Q2 2024 PTC Therapeutics Inc Earnings Call

August 8, 2024

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Operator: Good day, and thank you for standing by. Welcome to the PTC Therapeutics second quarter 2024 financial results.

Speaker Change: Good day and thank you for standing by. Welcome to the PTC Therapeutics second quarter 2024 financial results.

Operator: At this time, all participants are in a listen-only mode. 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 an automated message advising your hand is ready. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Ron Aldridge, Senior Director of Investor Relations.

Speaker Change: At this time, all participants are in a listen-only mode. 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 an automated message advising your hand is raised.

Speaker Change: To withdraw your question, please press star 11 again.

Speaker Change: Please be advised that today's conference is being recorded.

Ron Auburd: I would now like to hand the conference over to your first speaker today, Ron Auburd, Senior Director of Investor Relations.

Ron Aldridge: Good afternoon, and thank you for joining us today to discuss PTC Therapeutics' second quarter 2024 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 Strategy Officer, Kylie O'Keefe, and our Chief Financial Officer, Pierre Gravier.

Ron Auburd: Good afternoon and thank you for joining us today to discuss PTC Therapeutics second quarter 2024 corporate update and financial results.

Speaker Change: I'm joined today by our Chief Executive Officer, Dr. Matthew Klein, our Chief Business Officer, Eric Pauwels, our Chief Strategy Officer, Kylie O'Keefe, and our Chief Financial Officer, Pierre Gravier.

Ron Aldridge: 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 information about our forward-looking business. 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. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10-Q and annual report on Form 10-K filed with the Securities and Exchange Commission, as well as the company's other SEC filings.

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

Speaker Change: Please take a moment to review the slide posted on our Investor Relations website in conjunction with the call, which contains information about our forward-looking statements.

Ron Auburd: 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 Auburd: For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent quarterly report on Form 10-Q and annual report on Form 10-K filed with the Securities and 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. With that, let me pass the call over to our CEO, Matthew Klein.

Ron Auburd: We will disclose certain non-GAAP information during this call.

Ron Auburd: 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 Auburd: With that, let me pass the call over to our CEO , Matthew Klein. Matt? Matt? Matt? Matt?

Matthew Klein: Thank you, Ron, and thank you all for joining the call. I'm pleased to share our second quarter 2024 financial results and to provide an update on the progress of our development program. As we have discussed, our focus for 2024 is on executive. As we complete the first half of the year, I'm pleased to report that our teams have executed across all areas with solid revenue performance, on-schedule regulatory submission, and effective management of our operating expenses.

Matthew Klein: As we have discussed, our focus for 2024 is on execution.

Ron Auburd: As we complete the first half of the year, I am pleased to report that our teams have executed across all areas with solid revenue performance, on-schedule regulatory submission, and effective management of our operating expenses.

Matthew Klein: We had a very busy and productive second quarter, and I'll review some of the highlights.

Matthew Klein: Starting with commercial performance, we had another great quarter across the portfolio. Second quarter revenue totaled $187 million, including DMV franchise revenue of $118 million.

Matthew Klein: Based on this consistent, solid performance, we are updating 2024 Total Revenue Guidance to $700 million to $750 million. In addition to strong revenue, we also continue to effectively manage our operations, and will thus maintain the 2024 off-text guidance previously provided. In the second quarter, we also completed the sale of our gene therapy manufacturing business in Hopewell, New Jersey. As part of this transaction, PTC received an upfront cash payment of $27.5 million. In addition to the cash consideration, this transaction reduces expenses associated with the operation of the facility, including employee costs.

Speaker Change: Hey, for this consistent soft performance, we are updating 2024 total revenue guidance to 790-7150 million dollars.

Matthew Klein: In addition to strong revenue, we also continue to effectively manage our operating expenses and will thus maintain the 2024 Off-Tax Guidance previously provided.

Matthew Klein: In the second quarter, we also completed the sale of our Gene Therapy Manufacturing Business in Hopewell, the Jersey. As part of this transaction, PPC received an upfront cash payment of $27.5 million.

Matthew Klein: In addition to the cash consideration, its transaction induces expenses associated with operations of facilities including employee cost.

Matthew Klein: I'll now discuss the great progress our teams made across our development portfolio. As we shared last week, we submitted the NDA for sepia tarant for the treatment of PKU to the FDA. This is an important step towards our planned global launch of C-PIT care in 2025, as we bring a potential new standard of care to PKU patients around the world. The sepiaheron NDA includes significant and clinically meaningful evidence of efficacy from the Phase III Affinity Study, as well as data from the Open Label Extension Study demonstrating durability of the sepiaheron treatment benefits, as well as C. coli.

Speaker Change: I'll now discuss the great progress our teams made across our development portfolio.

Speaker Change: As we shared last week, we submitted the NDA for Cephea Tarrant for the treatment of PKU to the FDA.

Speaker Change: This is an important step towards our planned global launch of C-PIT care in 2025 as we bring a potential new standard of care to PKU patients around the globe.

Speaker Change: The sepiaheron NDA includes significant and clinically meaningful evidence of efficacy from the Phase III Affinity Study, as well as data from the Open Label Extension Study demonstrating durability of the sepiaheron treatment benefits, as well as C columns.

Matthew Klein: Recent data from the Feed Tolerance Sub-Study indicates that approximately 60% of subjects are able to increase their daily protein intake beyond the recommended daily allowance while still maintaining control of feedlots. These data support that sepia caring can provide significant benefit to PKU patients of all age groups and severity subtypes, including Classical PKU.

Speaker Change: Recent data from the Feed Tolerance Sub-Study indicates that approximately 60% of subjects are able to increase their daily protein intake beyond the recommended daily allowance while still maintaining control of feed levels.

Speaker Change: These data support that sepia carrying can provide significant benefits to PKU patients of all age groups and severity subtypes.

Matthew Klein: We plan to submit marketing authorization applications for sepia care in Japan and Brazil, as well as several additional countries in 2024 to support the global launch. Kiley will provide more details on our ongoing launch preparations. In July of this year, we also resubmitted the NDA for TransLARP. As discussed with the FDA, the submission is based on the results of Study 41, in which significant benefits were recorded across key endpoints in the IPT population, as well as on the long-term evidence of meaningful treatment benefits from this trial.

Speaker Change: Including classical PKU.

Speaker Change: We plan to submit marketing authorization applications for Supia Care in Japan and Brazil, as well as several additional countries in 2024 to support the global launch.

Speaker Change: Kylie will provide more details on our ongoing launch preparation.

Kylie: In July's plans, we also resubmitted the NDA for transplants. As discussed with the FDA, the submission is based on the results of study 41, in which significant benefits was recorded across key end points in the IPT population.

Kylie: as well as on the long-term evidence of meaningful treatment benefits from this drive register.

Matthew Klein: In the second quarter, we also shared the positive results from the 12-month interim data readout of the PIVOT-HD study of PPC518 in Huntington's disease patients. 12-Month Data Demonstrated Durable Dose-Dependent Lowering of Mutant HCP Protein in Blood, reaching 43% at the 10 milligram dose, along with dose-dependent lowering of mutant hunting tip protein in the CSF at levels similar In addition, at 12 months, there was no specific favorable clinical effect on key disease measurements, including the total motor score and the C-U-H-D-R-S.

Speaker Change: In the second quarter, we also shared the positive results from the 12-month interim data readout of the PIVOT-HD study of PPC518 in Huntington's disease patients.

Speaker Change: The 12-month data demonstrated durable, dose-dependent lowering of mutant HCP protein in blood cells, reaching 43% at the 10 mg dose level.

Speaker Change: along with dose-dependent lowering of mutant hunting protein in the CSF at levels similar to the blood in stage 2 patients.

Speaker Change: In addition, at 12 months, there was no specific favorable clinical effect on key disease measurements, including the total motor score and the C-UHDRS scale.

Matthew Klein: Importantly, the interim results also demonstrated PTC508 to be safe and have low tolerance. This combination of biomarker and clinical effect, along with favorable safety, positions PTC 518 as one of the most promising, if not the most promising therapy in development for Huntington's disease. We are in the process of preparing a meeting request to discuss with FDA the potential for accelerated approval based on the PIVOT-HD study results. In addition, we have begun work on the design of the Phase 3 efficacy trial of PTC518, which can serve as a confirmatory study in the context of an accelerated approval or as a registration study. We look forward to continuing to advance PTC 518 to the over 130,000 symptomatic Huntington's disease patients worldwide who desperately need a safe and effective disease modifier.

Speaker Change: Importantly, the interim results also demonstrated PTC508 to be safe and well-pollinated.

Speaker Change: This combination of biomarker and clinical effect, along with favorable safety, position PTC 518 as one of the most promising, if not the most promising therapy in development for Huntington's disease.

Speaker Change: We are in the process of preparing a media request to discuss with FDA the potential for accelerated approval based on the PIVOT-HD study results.

Speaker Change: In addition, we have a gun work on the design of the Phase III FFP trial at PCC 508, which can serve as a conservatory study in the context of an accelerated vehicle for as a registration trial.

Speaker Change: We look forward to continuing to advance PTC-518 to the over 130,000 symptomatic Huntington disease patients' world bodies who desperately need a faith and affect them to these mild-bomb families.

Matthew Klein: As we move into the second half of 2024, we remain on schedule for our planned regulatory activities and have set a milestone. We are in the process of preparing the NDA submission for vatiquinone for the treatment of freezer cataxia, which we expect to submit by the end of the year. This submission will be based on the findings of significant treatment benefits in pediatric and young adult patients on the Upright Stability subscale of the MFAR's Disease Rating Scale from the MOVE FA study, along with confirmatory evidence from the long-term open-label portion of the trial.

Speaker Change: As we move into the second half of 2024, we remain on schedule for our planned regulatory and clinical milestones.

Speaker Change: We are on the process of preparing the NDA's submission for the TIPWIL known for the treatment of future catastrophe, which we expect us to miss by the end of the year.

Speaker Change: This submission will be based on the findings of significant treatment benefits in pediatric and young adult patients on the Upright Stability subscale of the MFAR's Disease Rating Scale from the MOOC-FA study, along with confirmatory evidence from the long-term open-labeled portion of the trial.

Matthew Klein: As we have previously discussed, the Upright Stability Scale is the most sensitive and relevant portion of the MFARs for pediatric and young adult ambulatory patients and has been shown to be predictive of risk of long-term loss of ambulation.

Speaker Change: As we have previously discussed, the upright stability scale is the most sensitive and relevant torsions of the m-ballies for pediatric and young adult ambulatory patients, and has been shown to be predictive of risk of long-term loss of ambulance.

Matthew Klein: And most importantly, ticrinone also has a strong safety profile, including in children under age 16, for whom there are no approved FA therapies. Finally, we remain on schedule to share top-line results from the Registration-Directed Cardinals Trial of Utrilaxis Stats in ALS Patients in the 4th Quarter. Eculoxasat is the first compound being developed for ALS that specifically targets a pathway of oxidative stress and cell death demonstrated to be highly relevant to ALS cells. Given the recent changes in the ALS therapeutic landscape, positive results from the Cardinal study could enable Nutriloxistat to address the significant unmet need for ALS.

Speaker Change: Importantly, the Tiquinone also has a strong safety profile, including in children under age 16 for whom there are no approved FA therapies.

Speaker Change: Finally, we remain on schedule to share top-line results from the Registration-Directed Cardinals Trial of Utreloxistat in ALS patients in the fourth quarter. Utreloxistat is the first compound being developed for ALS that specifically targets therapeutics.

Speaker Change: A pathway of oxidative stress and cell death demonstrated to be highly relevant to ALS pathology.

Speaker Change: Given the recent changes in the ALS therapeutic landscape, positive results from the Cardinal study could enable utilisat to address the significant unmet need of ALS patients.

Matthew Klein: Closing. I'm proud of our team's continued execution. We achieved all of our objectives and remain on schedule to achieve the many milestones we have set for the remainder of 2020. I will now turn the call over to Eric and Kylie to discuss our commercial support. Thanks, Matt.

Speaker Change: and closing. I'm proud of our team's continued execution. We accomplished all of our objectives and we made on schedule to achieve the many milestones we have set in the remainder of 2020.

Speaker Change: I will now turn the call over to Eric and Kylie to discuss our commercial support.

Eric Pauwels: Our global customer facing team had a strong first half of the year, delivering $133 million in revenue in Q2 across our five marketed products. Our global DMD franchise had a solid quarter during which we delivered 118 million. We continue to actively commercialize TransLarna in all European markets and in other international markets as our geographic expansion continues to progress further. Our commercial teams are working closely with healthcare providers to ensure that patients continue to have access to treatment in Europe for as long as TransLarna remains authorized pending the re-examination and ratification processes.

Speaker Change: Eric

Eric: Thanks Matt. Our global customer facing team had a strong first half of the year delivering 133 million in revenue in Q2 across our five marketed products.

Speaker Change: Our global DMD franchise had a solid quarter during which we delivered $118 million.

Speaker Change: We continue to actively commercialize TransLarna in all European markets and in other international markets as our geographic expansion continues to progress further.

Speaker Change: Our commercial teams are working closely with healthcare providers to ensure that patients continue to have access to treatment in Europe. For as long as transformative remains authorized, pending the re-examination and ratification processes.

Eric Pauwels: In Brazil, we signed a new group purchase order with the Ministry of Health and delivered 50% of this order in the second quarter, with the remainder of the order delivered in the third quarter. As Matt mentioned, we have resubmitted the NDA for TransLearn in the US. And the team is well positioned to bring this important treatment to non-sense mutation DMD patients pending FDA approval. Now, turning to Implaza. In the second quarter, net revenue was $47 million.

Speaker Change: In Brazil, we signed a new group purchase order with the Ministry of Health and delivered 50% of this order in the second quarter.

Speaker Change: With the remainder of the orders delivered in the third quarter.

Speaker Change: As Matt mentioned, we have resubmitted the NDA for TransLearner in the U.S.

Matt: and the team is well positioned to bring this important treatment to non-sensification D&D patients pending FDA approval.

Matt: Now, turning to Implaza, second quarter net revenue was $47 million.

Eric Pauwels: We continue to work closely with health care providers, payers, and specialty pharmacies to dispense the brand. Additionally, we are leveraging PTC CARES patient programs, providing personalized services and support to each patient with insurance co-pays and timely shipments from specialty pharmacies. These efforts continue to reinforce the benefits of Enplaza for a significant number of new patient starts and maintaining existing patients on treatment, all of which are key revenue drivers for the brand here today. Now, I will hand it over to Kylie to update you on the progress of our current and future new product launches. Kylie?

Matt: We continue to work closely with healthcare providers, payers, and specialty pharmacies to dispense the brand.

Matt: We are leveraging PTC CARES patient programs, providing personalized services and support to each patient with insurance co-pays and timely shipments from specialty pharmacies.

Speaker Change: These efforts continue to reinforce the benefits of Enplaza for a significant number of new patient starts and maintaining existing patients on treatment, all of which are key revenue drivers for the brand here today.

Speaker Change: Now, I will hand it over to Kylie to update the progress of our current and future new product launches.

Kylie O'Keefe: We are extremely excited about the upcoming global launch of Sepiateran. As Matt mentioned, we have filed our NDA in the US, which is an important step in bringing Sepiateran to children and adults with PKU. In addition, in May, we received validation of our EU MAA filing, and review is ongoing.

Matt: Kylie?

Kylie: Thanks, Eric. We are extremely excited about the upcoming global launch of Sepiateran. As Matt mentioned, we have filed our NDA in the U.S., which is an important step in bringing Sepiateran to children and adults with PKU.

Speaker Change: In addition, in May, we received validation of our EU MAA filing and review us on going.

Kylie O'Keefe: Further submissions are planned in several additional countries in 2024, including Brazil and Japan, which, alongside the US and Europe, are considerable value drivers for the global launch. The Sepiaterin data package supports clear differentiation versus current therapies and includes data from the Phase 3 affinity trial, where 84% of the subjects achieved fee control in accordance with treatment guidelines of less than 360 micromolar per liter, and 22% of subjects had normalization of fee levels.

Speaker Change: Further submissions are planned in several additional countries in 2024, including Brazil and Japan, which alongside the U.S. and Europe are considerable value drivers for the global launch.

Speaker Change: The Sepia Terran Data Package supports clear differentiation versus current therapies.

Speaker Change: and includes data from the Phase 3 Affinity Trial where 84% of the subjects achieve fee control in accordance with treatment guidelines.

Speaker Change: of less than 360 micromolar per litre, and 22% of subjects had normalisation at fee levels.

Kylie O'Keefe: It also includes data from the Affinity Open Label Extension Study, which provides evidence of subjects being able to achieve protein intake above the age-adjusted recommended daily allowance for unaffected individual people while still maintaining fee levels less than 360 micromolar per liter.

Speaker Change: It all also includes data.

Speaker Change: from the Affinity Open Label Extension Study.

Speaker Change: which provides evidence of subjects being able to achieve protein intake above the age-adjusted recommended daily allowance for unaffected individual people while still maintaining fee levels less than 360 micromolar per litre.

Kylie O'Keefe: The ability to liberalize the diet is an important factor for physicians, payers, and patients alike and will drive uptake. We've been planning for our launch of SEPIATARAN for several years, and preparations are going very well. We have been working closely with geneticists, pediatric metabolic specialists, and dieticians to understand the needs of the PKU patients and to build a strong relationship with the PKU community. Our teams have a deep understanding of the PKU prescribers and their prescribing habits, as well as how to reach them. Unlike other rare diseases, PKU patients are identified through newborn screening and managed by well-defined PKU treatment centers.

Speaker Change: The ability to liberalize the diet is an important factor for physicians, payers and patients alike and will drive uptake.

Speaker Change: We've been planning for our launch ofsteppy appearance for several years and preparations are going very well.

Speaker Change: We've been working closely with geneticists, pediatric metabolic specialists, and dietitian. To understand the needs of the PKU patient and to build a strong relationship with the PKU community.

Speaker Change: Our teams have a deep understanding of the PKU prescribers and their prescribing habits, as well as how to reach them.

Speaker Change: Unlike other rare diseases, PKU patients are identified through newborn screening and managed by well-defined PKU treatment centers.

Kylie O'Keefe: We have mapped these key treatment centers globally and the key opinion leaders and treating physicians within each treatment center. In addition, we have an established rare disease global infrastructure with a footprint in over 50 countries. Our experienced teams understand the complexities of rare diseases, as well as the regulatory and payer landscape in each of the different regions and countries. All of this will enable us to have a rapid and highly targeted focus on key customers and stakeholders at launch, and reinforces our belief in the potential $1 billion plus global opportunity. Turning to the Upstate.

Speaker Change: We have mapped these key treatment centers globally and the key opinion leaders and treating physicians within each treatment center.

Speaker Change: In addition, we have an established rare disease global infrastructure with a footprint in over 50 countries.

Speaker Change: Our experienced teams understand the complexities of rare disease, as well as the regulatory and payer landscape in each of the different regions and countries. All of this will enable us to have a rapid and highly targeted focus on key customers and stakeholders at launch.

Speaker Change: and rain forces our beliefs in the potential $1 billion plus global opportunity.

Kylie O'Keefe: In May, we announced that the FDA had accepted the BLA and granted priority review with the target regulatory action date of November 13, 2024. Launch preparations in the U.S. are well underway. Globally, access and reimbursement discussions advance as we continue to treat patients in Europe through access and cross-border health care.

Speaker Change: Turning to Upstaider.

Speaker Change: In May we announced that the FDA had accepted the BLA and granted priority reviewed with the target regulatory action date of November 13, 2024.

Speaker Change: Launch preparations in the U.S. are well underway.

Speaker Change: Globally, access and reimbursement discussions advance as we continue to treat patients in Europe through access and cross-border health care.

Kylie O'Keefe: In addition, we secured approval in Taiwan and are preparing for additional filings and regulatory approvals globally. Moving to Tegceti and Weylebra in LATAM, we continue to make good progress across these franchises, with growth in both patients identified and treated across the region. Our geographical expansion continues with the recent approval of TxEDI in Mexico, following which we have initiated reimbursement discussions. In Brazil, we received a new group purchase order for Tegceti, of which 50% was delivered in the second quarter, and we anticipate delivering the remainder in the third quarter.

Speaker Change: In addition, we secured approval in Taiwan and are preparing for additional filings and regulatory approvals globally.

Speaker Change: Moving to Tegceti and Weylebra in Latam, we continue to make good progress across these franchises with growth in both patients identified and treated across the region.

Speaker Change: Our geographical expansion continues with a recent approval of Tech City in Mexico, following which we have initiated reimbursement discussion.

Speaker Change: In Brazil, we received a new group picture sort of for tag study of which 50% was delivered in the second quarter, and we anticipate delivering the remainder in the third quarter.

Kylie O'Keefe: Additionally, for WayLevera, in the second quarter, we delivered 50% of the new group purchase order. In conclusion, coming off a robust first half of the year, as Matt mentioned, we are updating our guidance with a 2024 total revenue guidance of $700 to $750 million. We have set a strong trajectory for 2024 and will continue to deliver and diversify our portfolio across our geographies, as well as to prepare for a successful global launch of Sepia Terran in 2025. I will now turn the call over to Pierre for a financial update. Pierre? Thank you, Kay.

Speaker Change: Additionally, for WayLevera, in the second quarter, we delivered 50% of the new group purchase order.

Speaker Change: In conclusion, coming off a robust first half of the year, as Matt mentioned, we are updating our guidance with a 2024 total revenue guidance of $700 to $750 million.

Matt: We have set a strong trajectory for 2024 and continue to deliver and diversify our portfolio across our geography, as well as to prepare for a successful global launch of Sapia Terran in 2025.

Speaker Change: I will now turn the call over to Pierre for a financial update. Pierre?

Pierre Gravier: I'll now share the financial highlights of our second quarter of 2020. Please refer to the earliest press release issued this afternoon for additional details.

Pierre: Thank you, Kylie.

Pierre: I'll now share the financial highlights of our second quarter of 2024.

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

Pierre Gravier: Beginning with top-line results, total revenue for the second quarter was $187 million, including D&D franchise revenue of $118 million. From Flana, net product revenue in a quarter was $70 million, while in FlaZa, net product revenue was $47 million. Moving to Evelyn,

Pierre: Beginning with top line results, total revenue for the second quarter was $187 million, including D&D franchise revenue of $118 million.

Speaker Change: From Flourna Net Product Review in the quali was 17 million, or in Flourna Net Product Review of 47 million.

Pierre Gravier: Second quarter global revenue of approximately $535 million was achieved by Roche, resulting in Roche's revenue of $53 million for PTC. Non-GAAP R&D expense was $123 million for the second quarter of 2024, excluding $9 million in non-cash stock-based compensation expense, compared to $117 million for the second quarter of 2023, excluding $16 million in non-cash stock-based compensation, The year-over-year reduction in R&D expenses reflects our strategic portfolio prioritization as the company continues to focus its resources on its differentiated, high-potential programs.

Pierre: Moving to SVG.

Speaker Change: Second quarter global review of approximately $35,000,000, you had $1,000 that she'd buy wash, resulting in ROC review of $63,000,000 for PTC.

Speaker Change: Norm Gapareny expanse was a hundred and twenty-three million for the second quarter of 2024, excluding nine million in non-cash stock-based composition expanse, compared to a hundred and seventy million for the second quarter of 2023, excluding 16 million in non-cash stock-based composition expanse.

Speaker Change: The year over year reduction in energy expenses reflects our strategic portfolio prioritization as the company continues to focus its resources on its differentiated high-plot-on-share program.

Pierre Gravier: Non-GAAP SG&A expense was $60 million for the second quarter of 2024, excluding $10 million in non-cash stock-based composition expense, compared to $75 million for the second quarter of 2023, excluding $14 million in non-cash stock-based composition expense. In the second quarter, TTC amended its agreement with Royalty Pharma and exercised one of its put options in exchange for $250 million in cash, less royalties. Cash, cash requirements, and marketable securities total $1.09 billion as of June 30, 2024, compared to $877 million as of December 31, 2020.

Jane: Non-Gap as Jane expands with 60 million for the second quarter of 2024, excluding 10 million in non-cash.base composition expands, compared to 75 million for the second quarter of 2023, excluding 14 million in non-cash.base composition extends.

Unknown Executive: Good day, and thank you for standing by.

Unknown Executive: Welcome to the PTC Therapeutics Second Quarter 2024 Financial Results. 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 11 on your telephone. You will then hear an automated message advising your hand is raised. To draw your question, please press star 11 again.

Speaker Change: In the second quarter, PTC amended its agreement with Royalty Pharma and exercised one of its put options in exchange for $250 million in cash less royalties received.

Speaker Change: Cash, cash requirements, and marketable securities total $1.09 billion as of June 30, 2024, compared to $877 million as of December 31, 2023.

Unknown Executive: Please be advised, so today's conference is being recorded.

Ron Aldridge: I would now like to hand the conference over to your first speaker today, Ron Aldridge, Senior Director of Investor Relations. 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 information about 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 for a detailed description of applicable risks and uncertainties.

Pierre Gravier: Our 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 sepia theory now. And I will now turn the call over to the operator.

Speaker Change: Our 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 sepia theory launch.

Speaker Change: and then we'll not turn the call over to the operator for a Q&A.

Operator: At this time, we will conduct the question and answer session. As a reminder, to ask a question, you'll need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A list. Our first question comes from the line of Kristen Kluska from Cantor Fitzgerald. Your line is now open.

Speaker Change: Operator.

Speaker Change: Thank you.

Speaker Change: At this time, we will conduct a question and answer session. As a reminder to ask a question, you need to press star 1-1 on your telephone and wait for your name to be announced.

Speaker Change: To withdraw your question, please press star 1 1 again. Please stand by while we compile the Q&A roster.

Speaker Change: Our first question comes from the line of Kristen Kluska from Cantor Fitzgerald. Your line is now open.

Kristen Kluska: Hi everyone. Good afternoon. Congratulations on a great quarter and thanks for taking my question.

Kristen Kluska: Hi everyone, good afternoon. Congrats on a great quarter and thanks for taking my question. The first one I had was on Huntington's disease. Obviously, looking at the field, we've seen a lot of data recently, but one thing that stood out is your approach seems to be one of the only ones where you're not seeing an increase in NFL through the therapy. Obviously, it's a prognostic biomarker of neurodegeneration, but other drugs have been shown to make it worse. So a question we've been getting is do we have a sense of how dangerous it is when NFL increases via drug targeting? And then second, is this a really important consideration for physicians on safety?

Kristen Kluska: The first one I had was on Huntington's disease. Obviously, looking at the field, we've seen a lot of data recently, but one thing that stood out was your approach seems to be one of the only ones where you're not seeing an increase in NFL through the therapy. Obviously, it's a prognostic biomarker of neurodegeneration, but other drugs have been shown to make it worse. So a question we've been getting is, do we have a sense of how dangerous it is when NFL increases via drug targeting? And then second, is this a really important consideration for physicians regarding safety?

Ron Aldridge: We encourage you to review the company's most recent quarterly report on form 10Q and annual report on form 10K filed with the Securities and Exchange Commission, as well as the company's other SEC filings. We will disclose certain non-gap information during this call. Information regarding our use of gap to non-gap financial measures and a reconciliation of gap to non-gap are available in today's earnings release.

Matthew Klein: Kristen, thanks very much for the question. So, you know, the goal here is to develop a therapy, a disease-modifying therapy, for patients with Huntington's disease that is both effective and safe. The safety of the product during development is incredible. When we talk about Huntington lowering as a therapeutic strategy, it makes a lot of sense. It's well understood.

Matthew Klein: With that, let me pass the call over to our CEO, Matthew Klein. Matt? Thank you, Ron, and thank you all for joining the call. I'm pleased to share our second quarter, 2024 financial result, and to provide an update on the progress of our development programs. As we have discussed, our focus to 2024 is on execution. As we complete the first half of the year, I'm pleased to report that our teams have executed across all areas with solid revenue performance on federal regulatory submission and effective management of our operating expense.

Kristen Kluska: Christian, thanks very much for the question. So, you know...

Christian: The goal here is to develop a therapy, a disease-modifying therapy, for patients with Huntington's disease that is both effective and safe. So, the safety of the product during development is of incredible importance.

Christian: When we talk about Huntington-Lowering as a therapeutic strategy,

Matthew Klein: Huntington's disease is a monogenetic disease caused by the production of a toxic mutant Huntington protein. The goal of Huntington lowering is to decrease that protein that is causing the disease. And, of course, there's a broad scientific literature substantiating that lowering Huntington protein, or mutant Huntington protein, is likely to result in clinical benefit. In the development of PTC 518, we really followed the playbook established by RISD for the development of a both safe and effective oral slicing agent for a whole brain disease-like hunting. Therefore, in the development, it's incredibly important to ensure that we're lowering Huntington protein so that we can have the desired therapeutic effect one would expect from reducing the cause of addiction.

Christian: It makes a lot of sense. It's well understood. Huntington's disease is a monogenetic disease caused by the production of a toxic mutant Huntington protein.

Christian: The goal of Huntington-Lowering is to decrease that protein that is causing the disease. And of course, there's a broad scientific literature substantiating that lowering Huntington protein, due to Huntington protein, is likely to result in clinical benefit.

Matthew Klein: We had a very busy and productive second quarter, and I'll review some of the highlights. Starting with commercial performance, we had another great quarter across the portfolio. Second quarter revenue totaled $187 million, including a DMG franchise revenue of $118 million. Made for this consistent solid performance, we are updating 2024 total revenue guidance to $700 million to $750 million. In addition to strong revenue, we also continue to effectively manage our operating expense. Census, and will thus maintain the 2024 off-text guidance previously provided.

Speaker Change: In the development of PTC-518, we really followed the playbook established by Ruby for the development of a both state and effective oral slicing agent for a whole brain disease like Huntington.

Christian: Therefore, in the development, it was incredibly important to ensure that we're lowering Huntington protein so that we can have the desired therapeutic effect one would expect from reducing the cause of a disease.

Matthew Klein: But at the same time, wanting to make sure that we're doing so safely, and that involves making sure that we have a molecule that is specific, and select it for the Huntington target, and it gets into the brain, gets to all regions of the brain, because Huntington's disease is a whole brain disease. And so when we look at these markers of safety like NFL, we're asking, are we seeing some harm to nerve cells?

Matthew Klein: In the second quarter, we also completed the sale of our gene therapy manufacturing business in Hopewell, New Jersey. As part of this transaction, PTC received an up-front cash payment of 27.5 million dollars. In addition to the cash consideration, this transaction reduces expenses associated with operation facilities, including employee costs.

Christian: But at the same time wanting to make sure that we're doing so safe, and that involves making sure that we have a molecule that is...

Christian: Stampic

Christian: And it's selected for the Huntington's target, and it gets into the brain, gets to all regions of the brain, because Huntington's disease is a whole brain disease.

Matthew Klein: Because the way that nerve cell injury can present itself is through NFL spikes, and this is something that has been seen in the development of a number of therapies. And it's the reason why, as you pointed out, NFL could be thought of as a marker of clinical benefit, but more importantly, Huntington's disease, over the shorter period of time of a clinical trial, it's really acknowledged to be more important as a marker of safety.

Christian: And so when we look at these markers of safety like NFL, we're asking, are we seeing some harm to nerve cells? Because the way that nerve cell injury can present itself is through NFL spikes.

Matthew Klein: How now discuss the great progress our teams made across our development portfolio?

Matthew Klein: As we shared last week, we submitted the MBA PTC affairing for the treatment of PKU to the FDA.

Matthew Klein: This is an important step towards our planned global law to see this affair in 2025, as we bring a potential new standard of care to PKU patients around the globe. The CPCAR and NDAs include significant and clinically meaningful evidence of efficacy from the Phase III Affinity Study, as well as data from the Open Label Extension Study demonstrating durability of the CPCAR and treatment benefits, as well as fee tolerance. Recent data from the fee tolerance study indicates that approximately 60% of subjects are able to increase their daily protein intake beyond the recommended daily allowance while still maintaining control of fee levels. These data supports that CPCAR and can provide significant benefit to PKU patients of all phase groups and severity sometimes, including classical PKUs.

Speaker Change: And this is something that has been seen in the development of a number of bees and bees and the reason why, as you point it out, and it felt could be thought of as a...

Speaker Change: Marker of clinical benefit, but more importantly, Huntington's disease over the shorter period of time of a clinical trial It's really acknowledged to be more important as a marker of safety

Matthew Klein: Are we delivering therapeutic benefit without causing spikes that show that we may also be causing harm? So the fact that we've not seen any evidence of treatment-related NFL spikes, and we continue to observe that PTC511 has been safe and well-tolerated in the PivotAge study, is an incredibly important finding for patients. And then to also say that we're having the desired biomarker effect of lowering Huntington's protein in the blood, we're seeing lowering of Huntington's protein in CSF, and importantly, as we reported, we're seeing early evidence of clinical benefit on key disease scales, like total motor score and CUHCRF, tell us that so far we're seeing that we're having the desired therapeutic benefit, one would hope, for disease-modifying therapy, but importantly, we're also having the safety that will be incredibly important for a successful therapy.

Speaker Change: are we delivering surgery to benefit without causing sites that show that we make also the cause and cause.

Speaker Change: So, the fact that we have not seen any evidence of treatment-related NFL spikes, and we continue to observe that PTC518 has been safe and well-tolerated in the PIVOT HC study, is an incredibly important finding for patients.

Speaker Change: and then to also say that we're having a design by a marker effect of lowering hunting and protein in the blood, receiving lowering and hunting and protein to CFF and importantly, as we reported, we're seeing fairly evidence of clinical benefit on key disease scales, until the motor score and to you each year at.

Matthew Klein: These plans have been marking operation applications for CPCAR in Japan and Brazil, as well as several additional countries in 2024 to support the global launch.

Speaker Change: tell us that, so far, we're seeing that we're having the desired therapeutic benefit and what we hope for disease-modifying therapy. But, importantly, we're also having the safety that will be incredibly important for a successful therapy.

Matthew Klein: Finally, we'll provide more details on our ongoing launch preparation.

Matthew Klein: In July of plans, we also resubmitted the NDA for transplants. As discussed with the FDA, the submission is based on a result of study 41 in which significant benefit was recorded across TN points in the IPC population, as well as on the long-term evidence of meaningful treated benefits from the strivers. In the second quarter, we also shared the positive results from the 12-month interim data readouts of the PIVIT HC study of PCC-518 and Huntington disease patients.

Kristen Kluska: Thanks for that, Matt. And then, if I may ask a second question, just on PKU, I think when we think about rare disease launches, the uptake curve is always different depending on the disease. So how would you think about this one for maybe the first two years? You already have a really good sense of where the patients are that you've identified that either don't respond or don't take the standard of care. Thank you again.

Speaker Change: Thanks for that Matt. And then if I may ask a second question just on PKU, I think when we think about rare disease launches the uptake curve is always different depending on this disease. So how would you think about this one for maybe call it the first two years? You already have a really good sense of where the patients are that you've identified that either don't respond or don't take standard of care. Thank you again.

Matthew Klein: The 12-month data demonstrated durable dose-dependent lowering of mutant HC-C protein and blood cells, reaching 40 few percent of the 10-millimeter dose levels, along with dose-dependent lowering of mutant HC-C protein and the CSF at level similar to the blood in phase 2 patients. In addition at 12-month, there was dose-dependent favorable clinical effect on C disease measurements, including the total motor score and a CUHDRF scale. Importantly, the engine results also demonstrated PTC-518 to be safe and no-followed.

Matthew Klein: Yeah, absolutely. And as Kyla mentioned in her comments, we've been preparing for several years now for a successful launch. I'll let Kyla talk about how we expect the ramp-up.

Speaker Change: Yeah, absolutely. And as Kyla mentioned in her comments, we've been preparing for several years now for a successful launch. I'll let Kyla talk about how we expect the ramp to be.

Kylie O'Keefe: Yeah, absolutely. Thanks, Kristen.

Kylie O'Keefe: As Matt said, and as I mentioned in my prepared remarks, we've been preparing for this launch for a number of years now, and it's been going really well. We have a focus across all of the different important prescribers, as well as the ancillary physicians that are relevant to this disease in the key treatment centers of excellence. And as you noted, we're also very close to the PKU community, understanding where the unmet medical need is and where these patients exist.

Kyla: Yeah, absolutely. Thanks Kristen. As Matt said, and as I mentioned in my prepared remarks, we've been preparing

Kyla: For this launch for a number of years now and been going really well, we have a focus across all of the...

Speaker Change: Different important prescribers, as well as the ancillary physicians that are relevant to this disease in the key treatment centers of excellence. And as you noted, we're also very close to the PKU community, understanding where the unmet medical need is and where these patients exist.

Matthew Klein: This combination for biomarker and clinical effect, along with favorable safety, position PTC-518 as one of the most promising, if not the most promising therapy in development for Huntington disease. We are in the process of preparing a needed request to discuss with FDA the potential for accelerated approval based on the PIVIT HC study results. In addition, we have begun work on the design of the Phase 3 Epipathy Trial of PTC 518, which can serve as a confirmatory study in the context of an accelerating approval for as a registration trial.

Kylie O'Keefe: And so, as you said, this is not your traditional rare disease launch in the sense that patients are identified through newborn screening at birth and well-known treatment centers of excellence. And so that, coupled with our expertise and our preparation, means that we are expecting a fast uptake, particularly in the U.S., where it's one market we're able to move fast with pricing and reimbursement. And then outside of the U.S., we'll look to each market that has named patient programs and early access programs to move quickly in those markets as well, while we progress with regulatory submissions and formal pricing and reimbursement. So across the board, I think we're looking at relatively fast and rapid uptake.

Speaker Change: And so, as you said, this is not your traditional rare disease launch in the sense that...

Kyla: Patients are identified through newborn screening at birth and well-known treatment centers of excellence. And so that coupled with our expertise and our preparation means that we are expecting a fast uptake, particularly in the US.

Kyla: where it's one market where we're going to move fast with pricing and reimbursement. And then outside of the U.S., we'll look at each market that has named patient programs in early access programs.

Kyla: can move quickly in those markets as well while we progress with regulatory submissions in formal pricing and reimbursement. So across the board, I think we're looking at a relatively fast and rapid uptake.

Matthew Klein: We look forward to continuing to advance PTC 518 to the over 130,000 symptomatic hunting symptoms of the patient's worldwide who desperately need a safe and effective disease-modified trial effect. As we move into the second half of 2024, we remain on schedule for our planned regulatory and suitable milestones.

Eric Joseph: Thank you. Our next question comes from the line of Eric Joseph of JP Morgan. Go ahead, Eric.

Kyla: Thanks, everyone.

Speaker Change: Thank you. Our next question comes from the line of Eric Joseph of J.P. Morgan. Go ahead, Eric.

Eric Joseph: Thank you, and good evening. We have a couple questions from us. First, on top-line guidance, I'm wondering if you could unpack that a little bit for what's anticipated in terms of net product sales marketed by PTC. Secondly, on PTC 518 and Huntington's, I'm wondering if you could give us a sense of when you hope to have a meeting with FDA for a Type B or Type C meeting on a potential registration path.

Matthew Klein: We are on the process of preparing the NDA submission for particular for the treatment of regicotactula, which we expect to submit by the end of the week. This submission, when we based on the findings of significant treatment benefits in pediatric and young adult patients, on the upright stability sub-scale of the hemp bars with these rating scale to move our face down along with confirmatory evidence in the long-term open labeled portion of the trial.

Eric Joseph: Thank you, and good evening. A couple of questions from us first on top line guidance. Why don't you if you can unpack that a little bit for what's anticipated in terms of?

Speaker Change: Net product sales marketed by PTC.

Speaker Change: Secondly, on PDC 518 and Huntington's...

Eric Joseph: I'm wondering if you could give us a sense of...

Speaker Change: When you hope to have a meeting with FDA for a type B or type C meeting on a

Matthew Klein: As we have previously discussed, the upright stability scale is the most sensitive and relevant portion of the hemp bars for pediatric and young adult ambulatory patients and has been shown to be predictive of risk of long-term loss of amuletion. Importantly, the PTC also has a strong safety profile, including in children under age 16, for whom there are no approved FA therapies.

Eric Joseph: And also wondering how you think about the merits of breakthrough therapy designation for this indication and whether that's something you intend to pursue with the compound. And then finally, on Vatiquinone, what's left to kind of get over the line for that submission in phagocytotoxia? I believe data from the Open Label Extension portion of MOVE-FA would be part of that. Thank you. Additional follow-up from that study, is that something you plan to share with STREET? Thanks very much.

Speaker Change: You know potential registration path and also wondering how you think about the merits of breakthrough therapy designation for this indication and whether that's something you intend to pursue with the compound.

Speaker Change: And then finally, on Vatiquinone, what's left to kind of get over the line for that submission in phagocytotoxia? I believe data from the Open Label Extension portion of MOVE-FA was part of that. Have you...

Matthew Klein: Finally, we remain on schedule to share top line results in the registration-directed cardinal trial of e-trolactyl stat and ALF patients in the fourth quarter. E-trolactyl stat is the first compound being developed for ALF that specifically targets pteroposis. A pathway of oxygenated stress and cell death demonstrated to be highly relevant to ALF knowledge. Given the recent changes in the ALF therapeutic landscape, positive results from the cardinal study could enable e-trolactyl stat to address the significant unmet needs of ALF patients.

Speaker Change: Reviewed. Additional follow-up from that study. Is that something you plan to share with STREET? Thanks very much.

Matthew Klein: Thanks for the questions, Eric. I'm going to go in reverse order and start with the third one first.

Matthew Klein: So the Tiquidone NDA is coming along. We expect the submission to happen before the end of the year. As I mentioned in my comments, that's going to be based on the 72-week placebo-controlled data from MOVE-FA, where we had a significant effect on upright stability and a number of other relevant disease measures, as well as long-term open-label data from MOVE-FA, as well as the long-term extension data from the earlier freezer catastrophe study done many years ago in adult patients.

Speaker Change: Thanks for the questions there, I'm going to go in reverse order or stop at the third one first. So the Lithuano and the A is coming along and the rest of the mission happened for the end of the year.

Speaker Change: As I mentioned in my comments, that's going to be based on the 72-week placebo-controlled data from MOOC-FA, where we had significant effects on upright stability in a number of

Matthew Klein: In closing, I'm proud of our team's continued execution. We accomplished all of our objectives and remained on schedule to achieve the many milestones we have set to the remainder of 2022.

Speaker Change: of other relevant...

Speaker Change: these measures, as well as long-term open label data, both from MOVE-FA, as well as the long-term extension data from the earlier free drug catastrophe studies on many years ago in adult patients.

Eric Joseph: I'll now turn the call over to Eric and Piley to discuss our commercial performance. Eric? Thanks, Matt. Our global customer facing team had a strong first half of the year, delivering 133 million in revenue in Q2 across our five marketed products. Our global DMD franchise had a solid quarter during which we delivered 118 million. We continue to actively commercialize Translana in all European markets and in other international markets as our geographic expansion continues to progress further.

Matthew Klein: We had previously done that long-term analysis, but that was published showing significant benefit over a 24-month period. At the FDA's request, we are going to repeat that analysis with newer natural history match data, and so we provided a statistical analysis plan to the FDA for their buy-in, and then we'll do that analysis. We're still waiting for the final long-term extension data from MOVE-FA to be collected. The data collection will be completed shortly, and then we'll be able to move forward with that long-term analysis and get the whole package together for submission.

Speaker Change: We had previously done that long-term analysis that that was published showing significant benefit over a 24-month period.

Speaker Change: At the FDA's request, we are going to repeat that analysis with newer natural history match data. And so we provided a statistical analysis plan to the FDA for their buy-in.

Speaker Change: We're still waiting for the final long-term extension data for move FA to be collected, those data will be collected. The data collection will be completed shortly, and then we'll be able to move forward with that long-term analysis and get the whole practice together for submission.

Matthew Klein: We do plan a pre-MDA meeting with the agency, as we always do, to review the content and structure of the FDA, and we will share data when we have it from those open-label studies that go into the FDA. On your second question regarding PTC 518 and the regulatory path, with the results from the interim results from PIVOT-HD, as we talked about, we are moving forward on two fronts. One is to have a discussion with the agency regarding the potential for Huntington-Bowring to serve as a surrogate endpoint likely to predict clinical benefits that could allow us to access the accelerated approval pathway, and also a separate interaction to discuss our endpoint strategy for the efficacy trial, which we've said would either be a registration study or, in the context of potential accelerated approval, could be a confirmatory trial.

Eric Joseph: Our commercial teams are working closely with healthcare providers to ensure that patients continue to have access to treatment in Europe for as long as Translana remains authorized, pending the re-examination and ratification processes. In Brazil, we signed a new group purchase order with the Ministry of Health and delivered 50% of this order in the second quarter, with a remainder of the orders delivered in the third quarter. As Matt mentioned, we have resubmitted the NDA for Translarning the US, and the team is well positioned to bring this important treatment to non-sense mutation D&D patients pending FDA approval.

Speaker Change: We do plan a pre-MDA meeting with the agency, as we always do, to review the contents and structure of the FDA, and we will share data when we have it from those open-label studies that go into the MDA.

Speaker Change: On your second question regarding PTC 518 and the regulatory path,

Speaker Change: with the results from the Inter-Results and Pivot HD, as we've talked about, we're moving forward on two phones.

Speaker Change: One is to have a discussion with the agency regarding the potential for Huntington ball ring

Speaker Change: to serve as a surrogate endpoint likely to predict clinical benefit that could allow us to access the accelerated approval pathway and also a separate interaction to discuss our endpoint strategy for the efficacy trial, which we've said would either be a registration study or in the context of potential accelerated approval could be a confirmatory trial.

Eric Joseph: Now, turning to influenza, second quarter net revenue was 47 million. We continue to work closely with healthcare providers, payers, and specialty pharmacies to dispense the brand. We are leveraging PTC care patient programs providing personalized services and support to each patient with insurance co-pays and timely shipments from specialty pharmacies. These efforts continue to reinforce the benefits of influenza for a significant number of new patient starts and maintaining existing patients on treatment, all in which are key revenue drivers for the brand here today.

Matthew Klein: We expect to have both of those interactions in the second half of this year. We're also, of course, looking at the other pathways that exist, including backtrack and breakthrough, but our priority right now is to have key interactions around the potential for surrogate endpoint pathways, as well as alignment on an endpoint strategy for the efficacy study. In terms of more detail on unpacking the revenue and the components and how we think about that, let me turn it over to you.

Speaker Change: We expect to have both of those interactions in the second half of this year. We're also, of course, looking at the other pathways that exist, in turn, including fast-track and breakthrough, but apparently right now, is to have the key interactions around a potential for certain endpoints, pathways, as well as a wine and a 10-point strategy.

Speaker Change: for the efficacy study. In terms of more detail on packing and revenue and the components and how we think about that, let me turn it over to Pat.

Matthew Klein: Perfect. Thanks, Matt.

Pat: Perfect, thanks Matt. Yeah so Eric on your question around just unpacking revenue a little bit I think one of the things that we're really happy to share is that we're updating guidance

Kylie: Now, I will hand it over to Kylie to update the progress of our current and future new product launches. Kylie? Thanks, Eric. We were extremely excited about the upcoming global launch of CEPIETERAN. As Matt mentioned, we have filed our NDA in the US, which is an important step in bringing CEPIETERAN to children and adults with PKU. In addition, in May, we received validation of our EU MAA filing and review as ongoing.

Eric Joseph: from the previous guidance to the 700 to 750 million for 2024. And this is driven by the fact that

Kylie: Further submissions are planned in several additional countries in 2024, including Brazil and Japan, which alongside the US and Europe are considerable value drivers for the global launch. CEPIETERAN data package supports clear differentiation versus current therapies, and includes data from the Phase III affinity trial, where 84% of the subjects achieved fee control in accordance with treatment guidelines of less than 360 micromolar and 22% of subjects had normalization at fee levels. It also includes data from the Affinity Open Label Extension Study, which provides evidence of subjects being able to achieve protein intake above the age adjusted recommended daily allowance for unaffected individual people while still maintaining fee levels less than 360 micromolar per liter.

Speaker Change: Originally the low side scenario had assumed that with a negative CH and P opinion.

Unknown Executive: Yeah, so Eric, on your question around just unpacking revenue a little bit, I think one of the things that we're really happy to share is that we're updating guidance from the previous guidance to the $700 to $750 million for 2024, and this is driven by the fact that, originally, the low-side scenario had assumed that with a negative CH&P opinion, TransLana European revenue would come out from Q2 onwards. And while this is not the case, because of the EC bouncing it back, we've been able to maintain it throughout 2024, and this has driven substantial upside for PTC, and this has also driven the updated guidance. In regards to your question around PTC-marketed products, of the $700 to $750 million, the majority of the revenue is coming from PTC-marketed products.

Speaker Change: TransLiner European Revenue would come out from Q2 onwards.

Speaker Change: While this is not the case because of the EC bouncing it back, we've been able to maintain it throughout 2024 and this has driven substantial upside for PTC and this has also driven the updated guidance. In regards to your question around PTC marketed products.

Speaker Change: of the $700-$750 million, the majority of the revenue is coming from PTC-marketed products.

Eric Joseph: Okay, great. Thanks for taking the questions.

Speaker Change: Okay, great. Thanks for taking the questions.

Kelly Shi: All right, our next question comes from the line of Kelly Shi from Jeffrey's. Your line is now open.

Speaker Change: Thank you.

Speaker Change: All right, our next question comes from the line of Kelly Shi from Jeffreys. Your line is now open.

Kelly Shi: Thank you for taking my questions. I'm curious about the regulatory front for TransLana in Europe; could you share what the most current status of TransLana is and what the timeline of next steps is if you have a new update, a newer update after last call? And also in the U.S., any other color you would be able to share the discussion with the regulatory agency after the NDA submission to FDA, and how are you thinking about the risk of U.S. approval? Thank you. Thanks very much, Kelly, for the question.

Kelly Shi: Thank you for taking my questions. So I'm curious on the regulatory front of TransLana.

Kelly Shi: In Europe, producer, what's the most encouraging status of Chris Lana and what are the timeline of next stabs that each of you have a new update in your update after last call and also in the U.S.

Kylie: The ability to liberalize the diet is an important factor for physicians, payers, and patients alike, and will drive uptake. We've been planning for our launch of CEPIETERAN for several years, and preparations are going very well. We've been working closely with geneticists, pediatric metabolic specialists, and diet patients, to understand the needs of the our teams have a deep understanding of the PKU prescribes and their prescribing habits, as well as how to reach them.

Speaker Change: Any other color you would be able to share the discussion with the regulatory agency after the NDA submission to FDA and how are you thinking about the risk of U.S. approval? Thank you.

Matthew Klein: Thanks very much, Kelly, for the question. On the European Transwater Front, we submitted our request for reexamination. We did that in early July. And, as you know, the calendar for reexamination is set. It's typically a 120-day process from the day of notification. We have 60 days to submit what is known as the grounds for reexamination, which is our briefing document supporting our reexamination request. And then within 60 days after that submission, we will receive an updated opinion. So we're on that timeline.

Speaker Change: Thanks very much Kelly for the question.

Kelly Shi: on the European Translator Prime to be submitted.

Kelly Shi: Our request for examination, we did that in early July, and as you know, the calendar for examination is...

Kelly Shi: is set. It's typically a 120-day process.

Kelly Shi: For the day of notification, we have 60 days of submit what is known as the grounds for examination, which is our briefing document supporting our examination request, and then within 60 days after last submission, we will receive an updated opinion.

Kylie: Unlike other rare diseases, PKU patients are identified through newborn screening and managed by well-defined PKU treatment centers. We have mapped these key treatment centers globally, and the key opinion leaders and treating physicians within each treatment center. Now. In addition, we have an established red disease global infrastructure with a footprint in those 50 countries. Our experience teams understand the complexities of red disease, as well as the regulatory and payer landscape in each of the different regions and countries.

Matthew Klein: We're still awaiting the assignment of new rapporteurs, which is another component of the reexamination process, and our grounds for reexamination are focusing on the evidence of benefit in Study 41. And we've also been able to address some of the concerns that were raised during the most recent review process. And so, therefore, we're able to say we can address concerns, particularly around the reliability of the strident analyses and are able to show that the evidence of multi-year protection against loss of population is well-supported and can be reliably attributed to trans-water treatment benefits in the long term.

Kelly Shi: So we're on that timeline and we're still awaiting the assignment of new rapporteurs, which is another component of the reexamination process.

Kelly Shi: and our round three examination are focusing on the evidence of benefit in 7.41 and we've also been able to address some of the concerns I will be during.

Kylie: All of this will enable us to have a rapid and highly targeted focus on key customers and stakeholders at launch and reinforces our beliefs in the potential $1 billion plus global opportunity. Turning to upstairs, in May, we announced that the FDA had accepted the BLA and granted priority review with a target regulatory action date of November 13, 2024. Launch preparations in the US are well underway. Globally, access and reimbursement discussions advance as we continue to treat patients in Europe through access and cross-border healthcare.

Kelly Shi: The most recent review process.

Kelly Shi: And so therefore, we're able to say we can address concerns, particularly around the reliability of the stride analysis and able to show that the evidence of multi-year protection against loss of ambulation is well-supported and can be reliably attributed to translong and treatment benefits in the long term.

Matthew Klein: Turning to the FTA, we resubmitted the NDA at the end of July. The resubmission process typically takes six months from submission to regulatory action. We expect to hear within 30 days of submission from the agency as to whether or not they'll accept the filing. So it's a slightly different timeline since it is a resubmission. As we previously shared, we had two separate meetings with the FTA to agree on the package for submission.

Kelly Shi: Turning to the FCA.

Kelly Shi: We resubmitted the NDA at the end of July .

Kelly Shi: The resubmission process typically takes six months from submission to regulatory action. We expect to hear within 30 days of submission from the agency as to whether or not they'll accept the filing. So it's a slightly different timeline since it is a resubmission.

Kylie: In addition, we secured approval in Taiwan and are preparing for additional filings and regulatory approvals globally. Moving to TechSetion, Wei-Liever, and LeTam, we continue to make good progress across these franchises with growth in both patients identified and treated across the region. Our geographical expansion continues with the recent approval of TechSetion in Mexico, following which we have initiated reimbursedment discussions. In Brazil, we received a new group purchase order for TechSetion, of which 50% was delivered in the second quarter, and we anticipate delivering the remainder in the third quarter.

Kelly Shi: As we previously shared, we had two separate meetings with the FTA to align on the package for submission, and I'll point out that this is, as I mentioned in the comments,

Matthew Klein: And I'll point out that this is, as I mentioned in the comment, what we really focused on in our discussions with the FDA was the evidence of significant benefit from Study 41 in the overall ITT population, not only on the primary endpoint of six-minute walk distance but all of the other key endpoints, including North Star and time function heads. And then that evidence of benefit from Study 41 will be confirmed, or the confirmatory evidence will come from the long-term data we have in the stride registry.

Kelly Shi: What we really focused on in our discussions with FDA was the evidence of significant benefit from Study 41 in the overall ITT population, not only on the primary endpoint of six-minute walk distance, but all of the other key endpoints, including North Star and time function tests.

Kelly Shi: And then that evidence of benefit from Study 41 will be confirmed, but the confirmatory evidence is from the long-term data we have in the STRIDE registry.

Kylie: Additionally, for Wei-Liever, in the second quarter, we delivered 50% of a new group purchase order. In conclusion, coming off a robust first half of the year, as Matt mentioned, we are updating our guidance with a 2024 Total Revenue Guidance of $700 to $750 million.

Matthew Klein: So those discussions with FDA were really about two things. One, what would be the structure and data package of the NDA and what would be needed in terms of additional analyses that would allow us to be reviewing the package. And so we believe we've been able to address all the agency's concerns.

Kelly Shi: So those discussions with FDA were really to align on two things. One, what would be the structure and data package of the NDA, and what would be needed in terms of additional analyses that would allow us to be reviewing the package.

Kylie: We have set a strong trajectory for 2024 and continue to deliver and diversify our portfolio across our geographies, as well as to prepare for a successful global launch of the Italian in 2025.

Matthew Klein: Their most recent feedback to us prior to submitting the NDA was that they believe any remaining questions they may have will be a matter of review. So we look forward to the review process. And of course, as always, I look forward to bringing the translator to Boys and Young Men with Nonsense Mutation, DMD in the U.S., for whom there remains a significant unresolved problem. Thank you very much. Thank you. The question from our next... The participant is going to come from the line of

Kelly Shi: So we believe we've been able to address all of the agency's concerns. Their most recent feedback to us prior to submitting the NDA was that they believe

Kelly Shi: Any remaining questions they may have will be a matter of review. So we look forward to the review process, and of course, as always, look forward to bringing TRANSBAR to Boys and Young Men with Nonsense Mutation, DMD in the U.S., for whom there remains a significant unlink here.

P.A.: I will now turn the call over to P.A, for a financial update. P.A.? Thank you, Kylie.

P.A.: I now share the financial highlights of our second quarter of 2024. She is referred to the earnings press release issued this afternoon for additional details. Beginning with stop-line results, Total Revenue for the second quarter was $187 million, including the UND franchise revenue of $118 million. From flora, net product revenue in a quarter was $17 million, while in flaza, a net product revenue of $47 million. Moving to everything, second quarter, global revenue of approximately $5 million and $35 million US dollars was achieved by Welsh, resulting in royalty revenue of $53 million for PTC.

Kelly Shi: Thank you very much.

Operator: The question from our next... Participant is going to come from the line of Sammy Cohen from William and Blair. Your line is now open. Hi, this is Brooke.

Kelly Shi: Thank you.

Speaker Change: Oh, the question from our next...

Speaker Change: Participant is going to come from the line of Sammy Klein from William and Blair, your line is now open.

Kelly Shi: Hi, this is Brooke Schuster on for Sandy. Thanks for taking our questions.

Speaker Change: We are wondering if you could provide some more color, you expect for the upcoming ALF trial, read out like the bar for efficiencies, and if you expect this read out to be at a medical conference or a company event.

Brooke Gray: Sure, thanks for the questions, Brooke. So as we've talked about the Cardinals, the ALS study is a registration-directed study of neutraloxistat in ALS patients. This study was designed to be a six-month placebo-controlled study with an endpoint strategy, that being the primary endpoint of the ALS FRS scale, such that if we were positive and we achieved statistical significance on the primary endpoint, it would support an NDA submission in the United States. This is a study that was designed leveraging the learnings made from other products that have been tested in ALS patients.

P.A.: Non-GAP R&D expense was $123 million for the second quarter of 2024, excluding $9 million in non-cash start-based compensation expense compared to $107 million for the second quarter of 2023, excluding $16 million in non-cash start-based compensation expense. The year-over-year reduction in R&D expenses reflects our strategic portfolio prioritization, as the company continues to focus its resources on its different shaded high-potential. Program. Non-gap as Jenny expands was 60 million for the second quarter of 2024, excluding 10 million in non-cash.bas composition expense compared to 75 million for the second quarter of 2023, excluding 14 million in non-cash.bas composition expense.

Speaker Change: Thanks to the questions books. We've talked about the Cardinals, and our last study is Registration Direct Study in Nutrolox, it's that. In our patients, the study was designed.

Speaker Change: to be a six-month placebo-controlled study with an endpoint strategy that being the primary endpoint of the ALS-FRS scale, such that if we're positive and we achieve statistical significance on the primary endpoint, it would support an NDA submission in the United States.

Speaker Change: This is a study that was designed leveraging the learnings made from other products that have been tested in ALS patients.

Speaker Change: Double Blind Placebo Controlled Study, Randomization 2-to-1 of Euteloxistat-2 placebo. We included an 8-week run-in in order to determine the baseline rate of progression, which again has been done in many previous ALS trials, so that we ensure that the primary analysis group is one that is moving at an appropriate disease rate so that we can practically record a treatment benefit.

Brooke Gray: We included an eight-week run-in in order to determine the baseline rate of progression, which has been done in many previous ALS trials, so that we ensure that the primary analysis group is one that is moving at an appropriate disease rate so that we can practically record a treatment benefit. So I would define success here as a statistically significant primary endpoint because that would then allow us to move forward with NDEs. We said that we expect to have top-line results in the fourth quarter. We expect that we'll share those results on a public call, as we typically do when we have top-line results.

P.A.: In the second quarter, PTC amended its agreement with Warty Pharma and exercised one of its put options in exchange for 216 million in cash less royalties received. Cash, cash recoverance and marketable security is total 1.09 billion dollars as of June 30, 2024, compared to 800 and 77 million dollars of December 31, 2022.

Speaker Change: So I'm going to find success here as a statistical significant primary employment because that would then allow us to move forward with any use of mission.

Speaker Change: We said that we expect to have top-line results in the fourth quarter. We expect that we'll share those results on a public call, as we typically do when we have top-line data.

P.A.: Our 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 psychiatry knowledge.

Unknown Executive: And then we'll now turn the call over to the operator for operating operator. Thank you.

Matthew Klein: All right, thank you. Our next question comes from the line of Brian Abraham from RBC Capital Markets. Your line is now open.

Speaker Change: All right, thank you.

Speaker Change: Our next question comes from the line of Brian Abraham from RBC Capital Markets. Your line is now open.

Unknown Executive: At this time, we will conduct a question and answer session. As a reminder, to ask a question, you will need to press star 111 on your telephone and wait for your name to be announced. To answer our question, please press star 111 again. Please stand by while we compile the Q&A roster.

Joe: Thank you for taking our question. So, going back to Huntington's, when looking at your and other developers' data collectively, which biomarker, other than HTT lowering, do you think has shown the best translatability to clinical benefits and support accelerator approval? And, I guess along these lines, have you had a chance to look at the correlation between HTT knockdown levels to functional measures at individual levels in your data? Thank you. Thanks,

Brian Abraham: Hi, this is Joe. I'm for Brian.

Speaker Change: Hi, this is Joe. I'm for Brian . Thank you for taking our question.

Joe: So, going back to Huntington's, when looking at your and other developers' data collectively, which biomarker, other than HTT lowering, do you think has shown the best translatability

Kristen Kluska: Our first question comes from the line of Krypton, Kluska from Cantor, Fitzgerald. Your line is now open. Hi, everyone. Good afternoon. Congrats on a great quarter and thanks for taking my question. The first one I had was on Huntington's disease. Obviously, looking at the field, we've seen a lot of data recently. But one thing that stood out is your approach seems to be one of the only ones where you're not seeing an increase in NFL through this therapy.

Speaker Change: to Clinical Benefits and Support Accelerator Parval. And I guess along these lines, have you had a chance to look at the correlation between HTTP, lockdown levels to functional measures at individual levels for your data? Thank you.

Matthew Klein: I think the only marker that's really been shown to correlate reliably with potential clinical benefit is Huntington's disease. And the rationale for Huntington disease lowering to be a surrogate endpoint that's likely to predict clinical benefit is based on several things. First, just basic principles. Huntington disease is a monogenetic disorder caused by a mutation in the Huntington gene that leads to the production of a disease-causing toxic mutant Huntington protein. And thus, it stands to reason, if you can lower the disease-causing protein, you're likely to have benefits. And that's been studied.

Speaker Change: I think the only marker that's really been shown to correlate reliably with potential clinical benefit is Huntington-Moll.

Kristen Kluska: Obviously, it's a prognostic biomarker of neurodegeneration, but other drugs have been shown to make it worse. So a question we've been getting is, do we have a sense of how dangerous it is when NFL increases via drug targeting? And then second, is this a really important consideration for physicians on safety?

Speaker Change: And the rationale for Huntington-Lowry to be a surrogate endpoint that's likely to predict clinical benefit is based on several things. First, just basic principles.

Speaker Change: Huntington disease is a modernized disorder caused by irritation in the Huntington gene at least simple.

Speaker Change: Production of a disease-causing toxic mutant-hunting 2-protein.

Matthew Klein: It's been studied extensively in a number of preclinical models, and they all demonstrate that if you can lower Huntington protein, it's been reported in a range of 10 to 50 percent, and that it's been associated with clear phenotypic benefit. There's also been an epidemiologic study that has demonstrated, sort of an experiment by Mother Nature, that if you are born with a single nucleopolymorphism in the promoter for the Huntington gene and make about 50 percent less mutant Huntington protein, you have an almost 10-year delay in the onset of disease and a slower disease progression.

Speaker Change: And thus it stands to reason, if you can lower the disease-causing protein, you're likely to have benefits.

Matthew Klein: Kristin, thanks very much for the question. So, you know, the goal here is to develop a therapy. A disease modifying therapy for patients with Huntington's disease that is both effective and safe. So the safety of the product turned development is an incredible important. When we talk about Huntington lowering as a therapeutic strategy, it makes a lot of sense. It's well understood. Huntington's disease is a monogenetic disease caused by the production of a toxic mutant Huntington protein.

Speaker Change: And that's been studied. It's been studied extensively in a number of preclinical models. And they all demonstrate that if you could lower Huntington protein, it's been reported in a range of 10 to 50 percent. That's been associated with clear phenotypic benefits.

Speaker Change: There's also been Epidine Logic study, which is demonstrated that

Speaker Change: So they experimented on mother nature, that if you are born with a single nuclear polymorphism in the promoter for the Huntington gene, and about 50% less Huntington protein, you have an almost 10-year lifespan.

Matthew Klein: The goal of Huntington lowering is to decrease that protein that is causing the disease. And of course, there's a broad scientific literature substantiating that lowering Huntington protein due to Huntington protein is likely to result in clinical benefit. In the development of PTC-518, we really followed the playbook established by RISD for the development of a both safe and effective oral slicing agent for a whole brain disease like Huntington. They are for it in the development.

Speaker Change: the lead in onset on disease, tend a slower disease progression. So when you put that scientific package together, the evidence is strong, got lowering, quantity and protein is likely to result in clinical benefits.

Matthew Klein: So, when you put that scientific package together, the evidence is strong that lowering Huntington protein is likely to result in clinical benefit. And not only is it lowering Huntington protein, but it's lowering it in that range I mentioned, as shown between 10 and 50 percent. And so when we now move to the clinical data, it's the type of data we've collected for the PhD to be able to show that we are lowering Huntington protein at that level that has been associated with benefits.

Speaker Change: And not only is it lowering the Huntington protein, it's lowering the Huntington protein in that range I mentioned that's been shown between 10 and 50 percent.

Speaker Change: And so that when we now move to the clinical data, the type of data we've collected for the DHT, to be able to show that we are lowering Huntington protein at that level that has been associated with benefit.

Matthew Klein: It's incredibly important to ensure that we're lowering Huntington protein so that we can have the desired therapeutic effect, one would expect from reducing the cause of the disease. But at the same time, wanting to make sure that we're doing so safe. And that involves making sure that we have a moral kill that is specific and selective for the Huntington target, and it gets into the brain, gets to all regions of the brain because Huntington's disease is a brain disease.

Matthew Klein: That's really the support and evidence that we'll use in our discussion with the agency around a potential accelerated approval path. We have not looked specifically at correlations thus far. As you recall, the PIVOT-HT readout was a relatively small data set, but we're clearly seeing dose-dependent lowering of Huntington protein in the blood, in the CSS, and dose-dependent benefits on the clinical endpoints that we've collected thus far

Speaker Change: That's really the support and evidence that we'll use in our discussion with the agency around a potential accelerated approval path.

Speaker Change: We've not looked specifically at correlation thus far, as you call it, the pivot Hc, feed out as a relative in small data set, but we're clearly seeing those dependent moral hunting and protein in the blood in the CSF and those dependent benefit on the clinical endpoints that we've collected.

Matthew Klein: And so when we look at these markers of safety like an SL, we're asking, are we seeing some harm to nerve cells? Because the way that nerve cell injuries can present itself is through an FL spikes. And this is something that has been seen in the development of a number of therapies and to reason why, as you pointed out, an FL could be thought of as a marker of clinical benefit, but more important Huntington disease, over the shorter period of time of the clinical trial, it's really acknowledged we've more important as a marker of safety.

Speaker Change: of the far.

Matt: Thank you, Matt.

Joseph Thum: Our next question comes from the line of Joseph Thum of T. Day Cohen. Your line is now open.

Matt: Thank you.

Speaker Change: Our next question comes from the line of Joseph Thum of T. Day Cohen. Your line is now open.

Joseph Thum: Hi there, good afternoon. Congratulations on the progress and thank you for taking the time to answer our questions. Maybe the first one, just to follow up on the ALS trial, I guess. Do you believe there's been any change in what the FDA wants to see for a pivotal package for ALS given the experience with the amylox compound? And then maybe second, on Huntington's, I know we're waiting on more data for the full data set from PIVOT in the first half of next year. Is there anything in that data set that you'd like to see before launching Phase 3? Thank you. Thanks for the questions.

Joseph Thum: Hi there, good afternoon, I'm Gravier from the progress that you've taken our questions. Maybe the first one just to follow up on the ALS trial. I guess do you believe there's been any change in what the FDA wants to see for a pivotal package for ALS given the experience with the AMOLED's compound?

Matthew Klein: Are we delivering therapeutic benefit without causing spikes that show that we may also be causing harm? So the fact that we've not seen any evidence of treating related NFL spikes, and we continue to observe that PTC-51 has been safe and well tolerated in the pivot age we've done, is an incredibly important finding for patients. And then to also say that we're having a desired biomarker effect of lowering Huntington proteins in the blood, we're seeing lowering the Huntington protein to CSF.

Speaker Change: And then maybe second, on Huntington's, I know we're waiting on more data in the first half of next year, the full data set from PIVOT. Is there anything in that data set that you'd like to see before launching a Phase 3? Thank you.

Matthew Klein: Thanks for the questions, Joe. On ALS, we worked closely with the agency to ensure that we had designed the cardinal study and that we were analyzing the data and had the right endpoints that would be consistent with what they would want to see in terms of an approval path. And so what we have in terms of our study design, the statistical analysis plan, and how we're approaching the analysis for the primary endpoint.

Speaker Change: Thanks for the question, Joe. On ALF, we worked closely to the agency to ensure that we had designed the Cardinal Study and that we were analyzing the data and how the light endpoints that would be consistent with they would want to see in terms of the proof of the package.

Matthew Klein: And importantly, as we reported, we're seeing thoroughly evidence of clinical benefit on key disease scales, like total motor score and CUHERAT. Tell us that so far we're seeing that we're having a desired therapeutic benefit, well, I hope for today's modifying therapy. But importantly, we're also having the safe that will be incredibly important for successful therapies.

Speaker Change: and so what we have in terms of our sudden design, the statistical analysis plan, how we're approaching the analysis for the primary endpoint.

Matthew Klein: And one important point here is something the agency really likes to see and understand is not only the change on the continuous variable of the ALS-FRS scale but also incorporating any deaths that might occur in the time to death as a second component of looking at the primary treatment effect. Therefore, I can say that we have certainly taken all of their advice and believe that we've designed the study and our analyses to be consistent with exactly the type of package they would want to see for approval, which is quite consistent with what their views have always been.

Speaker Change: And one important point here is something the agency really likes to see and understand is not only the change on the continuous variable of the ALS and PLS scale, but also incorporating any deaths that might occur in the time to death as a second component of looking at.

Kylie: Thanks for that, Matt. And then if I may ask a second question, just on PKU, I think when we think about rare disease launches, the uptake curve is always different depending on this disease. So how would you think about this one for maybe called the first two years, you already have a really good sense of where the patients are that you've identified that either don't respond or don't take standard of care.

Speaker Change: Primary Treatment Effect. Therefore, I can say that we have certainly taken all of their advice and believe that we've designed the study and our analyses to be consistent with exactly the type of package they would want to see for approval, which is quite consistent with what their views have always

Kylie: Thank you again. Yes, absolutely. And as Tyler mentioned her comments, we've been preparing for several years now for successful launch, and let's kind of talk about how we expect the rest of it. Yeah, absolutely. Thanks, Kristen. As Matt said, and as I mentioned in my prepared remark, we've been preparing for this launch for a number of years now and been going really well, we have a focus across all of the different important prescribers as well as the ancillary physicians that are relevant to this disease.

Matthew Klein: In terms of the HD question, in terms of timing of seeing more data and going on to phase three, Look, we designed Pivot HD in two different parts, part A and part B, to make sure that we were asking key questions, key drug development questions at the right time. The first 12 weeks were focused on pharmacology and pharmacogenetic effects, saying are we seeing the evidence of target engagement, evidence of the dose-dependent lowering of Huntington protein we would want to see, are we seeing it at the magnitude we need to see to know that the doses of 5 and 10 milligrams are likely to be appropriate for application? And are we seeing CMS exposure?

Speaker Change: in there.

Speaker Change: In terms of the PhD, a question in terms of time and seeing more data at 10 going on to phase 3. But we designed to be the two different parts, part and part B to make sure that we're asking key questions, key drug development questions at the right time.

Speaker Change: The first 12 weeks were focused on...

Kylie: In the key treatments and as of excellence, and as you noted, we're also very close to the PKU community, understanding whether unmet medical need is and where these patients exist. And so as you said, this is not your traditional rare disease launch in the sense that patients are identified through newborn screening at birth and well-known treatments and as of excellence, and so that coupled with our expertise and our preparation means that we are expecting a fast uptake, particularly in the US, where it's one market where we're able to move fast with pricing and reimbursement.

Speaker Change: Pharmacology and Pharmacogenetic Effects, saying are we seeing the evidence of target engagement, evidence of the dose-dependent lowering of Huntington protein we would want to see, are we seeing it at the magnitude we need to see to know that the doses of 5 and 10 milligrams are likely to be appropriate for applicants to see.

Kylie: And then outside of the US, we'll look to each market that has name patient programs and early access programs to move quickly in those markets as well while we progress with regulatory submissions and formal pricing and reimbursement. So across the board, I think we're looking at a relatively fast and rapid uptake. Thanks, everyone.

Speaker Change: And are we seeing CNS exposure? The answers to those were yes and yes.

Matthew Klein: The answers to those were yes and yes. As we move into the second part of the study, the nine-month study, there we're asking the question, okay, at the dose levels we know we're having pharmacodynamic effects and adequate and excellent CNS exposure. Are we starting to see changes in CNS biomarkers and clinical scales that give us confidence that, over time, we'll be able to register the efficacy necessary to have a therapy for patients with heart disease?

Speaker Change: As we move into the second part of the study, the nine-month study, there we're asking the question...

Speaker Change: Okay, at the dose levels, we know we're having pharmacodynamic effects and

Speaker Change: and the text one said at the exposure, are we starting, are we starting to see changes in CNS by markers of clinical skills that give us confidence that over time we'll be able to register the subject that the necessary to have a certain duplication of quantitatively.

Unknown Executive: Thank you.

Matthew Klein: And so when we had the data readout with that first group of patients, the answer, again, was yes. We saw what we needed to see in terms of biomarker effect, durability of Huntington's lowering, early movement of clinical cells, and then importantly, continued safety and tolerability at the five and ten millimeters. So for us, we've really checked all of those gating boxes to move forward into phase three. So that's why we're saying we're going to start phase three planning and continue to get aligned, develop the study design, the input strategy, get along with the regulatory authorities, and advance that study based on the data.

Jeffrey Hung: Thank you. Our next question comes from the line of Jeffrey Hung from Morgan Stanley. Your line is now open.

Speaker Change: and so when we had the day to read out.

Speaker Change: with that first group of patients.

Speaker Change: The answer again was yes. We saw what we needed to see in terms of biomarker effects, durability of hunting chip lowering, early movement of clinical cells, and then importantly, continued safety and tolerability at the 5 and 10 millivariate dose level.

Eric Joseph: Our next question comes from the line of Eric Joseph of J.P. Morgan. Go ahead, Eric. Thank you, and good evening. A couple of questions from us. First on top line guidance. I'm wondering if you could unpack that a little bit for what's anticipated in terms of net product sales marketed by PTC. Secondly, on PTC 518 in Huntington's, I'm wondering if you could give us a sense of when you hope to have a meeting with FDA for a type C or type C meeting on a potential registration path.

Eric Joseph: And also wondering how you think about the merits of breakthrough therapy designation for this indication and whether that's something you intend to pursue with the compound. And then finally, on the particular known, what's left to kind of get over the line for that submission and strategic attacks here. I believe data from the Open Legal Extension portion of MoveFA was part of that. Have you reviewed additional follow-up study that's something you plan to share with the street? Thanks very much. Thanks for the questions, Eric.

Speaker Change: So for us, we've really checked all of those gating boxes to move forward with Phase 3.

Speaker Change: So, that's why we're going to have to be able to start the facing planning and continue to get aligned.

Speaker Change: and develop the study design at post-strategy, get along with the regulatory authorities and advance that study based on the data we have this far.

Speaker Change: Perfect. Thank you very much.

Speaker Change: Thank you.

Speaker Change: Our next question comes from the line of Jeffrey Hung from Morgan Stanley . Your line is now open.

Jeffrey Hung: Hi, following the TransLunar resubmitted NDA, can you just provide more color in how you're thinking about the market opportunity and overall patient dynamics in the U.S., sort of in comparison to what we've seen in the EU?

Jeffrey Hung: Hi, I'm following the Translunter Reef Minute NDA. Can you just provide more color and high-rethinking about the market opportunity and overall patient dynamics in the U.S. sort of been comparison to what we've seen in the EU?

Matthew Klein: Thank you very much for the question. We, as we've talked about, have for a long time been ready to make TransLarma available to boys and young men with non-sense mutation D&D in the U.S. and a significant medical need, and to be able to resubmit to the NDA and have the opportunity to finally bring TransLarma to boys and young men in the U.S. would be a tremendous opportunity for I would kind of join in with some more color on how we would think about a launch.

Speaker Change: Thank you very much for the question.

Speaker Change: As we've talked about, for a long time, we're ready to make a turn as long as available to boys and young men's expectations D&D.

Speaker Change: TransLongitude Boilers and Young Men in the U.S. is a significant medical need and to be able to resubmit to the NDA and have the opportunity to finally bring TransLongitude Boilers and Young Men in the U.S. would be a tremendous opportunity for us and kind of join us in more color on how we would think about and launch.

Matthew Klein: May I go in reverse order? So the third one first. So the Tiquadone, NDA is coming along with expected submission happened for the end of the year, as I mentioned in my comments. That's going to be based on the 72 week placebo control data for MoveFA, where we have significant effects on upright stability and the number of other relevant disease measures, as well as long-term open label data. And both from MoveFA, as well as the long-term extension data from the earlier of regional attack, the study going on years ago in adult patient.

Unknown Executive: Yeah, absolutely. Thanks very much for the question. So, as Matt said, it's a higher medical need because there has been no other therapy for Targeted for Nonsense Mutation, DMD. And our team has had over five years of experience working embedded in the DMD community, working alongside physicians, working alongside patient advocacy groups, and also has strong infrastructure set up for PTC Cares to support patients from start to finish throughout their treatment experience.

Speaker Change: Yeah, absolutely. Thanks very much for the question. So as Matt said, it's a high-end medical need because there has been no other therapy.

Speaker Change: for targeted for non-sensitation DMD.

Speaker Change: So that this remains a high on medical need, and our team has had...

Speaker Change: Over five years of experience of working embedded in the DMD community, working alongside the physician, working alongside.

Matthew Klein: We had previously done that long-term analysis that was published showing significant benefit over a 24 month period. At the FDA's request, we are going to repeat that analysis with newer natural history match data. And so we provided a fiscal analysis plan to the FDA for their bottom and then we'll do that analysis. We're still waiting for the final long-term extension data from MoveFA to be collected. Those data will be collected. The data selection will be completed shortly and then we'll be able to move forward with that long-term analysis and get the whole package together for submission.

Speaker Change: the patient advocacy groups.

Speaker Change: and also has strong infrastructure set up for PTSD care to support the patients from start to finish.

Unknown Executive: In addition to that, through our experience within PLAZA, we have thousands of DMD patients that have been genotyped, and this allows us to move rapidly upon launch to understand where to go for the nonsense mutation DMD patients. And in addition to that, we also have a group of patients, more than 100, that are still on TransLana and have been on for over a decade in clinical trials, and we'll be able to look to put them on commercial drugs very quickly post-approval. So from a market dynamics perspective, we expect a very rapid uptake in this space.

Speaker Change: throughout their treatment experience.

Speaker Change: In addition to that throughout experience with influenza, we have thousands of DMD patients that have been gene-attacked.

Speaker Change: This allows us to move rapidly upon launch to understand where to go for the nonsense mutation DMD patients.

Speaker Change: And in addition to that, we also have a group of patients, more than 100.

Speaker Change: that I still on Translana and have been on for over a decade on clinical trials and we'll be able to look to put them on commercial drugs very quickly post post approval. So from a market dynamics perspective, we expect a very rapid uptake in this space.

Matthew Klein: We do plan a planned meeting with the agency, as we always do the meetings, the contents and structure of the FDA. And we will share our data when we have it from those open legal studies that go into the DNA.

Catherine: And I'm sorry, I forgot to mention, this is Catherine on for Jeff. This is a quick follow-up. Have you received any early feedback from physicians in the U.S. that might be indicative of what demand or the launch directory might look like there? Just curious. Thank you.

Catherine: Thank you, and I'm sorry, I forgot to mention, this is Catherine on for Jeff. Just as a quick follow-up, have you received any early feedback from physicians in the U.S. that might be indicative of what demand or the launch directory might look like there? Just curious, thank you.

Matthew Klein: On your second question regarding PEC-518, the regulatory task, with the results from the interresults and pivoted HD, as we've talked about, we're moving forward on two phones. One is to have a discussion with the agency regarding the potential for hunting and lowering to serve as a surrogate endpoint likely to predict clinical benefits that could allow us to access the accelerated approval pathway. And also a separate interaction to discuss our endpoint strategy for the efficacy trials, which we've certainly needed to be registering, study, or in the context of the potential acceleration approval could be a confirmatory trial.

Unknown Executive: Yeah, absolutely. Thanks, Catherine. We have obviously received a lot of feedback and we've been working very closely with the DMD physicians and there's a huge amount of pull from those physicians and also from the patients because they've known about TransLiner for a long period of time and PTC initiated the DMD space and they've been waiting to get access to that therapy and have struggled to understand why patients from all over the world can get access to TransLiner but patients in the U.S. could not and so we see the market opportunity in the U.S. larger than Europe and I think from that perspective with both the physician and the patient pull and the market landscape dynamics we talked about earlier just reinforces my point around fast uptake.

Speaker Change: Yeah, absolutely. Thanks, Catherine. We have obviously received a lot of feedback and we've been working very closely with the DMD physicians and there's a huge amount of pull from those physicians and also from the patients.

Speaker Change: because they've known about TransLana for a long period of time and PTC initiated the DMD space and they've been waiting to get access to that therapy and have struggled to understand why patients from all over the world can get access to TransLana but patients in the U.S. could not.

Matthew Klein: We expect to have both of those interactions in the second half of this year. We're also, of course, looking at the other pathways that exist, including fast track and breakthrough that are priority right now, to have the key interactions around the potential for surrogate endpoint pathways, as well as align and donate endpoint strategy for the efficacy study.

Speaker Change: And so we see the market opportunity in the U.S. larger than Europe , and I think from that perspective, with both the position and the patient pool and the market landscape dynamics we talked about earlier, it just reinforces my point around fast uptake.

Catherine: Great. Thank you so much for the color.

Speaker Change: Great, thank you so much for the color.

Jenna Wang: Thank you. The next question comes from the line of Jenna Wang from Barclays. Your line is now open. Thank you. I have two questions.

Jenna Wang: Of course. Thank you. The next question comes from the line of Jenna Wang from Barclays. Your line is now open. Thank you. First, you know, you will have several launches underway.

Eric Joseph: And in terms of more detail on unpacking and rebuing the components and how we think about that, let me turn it. So Eric, on your question around just unpacking revenue a little bit, I think one of the things that we're really happy to share is that we're updating guidance from the previous guidance to the 700 to 750 million for 2024 and this is driven by the fact that originally the low side scenario had assumed that with a negative CHNP opinion that Translano European revenue would come out from to 2022 onwards and while this is not the case because of the EC bouncing it back and we've been able to maintain it throughout 2024 and this is driven substantial upside to PTC and this is also driven the updated guidance in regards to your question around PTC marketed products of the 700 to 750 million the majority of the revenue is coming from PTC marketed products. Okay, great, thanks for taking the questions. Thank you.

Speaker Change: Of course.

Speaker Change: Thank you. The next question comes from the line of Jenna Wang from Barclays. Your line is now open.

Speaker Change: Thank you for a lot of questions.

Jenna Wang: First, you know, you will have several launches underway. Should we see a meaningful increase in STNA in 2025 and the beyond?

Speaker Change: And second question is regarding the vertucano in Frederick's ataxia. So the NDA in late 2024, and regarding the natural history data, when do you plan to share that data with investors?

Matthew Klein: Thanks for the questions, Gina. On the first question, as we've talked about, we have built the infrastructure, the global commercial infrastructure, to support not only the existing therapies but the potential therapies that are coming. And so we have the infrastructure, we have the expertise across the board to launch several products. And, in fact, you know, we're obviously quite proud to be in a situation where we've already submitted three new drug applications to BLA this year, and potentially a fourth this year. And we're incredibly proud of the team's accomplishments in being able to do this.

Speaker Change: Thanks for the questions, Gina. On the first question, as we've talked about, we have built the infrastructure, the global commercial infrastructure.

Speaker Change: to support not only the existing therapies, but the potential therapies that are coming. And so we have the infrastructure, we have the expertise across the board to launch several products. And in fact, you know, we're obviously quite proud to be in this situation where we've already submitted three new drug applications of BLAs this year, and potentially a fourth this year.

Matthew Klein: And if those therapies are all approved, we have the team set, ready to go, and we'll quickly get these therapies to the patients who desperately need them. And so we don't expect any increases in SGNA because the infrastructure is built and ready to go and scale with any number of new therapies that we can bring to patients in the near future. In terms of the particular data, as I mentioned, we're still in the process of completing the collection of the long-term data for MOVE-FA that will be compared to the Natural History Comparator.

Kelly Shi: All right, our next question comes from the line of Kelly Shi from Jeffries, your line is now open. Thank you for taking my questions.

Speaker Change: and we're incredibly proud of the team's accomplishments and being able to do this and those therapies are all approved. We have the team set ready to go and we'll quickly get these therapies and patients who desperately need them.

Matthew Klein: So curious on the regulatory front of Translano in Europe, could you share what's the most current status of Translano and what are the timeline of next steps if you have a new update, new update after last call and also in the US. Any other caller you would be able to share on the discussion with the regulatory agency after that and the submission to FDA and how are you thinking about the risk of a US approval.

Speaker Change: And so don't expect any increases in SGNA because the infrastructure is built and ready to go and scale with any number of new therapies that we can bring to patients in the near future.

Speaker Change: In terms of the particmanone data, as I mentioned, we're still in the process of completing the collection of the long-term data for MOVE-FA that will be compared to the Natural History Comparator. We've talked a lot about being in a fortunate situation with the FACRMS Natural History Registry. FARA and the FA community has done a model job in terms of building a natural history database that can be used for regulatory purposes.

Matthew Klein: We've talked a lot about being in a fortunate situation with the FACOMS Natural History Registry. FARA and the FA community have done a model job in terms of building a natural history database that can be used for regulatory purposes. We'll be first doing the analysis of the data previously collected in the trial conducted several years ago in adults, and that'll be a 24-month analysis of the patients treated for 24 months relative to the appropriate matched natural history comparison.

Matthew Klein: Thank you. Thank you very much Kelly for the question. On the European Translano front, we submitted our requests for re-examination. We did that in early July and as you know, the calendar for re-examination is set. Typically a 120% process of the day of notification. We have 60 days that submit what is known as the grounds for re-examination, which is our briefing documents supporting our re-examination requests. And then within 60 days after that submission, we will receive an updated opinion.

Speaker Change: We'll be first doing the analysis of the data previously collected in the trial conducted several years ago in adults, and that will be a 24-month period.

Speaker Change: Analysis of patients treated for 24 months relative to the appropriate matched natural history comparison, and then, of course, we'll be having the natural history comparator data.

Matthew Klein: And then, of course, we'll be having the Natural History Comparator data from the Long-Term Open Label Extension from MOVE-FA, and we will look forward to sharing those data when they are available. Thank you. Our next question comes from the line of David Lebowitz from Citi. Your line is now open.

Speaker Change: from the Long-Term Open Label Extension from MOVE-FA, and we will look forward to sharing those data when they are available.

Matthew Klein: So we're on that timeline and we're still awaiting the assignment of new raptors, which is another component of the re-examination process. And our grounds for re-examination are focusing on the evidence of benefit in study 41. And we've also been able to address some of the concerns that will lead during the most recent review process. And so therefore we're able to say we can address concerns particularly around the reliability of stride analyses. And we're able to show that the evidence of multi-year protection as well as evaluation is well supported. And it can be reliably to translong the treatment benefits in the long term.

Speaker Change: Thank you.

Speaker Change: Our next question comes from line of David LeBelitz, come city. Your line is not open.

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

David LeBelitz: Thank you very much for taking my question. Given the operating spend, we'll have to start accounting for potential launches of additional products.

David LeBelitz: mainly PKU. Could you run us through what your assumptions would be and expectations especially given there's the convert that's due next year?

David Lebowitz: Sure. So thanks for the question, David. First, let me clarify that we have a conversion rate, but that is up in 2026. And as I mentioned, the operating expenses and the level of OPEX we have now are at where they need to be in anticipation of potential launch. I'm not sure if that answers your question, Ramon. Thank you. Our next question comes from the line of Joseph Schwartz from

Matthew Klein: Turning to the FDA, we submitted the end of the end of July. The re-submission process typically takes six months from submission to regulatory action. We expected here within 30 days of submission from the agency as to whether or not they'll accept the file. So it's a slightly different timeline since it is a re-submission. As we previously shared, we had two separate meetings with the FDA to align on the package for submission.

Speaker Change: Brick.

Speaker Change: Sure. So thanks for the question, David. First, let me clarify that we have a convert, but that is up in 2026. And as I mentioned, the operating expenses and the level of OPEX we have now is at where it needs to be in anticipation of potential launches.

Speaker Change: Colin, as we talked about, I'm not sure if that answers your question or not.

Colin: Thank you.

Joseph Schwartz: Our next question comes from the line of Joseph Schwartz from Lyrinc Partners. Your line is now open. Hi, it's Jenny. I'm

David LeBelitz: Thank you.

Matthew Klein: And I'll point out that this is, as I mentioned in the comments, what we really focused on in our discussions with FDA, there's the evidence of significant benefit from study 41 in the overall IPT population. Not only on the primary and program of six-minute walk distance, but all of the other key end points, including North Star and time function set. And then that evidence of benefit from study 41 will be confirmed.

Speaker Change: Our next question comes from the line of Joseph Schwartz from Lyrinc Partners. Your line is now open.

David LeBelitz: Hi, it's Jenny. I'm for Joe. Thanks for taking our question.

Speaker Change: We've heard from a couple of other sponsors that the FDA is not a fan of Huntington protein as a potential surrogate marker.

Speaker Change: Support Accelerated Approval and Huntington's. Clearly you guys disagree. Why do you think that they might be thinking that way? And have you thought anything about other potential surrogate biomarkers that you guys might be able to use? Thanks.

Matthew Klein: And the extraordinary evidence is from the long-term data we have in this chart. Industry. So those discussions that they were really to align on two things. One, what would be the structure and data package of the NDA, and what would be needed in terms of additional analyses that would allow us to be reviewing the package. So we believe we've been able to address all the agencies concerns. Then most recent feedback does prior to submitted the NDA is that they believe any remaining questions they may have that would be a matter of review.

Matthew Klein: Yeah, thank you for the question. I'm not sure anyone could speak for what the FDA thinks or what the FDA believes. I think where we, certainly with Huntington's disease, we exist in a situation where no one had the opportunity to come before them and have a discussion a lot around surrogate endpoints. What we do know for sure is what the FDA publishes in its guidance. And they have very clear guidance around what the requirements are for a surrogate endpoint.

Speaker Change: Yeah, I, thank you for the question. I'm not sure anyone could speak for what the FDA thinks or the FDA believes. I think where we, certainly with Huntington's disease, we exist in a situation where no one had the opportunity to come before them and have a discussion remotely around certain endpoints. What we do know for sure is what the FDA publishes in their guidance.

Matthew Klein: And if you read their guidance regarding a surrogate, what's needed for a surrogate endpoint that's likely to predict clinical benefits and therefore support an accelerated approval application, what they would like to have is data, either scientific data that could be from preclinical studies or clinical studies that show how a certain biomarker could be shown to predict ultimate benefits. And so in the case of mutant Huntington's protein, the reason we believe that this is a worthwhile discussion is that there is a vast scientific literature clearly demonstrating that lowering Huntington's protein has been associated with benefits, both in preclinical models and in patients.

Speaker Change: And they have very clear guidance around what are the requirements for a surrogate endpoint.

Matthew Klein: So we look forward to the review process. And of course, as always, look forward to bringing the transition to boys and young men with non-sensitiation, DMD and U.S., for whom there may be significant unloads here. Thank you very much.

Unknown Executive: Thank you.

David LeBelitz: And if you read their guidance regarding what's needed for a surrogate endpoint that's likely to predict clinical benefits and therefore support an accelerated approval application, what they would like to have is data, either scientific data that could be from preclinical studies or clinical studies that show how a certain biomarker

Brooke Gray: The question from our next participant is going to come from the line of Sammy Corwin from William and Blair. Your line is now open. Hi, this is Brooke Schuster on for Sammy. Thanks for taking our question. We are wondering if you could provide some more color. You expect for the upcoming ALF trial readout, like the bar for efficiencies. And if you expect this readout to be at a medical conference or a company event.

David LeBelitz: Could be showing to predict ultimate benefits. And so in the case, I mean, it's hunting to protein. The reason we believe that this is a worthwhile discussion.

David LeBelitz: is because there's a vast scientific literature clearly demonstrating that lowering Huntington's protein has been associated with benefits, both in preclinical models and in patients.

Matthew Klein: Furthermore, Huntington's disease provides a very unique situation for a neurodegenerative disease in that it's monogenetic, and we absolutely understand what the cause is, a mutant Huntington protein, and therefore, it's quite logical that if you can lower the amount of the disease-causing protein, you should have benefits. And, of course, that has been borne out in the scientific literature. And then the other point, of course, that the FDA highlights in their guidance in terms of something they want to have in terms of discussion of a surrogate endpoint is not only having a biomarker that's likely to be a clinical benefit but some scientific evidence that says what level of reduction or change in that biomarker is needed to have that clinical benefit.

David LeBelitz: Furthermore, Huntington's disease provides a very unique situation for a neurodegenerative disease in that it's monogenetic and we absolutely understand what the cause is.

Matthew Klein: Sure, thanks for the questions, Brooke. So as we've talked about the Cardinals, ALF study is registration direct study of each relaxes that in ALF patients. The study was designed to be a six month with people controlled study with an end point strategy that being the primary end point of the ALF for red scale. So, such that we're positive and we choose to just do a significant from the primary end point. It would support an MBA submission in the United States.

David LeBelitz: a mutant Huntington protein. And therefore, it's quite logical that if you can lower the amount of the disease-causing protein, you should have benefits. And of course, that's been borne out in the scientific literature.

David LeBelitz: And then the other point, of course, that the FDA highlights in their guidance.

David LeBelitz: in terms of something they want to have in terms of discussion of a surrogate endpoint is not only having a biomarker that's likely to be a clinical benefit, but some scientific evidence that says what level of reduction or change in that biomarker is needed to have that clinical benefit. And again, in the case of Huntington's disease, we have the advantage of knowing that the literature not only demonstrates that lowering Huntington's protein has an associated benefit, but it gives a range of 10 to 50% as being the necessary bar to achieve that likely clinical

Matthew Klein: And again, in the case of Huntington's disease, we have the advantage of knowing that the literature not only demonstrates that lowering Huntington protein has an associated benefit, but it gives a range of 10 to 50 percent as being the necessary bar to achieve that likely, So I would say that, you know, just reading the FDA guidance, the Huntington protein fits squarely within what the FDA themselves have written and published in terms of what they want to see, and that'll be the basis of our conversation.

Matthew Klein: This is a study that was designed leveraging the learnings made from other products that have been tested in ALF patients. Double blind placebo control study randomization to one of each relaxes that to placebo. We included a eight week run in in order to determine the baseline rate of progression, which again has been done in many previous ALF trials so that we ensure that the primary analysis group is one that moving and appropriate disease rate so that we can practically record a treatment benefit.

David LeBelitz: So I would say that, you know, just reading the FDA guidance, the Huntington Protein sits squarely within what the FDA themselves have written and published in terms of what they want to see, and that will be the basis of our conversations.

Matthew Klein: So, I'm going to find success here as a statistically significant primary end point is that would that allow us to forward with any of these admission. We said that we expect to have top on results in the fourth quarter. We expect that we'll share those results on a public call as we typically do when we have top line.

Matthew Klein: All right, thank you. Well, this concludes our question and answer session. I would now like to turn our call back over to CEO Matthew Klein for closing remarks.

David LeBelitz: Alright, thank you. Well, this concludes our question and answer session. I would now like to turn our call back over to CEO of Matthew Klein for closing remarks.

Unknown Executive: All right. Thank you.

Matthew Klein: Thank you all for joining us on the call today. I'm incredibly proud of our team's performance in the first half of the year. As we mentioned on the call, we've achieved all of our milestones, and we continue to execute on all fronts. We've had three regulatory submissions. We have a strong balance sheet. We're managing operating expenses effectively, and we remain on schedule for a number of other important milestones in 2024. So we look forward to continuing to share our progress along this path, and I wish you all a good evening. Thanks.

Matthew Klein: Thank you all for joining the call today. I'm incredibly proud of our team's performance in the first half of the year. As we mentioned on the call, we've

Matthew Klein: achieved all of our milestones.

Matthew Klein: We continue to execute on all fronts. We have three regulatory submissions. We have a strong balance sheet. We're managing operating expenses effectively, and we make on schedule for a number of other important milestones in 2021.

Joe: Our next question comes from the line of Brian Abraham from RBC capital markets. Your line is now open. Hi, this is Joe. I'm for Brian. Thank you for taking our question.

Matthew Klein: So we look forward to continue to share our progress along this path, and I wish you all a good evening. Thank you.

Matthew Klein: So going back to Huntington's when looking at your and other developers got a collectively, which probably marker other than HTTP lowering do you think has shown the best translitability to clinical benefits and support accelerator approval. And I guess along these lines, have you had a chance to look at the correlation between HTTP knockdown levels to functional measures at individual levels for your data. Thank you. Thanks, Joe. The only marker that's really been shown to correlate reliably with potential clinical benefit is Huntington Mohr.

Operator: Thank you for participating in today's conference. This does conclude the program. You may now disconnect.

Speaker Change: Thank you for participating in today's conference. This does conclude the program you may now disconnect us.

Matthew Klein: And the rationale for Huntington Mohr is to be a surrogate endpoint that's likely to predict clinical benefit is based on several things, first, just basic principles. Huntington disease is a moderate disorder caused by an mutation in the Huntington gene that leads to a production of a disease causing toxic to the Huntington protein. And thus it stands to reason if you can lower the disease causing protein, you're likely to have benefits. And that's in study that's been studied extensively in a number of three clinical models.

Matthew Klein: And they all demonstrate that if you could lower Huntington protein, it's been reported in a range of 10 to 50%. That's been associated with clear phenotypic benefit. There's also been epidemiologic study, which is demonstrated that so the experiment that Mother Nature, if you are born with a single nuclear polymorphism, the promoter for the Huntington gene, and about 50% less using Huntington protein, you haven't almost 10 year the lead in onset of disease, 10 a slower disease progression.

Matthew Klein: So when you put that scientific package together, the evidence is strong that lowering Huntington protein is likely to result in clinical benefit. And not only is it lowering Huntington protein, it's lowering Huntington protein in that range. I mentioned that it's shown between 10 to 50%. And so that when we now move to the clinical data, the kind of data you collected to see to be able to show that we are lowering Huntington protein at that level that has been associated with benefit.

Matthew Klein: But that's really the support and evidence that we will use in our discussion with the agency around a potential accelerated approval path. We've not looked specifically at correlation thus far, as you recall, the PIVHC feedback was a relatively small data set, but we're clearly seeing dose dependent lowering Huntington protein in the blood in the CSF. And dose dependent benefit on the clinical endpoints that we've collected thus far. Thank you, ma'am.

Matthew Klein: Thank you.

Joe: Our next question comes from a line of Joseph Thome of T.D. Cohen. Your line is now open. Hi there. Good afternoon. Congrats on the progress. Thank you for taking our questions. Maybe the first one just to follow up on the ALF trial. I guess do you believe there's been any change in what the FDA wants to see for a pivotal package for ALF, given the experience with the AMOLEDX compound. And then maybe second on Huntington, they're nowhere waiting on more data in the first half of next year, the full data set from PIVHC. Is there anything in that data set that you'd like to see before launching a phase three? Thank you.

Matthew Klein: Thanks for the questions, Joe. On ALF, we worked closely with the agency to ensure that we had designed the carnal study and that we were analyzing the data and had the right endpoints that would be consistent with they would want to see in terms of improvement. Package, and so what we have in terms of our sudden design, the statistical analysis plan, how we're approaching the analysis for the primary endpoint, and one important point here is something you just see really likes to see, and understand is not only the change on the continuous variable of the ALS and forest scale, but also incorporating any depth that might occur in the time to time to get as a second component of looking at primary treatment effect.

Matthew Klein: Therefore, I can say that we have certainly taken all of their advice and believe that we design the study in our analyses to be consistent with exactly the type of package that we want to see for approval, which is quite the system to what this use has always been. And in terms of the key question in terms of timing, seeing more data and going on to phase three, but we design activity in the two different parts, part and part B, to make sure that we're asking key questions, key stroke development questions at the right time.

Matthew Klein: The first 12 weeks were focused on pharmacological data effect saying, are we seeing the evidence of target engagement, evidence of the dose dependent lowering of Huntington protein, we would want to see, are we seeing it at the magnitude we need to see to know that the doses of five and 10 milligrams are likely to be appropriate for accuracy. And are we seeing the CNS exposure the answers to those were yes and yes.

Matthew Klein: As we move into the second part of the study, the nine month study, there we're asking the question, okay, at the dose levels, we know we're having pharmacological data effect and adequate and excellent CNS exposure. Are we starting to see changes in CNS biomarkers and clinical skills that give us confidence that over time, we'll be able to register the efficacy necessary. And so when we had the data read out with that first with the patients, the answer again is with yes, we saw what we needed to see in terms of biomarker effect, durability of Huntington lowering early, moving the clinical cells and then importantly continue safety and tolerability at the five and 10 milligrams dose.

Matthew Klein: So for us, we really checked all of those dating boxes to move forward in the phase three. So that's why we're still able to start to face the planning and continue to get a line. Develop the study design. You get along with the regulatory salaries and advance that study based on the data we have this far. Perfect. Thank you very much. Thank you.

Jeff Hung: Our next question comes from a line of Jeffrey Haum from Morgan Stanley. Your line is now open. Hi, following the TransLunner, we submitted NDA. Can you just provide more color and highly thinking about the market opportunity and overall patient dynamics in the US, sort of in comparison to what we've seen in the EU? Yes, thank you very much for the question. We, as we've talked about, we've for a long time been ready to make TransLunner available to boys, young men, not just mutations, the NDA in the US in the significant medical need.

Jeff Hung: And you need to be able to recently end the area and have the opportunity to finally bring TransLunner to boys and young men in the US is would be a trend that's an opportunity for a kind of joining us to more color on how we would think about it. Yeah, absolutely. Thanks very much for the question. So as Matt said, it's a higher medical need because there has been no other therapies for targeted for nonsensmitation DMD so that this remains a higher medical need.

Jeff Hung: And our team has had over five years of experience of working embedded in the DMD community, working alongside the physicians, working alongside the patients, the patient advocacy groups. And also has strong infrastructure set up for PTC cares to support the patients from start to finish throughout their treatment experience. In addition to that, through our experience with influenza, we have thousands of DMD patients that have been genotype. And this allows us to move rapidly upon launch to understand where to go from from for the nonsensmitation DMD patients.

Jeff Hung: And in addition to that, we also have a group of patients more than a hundred that are still on transliner and have been on for over a decade on clinical trials. We'll be able to look to put them on commercial drug, very quickly post post approval. So from a market dynamics perspective, we expect to very rapid uptake in this space. Thank you. And I'm sorry, I forgot to mention this is Catherine on for Jeff.

Jeff Hung: This is a quick follow up. Have you perceived any early feedback from physicians in the US that might be indicative of what demand or the launch trajectory might look like there? Just curious. Thank you. Yeah, absolutely. Thanks, Catherine. We have obviously received a lot of feedback and we've been working very closely with the DMD physicians. And there's a huge amount of pull from those physicians and also from the patients because they've known about transliner for a long period of time.

Jeff Hung: And PTC initiated the DMD space and they've been waiting to get access to that therapy and have struggled to understand why patients from all over the world can get access to transliner, but patients in the US could not. And so we see the market opportunity in the US larger than Europe. And I think from that perspective, with both the position and the patient pool and the market landscape dynamics, we talked about earlier just reinforces my point around fast uptake. Great. Thank you so much for the color. Of course. Thank you.

Catherine: The next question comes from the line of Jenna Wang from Barclays. Your line is now open. Thank you.

Gina: I have two questions. First, you know, you will have several launches underway. Should we see a meaningful increase in SGNA in 2025 and beyond. And second question is regarding the took a note in just a taxi. So the NBA in late 2024 and regarding the natural history data. When do you plan to share that data with investors?

Matthew Klein: Thanks for the questions, Gina. On the first question is, as we've talked about, we have built the infrastructure, the global commercial infrastructure to support not only the existing therapies, but the potential therapies that are come. And so we have the infrastructure. We have the expertise across the board to launch several comments. And in fact, you know, we're obviously quite proud to be in this situation where we've already submitted three new drug applications of the LA.

Matthew Klein: I think the Sierra potentially afford this year and we're incredibly proud of the teams that accomplish some being able to do this. And those therapies are all approved. We have the team set ready to go. And we'll quickly get these therapies and patients who do, and so we don't expect, and it increases the next January because being constructed is built and ready to go and scale with any number of new therapies that we can bring to patients in the year in the future.

Matthew Klein: In terms of the particular data, as I mentioned, we're still in the process of completing the collection of the long-term data for new effects that we'll be compared to the natural history preparedness. We've talked a lot about being in the fortunate situation with the FACOMS natural history registry, FARA and the FAK community has done a model job in terms of building a natural history database that could be used for regulatory purposes.

Matthew Klein: We'll be first doing the analysis of the data previously collected in the trial conducted several years ago with adults and I'll be a 24 month analysis of analysis of the patients treated for 24 months, relative to the appropriate matched natural history comparison. And then of course, we'll be having the natural history comparator data from the long-term open legal extension from the FACOMS and we will look forward to sharing as data when they are available.

Unknown Executive: Thank you.

David Lebowitz: Our next question comes from a line of David Lebelit from City. Your line is now open. Thank you very much for taking my question.

Unknown Executive: Given could the operating spend will have to start accounting for potential launches for the additional product mainly PKU. Could you run us through what your assumptions will be and expectations, especially given those the convert that's due next year? Sure, so thanks for the question. Let me clarify that we have a convert, but that is up in 2026 and as I mentioned with the operating expenses and the level of office we have now is where it needs to be in anticipation of potential launches. Thank you.

Jimmy: Our next question comes from a line of Joseph Schwartz from Learing Partners. Your line is now open. Hi, it's Jimmy on for Joe. Thanks for taking our question. We've heard from a couple of other sponsors that the FDA is not a fan of Huntington Protein as a potential target marker to support accelerate approval and Huntington is clearly you guys disagree. Why do you think that they might be thinking that way and have you thought anything about other potential for biomarkers that you guys might be able to use?

Jimmy: Thank you. Thank you for the question. I'm not sure anyone could speak for what the FDA thinks of the FDA believes. I think where we certainly the Huntington disease will exist in a situation where no one has the opportunity to come before them and have a discussion. What we do know for sure is what the FDA publishes in their guidance. And they have very clear guidance around what are the requirements for a surrogate end point.

Jimmy: And if you read their guidance regarding a surrogate what's needed for a surrogate end point that's likely to predict clinical benefits and therefore support and if it's tolerated approval application. What they would like to have is scientific data that could be from pre clinical studies or clinical studies that show how a certain biomarker, could be shown to predict ultimate benefits. And so in the case that he's a hunter to protein, the reason we believe that this is a worthwhile discussion is because there's a vast scientific literature clearly demonstrating that lowering a hunter to protein has been associated with benefits, both in preclinical model and in patients.

Jimmy: This furthermore hunting to disease provides a very unique situation for nerve-egenerative disease in that it's modigenate and we absolutely understand what the cause of mutant hunting to protein. And therefore, it's quite logical that if you can lower the amount of the disease causing protein, you should have benefits. And of course, that's been borne out in the sounds of the glittering. And then the other points, of course, that the FDA highlights the 1990s in terms of something they want to have in terms of discussion of a surrogate end point is not only having a biomarker that's likely to be a clinical benefit, but some scientific evidence that says what level of reduction of change in that biomarker is needed to have that clinical benefit.

Jimmy: And again, in the case of hunting disease, we have the advantage of knowing that the literature not only demonstrates that lowering a hunter to protein has been associated with benefits, but it gives a range of 10% to 50% as being that a necessary bar to achieve that likely clinical benefit.

Matthew Klein: And so I would say that just reading the FDA guidance to hunting to protein fits squarely within what the FDA themselves have written and published in terms of what they want to see and that will be the basis of our conversations. All right, thank you.

Unknown Executive: Well, this concludes our question and answer session.

Matthew Klein: I would now like to turn our call back over to CEO of Matthew Klein for closing remarks. Thank you all for joining us. The call today is incredibly proud of our team's performance in the first half of the year. As we mentioned on the call, we achieved all of our milestones. We continue to execute on all fronts. We have three regulatory submissions. We have a strong balance sheet of our managing operating expenses effectively, and we may on schedule for another other important milestones in 2024.

Unknown Executive: So we look forward to continue to share our progress along this path, and I wish you all a good evening. Thank you.

Unknown Executive: Thank you for participating in today's conference. This desk can glue the program.

Unknown Executive: You may now disconnect. Thank you.

Q2 2024 PTC Therapeutics Inc Earnings Call

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