we you know rehab PTC five one day to the Robo calls splicing to reduce and.

And then from into the RNA, so that Theres, a premature stop codon. So that it will then be.

Unknown Executive: And what's its half-life and dosing frequency?

Unknown Executive: Yeah, so, you know, thanks. Thanks for that. Just to remind everybody that we have PTC 518. The role of this is to cause splicing to induce an intron into the RNA so that there's a premature stop going on so that it will then be, it would get prematurely stopped so you don't make the protein in the RNA.

Prematurely stops so you don't make the protein and the R&D.

And as rapidly and the grade and then so that's so we've designed this as an orally bio available small molecule that crosses the blood brain barrier.

All regions of the brain and I think most importantly, well one other major characteristics and.

Unknown Executive: [inaudible] is that many things can pass the blood-brain barrier, but the brain protects itself and moves out many things that it thinks are potentially toxic to it. And so that EFLUX, so there's many pumps that do that.

It's not out of the brain and.

Just for everyone. The reason that debt so critical of a property is that many things.

Pass the blood brain barrier, but the brain protects itself and moved out.

Unknown Executive: We've made sure that PTC 518 can pass the blood barrier and stay within that, and that's a critical property. So, therefore, you know the level of what you see in the blood is what you see in the cells within the whole brain. And so what we've shown in animal models is that HTT reduction was clearly titrated based on this exposure level, so that the degree of HTT inhibition can be tightly controlled.

And things that are per ton that they think and.

Potentially talk through it and so that eplex, so theres many pumps, but do that we've made sure of that.

PTC 501 day capacity footprint and stay within that and that's a critical properly.

For that and therefore, you know the level and what you see and the blood is what you see.

Sales within the whole brain.

And so what we've shown in animal models and stuff.

T T reduction was clearly titrated based on its exposure level for that the degree of HCC.

Lowering can be tightly controlled.

And I think that really distinguishes five one day because of the and achieved uniform exposure and that the huntington lowering and all cells of the tissues annualized.

Unknown Executive: And I think that really distinguishes 518 because it achieves uniform exposure and that the Huntington lower is in all cells of the tissues analyzed and in all cells within the brain and therefore shows a near one-to-one ratio between the PTC 518 levels that are observed in brain cells. And again, all parts of the brain. And what we see in the cells of the blood is because it passes the blood Brain Barrier. And so we see the same levels in the blood and brain. So we have a very good measurement to show that's indeed the case.

And then all cells within the brain and therefore it shows the near one to one ratio between the PTC <unk> levels that are observed and brain cells.

And all parts of the brain and what we see and and.

And the sales of the blood and that's because of the plane.

Blood brain barrier.

And so we see the same levels and blood and brain. So we have a very good and measurement for show that's indeed the case.

Unknown Executive: So when we think about the trials that we did, it was based on obviously working on the levels that we saw in the mouse, rat, and non-human primate, and based on our understanding of the experience that we've seen in splicing, that what we did was obviously screened from the molecules for specificity and biodistribution. So we selected the molecule based on that, then we moved to the clinic, and the levels that we did were based on the results that we saw in the animal models, and predictions of what we would see in people. That was how we chose the levels of the drug that we would begin with.

So when we think about the trials.

Trials that we did it was based on.

And obviously working on.

The levels that we saw and the.

Mouse rats, nonhuman primate and based on our understanding of them.

And the experience that we've seen them and <unk>.

<unk>, that's the kind of what we did is obviously screen from the molecules for specificity and viral distributions, but reflected really the molecule on that and we.

We moved into the clinic and the levels that from where you've been based on the results that we saw and the animal models and predictions from what we would see and people is how we chose the.

And so.

The level the levels of drug.

We will begin with so I think that's how we business where we identify when.

Unknown Executive: So I think that's how we did this, where we identified what we think is the right dose, start low and continue to move up to be within regions that we would predict are humans and have the look for what levels were changed. David, does that help you?

And what we think is the right dose start low and continue to move up to be within regions.

We predict to see.

T lowering.

And choose it based on there. So that's how we chose the doses.

And to go into.

Humans and half.

And.

And look for what levels for change.

Unknown Executive: Yeah, that's very good.

And with that help you.

Unknown Executive: That was very helpful. And just to follow up on that, Stu, I guess, you know, the question is, what level of HTT reduction are you looking for in healthy volunteers?

Yes, that's very helpful and just a follow up on that Stuart.

And I guess the question is what level of HCP reduction are you looking for in healthy volunteers.

Unknown Executive: I hope this helps to enable you to select a dose for Huntington's Disease patients in your next trial.

Enable you to select a dose for the.

The other hunton disease patients and Youre next.

Trial.

Yeah.

Unknown Executive: Yeah So, the way we think about this is, you know, we're going to do a single ascending dose and a multiple ascending dose. And so we'll be able to know what exposure gives us a targeted number to be able to move forward on. And so, and that's the beauty, the fact that it's really, really great that we're capable of identifying, knowing what the dose is, characterizing the exposure, and then measuring the level of RNA changes in RNA over time.

So the way we think about this is we're going to do a single ascending dose and multiple bolt.

And so it will be able to know what exposure and given the <unk>.

Target and a number to be about moving forward.

And so so and that's the beauty for <unk>.

<unk> of the fact, it's really really great that we're capable of identifying.

<unk>.

Knowing what the doses characterized from the exposure and then measuring the level of.

Our and it changes and the RNA over time.

And both doing that and the single ascending dose and <unk>.

Unknown Executive: And both doing that in a single ascending dose and a multiple ascending dose, we get a very good characteristic of what the dose that gives the steady state level of reduction is. And that's actually, you know, so we connect, and I think that's one of the major advantages that we have is that we have a small molecule where we know the exposure in the blood and in the brain, and we've shown that what you see in the blood is equal to what you see in the brain, and we've seen that across all of the animals, including non-human primates. So we're very comfortable knowing that.

Multiple ascending dose we've got a very good characteristic of what's the dose that gives a steady state level of reduction.

And that's actually you know.

So we connect and then.

And that's one of the major advantages that we have is that we have a small molecule.

We know the exposure and in and the blood and and the brain and we've shown that what you see in the blood is equal to what you see and the brand and we've seen that across all of the animals, including non human primates.

And so we're very comfortable knowing that so.

Unknown Executive: So what we're doing is, as we measure in people, we'll be measuring the levels of the drug and then the reduction of HTT RNAs in the blood. So we'll have a very good dose response level that we can type, so we can define what dose we want. So we're probably starting to think about looking at probably a 50% reduction within that. But, you know, and then we'll look for that in terms of clinical benefit.

And what we're doing this.

Measure and people will be measuring the levels, though.

Drug and then the reduction of H T R and eggs in the blood and so we'll have a very good.

And dose response level that we can prove we can tell you that we can define what dose we want and so we're probably starting to think about looking at probably a 50% reduction.

And within that.

But and so on.

And then we will look for that in terms of.

Clinical benefit and I think there is those results out there when you look at clinical data in terms of some snips that youll see and patients where if you. If you lowered 50% they have a substantial improvement in terms of nine years and greater.

Unknown Executive: I think there's results out there when you look at clinical data in terms of some SNPs that you see in patients where if you lower it 50%, they have a substantial improvement in terms of nine years greater without disease. This is demonstration. So there's pretty good clinical data that suggests that a 50% will have a benefit, but we're also

Without disease.

<unk> and so theres pretty good clinical data that.

Suggests that a 50% will have a benefit but we're also we're also have the capability.

Unknown Executive: We also have the capability that as we learn more, should we go lower or not, we can titrate that. But I think we're starting to look up when we can go lower if we think it's correct to do so. But we're starting to think about looking at the reduction by starting at looking at a 50% level. But we'll be able to identify if we can go lower and even further, what would be the Does that help you, David? Yes,

Then as we learn more if should we go lower or not we could titrate debt, but I think we're starting to look at when we can go lower free free.

We think it's correct to do so, but we're starting to think to look at the reduction.

Starting network and at a 50% level, but we'll be able to.

And if I, if we can go lower LOE.

Lowered even further what would be the dose that we couldnt will.

And we'll be able to define that dose.

Unknown Executive: Yes, absolutely. Very helpful. Thank you, Stu. I'm going to call back.

Does that help you David.

Yes, absolutely very helpful. Thank you Stuart about pullback from the queue.

Unknown Executive: Thank you. Thank you. Our next question comes from Alicia Young with Cancer. Your line is now open. Hey guys, this is Leigh-Anne Solicia.

Thank you Kim and next question comes from Alicia Young with Cantor. Your line is now open.

Hey, guys.

Typically I thought EPS and thanks.

Unknown Executive: Thanks for the update. I just wanted to, you know, follow up on the Huntington's Program, the Phase I study. Can you just give us a quick update on where you are in the trial now? And have you moved to the MET portion of the study?

Thanks for the update and.

Just wanted to follow up on and Huntington's program the phase one study.

Can you just give us a quick update on where you are and that trial now and have been able to the net portion of the study.

Unknown Executive: So you want to know, right? So as we've talked about in terms of the trial, we've obviously been doing the trial. We're looking at both the SAD, the single ascending dose, and then going into the multiple ascending dose trial. So we've obviously been doing both of those. So we're in the, you know, we said that we'd have it by within the first half of the year. So it's underway, and we've been moving forward.

Yes.

So you wanted to know right so as we've talked about.

In terms of.

But the trial, we've obviously been doing the trial, we're looking at both the sad single ascending dose and they go and so.

And a multiple ascending dose.

Charles.

We've obviously been doing.

The bulk of those so where and we said that we'd have about it within the first half of the year. So it's under why underway and that we've been moving forward and so just to remind everyone. That's right.

Unknown Executive: And so just to remind everyone, it's right here. Designed to capture, obviously, the safety and pharmacological data, and so what I said is that the single ascending dose study includes up to six cohorts, each with six patients who have active, six with active drugs, two with placebo. The MAD study is expected to have up to five cohorts, again with six, Subjects that can have the active drug while two would have placebo. And so things have been dosed and are moving forward without any issues. We're actually pretty excited about it.

Designed to capture obviously, the safety and pharmacological data.

And so what I've said and the single ascending dose study and includes up to.

Cohort.

<unk> six per.

Patients who have active six with active drug to placebo for MH.

The study is expected.

It could be up to five cohorts again with six.

Subjects that can have active drug and walk through it now for <unk>.

Placebo.

And so things have been dosed and moving forward without any issues, we're actually pretty excited about it.

Unknown Executive: And then just to remind everyone that in the phase one study, what we're monitoring is obviously the drug concentration and blood, the levels of the HCT messenger RNA and ultimately protein and blood cells. We will have one cohort that will measure PTC 5818 blood levels as well as blood levels in the CSF. Now, as a reminder, these are healthy volunteer studies, and the subjects don't have Huntington's disease. So we don't expect to have, you know, in a sense, the proteins of interest that people have talked about in the CSF.

And then just to remind everyone that and the phase one study and what we're monitoring this obviously for <unk>.

Doug concentration and the blood levels of the <unk>.

HCC messenger, RNA, and ultimately protein and blood cells.

We will have one cohort that will measure PTC five day one blood.

Blood levels as well as blood.

And those levels and the PSA.

Now as a reminder, these are healthy volunteer studies and the subjects don't have Huntington's disease. So we don't expect to have.

And the sense for proteins of interest that people have talked about and.

And.

Unknown Executive: The purpose is to do exploratory TK measurement studies in the CSF and to be able to correlate that with the blood. And then, you know, and at the end of the day, I think what you'll see is that we're going to show proof of splicing mechanisms, determine the pharmacokinetic characteristics of PTC 518, be able to define the dose, and be able to say what dose exposure levels that allow

CSF for purpose is to do exploratory teekay measurement studies done that and.

And the CSS and they'll be able to correlate that with the blood and the.

And at the end of the day I think what you'll see is that we're going to show proof of splicing mechanisms to determine the pharmacokinetic characteristics.

Characteristics for PTC, five one day be able to define the dose and to be able to say what those exposure levels that allow us to target.

And the level of HTC reduction that we're shooting for and didn't.

Unknown Executive: https://www.pptherapy.com

No if we wanted to go higher and what.

And when you would need for this and I think the results are going to be really analogous.

Unknown Executive: So these, and I think these results are going to be really analogous to what we were able to accomplish when we did the SMA trial, the RISTA plan, in the Healthy Volunteers study, which worked out really beautifully. So we're on track to share the data for PTC 518 for both the single-offending dose and the multiple-offending dose, and expect to have that within the first half of this year. And of course, we're planning to have a deep dive that will have, we will talk further with you, so you can see much of the data that the science and the data that we have in the preclinical studies ahead of that.

For what we're able to accomplish when we did the SMA trial there was the plan.

And the healthy volunteer subjects, which worked out really beautifully.

We're on track to share the data for.

For PTC five one for the both the single ascending dose and the multiple ascending dose.

And expect to have that within the first half of this year.

And of course, we're planning to have.

A deep dive event.

We'll have we will we will.

Talk further with you. So you can see most of the day does that.

And of the science and the data that we have and the preclinical studies.

Net of that.

Unknown Executive: Transcribed by https://otter.ai

No.

Right.

Okay.

Thanks for the color.

And then my second question is just on ADC, just wondering for you to file a BLA and second quarter.

Unknown Executive: Okay, thanks for the color. And then my second question is just on, you know, ADC. Just wondering what the remaining steps are for you to file a BLA in the second quarter. And, you know, and in terms of the cannular study, can you just give us an update on where you are right now?

What other remaining stats and you know.

And in terms of the Cannula study can you just give us and update it.

Where you are right now.

Sure.

Wanted to.

Remind you obviously went forward and talked a bit about it and again with fleet. This is a transformative gene therapy.

Unknown Executive: Sure. I just want to... This is a transformative gene therapy, and we've seen what it does for patients already, both in terms of durability and the 10-year post-treatment follow-up. We know about this quite well. And just to remind everyone in the EU,

And what we've seen what it does for patients already.

And the durability and the 10 year post treatment follow up Reno.

Bob.

For us quite well and just to remind everyone in the EU and its moving forward and we expect.

Unknown Executive: I'll get to each opinion in a second, but this year. Matt, do you want to talk a little bit about where we are right now?

Tim opinion and the second.

Quarter of this year.

Matt do you want to talk a little bit about where we are right now.

Matt: Yes, sure.

Yes sure for them.

Yeah. So thanks Stuart.

Matt: Thanks, Stu. As we've talked about before, one of the key gating factors for the submission of the BLA was conducting additional surgeries with the cannula we intend to use commercially. That cannula is CE marked in Europe for the delivery of gene therapy, which is why, obviously, it wasn't an issue with the MAA submission. It's been used in many gene therapies before, and it was just a matter of us getting experience demonstrating the safety of the cannula, delivering our specific gene therapy to our intended patient population.

We've talked about before one of the gating factors to gating factors for the submission and the BLA was conducting.

Additional surgeries with the cannula, we intend to use commercially and that Kenya is CE marked and Europe for the delivery of gene therapy, which is why obviously it wasn't an issue with the MAA submission.

It's been used and many gene therapies before and there was just a matter of us getting experience demonstrating the safety of the cannula and delivering our specific gene therapy to our intended patient population.

And so.

Matt: And so we've actually completed two of those surgeries already. The procedures went well. There were no complications from the surgery, and the patients recovered on schedule. And again, just as a reminder, these surgeries are to evaluate the safety of the cannula, given that we already have extensive safety and efficacy data that Stu mentioned accumulated over a number of years with the gene therapy product. We plan to conduct one additional surgery, and then once those data are collected, we'll align with the FDA and move forward with the BLA submission.

We've actually completed two of those studies two of those surgeries already.

And procedures went well and there were no complications from the surgery and recoveries on schedule and again just as a reminder, these surgeries are to evaluate the safety and battalion look given that we already have extensive safety and efficacy data that Stuart mentioned accumulated over a number of years with a gene therapy product we plan to conduct one additional surgery and then once those.

Data collected will align with the FDA and move forward with the BLA submission.

Okay, great. Thank you.

Unknown Executive: Okay, great. Thank you. Thank you, and our next question comes from Robyn Karnauskas with Truist Securities. Your line is now open. Hi, thanks, everyone, for taking our questions. This is Ninh on behalf of Robyn. Hey, so, yes, back on Huntington's, when you presented the data, are we going to get data from all the dose cohorts, or will it be whatever the trial has enrolled, and, you know, and that's what you're going to present? So maybe, possibly just a few cohorts from the SAD study. I guess just the first question around here.

Yes.

Thank you and our next question comes from Robyn <unk> mature Securities. Your line is now open.

Hi, Thanks, everyone for taking my question and this is Ben on for Robyn.

And so again and kind of Huntington's.

Presented data are we going to get data from other dose cohorts or will it be whatever they tayo as you know and rolled and.

And that's why you can present, so maybe possibly get some few cohorts from the sad study.

And the first question around there.

Unknown Executive: Yeah, so I think what we've said in the past, you know, we're going to have both. Obviously, what we have, we're on track to share the data for both the FAD and MND studies within the first half of the year. And that, you know, and what we were planning to have is a deep dive ahead of that. So if we get to that point, when we get to that point, we will have, by the end of the year, both the FAD and the MAD data on that. We'll share the dose level with you, you know, at that time.

Yes, So I think what we've said and the.

We're going to have.

Well you.

Obviously, what we have we're on track to share the data for both CSI DMM and D studies within the first half of the year.

And what we were planning to have.

The deep dive off ahead of that so if we if we get to that point and for you.

And when we get to that point and we would have by the end of the year, both the sad and Mad.

Data on that.

We'll share the dose level.

With you.

And what that time.

Unknown Executive: I see. And then, I guess, last question, where do you have an idea or sense of where the therapeutic dose may be and where that may fall in? And then, sorry, one more question as well. Yeah, I guess that one first. Any idea of where the therapeutic dose may fall within the MAD or SAD study?

I see and then I guess last question, where do you have an idea or a sense, where that therapeutic dose may be and where that may fall in and.

And then sorry, one more question as well, yeah, I guess that one for us and the ideal for what are your therapeutic dose may fall within the.

And Matt or Sad study.

Unknown Executive: Yeah, I think, you know, we're Again, we're, you know, based on the data and based on what we're, you know, what we're doing, we had a pretty good indication of what we thought that would be in terms of defining the dose. And so, you know, we've been, it's been moving forward.

Yeah, I think we're.

And again, where we are.

Based on the data and.

Based on what we are.

What we're doing we had a pretty good indication about what we thought that would be in terms of defining the dose and.

So it's.

It's been moving forward. So I think it will be and pretty good shape, we will be able to have inc.

Unknown Executive: So I think we'll be in pretty good shape when we're able to have a dose response curve in terms of measuring, you know, both the splicing and where the dose is. So we'll know, we'll be able to give you a pretty accurate prediction of what dose gives a particular exposure that leads to, in the sense of, we want to see a 30% or 50% or 70% reduction in HTT.

A dose response curve in terms of measuring.

Both the splicing and number and where for doses, we'll know we'll be able to give you a pretty accurate prediction of what.

And what dose gives a particular exposure that leads to.

That leads to and the sense of free.

And we wanted to say, a 30% or 15% or 70% reduction of H C. I think it will be and a pretty good position to be able to tell you that.

Unknown Executive: I think we'll be in a pretty good position to be able to tell you that, and then we will be able to move forward based on that. And between the SAD and MAD, we're gonna have a very good picture in terms of both safety, as well as the dose, the exposure, and the, and the, and the, and the level of junction by the, you know, and I said it was the first half, by the end of the first half of this year.

And then and to be able to move forward based on that and between the <unk> and M and we're going to have a very good picture in terms of both safety as well as the dose exposure and.

The other.

And the.

And and.

And the level of trucks and by the you know and I said.

This is the first half.

And by the first half for.

At the end of the first half of this year.

Unknown Executive: Got it, that's helpful. And then last question, regarding your comments around titration. Will you have enough? I guess enough sense to know whether there's more safety risk that would come on with going with a greater than 50% reduction. I guess, you know. How do you know there won't be any longer-term safety risk that this trial may not be able to measure should you push beyond 50%?

Got it that's helpful. And then just last question regarding on your comments around titration and I guess.

Do you have enough.

I guess enough sense to know whether there's more safety risk that would come on with going with a great and 50% reduction I guess no.

How do we know they're lumpy and your longer term safety risk.

This trial and may not be able to measure.

Would you push beyond 50%.

Yes.

Well, so I think what we're shooting for right now is around that.

Unknown Executive: Well, nothing. Well, so I think what we're shooting for right now is around My point, you know, the way I think about this is that there's plenty of data in

By.

The way I think about this as debt.

There's plenty of data in terms of the path people either won or legal or.

Unknown Executive: have either one or leave.

As a consequence for that and people are.

Unknown Executive: https://www.patreon.com

There are and those safety findings that we see of that so I don't think there is.

Unknown Executive: You know, there are no safety findings that we can see of that.

And to be a risk in terms of that in terms of going lower.

Unknown Executive: There's going to be a risk in terms of that. In terms of going lower, there isn't really a lot of data beyond that. We clearly know that it's important in early embryonic development, but there isn't a lot of data that says after that. After that, what is the limit? How low can you go? I could tell you from, as a geneticist's point of view, when you look at the level of most things, of most, you know, most things that, you know, when you say, well, how much do you normally need?

Is it really a lot of data beyond that we clearly know that it's important and Terry earley umbrella.

<unk>, but there isn't a lot of data that says after that.

After that what is the how low can you go I can tell you from other genetics point of view when you look at the level of <unk>.

Most things.

Most most things.

When you say how much do you normally need I mean, if you have.

And you have like some of the factors would be up 10% of them.

And you're pretty much normal so the question is at what level.

How far can you go and where you don't see any effect and so I think there are some ways, where we're thinking of being able to test that and animal models that have.

Unknown Executive: I mean, if you have, you know, some of the factors, if you have 10% of them, you're pretty much normal. So the question is, at what level, how far can you go where you don't see any effect? And so I think there are some ways where we're thinking of being able to test that in animal models that have human HTT, where we can actually.

And that have.

Human H T T, where we can actually use titration of our compounds for reduce it for the level of interest and we might be able to do some animal studies to be able to.

Define that and and the reason we would be able to do that with five one day with.

The human eye.

The mouse.

Is that were really capable of doing for you.

No harm exposures that continually reduce.

Levels for the three one and 50% down we could see 50% down and virtually every tissue in the body and certainly.

Unknown Executive: Use titration of our compounds to reduce them to the level of interest

And the brain.

Unknown Executive: and we might be able to do some animal studies to be able to define that. And the reason we would be able to do that with 518 in a humanized HTT mouse is that we're really capable of doing such uniform exposures that continually reduce.

<unk> the cortex strategy cerebellum, and every other tissue and sales.

And the brain. So we know that from the work we've done and.

And so we've been working with the groups for Idaho.

To be able to build a model.

And if we're able to do that we can actually and <unk>.

Unknown Executive: [inaudible] At least get some data that would suggest whether you can go lower or not. But we're obviously shooting for 50% right now, and I think that's a target that I think we'll certainly be able to achieve.

Get some data.

And that would suggest can you go low or not but we're obviously free for 50% right now and I think that that's it.

Yes.

And what assortment and vehicles.

Joel Beattie: Great, thank you so much, Sue. Thank you. Our next question comes from Joel Beattie with Citi. Your line is now open.

Great. Thank you so much sales.

Thank you. Our next question comes from Joel Beatty with Citi. Your line is now open.

Joel Beattie: Thanks for taking the questions. First, are there ways to assess, you know, using biomarkers in the clinical data for PTC 518, if you're generating uniform knockdown throughout the body, or how important is it to assess that clinically?

Hi, Thanks for taking the questions.

Are there ways to assess using biomarkers and clinical data and for PTC 501 day, if you're generating uniform knockdown throughout the body or how important is it to assess clinically.

Unknown Executive: Yeah. Yeah, I think clinically, I mean, the biomarker that we're choosing is looking at a reduction in Huntington levels within the blood, which we've done extensive analysis in both mouse, rat, and non-human primates. And we've been able to show that the reduction there goes along with the reduction that we've seen in other tissue types. So, that's going to be a pretty good biomarker. And that's in the, you know, obviously, just so everyone knows that HTT is an intracellular protein, right?

Yeah.

Yes, I think clinically.

And the Biomarkers that we're choosing us.

Looking at for reduction of Huntington level.

Within the blood.

We've done extensive analysis from both models.

Non human primates and <unk>.

Been able to show that the reduction there it goes along with the reduction that we've seen and other tissue types. So that's going to be a pretty good biomarker and thats in the.

Obviously, just so everyone knows <unk> intracellular intracellular proteins right. So we're looking when we do the analysis and we're looking directly within the cells from the blood cells are good marker for.

Unknown Executive: So, we're looking, when we do the analysis, we're looking directly within the cells, and blood cells are a good marker for the level of reduction that we've seen there, we've seen in all other tissues when we look at mouse models. So we know we'll be able to do that direct correlation based on the blood and what we see the reduction in protein and RNA levels. Does that help you, Joe?

And the level of reduction that we've seen where we've seen and all other tissues we booked.

And mouse models. So we know we'll be able to do that direct correlation based from the blood and what we see.

The reduction and protein and RNA levels.

Does that help you and Joe.

Unknown Executive: Yeah, yeah, great. And then maybe, switching gears for RISD, can you remind us what additional potential funds we may need?

Yeah, Yeah, Great and then maybe switching gears for a bursty could you remind us what additional potential sounds women.

And then what.

Unknown Executive: Any what?

Unknown Executive: Milestone Payments

Yeah.

Milestone payments.

Hello, Myles so yes sure.

Emily Luisa Hill: Oh, Miles. Oh, yeah, sure. Emily thought she wasn't going to talk today, but I'll pass this on to her.

I'm always thought she was going to talk today, but I'll give and pass at that moment.

Thank you so much thanks, Joel for the question and I appreciate it.

Emily Luisa Hill: Thank you so much. Thanks, Joel, for the question. I appreciate it. So you are correct.

So you have you are correct. We have retained all of our milestones for every day and with the.

Unknown Executive: We have retained all of our milestones for Eversy with the After the royalty monetization, and we do have about $300 million in milestones remaining largely sales-based and regulatory. The most real-term, near-term milestones upcoming are about $55 million in total potentially for 2021. $20 million would be for the first commercial sale in the EU, $10 million for the commercial sale in Japan, and then a potential $25 million sales-based milestone upon Roche hitting $500 million. Great, thank you. Thank you. Our next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is open.

After the royalty monetization and we do have about $300 million and milestones remaining largely.

And.

Regulatory the most real term near term milestones.

Upcoming are about $55 million and total potentially for 2021 $20 million would be and the first commercial sales in the EU 10 million for the commercial sales in Japan, and then potential 25 million sales based milestone upon roche hitting $500 million and sales.

Great. Thank you.

Thank you.

Thank you.

Our next question comes from the line of Brian Abrahams with RBC capital markets. Your line is open.

Hi, there. Thanks, so much for taking my questions a few on the Huntington's program.

Given what's known or not known about HGT protein turnover and the context of the timeframe and the study I was wondering how you guys are thinking about looking at mrna versus protein changes.

Brian Corey Abrahams: Hi there, Thanks so much for taking my questions.

Brian Corey Abrahams: A few on Huntington's program. Given what's known or not known about HTT protein turnover in the context of the time frame of the study, I was wondering how you guys are thinking about looking at mRNA versus protein changes. What's going to guide your decision as to whether to move into those additional two MADD cohorts versus just running three? And then, as you sort of look past the study, how do you think about how the blood-brain barrier properties in Huntington's patients might impact the overall plasma-to-CSF ratio and how you might be thinking about dose adjusting when you go into patients?

And what's kind of guide your decision as to whether to move into those additional two mad cohorts versus just running three and then as you sort of look past. This study how do you think about how the blood brain barrier properties and Huntington's patients might impact the overall plasma to CSS ratio and how you might be thinking about those suggesting when you go into patients.

Yes, Thanks, Brian.

So the.

And obviously, what we're you know when we think about that the drug concentration with the blood and the levels that won't be.

And the reduction that we'll see and the T mrna and protein within the sales were off.

Also taking the CSF that will what we anticipate that the level that we see and blood and CSF levels.

Unknown Executive: Yeah, thanks, Brian. So the answer is the. You know, obviously what we're talking about when we think about... The other thing I want to point out is that the drug concentration within blood and the levels that will be in the reduction that will be in the HTM RNA and protein within the cells. You know, we're also taking the CSF that will, what we anticipate is the level that we see in blood, and the CSF level would be equal, and that's similar to what we've done in non-human primates.

And would be equal and that's similar to what we've done.

And non human primates. So we think that's going to be.

That's going to be very telling to us and so we will be able to.

Just confirm the ratio of debt where it.

So I think that's good at least will have a potential for <unk>.

And that's what's going on.

Help us in terms of.

To fine tune the findings and what the exposure is in terms of <unk> and what that would be and so that's the way one could look at that and sort of and make sure that you see that the correct level and that could be done elsewhere as well, but I think that's a really important way for us to be able to be sure in terms of the PK.

Unknown Executive: So we think that's going to be very telling to us. And so we'll be able to, you know, just confirm the ratio that we've seen previously. So I think that's good. At least we'll, you know, have the potential to see that. So that's what's going to help us in terms of defining what the exposure is in terms of and what that would be. And so that's the way one could look at that in terms of the make.

And then creating the PK to reduction of R&D and appropriate and you bring up actually a pretty good point in terms of you know.

When you think about RNA and protein and a lot depends on the half life of the protein and the RNA and so we'll be able to get a pretty good handle on that.

Unknown Executive: Thank you. Thank you.

Unknown Executive: Unknown Speaker I think that's a really important way for us to be able to be sure in terms of the PK and then equating the PK to reduction of RNA and protein. You bring up a really good point in terms of the, you know, when you think of RNA and protein, a lot depends on the half-life of the protein and the RNA. And so we'll be able to get a pretty good handle on that in the multiple ascending dose with both the R&A level.

From a multiple ascending dose and <unk>.

Looking for what happened.

With both the RNA level and what we're obviously trying to do is to.

And the multiple ascending dose as the reach steady state and then there'll be able to monitor.

The HD RNA and proteins and so we know that.

In some ways they have.

H D has.

Leaky blood brain barrier.

I think thats, what youre, referring to so.

Unknown Executive: And what we're obviously trying to do is to, you know, in the multiple ascending doses, reach steady state and then to be able to monitor RNA and proteins. And so we know that in some ways they have a, I think that's what you're referring to. So So, you know, but so, I think that... You know, something that we'll have to take into consideration as we monitor. The PK of them is in paper form.

<unk>.

So but so.

So I think that.

Something that we will have to take.

The duration is we monitor.

Okay.

And that means and pension.

Got it and thanks, so much.

Great and then I was just might be other appointments and we don't have issues with the east block so that shouldnt.

Oh caused any sort of issues for us.

Thanks, Tim.

Okay.

Thank you.

Our next question comes from the line of this and Chin with Bernstein. Your line is open.

Thank you very much for taking the questions and congrats on all progress.

And more for you on Huntington's disease and <unk>.

Unknown Executive: Got it. Thanks so much.

And your preclinical RNA seek experiments how many other RNA splicing events for identified that are modulators by PTC, five Asa, which ones and and how much for a modulator and then the second question is.

Unknown Executive: Thank you very much. We don't have issues with eFlux, so that shouldn't... Unknown Speaker Yes, for any sort of issues with us.

Unknown Executive: Our next question comes from Alana Besson-Chin, with Byrd's name. Thank you very much for taking the questions and congratulations on all the progress. A couple more questions for you on Huntington's disease. The first is, in your pre-clinical RNA-seq experiments, how many other RNA splicing events were identified that were modulated by PTC518? Which ones and how much were they modulated? And then the second question is, thinking about the ongoing study, how many doses do the MAD-healthy volunteers get? And what's your sense of how much run-out is needed to assess the risk of off-target toxicity? Yes, so I think...

Thank you.

The ongoing study how many doses do the.

And B.

Matt and healthy volunteers, yet and whats your sense for how much and run out as needed to assess the risk of off target toxicity.

Yes, so I think.

So the.

So the.

Yeah.

Could you just say the first question one more time.

Sure sure.

The preclinical RNA seek experiment that you did how many other RNA splicing and best for identified and of our modulators and by PTC, <unk>, which ones, where they and and how much <unk> modulators.

So maybe it's worth talking a little bit.

About.

How do we optimize the compounds and general electric that flexibility.

And important point, so when we did.

Okay.

Way, we do the optimization.

Alana Besson-Chin: So there's...that's the...the...the... Could you just say the first question one more time?

And looking for and.

Selectivity.

Unknown Executive: Sure, sure. In the preclinical RNA-seq experiments that you did, how many other RNA splicing events were identified that were modulated by PTC518? Which ones were they, and how much were they modulated?

So selective and is a pretty important point for us and so we begin when we do the high throughput screening with a small molecule other.

And we screen them and the Huntington's and fibroblast for them and then we optimize those molecules for Africa.

Unknown Executive: Yeah, so maybe it's worth talking a little bit about how we optimize compounds in general. I think that's actually an important point.

Potency, which also includes selectivity and pharmaceutical properties. So we look very much so.

For the select for molecules that may started out to be less collective billed and collected as much.

Unknown Executive: So when we, you know, the way we do the optimization and look for selectivity, selectivity is a pretty important point for us. And so we begin, you know, when we do the high-throughput screening with the small molecules, we screen them in Huntington's disease, in fibroblasts for them, and then we optimize those molecules for us. In the animal motto, strong, potent, and ability, and a pretty selective HCT that alters the selectivity of the selection you know we learn a lot about the selectivity of that. And the specificity of that.

So activity as we can so at the end of the day. We found we've identified these molecules from obviously spent a lot of time to show that they really do have a favorable properties.

Safety window that we've seen and the cycle and the in the animal models strong potency.

And the ability and the print.

And the collective.

T that alters the select we learned a lot about the mechanism and the specificity of that and.

Unknown Executive: And, you know, just contrast that with, for instance, a competitor molecule that was for one molecule and then the other. I can tell you that, for instance, the specificity of our molecule versus SMA is substantially different. [inaudible] works to where we can build in selectivity in the RNAseq. I think, you know, and in the deep dive that's coming up, we'll spend some more time on the questions that you're asking, and probably we'll be discussing that more during the deep dive time.

Just contrast that with for instance for competitor molecule that worked for one molecule and then.

I can tell you that for instance.

Sufficiently Oh Oh.

Our molecule versus SMA.

And so the difference.

Selectivity, that's built in is far more selective.

For SMA and then.

For HD and SMA and that was the consequence of really spending the time to build and the selectivity within the molecule for being able to do that and that's really a consequence of both understanding the specific sequences. The differences between them understanding how you won there works for where we can.

Building, the selectivity and by RNA seat I think and in the deep dive that's coming up and we'll spend some more time on the question that you're asking.

And we'll be discussing that more during the deep dive time.

Alana Besson-Chin: I see that that's very helpful. And I guess the second question was simply how many doses did the healthy volunteers in the multiple ascending dose study get? And what's your sense for how much run-out you would need to assess the risk of off-target toxicity? If I think about splicing toxicity, how quickly would you expect those to show up? And how much run-out do you need?

That's very helpful and I guess, the second question and I will just simply how many doses do the debt.

Healthy volunteers in the and the multiple ascending dose study yet and.

What's your sense for how much run out you would need to assess the risk of off target toxicity.

And it was slightly positive how quickly would you expect those to show up and how much run out for you.

Yes.

Unknown Executive: So, you know, obviously, for the multiple ascending dose, that's a 14-day dosing period followed by 28 days of observation. And so that's, you know, what we do in terms of defining the dose. But you've got to remember also that we're also doing, completing the long-term safety toxicity studies that will help us. And, you know, I just don't, you know, I don't want anyone in the community, in the, the folks that are listening to think there's something different about splicing toxicity versus any other toxicity, whether it's off-target for splicing or any other molecule The key is, you know, we spent a lot of time looking for selectivity and specificity.

So obviously for the multiple ascending dose 14 day dosing period, followed by <unk>.

28 days of observation and.

So that's so that's what we do in terms of defining the dose but didn't make other remember also that we're all flow Julie.

Completing the long term safety toxicity studies that will help us and I just don't.

I don't want it and.

And the community and the.

To the folks that are listening that there is something different about splicing.

If there's any other taxes for me whether.

Whether it's all targets for splicing and there are other moller for.

Some other function the key and we spent a lot of time looking for selectivity and specificity and.

Unknown Executive: And, you know, and then we look at toxicity could be for off-target, and it could be for whatever the reason is. And so that's why we do those studies to look for off-target toxicity. But I don't think you can make the argument that there's something unique about these toxicities versus any other drug's toxicity. And that's why we do these experiments, safety toxicology, to be able to identify the toxicity, understand the risk, and be able to move forward.

And then we look at toxicity could be for.

The off target and that could be for.

Whatever the reason there and.

So that's why we do those studies to look for the off target.

But I don't think you can make the argument there's something unique about these texas the resources and the other drugs toxicity and Thats why we use the experiment the safety and toxicology.

And experiments to be able to identify the toxicities and understand the risk to be able to move forward and I think this is a.

A very standard and step wise approach that and the targeting of slicing and no different than doing time day soon.

Unknown Executive: [inaudible]

Unknown Executive: I see, I see. Yes, yeah, very helpful. Thank you, Verticale, and congrats again on all the progress.

For the paces.

Scripps and factors other things that other people do I wouldn't try and make it for something special here versus non per se.

Unknown Attendee: Thank you a lot. I appreciate it.

Unknown Executive: Thank you. Our next question comes from the line of Raju Prasad with William Blair. Your line is open. Hi there, this is Sami on behalf of Raju.

Alright.

Yes, yes.

Very helpful. Thank you. Thank you for the color and congrats again ill and progress.

Thanks, a lot and I appreciate it.

Thank you.

Our next question comes from the line of Raju Prasad with William Blair. Your line is open.

Unknown Executive: Thanks for taking my question. I was curious if there's any update on your Angelman syndrome gene therapy. And I believe previously you said that the Angelman program and Frederick's ataxia gene therapy programs were delayed because of COVID. I'm just wondering if that's still the case or if there's any other behind the scenes things going on?

Hi, there this is Sam and for Rajiv and thank you for taking my question and I was curious if theres any update on your.

Angelman syndrome gene therapy, and I believe previously you said that the Angelman program and <unk> ataxia gene therapy programs were delayed because of Covid and <unk>.

Just wondering if that's still the case or if theres any other behind the scenes things going on and.

Unknown Executive: And then just secondly, how are you thinking in terms of the FDA's recent guidance for gene therapies for CNS diseases? How do you think that guidance will influence those trial designs? And do you plan on using the same endpoints that will be used for the Taquinan trial for

And just secondly.

How are you thinking in terms of and the Fda's recent guidance for gene therapies for CNS.

CNS diseases.

How do you raise EBITDA guidance influencing this trial designs and.

And do you plan on using the same endpoints that will be used for a day.

The chocolate in trial for Patrick for tax yes. Thank you.

Matt: Sure. So yeah, you're right.

Sure. So you're right we've talked about this from the past.

Unknown Executive: We've talked about this in the past, and I do think one of the things that happened during the pandemic is that there are really COVID-related delays that push programs out, but we're really working hard, and we're progressing on the FH gene therapy program that affects human dosing before year-end. Similarly, we're pushing hard on the Angelman syndrome. We're moving forward with that, and we'll probably talk more about that as we get closer. So, you know, and we'll, we'll, we'll, we'll talk through it over time as we do this. And so maybe, Matt, you want to... Do you want to add any other colors?

And I do think one of the.

For one of the things that happened during the pandemic is that there are really COVID-19 related delays that pushed program about.

But we're really working hard and we're progressing on the <unk> gene therapy program and the.

Effect.

Human dose.

Before year end.

And we're pushing hard on.

The Haynesville net syndrome, I don't think we actually Gabe.

Particularly timelines on that but there has been.

Some you know.

We're moving forward on that and we'll probably talk more about that and as we get closer.

So.

And we'll we will we'll talk through overtime.

This.

And so maybe Matt you want to.

Do you want to add any other color to this.

Matt: Yeah, sure. Thanks for the questions, Tammy.

Yes sure. Thanks for the question Sami So army and I think you had some questions about our Friedrich ataxia gene therapy program and the recent FDA guidance and maybe I'll just tackle the guidance first.

Matt: So on me, I think you had some questions about our Fregio Pataxio gene therapy program and the recent FDA guidance. Maybe I'll just tackle the guidance first. You know, quite frankly, not a lot of surprises there.

Quite frankly, not a lot of surprises there and it's sort of red berries standard FDA guidance and the development of therapies for Neurodegenerative diseases, and I think obviously communicating the need to have rigorous control groups even for gene therapy, and then obviously also wanted to spend a lot of time talking about the importance of device and.

Matt: It's sort of read very standard FDA guidance for the development of therapies for neurodegenerative diseases. I think that they're obviously communicating the need to have rigorous control groups, even for gene therapy. And they obviously also wanted to spend a lot of time talking about the importance of that. Right, and Device Comparability and making sure that your product works well with the device and having consistency throughout the development program. So all things that, you know, one, not really different from general guidance around CNS drug development and then specing with specifics to gene therapy, it's all things that we've learned and become quite familiar with along the way with our experience in gene therapy development. And, you know, I think the other thing that we obviously have in our programs, which is very important, is we're taking a targeted CNS approach. And one of the few benefits to that one,

And device comparability and using making sure that your product works, so and with the device and having consistency throughout the development program and so all things that.

And one.

Different from general guidance around CNS drug development, and then second with specifics for gene therapy is all things that we've learned and become quite familiar with a long long way with our experienced gauging therapy development.

Development.

And I think the other thing that we're obviously, having a program which is very important and we're taking a targeting CNS approach and one of the.

A few benefits for that one is that we're able to deliver and a gene therapy product for the specific anatomic areas, where the pathology that seems really results from so for example, and our ADC program and delivering our gene therapy products obtained and which is really key.

Dopaminergic neurons function and cage cash.

And we are delivering and gene therapy precisely to pedantic and close the sale.

Obviously, the cerebellum as a key component of taxi, which is obviously a key component of the <unk> ataxia disease, and so by doing targeted gene therapy, not only us.

Matt: Deliver the Gene-Fabric product.

Matt: Dr. Joseph Joseph, Brian Abrahams, David Lebowitz, Judah Frommer, Joseph Schwartz, David Lebowitz, Judah Frommer, Joseph Schwartz, David Lebowitz, Judah Frommer, Joseph Schwartz, Switching now to your questions regarding the phagocortaxia gene therapy program, I think we're actually incredibly excited to be able to be developing two therapies for phagocort We have our oral small molecule, Tiquinone, which has broad distribution to the CNS and other organ systems, as well as our gene therapy program, which is delivering for taxon-targeted dentate nucleus.

It allows us to have lower doses, which obviously and lowers risk and exposure.

Two two the vectors and obviously also.

Manufacturing burden.

Switching now to your question is regarding the <unk> ataxia and gene therapy program and I think we're actually incredibly excited to be able to be developing to therapies for patients and tax here, we have our oral small molecule <unk>.

<unk> has broad distribution for CNS and other organ systems as well and that was our gene therapy program, which is delivering and for cap rates targeted protecting nucleus.

Matt: I think these are really... complementary approaches. I think while phagocytopoxia has a great deal of pathology resulting from the dentate nucleus, it's also a whole brain disease and a whole body disease, as the heart, for example, is a significant source of disease morbidity and mortality risk in phagocytopoxia. So we view our approaches as incredibly complementary and are excited to be able to offer both of these therapies in a complementary way.

I think for either really.

It's.

Complementary approaches I think while I appreciate the tax here has a greenfield pathology, resulting from COVID-19 nucleus. It's also a whole brain disease and a whole body disease.

The heart for examples and Cigna.

Significant source of disease morbidity and mortality risk.

Taxes, so we view our approaches incredibly complementary and are excited to be able to offer both of these therapies and a complementary way in terms of the development itself and endpoint selection I think one of the advantages of working with <unk> ataxia.

Matt: I think one of the great advantages of working at Fugitive Catastrophe is the well-established natural history. The community is well aggregated and has a very rigorous natural history, particularly around the disease rating scale that was developed by the community, as well as the activities of daily living scale. So as we think about gene therapy, the gene therapy development program, obviously, we're looking at those where there's significant natural history so we can really appreciate the impact of gene therapy on the long-term trajectory of the disease.

Well established natural history.

And as well aggregating and has very rigorous natural history, particularly around the disease rating scale that was developed by the community as well as the activities of daily living scale. So as we think about gene therapy.

And gene therapy development program, obviously and looking to those where there is significant natural history. So we can really appreciate the impact of a gene therapy on a long term trajectory and the disease, but obviously and our first in human studies will also be exploring other end points.

Matt: But obviously, in our first-in-human studies, we'll also be exploring other endpoints that are both biomarkers, biochemical means, imaging modalities, and also other clinical endpoints that we know to be important in disease and that would certainly capture the ability of a gene therapy to have a significant effect on a disease trajectory.

Both biomarkers biochemical mediators imaging modalities and also other clinical endpoints that.

And we noted being important for disease, and I would certainly cash or the ability of a gene therapy to have significant effect on it.

And the trajectory.

Matt: Great. Thanks for the clarification.

Great. Thanks for the clarity.

Unknown Executive: Thank you. Our next question comes from the line of Danielle Brew, with Raymond James. Your line is open. Oh, hi, guys. This is...

Thank you.

Our next question comes from the line of Danielle Brill with Raymond James Your line is open.

Hi, guys. This is and you'll get the Olin on for Danielle. Thank you for taking the question.

Danielle Brew: This is Daniel Gutta-Ullin on behalf of Danielle. Thank you for taking the question. On the 518, I had a question on the 518 about how uniform the people were...

On the fly for one eight had a question on the table and they told me uniform was the HTC and reduction in animal models for a given dose and if the reduction of Hudson for the length of nuclear and hydro piece or any other factor that you could identify.

Unknown Executive: https://www.kenhub.com

Unknown Executive: And is the reduction affected by the length of nucleotide repeats or any other factors that you can think of?

Unknown Executive: Yeah, sure. Thanks for the question.

Yeah sure. Thanks for the question so actually.

Unknown Executive: So actually, that's the beauty of the fact that one thing that I think really distinguishes PTC 518 is that it really achieves uniform exposure. So when we look, for instance, for ATT lowering in these cells and tissues analyzed, we'll see if we see a 50% reduction in blood. We saw in animal models a 50% reduction within the brain, and in particular a 50% reduction in the cortex, striatum, and cerebellum. So it's amazingly uniform.

And that's the beauty.

Fact that.

One thing that I think really distinguishes <unk>.

PTC pipeline.

And really achieves uniform exposure so when we look for instance.

And for <unk> T lowering and the cells and tissues and analyzed.

We'll see if we see a 50% reduction and blood, we saw and animal models and 50% reduction.

Within the brain and in particular for 50% reduction and the cortex and incomes cerebellum. So it's amazingly.

Uniform and.

Unknown Executive: And that's good, right? That's a demonstration of really, as I said, we had a one-to-one ratio in terms of what we saw lowering in the blood within the brain. But that's true within all tissues as well. So, and that actually turns out to be, I think, very important because, you know,

That's good right.

Demonstration.

And really as I said, we had a one to one.

<unk> ratio in terms of what we saw lower and the block within the fragrance, that's true roots and all tissues as well.

And so and that actually turns out to be.

Very important because.

Unknown Executive: So I know people have talked about Huntington's disease and so on.

I know people have talked about 110 and sort of on Australia and.

Cortex, but I think when you look you see that as Huntington's disease is a whole brain disease. So it's very important to emphasize that based on a per clinical results.

Unknown Executive: I think when you look at Huntington's disease, you see that it's a whole brain disease. So it's very important to emphasize that, based on our preclinical results, we'll see a dose-dependent reduction of the HCT mRNA protein in all cells within the brain. That includes the striatum, cortex, and cerebellum. And so it gets everywhere. And then, again, I think a really critical point is that, and this is, I think, a real issue, and this was true for SNA, I think it's going to be true here as well, since we can determine that within the blood and that that same ratio that we see in the blood occurs in other tissues as well.

That will see a dose dependent reduction of the TMR RNA and protein and all cells within the brain that includes the striatum cortex, and cerebellum and so it gets everywhere.

And then again I think they're really critical point is that and the and this is I think a route and this was true for SMA I think that's going to be true here and as well as debt.

And that we have the ability to measure.

Reduction based on the exposure since we could we could determine that and whats in the blood and that same ratio that we see and the blood occurs and other tissues as well.

Alright. Thank you that's helpful, but in terms of day and like the HTC.

Unknown Executive: All right, thank you. That's helpful. But in terms of the, like, HTTG,

<unk> itself and the variation and the nucleotide repeat because and HGT.

Unknown Executive: The variation in the nucleotide repeat rate...

Kevin you effect on H and two reduction.

Unknown Executive: No, no, it doesn't.

No no it's for a given dose.

Yeah, that's that's near and that's in a different location and that's the way. This is working this.

Unknown Executive: Yeah, that's that's near that's in a different location. It's the way this is working is there's a It's within an intron of the pseudo exomes the piece of the RNA within the intron that gets that normally doesn't get spliced in but because of the molecule it does get spliced into the mRNA and that leads to Again premature termination and rapid degradation of the RNA that's not in the CAG repeat And it doesn't matter as a consequence of that so So, there is no issue with that, and therefore, and that's the beauty of this, this will be good for, you know, all patient types.

It's within and intron.

And the pseudo exon.

Piece of the RNA within the in transit and gifts.

Normally doesn't get spikes in but because of the molecule and it does get supplies and somebody Yamaha and thing and that leads to.

And again premature termination and rapid degradation and the RNA, that's not in the CNC repeat and it doesn't matter.

The consequence of that so.

So so.

There is no issue with that and therefore and Thats the beauty and because this will be good for all.

All patient types and.

Unknown Executive: And obviously, in the long run, as you can see, because Oral-E-Bi is available, the advantage here is that, over time, we would anticipate that it would be for patients, while we'll be looking initially at those that are manifesting symptoms, that you can imagine over time we would be able to do that for patients before they have symptoms because it's so easy to take. So I think that's important.

Obviously and the long run once you you can see it because it is orally by available.

The advantage here is that we would anticipate over time that it would be for patients well well well for you.

Looking at initially and those other manifest symptoms and then you can imagine over time, we would be able to do that.

And.

For patients before they have some.

Symptoms because it's so easy to take.

So I think that's important so at the end of the day. The answer to your question is that a pseudo exon and corporation occur regardless of the degree of interest you can expansion.

Unknown Executive: So, at the end of the day, the answer to your question is that pseudo exon incorporation occurs regardless of the degree of HGT expansion.

Unknown Executive: Okay, thank you very much.

Okay. Thank you very much share.

Joseph Patrick Schwartz: Thank you. Our next question comes from the line of Joseph Thome with Cohen & Company. Your line is open.

Sure.

Thank you.

Our next question comes from the line of Joseph Thome with Cowen and company. Your line is open.

Unknown Executive: Hi there, thank you for taking my question. Just one on the BioE platform. I'm curious, with PTC 8.5

Hi, there. Thank you for taking my question, just one and the bio E platform I'm curious with PTC 857 FTC. These these healthy volunteer data maybe what are you looking for and kind of when can we see that advancement into a potential GBA Parkinson's study and then as 857 and particularly on both.

Unknown Executive: 857, after you see these healthy volunteer data, maybe what are you looking for and kind of when can we see that advancement into a potential GBA Parkinson's study? And then, as 857 and vitiquinone both target 15-LO, can you kind of tell us what are the differences that make 857 maybe more amenable to the Parkinson's disease indication? Thanks.

Target 15 can.

Can you kind of tell us what other differences that make a five seven and maybe more amenable to the Parkinson's disease indications.

Unknown Executive: Yes, sure. You know, so I think part of what we're doing, it does have different properties in terms of That probably would be an advantage for something that we're taking long-term for a lot of people. Again, it's an orally bioavailable molecule, and for indications like GBA, what you said, like Parkinson's, obviously it's different, it's in a different number of patient populations versus vatiquidone and where that's going now. So we thought it would be best to have a different molecule with perhaps different properties.

Yes sure.

Part of what we're doing it does have different properties and.

In terms of debt.

And probably would be an advantage for something that we're taking a long term for a lot of people again. This is an orally bio available molecule and.

For <unk>.

Indications like GPA, but you said.

Parkinson.

Obviously, its a different its and the different.

Number of patient population versus.

And particularly on them and where that's going now so we thought it would be best to have a different molecule with perhaps different properties.

And so that's sort of the and.

Sensitive and different value for for the.

And the size of the patient population.

And so we thought it was important to have another molecule, Matt you want to talk a little bit of where we're at in terms of the <unk>.

Unknown Executive: And so that's sort of, in a sense, it has a different value for the size of the patient population. And so we thought it was important to have another molecule. Matt, would you like to talk a little bit about where we are in terms of the trial and what we're thinking about?

Trial, and what we're thinking about.

Yeah absolutely.

Joseph Thanks for the question so.

So as you mentioned, we've been studying a $5 seven and in the Phase one study, which was a single ascending and multiple ascending dose study is fairly standard and healthy volunteer studies, where and our focus has really been safety and pharmacology and we completed the dosing in those studies and were.

Unknown Executive: Yeah, absolutely. Joseph, thanks for the question.

And the process of doing the analysis and really what we're looking for here is and understanding the pharmacology and making sure that debt.

Matt: So, as you mentioned, we've been studying A57 in the phase one study, which was a single ascending and multiple ascending dose studies, fairly standard healthy volunteer studies where the focus has really been safety and pharmacology. We completed the dosing in those studies, and we're in the process of doing the analysis. And really, what we're looking for here is understanding the pharmacology, making sure that the molecule behaves in humans as we've been able to model it from the preclinical studies, and also identifying the dose level that gets us the exposures that we saw to be efficacious in all the preclinical work that we've done.

Molecules behaving and humans as we've been able to model it tend to take clinical studies and also identifying.

Most level that gets us the exposures that we saw it to be efficacious and all the preclinical work that we've done so we want to walk away from this study with the dose level that we know the space that has predictable pharmacology and would be consistent with delivering the exposure and that's necessary and achieved the.

And take clinical effects, you've seen now.

And <unk>.

A bit of background.

<unk> set a target 15, lipoxygenase, which is a key governor of a number of pathways, which independently acknowledged to be important in Parkinson's disease pathology, such as Michael glial activation offer same day and observation obligation glutathione depletion and look at base oxidative stress and so what we're able to do by talking to 15 alone is effect.

Matt: and lipid-based oxidative stress. And so, what we're able to do by targeting 15-LO is affect all four of those pathways simultaneously. And so, we do have an extensive amount of preclinical work demonstrating effects. And again, what we want to see in the Phase I study is identifying that dose level that brings us that exposure that matches up with what we've seen in the preclinical studies, and then we'd be in a position to move forward with the next stage of development.

And to say all four of those pathways and so when we do have an extensive amount of preclinical work demonstrating effective and again, what we want to see and the phase one study and identifying a dose level and that things aside exposure that matches up with what we've seen and preclinical studies and then we'd be in a position to move forward with the next stage of development.

Unknown Executive: Thanks, Matt. I think the really important point here as well is that, you know, oxidative stress, right? You know, really, extra electrons that cause oxidative stress. There are multiple diseases that we could go into.

Thanks, Matt and I.

I think the really important point here as well as debt.

No oxidative stress.

Really extra electrons and the cause of oxidative stress.

Multiples and things does that go.

Seven and so having another molecule to go into other indications with.

Unknown Executive: So having another molecule to go into other indications with different properties is going to be valuable.

And with different properties, and we think that's going to be valuable.

Great. Thank you so much.

Unknown Executive: Great, thank you so much. Thank you. I'm not showing any further questions. I will now turn the call over to Stuart Peltz for closing remarks.

Thank you.

I'm not showing any further questions I will now turn the call over to Stuart Peltz for closing remarks.

Unknown Executive: Well, thanks. Thanks a lot for joining us today. And as many of you may be aware, Rare Disease Day is coming up this Sunday, and this is oftentimes where we take stock of where we've been and where we're going as a company. And it serves as a report and reminder to us that we do this work ultimately to benefit the patients. And I hope that you see just how strong our execution has been in 2020 and how this sets us up for really for us to achieve many value-creating milestones in 2021.

Oh well thanks.

Thanks, a lot for joining us today and.

And as many of you may be aware the rare disease day is upcoming for Sunday and this is oftentimes, where we take stock of where we've been and where we're going as a company.

And it serves as a report and a reminder to us.

That we do this work ultimately the benefit for patients and.

Hope that you see just how stronger execution and.

In 2020, and how this sets up for really for us for many value creating milestones in 2021. So we're excited about the programs that we have and we look forward to.

And in particular I know everyone's been interest you can see by the question.

And the phase and the.

Phase one huntington's disease readout, and we look forward to share that with you, but within the second quarter again, and thank you for joining us.

Unknown Executive: So we're excited about the programs that we have and we look forward to, in particular, I know everyone's been interested, you can see by the questions, the interest in the phase one Huntington's disease readout, and we look forward to sharing that with you in the second quarter. Again, thank you for joining us. Have a good evening.

Good evening.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation you may now disconnect.

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Unknown Executive: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation.