Q4 2023 PTC Therapeutics Inc Earnings Call

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Okay.

Unknown Executive: Good day, and thank you for standing by. Welcome to PTC's fourth quarter 2023 financial results. At this time, all participants are in a listen only mode.

Speaker Change: Good day, and thank you for standing by welcome to the PTC fourth quarter 2023 financial results.

Speaker Change: At this time all participants are in a listen only mode.

Unknown Executive: After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear a message advising that your hand is raised. To withdraw your question, press star one one again.

Speaker Change: After the speaker's presentation, there will be a question and answer session.

Speaker Change: Ask the question during the session you will need to press Star one one on your telephone you will then hear a message a dicey your hand. This race to withdraw your question Press Star. One again. Please note that today's conference is being recorded I would now like to pass the call over to the senior director of Investor Relations Ron Aldridge.

Ron Aldridge: Please note that today's conference is being recorded. I would now like to pass the call over to the Senior Director of Investor Relations, Ron Aldridge. Good afternoon, and thank you for joining us today to discuss PTC Therapeutics' fourth quarter and full year 2023 corporate update and financial results. I'm joined today by our Chief Executive Officer, Dr. Matthew Klein, our Chief Business Officer, Eric Pauwels, our Chief Commercial Officer, Kylie O'Keefe, and our Chief Financial Officer, Pierre Gravier. Today's call will include forward-looking statements based on our 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 such statements are subject to risks that can materially and adversely affect our business and results of operations.

Ron Aldridge: Good afternoon, and thank you for joining us today to discuss PTC therapeutics fourth quarter and full year 2023, corporate update and financial results I'm joined today by our Chief Executive Officer, Dr. Matthew Klein, our Chief Business Officer, Eric Powell.

Ron Aldridge: Our chief commercial officer, Kyle Yokeag, and our Chief Financial Officer P. Eric Ravi.

Ron Aldridge: Today's call will include forward looking statements based on our current expectations.

Ron Aldridge: Let's take a moment to review the slides 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.

Ron Aldridge: Such statements are subject to risks that can materially and adversely affect our business and results of operations.

Matthew Klein: For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent annual report on 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 to non-GAAP financial measures and the reconciliation of GAAP to non-GAAP is available in today's earnings report. With that, let me pass the call over to our CEO, Matthew Klein, Matt. Thank you, Ron.

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

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

Ron Aldridge: With that let me pass the call over to our CEO Matthew Clark Matt.

Matthew Klein: Good afternoon, and thank you all for joining today's call. I'm pleased to share our fourth quarter and full year 2023 results and to provide an update on the progress of our pipeline programs as we move into what will be an exciting 2024 with a number of potential significant milestones. As we closed out 2023, we had another solid quarter of commercial performance, with total fourth-quarter revenue of $307 million and full-year 2023 revenue of $938 million, representing 34% growth over 2022. Our DMV franchise revenue totaled $143 million in the quarter and $611 million for the full year.

Matthew Klein: Thank you Ron good afternoon, and thank you all for joining today's call I'm pleased to share our fourth quarter and full year 2023 results and to provide an update on the progress of our pipeline programs as we move into what will be an exciting 2024 with a number of potential significant milestones.

Matthew Klein: As we closed out 2023, we had another solid quarter of commercial performance with total fourth quarter revenue of 370 billion and full year 2023 revenue of $938 million, representing 34% growth over 2022.

Matthew Klein: Our DMD franchise revenue totaled $143 million in the quarter and $611 million for the full year Eric.

Matthew Klein: Eric and Kylie will provide additional detail on our commercial performance shortly. Our revenue performance reflects the continued outstanding work of our global customer-facing teams and our successful efforts in geographic expansion. With this infrastructure and track record of execution, I remain confident in our team's ability to succeed with our next product launches, including Sepia tarant for the treatment of PKU. As you know, in January, we received a negative opinion from the CHMP on the continued conditional marketing authorization for TransLarna in the EU. This opinion is expected to be ratified by the EC in late March or early April.

Matthew Klein: Eric can currently will provide additional detail on our commercial performance shortly.

Eric Powell: Our revenue performance reflects the continued outstanding work of our global customer facing teams and our successful efforts in geographic expansion with this infrastructure and track record of execution I remain confident in our team's ability to succeed with our next product launches, including <unk> for the treatment of PKU.

Eric Powell: Most of you are aware in January we received a negative opinion from the <unk> and the continued conditional marketing authorization for Translarna in the EU.

Eric Powell: <unk> opinion is expected to be ratified by the EC in late March or early.

Matthew Klein: Importantly, TransLarna remains on the market until ratification occurs. In addition, we continue to commercialize TransLarna in several regions outside of the EU where independent authorizations exist. While we are, of course, disappointed in the CHMP opinion and the potential impact it has on patients in Europe, PTC is well positioned to withstand this outbreak. As I have previously emphasized, through our efforts to focus our R&D portfolio, right-size the organization, and strengthen our balance sheet, we have a solid foundation for building the company forward and continuing to deliver on our goal of discovering, developing, and commercializing transformative therapies for patients. As we look forward to 2024, we have a number of important potential regulatory and clinical milestones for a number of our programs. I will begin with our CPTAREN program for the treatment of children and adults with PKU.

Eric Powell: Importantly, trans Weiner remains on the market until ratification occurs. In addition, we continue to commercialize translarna in several regions outside of the EU, where independent authorizations exist.

Eric Powell: While we are of course disappointed in the <unk> and the potential impact it has on patients in Europe, PTC is well positioned to withstand this happen.

Eric Powell: I have previously emphasized to our efforts to focus our R&D portfolio right size, the organization and strengthen our balance sheet. We have a solid foundation for building the company's stored and continuing to deliver on our goal of discovering developing and commercializing transformative therapies for patients.

Eric Powell: As we look forward to 2024, we have a number of important potential regulatory and clinical milestones for a number of our programs.

Eric Powell: I will begin with our <unk> program for the treatment of children and adults with PKU.

Matthew Klein: We remain on schedule to submit the MAA for sepia tarin to the EMA in the first quarter of this year and to submit the NDA to the United States no later than the third quarter of this year. As we continue to collect data from the Open Label Extension Study following the Phase 3 Affinity Trial, we continue to see durability of sepia parent treatment and the ability of patients on sepiaterrin to tolerate increases in dietary protein intake beyond the recommended daily allowance. This liberalization of diet is incredibly meaningful to patients and further supports the potential of sepia tarot to fill the persistent unmet medical needs of the majority of the 58,000 PKU patients worldwide.

Eric Powell: We remain on schedule to submit the MAA for <unk> into the EMEA in the first quarter of this year.

Eric Powell: Submit the NDA in the United States No later than the third quarter of this year.

Eric Powell: As we continue to collect data from the open label extension study following the phase III affinity trial, we continue to see durability of <unk> treatment effect and the.

Eric Powell: <unk> of patients both teekay parent to tolerate increases and dietary protein intake beyond the recommended daily allowance.

Eric Powell: This liberalization diet is incredibly meaningful to patients and further supports the potential of CPA Tara to fill the persistent unmet medical needs of the majority of the 58000 PKU patients worldwide.

Matthew Klein: Moving to our Participant Owned Program for 3-year Pataxia. We had a Type C meeting with the FDA earlier this quarter. Based on discussions with FDA, we now have a path to potential NDA filing based on the placebo-controlled results of the MOVE-FA study, in combination with long-term open-label extension data currently being collected. The open-label data will be compared to a natural history population from the robust Friedrich ataxia patient registry, using analyses similar to those provided to FDA by RIATA as part of the Squy-Claris N

Eric Powell: Moving to our particularly on programs with taxes, we had a type C meeting with the FDA earlier this quarter.

Eric Powell: Based on discussions with FDA, we now have a path to potential NDA filing based on the placebo controlled results from the <unk> study in combination with long term open label extension data currently being collected the open label data will be compared to a natural history population from the robust Friedrich ataxia patient registry using analysis.

Eric Powell: Similar to those provided to FDA by Rihanna as part of its quite claret NDA.

Matthew Klein: Based on the time needed to collect sufficient long-term open-label data, we expect to be able to submit an NDA in late 2020. We are very excited about the potential of Tiquanone to fill the significant remaining unmet need for pediatric and adolescent FAA patients. In other regulatory updates, we remain on track to submit the BLA for apstaza to the FDA in March and are also scheduled to meet with FDA in March to discuss the contents of a potential NDA resubmission for TRN1. Turning to our ongoing clinical trials, we expect to share interim 12-month results from the PIVHD trial of PTT518 in HD patients in the second quarter of this year from the initial cohort of subjects on whom we The 12-month results will include additional safety and tolerability data, as well as biomarker data, including CSF Huntington protein levels, NFL levels in the blood and in the CSF, and volumetric changes on MRI.

Based on the time needed to collect sufficient long term open label data, we expect to be able to submit an NDA in late 2024.

Eric Powell: We are very excited about the potential of particular note to fill the significant remaining unmet need for pediatric and adolescent patients.

Eric Powell: In other regulatory updates we remain on track to submit the BLA, perhaps data to the FDA in March and are also scheduled to meet with FDA in March to discuss the context for the potential NDA Resubmission portrays Florida.

Eric Powell: Turning to our ongoing clinical trials, we expect to share interim 12 month results from the <unk> HD trial of PTC 508 in HD patients in the second quarter of this year from the initial cohort of subjects in whom we reported data last summer.

Eric Powell: The 12 month results will include additional safety and Tolerability data as well as biomarker data, including CSF Huntington protein level NFL levels in the blood and in the CSF and volumetric changes on MRI.

Matthew Klein: We will also be sharing data from the clinical outcome measures collected as part of the study. Finally, we expect to share top-line results from the Cardinals Registration Directed Trial of Utreloxistat and ALS patients in the fourth quarter of this year. In closing, we are well-positioned for an exciting 2024. We have the team, the capital, and the strategy that position us to execute on the many impactful opportunities that lie ahead. I will now turn the call over to Eric and Kylie to discuss our commercial performance.

Eric Powell: We will also be sharing data from the clinical outcome measures collected as part of the study.

Eric Powell: Finally, we expect to share top line results from the Cardinals registration directed trial of mutual lock the stat in ALS patients in the fourth quarter of this year.

Eric Powell: In closing we are well positioned for an exciting 2024, we have the team the capital and a strategy that positions us to execute on the many impactful opportunities that lie ahead.

Eric Powell: I will now turn the call over to Eric to discuss our commercial performance Eric.

Eric Pauwels: Thanks, Matt. Our global customer-facing team has delivered yet another strong quarter. Continuing the significant momentum we have built, we see ongoing growth from our portfolio products in more mature markets, such as the US and EU, and also new markets where we have invested in geographic expansion in Latin America, the Middle East, North Africa, and the Commonwealth of Independent States, where there has been robust year-over-year growth. In the fourth quarter, we delivered $155 million of revenue for PTC marketed products, which represents 22% growth year over year for the DMV franchise. We close out the year. With a strong fourth quarter for both TransLarna and MFLASA, delivering an impressive $143 million in net revenue, which is 25% growth compared to the fourth quarter of 2022, with a strong four-year performance of $611 million. For TransLarna, we achieved $75 million in revenue this quarter with annual sales of $356 million, which is a robust 23% growth over the same annual period last year.

Eric Powell: Thanks, Matt.

Eric Powell: Our global customer facing team has delivered yet another strong quarter.

Eric Powell: <unk> the significant momentum we have built.

We see ongoing growth from our portfolio of products and more mature markets such as the U S and EU and also new markets, where we have invested in geographic expansion in Latin America, the Middle East North Africa, and the Commonwealth of independent States.

Eric Powell: There has been a robust year over year growth.

Eric Powell: In the fourth quarter, we delivered $155 million of revenue for PTC marketed products, which represents 22% growth year over year.

Eric Powell: For the DMD franchise.

Eric Powell: We closed out the year.

Eric Powell: With a strong fourth quarter for both Trans Lauder, and <unk> Plaza, delivering an impressive $143 million in net revenue, which is 25% growth compared to the fourth quarter of 2022 with a strong full year performance of $611 million.

For Translarna, we achieved $75 million in revenue this quarter with annual sales of $356 million, which is a robust 23% growth over the same annual period last year.

Eric Pauwels: I'm very proud of the team's efforts and determination these last few months, as they have worked tirelessly to ensure that every single translarna patient in Europe continues to receive treatment until the ratification of the CHMP opinion. And we are actively evaluating local country options for ongoing Access to Treatment. Additionally, we continue to diversify our TransLarda franchise globally, as we brought this treatment to patients in seven new countries last year, as part of our ongoing expansion geographically around the world. Now, turning to IMPLOD.

Eric Powell: I'm very proud of the team's efforts and determination. These last few months as they have worked tirelessly to ensure that every single traded Florida patient in Europe continues to receive treatment until the ratification of the <unk> opinion, and we are actively evaluating local country ops.

Eric Powell: <unk>.

Eric Powell: For ongoing access to treatment.

Eric Powell: Additionally, we continue to diversify our trends, Florida franchise globally as we brought this treatment to patients in seven new countries last year as part of our ongoing expansion geographically around the world.

Eric Powell: Now turning to <unk>.

Eric Pauwels: Quarterly net revenue was $67 million, with $255 million of net revenue in 2023, which is a 17% growth over 2022. The team has implemented a multi-pronged strategy to ensure that we protect our Implaza business in anticipation of loss of exclusivity in Q1 this year. Our U.S. team continues to engage with health care professionals by providing meaningful clinical differentiation compared to prednisone and has implemented other strategies to ensure an influx of brand loyalty for new and existing patients. We continue to support DMV patients and their caregivers with outstanding service from our PTC Cares team. By enhancing the customer experience, providing easier access to treatment, facilitating co-pay assistance, and improving adherence for patients in the US. PTC is also partnering with specialty pharmacies and contracting with targeted payers to dispense the Implaza brand.

Eric Powell: Quarterly net revenue was $67 million.

Eric Powell: With $255 million of net revenue in 2023, which is a 17% growth over 2022.

The team has implemented a multi pronged strategy to ensure that we protect our implant business in anticipation of loss of exclusivity in Q1 this year.

Eric Powell: Our U S team continues to engage with health care professionals by providing meaningful clinical differentiation compared to prednisone and have implemented other strategies to ensure and plaza brand loyalty for new and existing patients.

Eric Powell: We continue to support DMD patients and their caregivers with outstanding service from our PTC Care's teams.

Eric Powell: By enhancing customer experience, providing easier access to treatment.

Eric Powell: Still attaining co pay assistance and improving adherence for patients in the U S.

Eric Powell: PTC is also partnering with our specialty pharmacies and contracting with targeted payers to dispense the plaza brands.

Kylie O'Keefe: We continue to communicate and support our exclusivity for two to five-year-old DMV patients, which continues into 2026. And we are also leveraging patient advocacy in support of the benefits and value of EMPLOD. Now, I will ask Kylie to update the progress of our current and future new product launches.

Eric Powell: We continue to communicate and support our exclusivity for two to five year old DMD patients, which continued into 2026 and we're also leveraging patient advocacy in support of the benefits and value of implausible.

Eric Powell: Now I will ask Charlie to update the progress of our current and future new product launches.

Kylie O'Keefe: Thanks, Eric. Let me begin with Upstazer, the first and only approved gene therapy infused directly into the brain, where we continue to see transformative results. In October, we presented stays of data at the CNS conference, showing cognitive improvement and continued increase in long-term motor milestones. Our rollout across Europe continues to progress with new patients treated in the quarter. Furthermore, we are continuing the global expansion of the franchise with additional regulatory filings in Asia-Pacific countries and have recently received regulatory approval in Israel, where the team is working actively to treat our first patients. Globally, patient identification, treatment center readiness, and access and reimbursement discussions continue to advance. Moving to the Texetian Way Libre in Latin America.

Eric Powell: Great.

Charlie: Thanks, Eric.

Charlie: Let me begin with the first and only approved gene therapy and feeds directly into the Brian where we continue to see transformative results.

Charlie: In October we presented updated data at the CNS conference showing cognitive improvement and continued increase in long term motor milestones.

Charlie: A rollout across Europe continues to progress with new patients treated in the quarter.

Charlie: Furthermore, we are continuing the global expansion of the franchise with additional regulatory filings in Asia Pacific countries and have recently received regulatory approval in Israel, where the team is working actively to treat our first patient.

Charlie: Globally patient identification treatment center readiness.

Charlie: Access and reimbursement discussions continue to advance.

Charlie: Moving to <unk> way Libra in Latin America, we closed out the year with robust growth for both the <unk> libra more than doubling our revenue in the region.

Kylie O'Keefe: We closed out the year with robust growth for Texetian Way Libre, more than doubling our revenue in the region. Patient identification is robust, and the number of patients on treatment continues to grow across the region, including first-time revenue in new countries. In Brazil, we received a new group purchase order for Weylivre, which is in recognition of the increased number of patients that rely on these life-changing treatments. We anticipate fulfilling this group purchase order in the first quarter. As previously discussed, we are updating our total revenue guidance following the CH&P opinion for Transylvania. With growth continuing across the portfolio for Evrizzi, Upstazer, Tech City, and WayLibre, our efforts to protect the Implaza business, and expected TransLana revenue in geographies outside of Europe, we are updating our annual total revenue guidance to $600 million to $680 million.

Charlie: Patient identification is robust and the number of patients on treatment continues to grow across the region, including first time revenue and new countries.

Charlie: In Brazil, we received a new group purchase order for way Libre, which is in recognition of the increased number of patients that rely on these life changing treatment.

Charlie: We anticipate fulfilling this group purchase order in the first quarter.

Charlie: As previously discussed we are updating our total revenue guidance following the <unk> opinion for transplant.

Charlie: With growth continuing across the portfolio as risky upstage Doc Tech city and way Libra.

Charlie: Efforts to protect them Plaza business unexpected trend line of revenue in geographies outside of Europe. We.

Charlie: We are updating our annual total revenue guidance to 602 $680 million.

Kylie O'Keefe: We continue to plan for our global launch of Sepia Tarin. Feedback from the PKU community is extremely positive, and there is a widespread recognition amongst metabolic specialists, geneticists, and dieticians of the potential of sepiateran to meet the significant unmet needs of many of their PKU patients. Not just patients who have been unresponsive to Kuvan but also those who are poorly controlled on this drug and could potentially do significantly better on sepiatarin, as we saw for numerous patients in the affinity trial, as well as classical PKU patients.

We continue to plan for our global launch of Serbia Taryn feeds.

Charlie: Feedback from the PKU community is extremely positive and there is a widespread recognition among metabolic specialists geneticist and dietitians.

Charlie: Potential of Serbia Taryn Toomey.

Charlie: Mythical unmet needs for many of the PKU patients.

Charlie: Not just patients who have been unresponsive to prevent but also those who upholding controls on this drug.

Charlie: Potentially significantly better on the apparel.

As we saw for numerous patients and the affinity trial.

Charlie: As well as classical PKU patients.

Kylie O'Keefe: More importantly, we continue to see durability of the treatment effect and the ability for patients on sepiaterin to increase their dietary protein intake beyond the recommended daily allowance while still maintaining control of feed levels in the long-term extension study. In addition, we have heard from patient advocacy groups around the world that PKU patients are excited as they've been waiting for a therapy that combines efficacy through both fee reduction and improved fee tolerance with tolerability. Both the physician and patient excitement continues to give us the confidence that we can reach over a billion dollar opportunity, and we look forward to taking a step closer to realizing this upon our first global approval. In conclusion, the strong fourth quarter rounds out what was a strong 2023 for our commercial team.

Charlie: More importantly, we continue to see durability of treatment effect may one.

Charlie: Ability for patients from Serbia, Taryn can increase their dietary protein intake beyond the recommended daily allowance, while still maintaining control of fee levels in the long term extension study.

Charlie: In addition, we have heard from patient advocacy groups around the world. The PKU patients are excited as they've been waiting for a therapy that combines efficacy through both fee reduction and improved fee tolerance with tolerability.

Charlie: Both the physician and patient excitement continues to give us the confidence that we can reach over $1 billion opportunity and we look forward to taking a step closer to realizing this upon our first global approval.

Charlie: In conclusion, our strong fourth quarter rounds out what was a strong 2023 for our commercial teams.

Kylie O'Keefe: Our team is well positioned to continue to execute across all our commercial products and across all geographies, together with building out the foundation for Sepia Terran for success in 2024 and beyond. I will now turn the call over to Pierre for a financial update.

Charlie: Our team is well positioned to continue to execute across all our commercial products and across all geographies.

Charlie: With building out the foundation of the Serbia Taryn for success in 2024 and beyond.

Charlie: I will now turn the call over to Peter for a financial update.

Pierre Gravier: Thank you, Kylie. I'll now share the financial highlights of our fourth quarter of our full year 2022. Please refer to the earnings press release issued this afternoon for additional details. Beginning with top-line results, total revenue for the fourth quarter was $307 million.

Charlie: <unk>.

Peter: Thank you Kelly.

Peter: I will now share the financial highlights of our fourth quarter of a full year 2023.

Peter: Please refer to the earnings press release issued this afternoon for additional details.

Peter: Beginning with top line results.

Speaker Change: Total revenue for the fourth quarter was $307 million.

Pierre Gravier: This consisted of DMV franchise revenue of $143 million and other revenue of $164 million, starting with the DMD French. Transflona Net Product Revenue in a quarter was $75 million, while Mfladza Net Product Revenue was $67 million. Moving to Everyday. Fourth quarter global revenue of $354 million, which equates to about $400 million, was achieved by Roche, earning royalty revenue of $51 million for PTC. We also achieved 100 million milestones for EVG, achieving more than $1.5 billion in 2020. Our total revenue for full year 2023 was $938 million, for year-over-year growth of $34.5 million. This included DMV revenue of $611 million, which represented 21% year-over-year growth.

Speaker Change: This consisted of DMD franchise revenue of 143 million and other revenue of $164 million.

Speaker Change: Starting with the DMD franchise.

Speaker Change: <unk> net product revenue in the quarter was $75 million.

Speaker Change: <unk> net product revenue of 67 million.

Speaker Change: Moving to everybody.

Speaker Change: Fourth quarter global revenue of 354 million switch banks, which equates to about $400 million was achieved by Walsh, earning royalty revenue of $51 million for PTC.

Speaker Change: We also earned a $100 million milestone forever, yet should be more than $1 $5 billion in 2023.

Speaker Change: Our total revenue for full year, 2023 was $938 million or year over year growth of 34%.

Speaker Change: This included <unk> revenue of 611 million, which represented 21% year over year growth.

Pierre Gravier: Every day royalties for the year grew 49% to $169 million year over year. Non-GAAP R&D expense was $113 million for the fourth quarter of 2023, excluding $8 million in non-cash stock-based composition expense, compared to $175 million for the fourth quarter of 2022, excluding $14 million in non-cash stock-based composition expense. The year-over-year reduction in R&D expenses reflects strategic portfolio prioritization as the company continues to focus its resources on its differentiated, high-potential R&D plans. Non-GAAP SG&A expense was $68 million for the fourth quarter of 2023, excluding $8 million in non-cash stock-based composition expense, compared to $79 million for the fourth quarter of 2022, excluding $13 million in non-cash stock-based composition expense. This expense reduction reflects lower employee costs as a result of the reduction in the workforce.

Speaker Change: If we get royalties for the year grew 49% to 169 million year over year.

Speaker Change: non-GAAP R&D expense was $113 million for the fourth quarter of 2023.

Speaker Change: Excluding $8 million noncash stock based compensation expense compared to $175 million for the fourth quarter of 2022, excluding 14 million in noncash stock based compensation expense.

Speaker Change: The year over year reduction in R&D expenses reflects the strategic portfolio prioritization of the company continues to focus its resources on these differentiated hybrid unshell R&D programs.

Speaker Change: non-GAAP SG&A expense was $68 million for the fourth quarter of 2023.

Speaker Change: Excluding $8 million noncash stock based compensation expense compared to $7 million to $9 million for the fourth quarter of 2022, excluding $13 million in noncash stock based competition expense.

Speaker Change: Okay.

Speaker Change: This expense reduction reflects lower <unk> cost as a result of the reduction in the workforce.

Pierre Gravier: We're maintaining the guidance we provided in January for GAP, R&D, and SDNA expense of between $740 and $835 million. We are also maintaining our guidance for non-GAAP R&D and SG&A expense of between $660 million and $755 million, including expected R&D expense milestone payments of up to $65 million and excluding estimated non-cash stock-based compensation expense of $80 million. Cash, cash equivalents, and marketable securities total approximately $877 million as of December 31st, 2023, compared to $411 million as of December 31st, 2020.

Speaker Change: We're maintaining our guidance we provided in January for GAAP, R&D and SG&A expense of between $740 835 million.

Speaker Change: We are also maintaining our guidance for non-GAAP R&D and SG&A expense of between 660 $755 million.

Speaker Change: Including expected R&D expense milestone payments of up to $65 million and excluding estimated non cash stock based compensation expense of $80 million.

Speaker Change: Cash cash equivalence and marketable securities totaled approximately $877 million as of December 31, 2023, compared to $411 million as of December 31, 2022.

Unknown Executive: The strong balance sheet provides PTC with the resources to execute on our strategy and to achieve our milestones over the next several years, including the anticipated CPAP tear-off. And I will now turn the call over to the operator for Q&A. Operator.

Speaker Change: The strong balance sheet provides PTC with the resources to execute on our strategy and to achieve our milestones over the next several years.

Including the hemp CBD to tick up during March.

Speaker Change: I will now turn the call over to the operator for Q&A operator.

Unknown Executive: Thank you so much. And as a reminder to press star one one to get in the queue, and to remove yourself, press star one one again. One moment while I compile the Q&A roster. Our first question is from Sammy Corwin with William Blair. Please proceed. Hi, this is Brooke Schuster on behalf of Sammy.

Speaker Change: So much MSR reminder, to press star one one to get in the queue and to remove yourself press star one again, one woman wire compile the Q&A roster.

Speaker Change: Our first question is from Sami Corwin with William Blair. Please proceed.

Speaker Change: Hi, This is Bret Schuster on for Sammy Thanks for taking our question. We were wondering if you could provide more details on the transition of sales forces and resources, where trends lineup with the removal of the EU market.

Unknown Executive: Thanks for taking our question. We were wondering if you could provide more details on the transition of sales forces and resources for TransLarna with the removal of the EU market and if there will be any effect on the SG&A outlook for 2024. Thank you very much, Brooke, for the question. As we talked about... Previously, obviously, we still are marketing TransLara in the first quarter in Europe until the ratification of the CHSE opinion occurs, and then it'll be a very rapid transition of that infrastructure to get ready for the SepiaTarin launch. As we discussed, we'll be submitting the MAA for SepiaTarin in the first quarter, and that infrastructure that we built will be well-positioned for a successful, what we So, the OPEX guidance that we've given for the year incorporates what we plan to have today and also already accounts for what we're going to need tomorrow for the SepiaTarin launch and any other product launches.

There will be any effect on the SG&A outlook for 2024.

Speaker Change: Okay. Thank you very much.

Speaker Change: Great question.

Speaker Change: Talked about.

Speaker Change: Previously the obviously, we still are marketing trends.

Speaker Change: First quarter in Europe until the ratification.

Speaker Change: See HMP opinion occurs and then it will be a very rapid transition of that eight restructure to get ready for it.

Speaker Change: The separate account launch as we've discussed we're be submitting the MAA vascepa territory in the first quarter and that infrastructure that we built we will be well positioned for a successful what are we planning a successful launch of CPO tiara in Europe. So the.

Speaker Change: Opex guidance that we've given for the year incorporates what we plan to have today. It also already accounts for what we're going to need tomorrow for the sequel launch and any other product launches that we have upcoming.

Matthew Klein: Thank you. Thank you. One moment for our next question, please. And it comes from the line of Kristen Kluska with Cantor Fitzgerald. Please proceed. Hi, this is Rick Miller on behalf of Kristen.

Speaker Change: Thank you.

Speaker Change: Thank you one moment for our next question. Please.

Speaker Change: And it comes from the line of Kristen <unk> with Cantor Fitzgerald. Please proceed.

Speaker Change: Hi, This is Rick Miller on for Kristen, Thanks for taking our questions.

Matthew Klein: Thanks for taking our questions. Maybe on FAA for Vatiquinone, can you speak to anything about the ongoing regulatory strategy in the U.S. versus Europe with two guided regulatory interactions? Do you plan on making similar arguments around the data and moving FAA to the different regulatory bodies? Or could there be some sort of different strategies when it comes to the FDA and EMA based on what they're looking for? Any color would be helpful here.

Unknown Attendee: Maybe on <unk>.

Unknown Attendee: For <unk> can you speak to anything on kind of an ongoing regulatory strategy in the U S versus Europe.

<unk> guided regulatory interactions do you plan on making similar arguments around the data and move FAA to the different regulatory bodies or could there be sort of different strategies. When it comes to the FDA and EMA based on what you are looking for any color here can be helpful. Thank you.

Matthew Klein: Thank you. Sure, Rick. As we shared on the call, we were very pleased to announce that we had a very productive discussion with the FDA regarding the Phagocataxia program earlier in the first quarter. Based on those discussions, we now have a path to NDA submission, we believe, late in the year. There was a sense of discussion regarding the clear evidence of benefits in the MoveFA placebo control study, particularly an upright stability scale, which is now clearly recognized as the most applicable part of the entire MFAR score for assessing ambulatory, pediatric, adolescent, and young adult patients that made up the majority of the population of the MoveFA study. So, after that discussion, it was agreed that we have the ability to essentially submit an NDA based on MoveFA, along with confirmatory evidence from the long-term open-label extension portion of MoveFA, comparing those data to natural history data, very much like Briada did with the Claris NDA. So, this idea that we're combining solid, reliable, strong evidence of clinical benefit in the MoveFA study, along with confirmatory evidence So we're very excited to do those projects. Okay, thank you. Thank you so much. And one moment for our next question, please. This is from the line by Kelly Shi with Jeffries.

Speaker Change: Yes, sure Rick as we shared on the call.

Speaker Change: We're very pleased to announce that we had a very productive discussion with the FDA regarding the digital taxi program earlier in the first quarter based on those discussions we now have a path to NDA submission.

Speaker Change: Believe me in a year.

Started discussion regarding the clear evidence of benefit in the move of our vehicles IBO controlled study, particularly an upright stability scale, which is now clearly recognized as the most applicable part of the entire in Fars score for assessing ambulatory pediatric adolescent and young adult patients that made up the majority of the population of the move.

Speaker Change: Got it.

Speaker Change: After that discussion it was agreed that we have the ability to essentially submit an NDA based on move FAA along with confirmatory evidence from the long term open label extension portion of move assay comparing those data to natural history data very much like.

Speaker Change: Priority Carousel.

Speaker Change: Combining solid reliable strong evidence of clinical benefit.

Speaker Change: This study along with confirmatory evidence from the open label portion of that study.

Speaker Change: We're very excited to be able to progress.

Speaker Change: Okay. Thank you.

Speaker Change: Thank you so much and one moment for our next question. Please.

Speaker Change: Okay.

Speaker Change: Is from the line of Kelly <unk> with Jefferies. Please proceed.

Matthew Klein: Please proceed. Hi, this is Yihan for Kelly. Thanks very much for taking the question. First question on influenza. Have you seen any patients switching from influenza to generics? And I know that you cannot speak for patients, but if patients were to speak, sorry, were to switch, or were not to switch, do you know what could be the reason driving their decision, please? And I have a follow-up question.

Speaker Change: Hi, This is <unk> for Kelly, Thanks, very much for taking the question.

Speaker Change: Question on <unk> Plaza.

Speaker Change: Have you seen any patient switching from <unk> to generic and I know that you cannot speak for patient, but patient work to speed. So we're to switch or were not switch do you know what.

Speaker Change: Could be there.

Speaker Change: Driving patient decision, please and I have a follow up question. Please.

Kylie O'Keefe: Thank you very much for the call. Kyrie, do you want to comment on what leads into WSSAA, revenue projections, and the potential impact of generics? Yeah, absolutely. So thank you very much for the question. As we've said in the past, obviously, we have had the fact that loss of exclusivity has been on the horizon. And we've been preparing for this; the team has a number of strategies in place to do everything they can to protect the business.

Speaker Change: Yes. Thank you very much for the call Terry do you want to comment.

Speaker Change: <unk>.

Speaker Change: Sure.

Speaker Change: Okay.

Terry: Yes, absolutely.

Terry: Thank you very much for the question as you said.

Terry: Okay.

Terry: So that exclusivity has been on the horizon and we've been preparing for this the team is.

Terry: Has a number of strategies in place to do everything they can to protect the business and obviously, Eric outlined a number of days in the prepared remarks.

Kylie O'Keefe: And obviously, Eric outlined a number of these in the prepared remarks. So I think from that perspective, we've talked about contracting with specialty pharmacies, we've talked about contracting with payers, a number of initiatives highlighting clinical differentiation to prednisone, ensuring brand loyalty through our patient PTC CARES team, and a number of these programs are in place to ensure that we can protect the business upon the loss of exclusivity

Terry: Think from that perspective, we've talked about contracting with specialty pharmacy, <expletive> talked about contracting with payers.

Terry: Number of initiatives, highlighting clinical differentiation to pregnant dine, ensuring brand loyalty through outpatient.

PTC CAD team.

Terry: And there's a number of these programs are in place to ensure that we can protect the business upon the loss of exclusivity.

Kylie O'Keefe: From that perspective, I think it's too early to say if we're seeing switches. There's nothing that we've seen so far. And I think what we have seen and understand through speaking to both physicians and patients in the community is that there is strong brand loyalty to Inflaza. There are a number of programs in place to ensure that brand loyalty.

Terry: From that perspective, I think it's too early to say flipping switches.

Terry: There's nothing that we've seen so far.

Terry: And I think what we have seen and understands we're speaking to both physicians and patients and the community is that there is a strong brand loyalty to an plaza.

Terry: A number of programs in place to ensure that brand loyalty and say from our perspective, we've done everything we can to maintain that business and our revenue guidance is projecting that as well.

Matthew Klein: And so from our perspective, we've done everything we can to maintain that business, and our revenue guidance is projecting that as well. Okay, great. And then on the Huntington's disease program, has the FDA given you specific guidance in terms of criteria and timeline to lift the clinical hold, please? Thank you very much.

Speaker Change: Okay, Great and then on the Huntington.

Huntington's disease program.

Speaker Change: Yes.

Speaker Change: Can you give specific guidance in terms of criteria and timeline to lift the clinical hold please thank.

Matthew Klein: Yes, as we previously shared, we had a very productive discussion with the agency in the fall of last year, where they shared that the data we've collected so far in the PIVOT-HD study through 12 weeks should be sufficient to allow the conduct of that study for 12 weeks. And if we wanted to be able to do the full protocol of 12 months, they would like to see six months' worth of safety data. So that's obviously very encouraging because, as we shared last June, there's very strong evidence of safety and tolerability thus far, with no evidence of NFL spikes seen, and also no treatment-related serious adverse events. The profile continues to be safe as we continue to collect more data, so we look forward to being able to share with the FDA the six-month data they'd like to see to lift the partial clinical hold, which we will expect to do as we get those data in a couple of weeks. Thank you. Thank you. One moment for our next question. And it's from the line of Eric Joseph with J.P. Morgan.

Speaker Change: Thank you very much.

Speaker Change: As we previously shared we had a very productive discussion with the agency in the fall of last year.

Speaker Change: They shared that data we've collected so far in the pivot HD study from 12 weeks should be sufficient to allow conduct of that study for 12 weeks duration and if we wanted to be able to do the full protocol at 12 months.

Speaker Change: We'd like to see six months worth of safety data.

Speaker Change: Obviously very encouraging because we.

Speaker Change: As shared last June there is very strong evidence of safety and Tolerability, thus far with no evidence of NFL spikes seen and also no treatment related serious adverse events profile continues to be safe as we continue to collect more data. So we look forward.

Speaker Change: To being able to share it with the SBA. The six month data they'd like to see with the partial clinical hold which we will expect to do.

Speaker Change: David a couple of months.

David: Thank you.

David: Thank you maam and for our next question.

David: Okay.

David: And he is from the line of Eric Joseph with Jpmorgan. Please proceed.

Eric William Joseph: Please proceed. Thank you. I just wanted to touch on Patikwinone and FAA. It's nice to see that opportunity back on the table.

Eric William Joseph: Thank you.

Eric William Joseph: I just wanted to touch on in particular.

Eric William Joseph: And that's why it's nice to see that opportunity back on the table can you just talk a bit more about sort of what.

Matthew Klein: Can you just talk a bit more about sort of what has got FDA a little more constructive? Were they, Was any new data from the Open Label Expansion discussed? Or is it more about just sort of getting them on board with upright stability as a key functional endpoint?

Eric William Joseph: I, just got off to a little more constructive.

Speaker Change: Were they.

Speaker Change: With any new data from the open label extension discussed or is it more about just sort of.

Speaker Change: Getting them on board with effort stability other key.

Matthew Klein: And just to, kind of looking back on your commentary where they previously seemed to want a confirmatory study. If you proceed with an NDA submission here, would that be for full approval or accelerated approval? Thanks for the question, Eric. So the discussion with the agency really focused on the Upright Stability Scale. I think as we've talked about when we started the MOVE FA study, what wasn't quite appreciated was that for the population you were looking at, ambulatory patients, the only sensitive portion of that scale is the upright stability scale. Now, over the past couple of years, there have been several publications, and there's also been an FDA-funded study looking at pediatric phregic ataxia patients. All of these studies have shown clearly that if you want to assess the treatment effect in a young adolescent ambulance patient population, that upright stability is the only way to do it.

Speaker Change: Functional endpoint.

Speaker Change: Just.

Speaker Change: Just kind of looking back on your commentary worthy previously you've seen what a confirmatory study. If you proceed with an NDA submission here that would be for full approval or accelerated approval. Thanks.

Speaker Change: Thanks for the question Eric So the discussion with the agency really focused on the upright stability scale I think as we've talked about when we started to move at a study.

Speaker Change: <unk>.

Speaker Change: It wasn't quite appreciated was that for the population youre looking at ambulatory patients the only sensitive portion of that scale.

Speaker Change: The upright stability scale now over the past couple of years between several publication.

Speaker Change: And there's also been an FDA funded study looking at pediatric <unk> patients. All of these studies have shown clearly that if you want to assess the treatment effect.

Speaker Change: In a young adolescents ambulant patient population that the upright stability is the only way to do it started to even look at the placebo data in our trial.

Matthew Klein: In fact, if you even look at the placebo data in our trial, you see that the placebo group barely changed on any of the other parts of the MPARs. It was really only on upright stability that you could see disease progression in that population over 72 weeks. When you are able to show those data and talk about those data and provide evidence to the agency, including evidence from a study they've funded, It becomes very clear that while the primary endpoint itself at MFAR didn't hit, we demonstrated significant benefits on the only thing you possibly could show significant benefits on disease progression, and that's the Upright Stability Scale. So, I think that data and that understanding, along with the supportive evidence of the fatigue scale, which had statistical significance as well as was recognized as the most burdensome symptoms for afflicted patients in some correlation with walk tests, all of that together, I think was very helpful in having a constructive discussion with the agency and being able to talk about a path forward to NDA based on the data. We have not yet done the analysis of the open-label data. Those weren't shared either.

Speaker Change: You see that the placebo group barely changed on any of the other parts of the Empire. So it was really only on a price stability that you see disease progression in that population over 72 weeks and so when we are able to show those data and talk about those data and provide evidence to the agency, including evidenced in the study they funded.

Speaker Change: Yeah.

Speaker Change: It becomes very clear that while the primary endpoint itself with Empire is getting hit.

Speaker Change: We demonstrated a significant benefit on the only thing you possibly could.

Speaker Change: So significant benefit on disease progression and that's the upright stability and scale. So I think those data and that understanding along with the supportive evidence of the fatigue scale, which has also statistical significance is well recognized as the most burdensome symptom for application some correlation with.

Speaker Change: <unk> has all of that together I think it was very helpful.

Speaker Change: And having a constructive discussion with the agency and being able to talk about our path forward to NDA based on the data we have not done the analysis yet of the open label data those werent sure well, obviously preparing analysis plan.

Matthew Klein: We'll obviously prepare an analysis plan for those data and share it with the agency ahead of doing those analyses. In terms of this being accelerated or full approval, we're still having those discussions at this point. But what we're most excited about, obviously, is being able to have the potential to submit an NDA based on the move that they study and still what is still a significant unmet need for pediatric and adolescent and pre-dipotaxone patients. And also to be able to have a therapy that would provide benefit to ambulatory patients who are who are young adults or adults. Okay, I appreciate the commentary there. Maybe just on that.

Speaker Change: Are those were those data share with the agency and doing those analyses.

In terms of this being accelerated or full approval, we're still having those discussions at this point, but what we're most excited about obviously is being able to have the potential to submit an NDA based on the moves at a Saturday and Phil what is still a significant unmet need for pediatric and adolescent stage of attacks in patients and also to be able to have a therapy that will provide benefit to you.

Speaker Change: Ambulatory patients who are who are young adults adults ages ago.

Speaker Change: Okay I appreciate the commentary there maybe just.

Matthew Klein: The sequencing of... The Open Label Extension Analysis and sharing those data with FDA, I guess, will you be updating the street with those data ahead of further interactions with the agency? Yes, we expect those open-label data to be collected over the next several months and would expect then to complete the analysis once they've collected all the data. We'll also be doing an analysis of the original study. As you know, we've previously shown that in the long term follow-up from the initial particulate on study, we had a highly significant benefit when looking at those patients treated for twenty-four months, first and age stage, and natural history match. We'll be updating that analysis as well and including that as a source of confirmatory evidence to the exact sequencing of having the data shared in the FDA and updating the street. We'll certainly keep you posted as we move towards towards the NDA, including a. Okay, great.

Speaker Change: Sure.

Speaker Change: The open label extension analysis.

Speaker Change: And sharing those data with FDA I guess.

Speaker Change: Will you be updating the street with those data ahead of us.

Speaker Change: Further interactions with the agency.

Speaker Change: Yes, so we expect those open label data to be collected over the next several months.

Speaker Change: Then to complete the analysis.

Speaker Change: And collect all the data will also be doing.

Speaker Change: A a analysis of the original study.

Speaker Change: Previously shown in the long term follow up from the <unk>.

Speaker Change: Initial particularly on study with a highly significant it's.

Speaker Change: Benefit when looking at my preparing those patients treated for 24 months person.

Speaker Change: Actual history match will be updating that analysis.

Speaker Change: As well, including that as a source of confirmatory evidence.

Speaker Change: So the exact sequencing of having the data share with the FDA and updating the street, we will certainly keep the sea posted as we move towards towards the NDA.

Speaker Change: <unk> a pre NDA meeting.

Matthew Klein: Thanks for taking the question. Thank you. One moment for our next question, please. And it's from Jeff Hung with Morgan Stanley. Please proceed.

Okay, great. Thanks for taking my questions.

Speaker Change: Thank you one moment for our next question. Please.

Speaker Change: And he is from Jeff hung with Morgan Stanley. Please proceed.

Jeff Hung: Thanks for taking my questions. For TransLauna, are you aware of any communication between the EMA and the Brazilian Health Regulatory Agency after the recent EMA decision given their data sharing agreement? You know, roughly how much of your data comes from Brazil?

Jeff Hung: Thanks for taking my questions for <unk> are you aware of any communication between the EMA in the Brazilian health regulatory agency. After the recent EMEA decision given their data sharing agreement roughly how much you expect from.

Matthew Klein: and then I have a follow up. Yeah, Jeff, we're not aware of any correspondence. I think Brazil has traditionally been quite independent.

Jeff: From Brazil.

Speaker Change: And then I have a follow up.

Speaker Change: Yes.

Speaker Change: Yes, Jeff we're not aware of any correspondence I think Brazil has traditionally been quite into clinic.

Matthew Klein: I expect that to continue to be the case, and the indications we've had are that they will continue to act independently in making their assessments of the benefits. Thanks. And then for the CEPI after an NDA. What other data might be needed beyond the TOCS data?

Speaker Change: I expect that to continue to be the case.

Speaker Change: And.

Speaker Change: The indications we had is that they will continue to act independently and making their assessment of the benefit of trademark.

Okay. Thanks, and then for the <unk> after an NDA submission.

Speaker Change: What other data might be need to be on the tox data.

Matthew Klein: Could the FDA look for clinical data versus QVAN in classical PKU patients, or have they ever asked you or sent you about running a head-to-head study against QVAN? Thanks. Yeah, so as we previously talked about, the only outstanding or the only gating item for the NDA submission was the completion of the mouse study. We started that, as expected, in December. Now that we have visibility into those timelines, we look forward to discussing being able to possibly submit the NDA sooner than the third quarter. I look forward to those discussions. In terms of comparison to QVAN, I think that's something we've never been asked for.

Look for clinical data versus Kuban in classical PKU patients or.

Speaker Change: Have you ever asked you are sensitive about running ahead study against Kuban. Thanks.

Speaker Change: Yes, we had previously talked about the only outstanding or the only gating item for the NDA submission was the completion of the mouse study we started that as expected.

Speaker Change: December now that we have visibility to those timelines, we look forward to discussing and being able to possibly submit the NDA in the fourth quarter.

Speaker Change: No.

Speaker Change: We look forward to those discussions in terms of comparison to Suzanne I think.

Speaker Change: That's something we've never been asked for and in fact, what we've been able to show FDA and other regulatory authorities as well.

Matthew Klein: In fact, what we've been able to show FDA and other regulatory authorities as well, that we had the phase two study, which was a head-to-head comparison of QVAN, which showed a statistically significant benefit of c-cutanine over QVAN. And then, of course, the affinity study, where we had that number of patients, 27 patients who came into the study on QVAN, we washed them out of it, and then we had a 50%, roughly 50% greater, lower phenylalanine once those patients switched over to cepiotarin. Again, clearly demonstrating that we're able to provide a significantly greater benefit to these patients. And then, of course, the evidence in the classical PKU patients in the affinity study with a mean induction of 69% in the placebo-controlled portion, I think is again very supportive of the potential for cepiotarin to provide benefit to the full spectrum of PKU patients, that is, patients of all ages and all degrees of severity, and also reinforcing that if patients have demonstrated responsiveness to BH4 in the past, we can Great, thanks so much.

Speaker Change: Phase II study, which was a head to head comparison, couvade, which showed statistically significant benefit of <unk> and then of course, the affinity study, where we had that number of patients 2007 patients who came into the study on crude and you've got washed out of it.

Speaker Change: A 50%, 50% roughly 30% greater lowering phenylalanine once those patients switched over to CPO tariff guidance clearly demonstrating that we're able to provide significant greater benefit to these patients and then of course the evidence in the classical PKU patients.

Speaker Change: Starting with a mean reduction of 69% placebo controlled portion I think is again very supportive of that.

Speaker Change: Just to <unk> to provide benefit to the full spectrum of PKU patients that being of all ages and all degrees of severity and also reinforcing that our patients have demonstrated responsiveness to ph for the past. So we can certainly expect to much greater response.

Speaker Change: Honestly Goodyear.

Great: Great. Thanks, so much.

Matthew Klein: Thank you. One moment for our next question, please. And it's from the line of Brian Adam Abrahams with RBC Capital Markets. Please proceed. Hey, good afternoon.

Speaker Change: Thank you one moment for our next question. Please.

Speaker Change: And he is from the line of Brian Adam Abrahams with RBC capital markets. Please proceed.

Brian Corey Abrahams: Thank you for taking my questions. On the 518 Huntington's program, I have two questions. First, I'm curious how your views have evolved on whether there could be a potential path for accelerated approval for that drug based on NFL and brain volume. And then, secondly, I know there's an additional cohort of patients that you guys were enrolling, the ones that weren't presented last year and included early stage three patients. Just wondering where you are with that cohort, if we might see interim results from less than 12 months in the second quarter as well, and your latest thoughts on moving to a 20 milligram dose. Thanks.

Speaker Change: Hey, good afternoon. Thank you for taking my questions.

Speaker Change: This $5 eight Huntington's program.

Speaker Change: I guess two questions first I'm curious how your views have evolved on whether there could be a potential path for accelerated approval for that drug based on NFL <unk> brain volume and then secondly, I know theres, an additional cohort of patients that you guys were enrolling the ones that Mark presented last year and included early.

Speaker Change: Stage three patients just wondering where you're at with that cohort if we might see interim results.

Speaker Change: From.

Speaker Change: From less than 12 months timeframe.

Speaker Change: The second quarter as well and your latest thoughts on moving to a 20 milligram dose. Thanks.

Matthew Klein: Thank you very much, Brian, for the questions. So on your first question, look, I think it's very clear that SBA as a whole, and the neurology division in particular, has been looking at the accelerated approval path as one that is rational for neurodegenerative diseases, where it's typically many years and a very, very large study needed to register clinically meaningful effects. So to be able to have a biomarker that is likely to predict clinical effects makes perfect sense. So you can have an accelerated approval, get patients who need a drug access to therapy while you collect that longer-term data. Obviously, if it makes sense for neurodegenerative disease in general, it certainly makes sense for a disease like Huntington's disease, which, of course, is an indolent disease, and, you know, the efficacy study will necessarily need to be large and long. In terms of potential biomarkers for HD, we think there are several, as we mentioned, both NFL and brain volume. Certainly, in a disease of inflammation-oxidative stress, to be able to show a benefit on a marker of inflammation-oxidative stress like NFL, should be likely to predict clinical benefit.

Speaker Change: Thank you very much Brian for the question. So on your first question.

Speaker Change: Okay.

Speaker Change: It's very clear that SBA as a whole in the neurology division in particular has been looking at an accelerated approval path as one that is rational.

Speaker Change: For our Neurodegenerative diseases, where it's typically many years of very very large study needed to register a clinically meaningful effect so to be able to have a biomarker that is likely to predict clinical effect. It makes perfect sense that you could have an accelerated approval get patients in need of drug access to therapy, one collect that longer term data.

Speaker Change: Obviously, if it makes sense for Neurodegenerative disease in general it certainly makes sense for diseases like Huntington's disease, which of course is in indolent disease.

Speaker Change: The efficacy study will necessarily need to be larger mall.

Speaker Change: In terms of potential Biomarkers for HD, we think there are several as you mentioned.

Speaker Change: Both NFL in brain volume certainly in a disease inflammation oxidative stress to be able to show a benefit on a marker of inflammation oxidative stress like NFL, certainly likely to predict clinical benefit.

Matthew Klein: And similarly, for something like brain volume, where the pathogenesis of disease is cell injury, cell death, loss of brain volume, and then symptoms that present themselves in ultimate clinical neurodegeneration, if you could show that process of brain atrophy, that certainly suggests you should be able to influence the progression of disease. So we see those both as potential biomarkers. Of course, it's going to be a matter of having the data, having the discussions with the agency, because we'd be the first ones through that portal. But I definitely think that the agency is showing openness to leveraging the accelerated improvement pathway in the case of diseases like HD, and we certainly would look to avail ourselves of that opportunity. In terms of your second question, that is, phase 3 enrollment has gone quite well.

Speaker Change: Currently for something like brain volume the pathogenesis diseases Selinger, we felt that loss of brain volume and that symptoms that presents itself an ultimate clinical data generation that you could sell that process of brain atrophy that certainly suggests you shouldnt be able to influence the progression of disease. So we see those both taz.

Speaker Change: Potential biomarkers.

Speaker Change: It's going to be a matter of having the data having the discussions with the agency.

Speaker Change: We'd be the first one is through that portal, but I definitely think that the agency has shown an openness to leveraging an accelerated approval pathway in the case of diseases like HD and we certainly would look to avail ourselves of that opportunity.

Speaker Change: In terms of your second question.

Speaker Change: That's the phase III enrollment has gone quite well and in fact.

Matthew Klein: In fact, overall enrollment really picked up after we shared the June data, and we were able to reassure both the patient community and the physician community that you can develop a drug for Huntington's-Muller that is safe and well-tolerated and has the necessary bio-distribution and fungal and adduct effect necessary for therapeutic benefit. So we've seen excellent enrollment, and we will be sharing, in addition to the 12 month data in the second quarter, interim data from 12 weeks on the other stage 2 patients as well as some of the stage 3 patients. So we look forward to sharing all of this data with you all in the second quarter. Regarding your third question regarding the 20 milligram dose, our view remains as it was when we talked about it. I think what we're seeing with the 10 milligram dose and the preferential distribution to the CNS with a 1 to 1.5 ratio of plasma and CSF exposure, we very much believe that 10 milligrams is probably the dose that we need.

Speaker Change: Overall enrollment.

Speaker Change: <unk> picked up after we shared the June data and we're able to reassure.

Speaker Change: Both the patient community physician community that you can develop a drug for Huntington lowering that it's safe and well tolerated.

Speaker Change: And Tycho necessary.

Speaker Change: Distribution bucket it out of the fact necessary for therapeutic benefit.

We've seen excellent enrollment that we will be sharing in addition to.

Speaker Change: The 12 month data in the second quarter interim data from 12 weeks on.

Speaker Change: The other stage two patients as well as some of the stage III. So we look forward to sharing all of those data.

Speaker Change: <unk>.

Speaker Change: With you all in the second quarter.

Speaker Change: Third question regarding the 20 milligram dose our view remains as it was when we talked about in June I think what we're seeing with the 10 milligram dose and the.

Speaker Change: Preferential distributions in the CNS with a 1% to one five ratio of plasma and CSF exposure that we very much believe that 10 milligrams is probably the dose that we need so right now we're committed to moving forward with five milligrams and 10 milligrams of Aro more about it of course, we do have that opportunity to titrate up to 20 milligrams if any.

Matthew Klein: So right now, we're committed to moving forward with 5 milligrams and 10 milligrams and learning more about it. Of course, we do have that opportunity to titrate up to 20 milligrams, if need be, but right now, we believe that we may very well be sitting at dose levels that are the right ones to safely achieve the desirable Huntington protein to provide clinical benefits. Thanks so much, Matt. Thank you so much. One moment for our next question, please. And it's from the line of Peyton Bohnsack with T.D.

Speaker Change: But right now we believe that we may very well be sitting with dose levels that are the right ones to achieve to safely achieve the desired borrowings of Huntington protein tech can provide clinical benefit to patients.

Speaker Change: Thanks, so much Matt.

Speaker Change: Yes.

Speaker Change: Thank you so much one moment for our next question. Please.

Speaker Change: And he is from the line of Baytown Bon Sakowitz TD Cowen. Please proceed.

Joseph John: Cowan. Please proceed. Hi guys, could you possibly elaborate on the reauthorization process for TransLarna in Brazil and Russia, and maybe the process for national assessment in the United Kingdom? It looks like in Brazil specifically, the renewal is up in April.

Speaker Change: Hi, guys.

Speaker Change: Yes for us could you, possibly elaborate on the reauthorization process for Translarna in Brazil, and Russia, and maybe the process for National assessment in the United Kingdom, and it looks like in Brazil, specifically the renewal is up in April is that the case and do you expect I know you mentioned earlier that there was a new Ross.

Matthew Klein: Is that the case? And do you expect, I know you mentioned earlier that there was new cross-chatter between the two agencies, but do you expect the recent EU decision will have any implications here? Thanks. Thank you for the questions. So, as you mentioned, we're up for reauthorization in Brazil. That process is ongoing. Every indication we have is that this will continue to be an independent assessment. They remain very interested in following their own assessment, beyond the view of KOLs and others in Brazil that are not influenced by the CHMP's decision. I'd say that we're seeing similar things in the UK, where they have also said that they want to do their own independent national review and national authorization.

Speaker Change: Between the two agencies do you expect the recent EU decision would have any obligations here. Thanks.

Speaker Change: Yes. Thank you for the questions. So as you mentioned, we were up for reauthorization in Brazil that process is ongoing every indication. We have is that this will continue to be an independent assessment and remain very interested in following their own assessment beyond the deload kols and others in Brazil are not influenced by the <unk> decision.

Speaker Change: I would say that what we're seeing similar things in the U K, where they also have said that they wanted to do their own independent National review and a national authorization.

Matthew Klein: So, the signals that we're getting very clearly are that there is a strong desire in countries to do their own assessments and not follow the lead of the CHMP. Great, thank you. And then I guess maybe just a quick follow-up question. When you're looking at the open label data, have you guys reached alignment with exactly what the national history like external cohort group will look like with the FDA? Or is that still ongoing?

Speaker Change: Signals that we're getting very clearly that there is a strong desire countries to do their own assessment and not follow the lead of the CHF two.

Speaker Change: Okay.

Speaker Change: Great. Thank you and then I guess, maybe just a quick follow up question when Youre looking at the open label data have you guys reached alignment with exactly with the national III like external cohort.

Speaker Change: Cohort group will look like with the FDA or is that still ongoing.

Matthew Klein: So, Payne, I assume you're talking about the pre-gifted tax year? Yeah, sorry for betcha. Yeah, yeah, I think where it is really a luxury, the pediatric ataxia community has really been a model community in doing the necessary hard work of creating a robust patient registry. FACOMS, the FACOMS Natural History Registry, is a robust repository of patient data that has several years' worth of data on things like the MFARs, including the Upright Stability Scale. And this is something that Reata was able to leverage as part of their NDA, and we look forward to doing the same. I think the FDA acknowledges this. I think the FDA has publicly acknowledged the great work that the pediatric ataxia community has done in building this registry. And obviously, it's something that's incredibly useful to drug developers like us, like Reata, and others, who can now leverage that natural history database to contextualize the long-term beneficial effects of therapies. So I think there's no question that this is the registry.

Speaker Change: Okay, and I assume youre talking about for project ataxia.

Speaker Change: Yes, sorry for that.

Speaker Change: Yes, I think where it is.

Speaker Change: It's really a luxury depreciate you're taxing your community has really been a model community and doing the necessary hard work of creating a robust patient registry.

Speaker Change: That's the background natural history registry is a robust repository of <unk> data that has several years' worth of data on things like the borrowers, including their price stability scale and this was something that reorder was able to leverage as part of their NDA and we would look forward doing the same.

Speaker Change: The FDA acknowledged this I think the FDA publicly acknowledge the great work that the future for taxi community has done in building the strategy and obviously thats something thats incredibly useful to.

Speaker Change: Develop drug developers like us like <unk> and others.

Speaker Change: Our leverage that natural history database to contextualize, the long term beneficial effects of therapies.

Speaker Change: I think Theres no question that this has been registry.

Matthew Klein: We will, as needed, develop a statistical analysis plan that precisely details how we'll do what will be a propensity score match to ensure that we have an apples-to-apples comparison between the patients in the USA, and particularly known, and the natural history patients. And that should give us the necessary natural history data needed, or the long-term treatment data needed to provide that confirmatory evidence. Great, thank you so much for taking our question. Thank you. One moment for our next question, please. And it's from the line of David Lebowitz with Citi.

Speaker Change: We'll as.

Speaker Change: Needed develop a statistical analysis plan for <unk>.

Speaker Change: <unk> details I will do what will be propensity score match with.

Speaker Change: To ensure that we have an apples to apples comparison between the patient can move FAA and particularly in the natural history patients.

Speaker Change: And that should provide us the necessary natural history data needed.

Speaker Change: Long term treatment.

Speaker Change: I needed to provide that confirmatory evidence of the NDA.

Speaker Change: Great. Thank you so much for taking our questions.

Speaker Change: Thank you one moment for our next question. Please.

Speaker Change: And it's from the line of David Lebowitz with Citi. Please proceed.

David Neil Lebowitz: Please proceed. Thank you very much for taking my question. Could you compare the regulatory process for 505B2 and 505B1, and talk about how the data to this point for the sepia tariff... fits into the submission, and what additional components or different ways of looking at the data might be required? Yeah, thanks, David.

David Neil Lebowitz: Thank you very much for taking my question could.

David Neil Lebowitz: Could you compare the regulatory process for 505, B, two and <unk> one.

David Neil Lebowitz: And talk about how the data at this point for Sip, you turn fits into the submission.

David Neil Lebowitz: What additional components or different ways of looking at the data might be required.

Speaker Change: The FDA.

Speaker Change: Yes, Thanks, David I think.

Matthew Klein: I think just for context, as we've talked about, the initial sepia tear and development path was 505B2, which was a decision made by SENSA when they were developing the compound. I think it was likely thought to be a path that would be maybe faster or less resource intensive, but when we license the therapy, and it's very clear, it is not the appropriate path. That's more, it's really not for a molecule like sepia tear. Sepia tear has a novel composition, a novel mechanism of action, a novel bio distribution, a novel pharmacology, and clearly differentiated therapeutic benefits.

Speaker Change: Just for context.

Speaker Change: <unk> talked about the initial Cta Taryn development path was $505, two which was a decision made by sensor.

FDA: When they were developed in the compound.

Speaker Change: It was likely thought to be a path that would be maybe faster.

Speaker Change: Resource intensive but when.

Speaker Change: When we licensed the therapy and its very clear it is not the appropriate path that's more.

Speaker Change: For a molecule like <unk>.

Speaker Change: Novel.

Speaker Change: Composition novel mechanism of action novel Bio distribution novel, Pharmacology, and clearly differentiated therapeutic benefit so it doesn't fit into the sort of mid two 502 parallel. It's a novel therapy that is and should be part of the 500 <unk> one development pathway.

Matthew Klein: So it doesn't fit into the sort of me to 505B2 paradigm. It's a novel therapy that is, and should be part of, the 505B1 development path. As such, it's necessary then to provide a full slate of non-clinical studies, including things like writing pharmacology studies, toxicology studies, maternal fetal studies, all those types, juvenile toxicity, all of those studies then become necessary to be part of our program, all of which we'll have. And in terms of being ready to submit the NDA under 505B1, as we said, the only outstanding item is the mouse study, So it's really a matter of, I think it was probably not appropriately started in the 505B2 pathway; it was really a matter of putting it where it belongs for novel differentiated therapy, like supraterans, 505B1. Does the FDA require any type of head-to-head comparison? in this particular process. Not at all.

Speaker Change: As such its necessary to provide a full slate of non clinical studies, including seamless slide.

Speaker Change: Yes.

Speaker Change: Right Pharmacology study toxicology study.

Speaker Change: Maternal fetal studies.

Speaker Change: All of those types of juvenile toxicity all of those studies then become necessary to be part of our program all of which will have.

Speaker Change: In terms of being ready to submit the NDA and apparel one as we said the only outstanding item is the.

Speaker Change: Study, which I had mentioned earlier on the call. So it's really a matter I think it was probably not appropriately started in five of the 500 <unk> pathway and it was really a battle.

Speaker Change: Volumes for novel differentiated therapy like Super Terence fibre for everyone.

Speaker Change: Does the FDA require any type of head to head comparisons.

Speaker Change: And this particular process.

Matthew Klein: I think the one thing we could say is, I think we're in a situation that is precedented. There have been approved therapies for PKU. There's a well established Clinical Trial Design Endpoint, and what the FDA likes to see. And that's exactly what we follow.

Speaker Change: Not at all I think the one thing we did say that.

Speaker Change: We're in a situation that is precedented there had been approved therapies for PKU Theres, a well stay on established.

Speaker Change: Okay.

Speaker Change: Clinical trial design endpoints and what the FDA likes to say.

Speaker Change: That's exactly what we thought.

Matthew Klein: We, including the secretarian, The Registration program looked a lot like the QVAN program in terms of having a responder analysis to identify those that responded, then having a placebo-controlled study, and then having the necessary data to demonstrate durability and long-term safety, all of which we have. I say the only difference in our program is the significantly greater responder rate and the significantly greater magnitude of treatment benefits. So those are the components of the data needed to support the NDA submissions, to support the efficacy. It's the evidence of effectiveness that is needed, it's the evidence of effectiveness that we have, and we look forward to being able to submit that NDA. And just jumping over to FA, have you received the minutes from the meeting yet? And what are the next steps?

Speaker Change: <unk> the secret Taryn.

Speaker Change: Distribution program looks a lot like the <unk> program in terms of having a responder analysis to identify those that responded.

Speaker Change: A placebo controlled study.

Speaker Change: Necessary data to demonstrate durability and long term safety all of which we have I would say the only difference in our program is significantly greater responder rate, that's significantly greater magnitude of treatment benefit.

Speaker Change: Those are the components of the data needed to support the NDA submissions to support the efficacy the evidence of effectiveness that are needed and as the evidence of effectiveness that we have and we look forward to being able to submit that NDA as soon as possible.

Got it and just jumping over to Fay.

Fay: Have you received the minutes from the meeting yet and what are the next steps.

Fay: And the process.

Matthew Klein: Yeah, so I think at this point where we are, we're still, as I mentioned, having some back and forth with FDA regarding whether this could be an accelerated approval or a full approval. That's something that we look forward to getting written correspondence on in the near future. And I think for us right now, it's also moving forward and collecting the open-label data and getting together the statistical analysis plans that can support the confirmatory evidence. And so that's what our team is focused on. I got it.

Yes.

Fay: At this point, where we are is we're still as I mentioned, having some back and forth with FDA regarding whether this could be accelerated approval or.

Fay: Or a full approval that's something that we look forward to getting written correspondence thoughts in the near future.

And I think for US right. Now is also moving forward in collecting all of the open label data and getting together statistical analysis plans that can support the confirmatory evidence.

Fay: So that's what our team is focused on right now.

Matthew Klein: Thank you for taking my question. Thank you. One moment for our next question, please. When it comes from the line of Gina Wang with Barclays, please proceed. Thank you. I would just ask one more question regarding ventricular MSA.

Speaker Change: Got it thank you for taking my question.

Speaker Change: Thank you one moment for our next question. Please.

Speaker Change: When it comes from the line of Gena Wang with Barclays. Please proceed.

Huidong Wang: Thank you I would just ask one more question regarding the Tucano NSA.

Huidong Wang: So, did the FDA suggest any specific statistical methodology to analyze data? Since, you know, this will be comparing to the natural history data as well as open-label extension studies. Yeah, thanks, Gina. They were not prescriptive.

Huidong Wang: <unk>.

Huidong Wang: Did the FB suggest any specific statistical methodology to analyzing data.

Huidong Wang: This will be comparing to the natural history data as well.

Huidong Wang: Open label extension study.

Speaker Change: Yes, Thanks Gena.

Matthew Klein: I think we've gone to them, and they said we would look to do a propensity analysis approach. You know, again, we're in a realm here of precedent. They recently approved an NDA for Scott Claris based on a study, a placebo-controlled study, along with open-label data compared to FACOMS natural history data based on propensity score matching. So, we have a lot we can follow here, but to be sure, we'll submit a statistical analysis plan that will fully detail our approach, not only in the propensity model, but also into what's likely to be Okay, and very quickly, you know, did the FD give guidance on what type of data you need to hit in order to, you know, be approvable? from the Open Label Registry for the open label portion.

Speaker Change: They were not prescriptive I think we've gone to them and they said that we would look to do a propensity analysis approach.

Speaker Change: Then we're in a round here of precedent.

Speaker Change: <unk> recently approved an NDA for Scott Clarus based on a study.

Speaker Change: Placebo controlled study along with open label data compared to the <unk> natural history database seasonal propensity score matching so we have a lot we can follow up here.

Speaker Change: And but to be sure we will submit a statistical analysis analysis plan that were fully detail our approach not only in the propensity model, but also likely be mixed effects modeling to provide the appropriate longitudinal estimate of treatment benefit relative to natural history.

Speaker Change: Okay, and very quickly did the FD.

Speaker Change: You gave a guidance what type of data you need to hit in order to.

Speaker Change: Could be approvable.

Speaker Change: From the open label registry.

Speaker Change: Thank you.

Speaker Change: The open label portion.

Matthew Klein: Yeah, no, there was no. There was nothing prescriptive. I think this is viewed as the, you know, in a regulatory framework, we have persuasive evidence of effectiveness from, we would be putting together an NDA based on our ability to demonstrate persuasive evidence of effectiveness in the placebo-controlled portion of the move that they study, along with confirmatory evidence that we said will consist of the comparing the open label data to natural history, showing that there's a benefit over a longer period of time from both move SA as well as the NDA, as I mentioned earlier to Eric's question also with data, open label data, with the natural history comparison from the first FA study that was in a slightly different population that consisted mostly of adults, both ambulatory and non-ambulatory, where we've previously done these types of analyses to show a significant long term benefit relative to the natural history. Okay, thank you. Thank you. One moment for our next question, please. And it comes from the line of Paul Choi with Goldman Sachs.

Speaker Change: Yes, no there was no specific store.

Speaker Change: There was nothing perspective, I think this is viewed as the.

Speaker Change: And regulatory framework, we have persuasive evidence of effectiveness.

Speaker Change: Would be putting together an NDA based on our ability to demonstrate persuasive evidence of effectiveness in the placebo controlled portion of the move that they study along with confirmatory evidence that reset will consist of the comparing the open label data to natural history has shown that there is a benefit over a longer period of time from both move let's say as well as I mentioned.

Speaker Change: Earlier Doug.

Speaker Change: Eric's question also with data open label data with the natural history comparison from the first study that was at a slightly different population that consisted mostly of adults both ambulatory and non ambulatory where we've previously done these types of analyses to show.

Speaker Change: Looking at long term benefit relative to the natural history matched.

Speaker Change: Okay. Thank you.

Speaker Change: Thank you one moment for our next question. Please.

Speaker Change: And it comes from the line of Paul Choi with Goldman Sachs. Please proceed.

Paul Choi: Please proceed. Hi, good afternoon, and thanks for taking our question. I want to just change gears for a moment and maybe ask you to take a look at ALS. And I was wondering if you could maybe, ahead of the cardinal study coming out later this year, sort of frame your thoughts on potential, you know, and areas of differentiation versus the approved therapy from AMLEC. And my second question is, under a scenario where AMLIC has a positive Phoenix Confirmatory Study for World Rio, can you maybe just comment on what your regulatory strategy might be, should they garner full approval there following a positive confirmatory study? Thanks for taking our question. Thanks very much, Paul, and thanks for the question on the Euteloxostat ALS program.

Paul Choi: Hi, good afternoon, and thanks for taking our question.

Paul Choi: Just change gears for a moment, maybe asking about have you tried to look that and lastly, and I was wondering if you could maybe ahead of the Cardinal study reading out later this year.

Paul Choi: To frame your thoughts on potential.

Paul Choi: The treatment effect and or areas of differentiation versus the approved therapy relative to <unk> from <unk>.

Paul Choi: And my second question is.

Paul Choi: Under a scenario where <unk>.

Paul Choi: Positive.

Paul Choi: The composite confirmatory study for <unk> can.

Paul Choi: Can you maybe just comment on what your regulatory strategy might be.

Paul Choi: Should they get garner full approval there following a pocket of the confirmatory study thanks for taking our question.

Speaker Change: Yes, thanks very much Paul.

Speaker Change: Thanks for the question I mean, we saw lots of <unk> ALS program. This is a program. We're very excited about given what has become very clear now is that link between teratosis.

Matthew Klein: This is a program we're very excited about, given what's become very clear now as a link between therapeutosis and ALS. I think that that therapeutosis pathway is now seen as a really important pathway in disease progression. And of course, Euteloxostat was developed to specifically target that pathway. But we did a lot of the preclinical development work with Euteloxostat benchmarking to Adarabone, which is also another approved therapy for ALS, and found that it has a much more generic, non-specific effect on elements of oxidative stress in the therapeutosis pathway.

Speaker Change: I think that that Teratosis pathway is now seen as really important pathway in disease progression and of course your two lots of <unk> that was developed to specifically target that pathway. We did a lot of the preclinical development work.

Speaker Change: You too lots of benchmarking towards <unk>, which is also another approved therapy for AOS.

Speaker Change: Has a much more subtle generic nonspecific effect on elements of oxidative stress in the <unk> pathway and as we've talked about we've been able to show a 25% to 30 times, the potency and the spinal apps.

Matthew Klein: And as we've talked about, we were able to show 25 to 30 times the potency in the spinal astrocyte model. And we were also able to show important protective effects on benchmarks against Adarabone and a number of other disease-relevant preclinical test models. In terms of the study design, I think, again, we're in an element, as I mentioned with David's question in PKU, where there's clearly precedent for the design of an ALS study. And our discussions with the FDA were very constructive in ensuring that this is a protocol that could support registration if positive. We designed the study with a two-to-one randomization with a treatment effect of roughly a 2.5 treatment difference between the treatment groups and the placebo groups, which gives us roughly 85% power to detect that difference. And I think that positions us very well to capture significant treatment benefits. I think the regulatory pathway doesn't change at all based on what happens with the amyloxis compound.

Speaker Change: Just type model, we've also been able to show important protective effects when benchmarked against a.

Speaker Change: A number of other disease relevant.

Speaker Change: Preclinical test models in.

Speaker Change: In terms of the study design I think again, we're in an element as I mentioned with David's question in PKU, where there's clearly precedence for the design of an AML study.

Speaker Change: With the FDA were very constructive and ensure that this is a protocol that could support registration if positive. We designed the study with a two to one randomization with a treatment effect in.

Speaker Change: Roughly a two five treatment difference between.

Speaker Change: Our treatment groups and placebo groups, which gives us roughly 85% power to detect that difference.

Speaker Change: And I think that positions us very well to capture a significant treatment benefit I think the regulatory pathway doesn't change at all.

Speaker Change: Just on what happens with amalek compound and obviously the commercial opportunity and the differentiation will be based on the data what we see on ALS FRS score what potentially we could see in terms of pulmonary function and also what we might see in terms of mortality.

Matthew Klein: And obviously, the commercial opportunity and the differentiation will be based on the data. So what we might see in terms of an ALS FRS score, what we could potentially see in terms of pulmonary function, and also what we might see in terms of mortality. You'll recall that the FDA has always been very keen on understanding both changes in ALS FRS and mortality risk. I think it's also become very well accepted in the ALS community that, given the aggressiveness and the complexity of ALS, this is probably not going to be a single therapy disease. I think it's probably going to require more than one.

Speaker Change: You'll recall that the FDA has always been very keen on understanding both changes in the ALS FRS and mortality risk I think it's also become very well accepted in the ALS community given the aggressiveness and the complexity of ILS that this is probably not going to be a single therapy.

Disease, I think it's probably.

Matthew Klein: But again, I think the specifics of return in terms of head-to-head comparison with amyloxis compound are really going to be data-driven, and we look forward to seeing the results from the cardinal study. Great, thanks for that and thank you for taking our questions. Thank you. One moment for our next question, please. And it's from the line of Danielle Brill with Raymond James. Please proceed. Hey guys, this is Alex Hunter-

Speaker Change: It required more than one but again I think the specifics I'll return in terms of head to head comparison, while with <unk> compound is really going to be data driven and we look forward to seeing the results from some of the Cardinal study.

Speaker Change: Great Thanks for that and taking our questions.

Speaker Change: Thank you one moment for our next question. Please.

Speaker Change: And he is from the line of Danielle Brill with Raymond James. Please proceed.

Speaker Change: Yes.

Speaker Change: Hey, guys. This is Alex on for Danielle.

Danielle Brill: Just looking at the Huntington's, just kind of curious about what assay you're using for CSF mutant Huntington's detection and wondering if you would expect to have similar issues that a recent competitor had, and how reliable the results are in an early HD population. Yes, great questions. There are two separate issues. There's assay reliability and then assay sensitivity based on the population. Let me take that each in turn.

Alex: Just looking at the Huntington's.

Just kind of curious about what assay you're using for <unk>.

Alex: CSF mutant Huntington's detection wondering if you would have expect to have similar issues that a recent competitor had.

Alex: And how reliable the results are in an early HD population. Thanks.

Speaker Change: Yes, great questions I think there are two separate issues stairs assay reliability, and then assay sensitivity based on the population let me take those in turn.

Matthew Klein: You know, we've worked very hard to ensure that we have robust assays that are accurate and precise. And I think, you know, one of the things we know very well about assays and clinical studies is it's not just the assay itself. There's making sure that you have care and sample acquisition, sample processing, sample storage, sample transport, and then ultimately sample analysis.

Speaker Change: We've worked very hard on ensuring that we have robust assays that are accurate and precise.

Speaker Change: And I think one of the things, we know very well about assays and clinical studies is it's not just the assay itself. There is making sure that you have care and sample acquisition sample processing samples stored samples transport and then ultimately sample analysis and those are things that we pay very close attention, obviously always minimized any confounding elements that could influence the asset.

Matthew Klein: And those are things that we pay very close attention to so that we minimize any confounding elements that could influence the assay results. And we know the other part that's important as well is that these assays tend to work much better when you have a larger number of samples. So something that we've been very thoughtful about is ensuring that we have batch samples. So each time we run these analyses, we're doing them on as many samples as makes sense at that time.

Speaker Change: We know the other part that's important as well as incentive work much better when you have a larger number of samples so something that we've been very thoughtful about is ensuring that we have batch campus. So each time, we run these analyses were doing in the auto as many samples.

Speaker Change: Does it make sense at that time, so again, all things that we can do to try to reduce the variability and increase the fidelity of those assay results you bring up another point that is very very important which is assay sensitivity based on disease stage as well no.

Matthew Klein: So, again, all things that we can do to try to reduce the variability and increase the fidelity of those assay results. But you bring up another point that's very, very important, which is assay sensitivity based on disease stage. Now, it's well known that in very early stage or pre-symptomatic HD patients, mutant Huntington protein is not detectable in a CSF because it's incredibly – the concentration is incredibly low. We're talking about picomolar concentrations and maybe even lower.

Speaker Change: Early stage or pre symptomatic.

Speaker Change: <unk> HCM patients.

Speaker Change: And protein not detectable in the CSF because its incredibly.

Speaker Change: The compensation is incredibly love talking about Picomolar concentrations and maybe even lower as we move into the phase II patients who have kidney Huntington trial of course. These are patients. We believe there is detectable huntington protein in the CSF, we've seen that so far but of course, obviously something we'll watch very carefully.

Matthew Klein: As we move into the stage 2 patients we have in the Huntington trial, of course, these are patients we believe there is detectable Huntington protein in the CSF. We've seen that so far. But, of course, obviously, something we'll watch very carefully in those patients is where we are on that in terms of the limit of detection for the acid. But that's something we're very thoughtful about. Of course, the benefit now having stage three patients is those are patients that, of course, are going to be a bit further in their progression and will likely have much higher baseline mutant hunting protein levels that will make that sensitivity issue really not. Thanks so much.

Speaker Change: And those patients days, where we are on that in terms of the.

Speaker Change: Limit of detection for the asset, but that's something we're very thoughtful about and of course the benefit now how big the stage III patients disposal patients of course, theyre going to be a bit further on their progression and will be.

Speaker Change: We'll likely have much higher baseline mutant Huntington protein levels that will make that sensitivity issue really not in Michigan.

Matthew Klein: Thank you. One moment for our last question. And he's on the line with Joseph Schwartz with Lear Inc. Partners.

Speaker Change: Thanks, so much.

Speaker Change: Thank you one moment for our last question.

Speaker Change: And he is from the line of Joseph Schwartz with Leerink partners. Please proceed.

Joseph Patrick Schwartz: Please proceed. Thanks so much for fitting me in. So, I wanted to ask, since it's been a while since QVIN and PEG-Values were approved, I'm just wondering whether, first at the end, you've been able to establish with the FDA that data focused on fee lowering will be sufficient and that clinical outcomes assessments won't be required for approval in PKU, and then I have a follow-up. Yeah, Joe, obviously, one of the most important I think traditionally, if you look at the FDA, when they have made a decision on approval based on something that doesn't change with time, it actually gives them confidence that they can interpret your study results in a meaningful way. So, we, of course, made sure that there was alignment on fee as the endpoint. Fee was the endpoint.

Joseph Patrick Schwartz: Thanks, so much for fitting me in.

Joseph Patrick Schwartz: So I wanted to ask since it's been a while since kuvin and peg values were approved.

Joseph Patrick Schwartz: I was wondering weathers throughout the afternoon.

Joseph Patrick Schwartz: Been able to establish with the FDA the data focused on C. Lowering will be sufficient clinical outcomes assessments will be required for approval in PKU and then I have a follow up.

Speaker Change: Yes, so obviously one of the most important things we did prior to commencing the phase II study is to make sure. We have full alignment on the study design, including the primary endpoint of fee reduction I think traditionally if you look at the FDA when they have made a decision on an approval based on something that doesn't change with time, it actually gives them confidence that they can.

Speaker Change: I can interpret your study results in a meaningful way. So we of course made sure there was alignment on fee as the endpoint was the endpoints and of course, we're very happy to have seen not only that we have a significant effect, but as I've talked about earlier on the call.

Matthew Klein: And, of course, we're very happy to have seen not only that we had a significant effect, but, as I've talked about earlier on the call, results that are highly statistically significant and of much greater magnitude than we've seen with previous oral therapies. So, I think that it will be very easy for them to see the not only statistically significant, but highly clinically meaningful benefit that we were able to demonstrate in the affinity trial. And, of course, one of the elements of the pre-NDA meeting was ensuring that we have the safety and efficacy data necessary to support that NDA submission. And the answer was, yes, yes, we do.

Speaker Change: Results are highly statistically significant at much greater magnitude than we've seen with previous all therapies. So I think that it becomes very easy for them to see not only signet statistically significant and highly clinically meaningful benefits, we've been able to demonstrate in the affinity trial and of course, one of the elements of the pre NDA.

Speaker Change: Meeting was ensuring that we have the safety and efficacy data in this.

Necessary to support that NDA submission and the answer was yes, yes, we do.

Matthew Klein: And then, since strong patient advocacy seemed to be key for SkyClaris to get traction with the FDA, Unknown Speaker, Unknown Attendee, Tazeen Ahmad, Kyuwon Choi, John Bohnsack, Yihan Li, As I mentioned earlier, Joe, I think the Pregiocataxia community, led by the Pregiocataxia Research Alliance, is really a model disease community in terms of aggregating the patients, I'm proud to say that we have partnered with Pharis since the beginning of the clinical development of Equinone many years ago, and we've been incredibly grateful for their partnership, not only in helping us understand how to best design trials, but also in their work in establishing a patient registry that will obviously be very important in us putting together a data package for our NDA, and, quite frankly, the work that they helped lead with the physician So, I can probably say that they've been a part of ours, and we think that's been an incredibly important part of the Equinone journey, and we think that partnership will continue to be an important part as we move forward to submit an NDA. Great, thank you.

Speaker Change: Okay, and then since strong patient advocacy you seem to be.

Speaker Change: Key for Scott clearance to get traction with the FDA wasn't onboard with three out of being able to file.

First I was wondering if you could give us any insight into how much the FAA patient or physician communities has been lending support behind your effort to pursue filing synthetic winner.

Speaker Change: As I mentioned earlier, John I think the <unk> attach rates will be led by the Egypt Ataxia Research Alliance is really a model disease community in terms of aggregating.

Speaker Change: The patients the physicians as well as industry and being able to really lead the charge in ensuring that those therapies developed.

Speaker Change: And develop successfully for the treatment of <unk> ataxia patients I'm proud to say that we have partnered with <unk> since the beginning of the clinical development of <unk> ongoing many years back and we've been incredibly grateful for their partnership not only in helping us understand how to best design trials their work and establishing a patient registry that will obviously.

Speaker Change: They're very important to us putting together a data package for NDA and quite frankly, the work that they have helped lead with the physician community and research community on demonstrating the importance of upright stability for pediatric and adolescent ambulatory patients. So I can probably say that they've been a partner of ours.

Speaker Change: And we think that's been an incredibly important part of that particular journey and we think it will continue to be in that partnership will continue to be an important partisan look forward and look to submit an NDA.

Speaker Change: Great. Thank you.

Matthew Klein: And thank you. I would like to conclude the Q&A session now, and I'll thank you all who participated and turn it back to the CEO, Dr. Matthew Klein, for additional comments. I just want to thank everyone again for joining the call today. As we've discussed, we look forward to an exciting 2024 with a number of important and valuable potential milestones ahead. We look forward to sharing the journey with you all, and thank you all for participating. You may now disconnect. Thank you for watching!

Speaker Change: And thank you.

Speaker Change: We'd like to conclude the Q&A session now and now thank you to all who participated and turn it back to the CE auto Matthew client for additional comments.

Matthew: I just want to thank everyone again for joining our call today as Steve discussed we look forward to an exciting 2024 with a number of important and valuable potential milestones ahead, and we look forward to sharing the journey with you all as we move forward. Thank you again.

Speaker Change #100: And thank you all for participating and you may now disconnect.

Speaker Change #100: Okay.

Speaker Change #100: Okay.

Speaker Change #100: [music].

Speaker Change #100: Okay.