Q3 2026 Stoke Therapeutics Inc Earnings Call

October 29, 2026

Operator: Welcome to Stoke Therapeutics' Q3 2026 business update conference call. At this time, all participants are in a listen-only mode. After the speakers' 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 that your hand is raised. Please be advised today's conference may be recorded. I will now hand the conference over to your first speaker for today, Thomas Leggett, Chief Financial Officer. Please go ahead, sir.

Speaker #1: 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 1-1 on your telephone.

Speaker #1: You will then hear an automated message advising that your hand is raised. Please be advised that today's conference may be recorded. I will now hand the conference over to your first speaker for today, Thomas Leigen, Chief Financial Officer.

Speaker #1: Please go ahead, sir.

Thomas Leggett: Good evening, and welcome to Stoke Therapeutics' Q3 2026 business update conference call. I am Thomas Leggett, the Chief Financial Officer at Stoke Therapeutics. Joining me on today's call, Ian Smith, our Chief Executive Officer, Dr. Barry Ticho, Chief Medical Officer, and Jason Hoitt, Chief Patient Officer. As a reminder, today's webcast presentation is available in the Investors section of our website. This webcast is being recorded and will be available for replay later this evening. Before we begin, please note that today's discussion includes forward-looking statements. These forward-looking statements are subject to risks and uncertainties, and actual results may differ materially. Please refer to our filings with the SEC for additional information. With that, I will turn the call over to Ian.

Speaker #2: Good evening, and welcome to Stoke Therapeutics Q3 2026 business update conference call. I'm Thomas Leigen, the Chief Financial Officer at Stoke Therapeutics. Joining me on today's call are Ian Smith, our Chief Executive Officer; Dr. Barry Teko, Chief Medical Officer; and Jason Hoyt, Chief Patient Officer.

Speaker #2: As a reminder, today's webcast presentation is available in the investor section of our website. This webcast is being recorded and will be available for replay later this evening.

Speaker #2: Before we begin, please note that today's discussion includes forward-looking statements. These forward-looking statements are subject to risks and uncertainties, and actual results may differ materially.

Speaker #2: Please refer to our filings at the SEC for additional information. With that, I'll turn the call over to Ian.

Ian Smith: Thank you, Thomas, and thank you to everyone joining us this evening. It has been a busy quarter at Stoke. Tonight, we will discuss our recent progress, including an update on the advancement of patients through key time points in the EMPEROR phase III registrational study of zorevunersen. Our recent discussion with the FDA related to our NDA planning and the latest on our commercial readiness activities. I will start with some highlights from our phase III study. To date, approximately 110 of 162 enrolled patients have completed their week 28 visit. This is the time point at which data for the primary endpoint of change in major motor seizure frequency is captured. Approximately 20 patients have also completed their week 52 visit, marking the end of the study treatment period and the time point at which key secondary endpoint data will be captured.

Speaker #3: Thank you, Thomas, and thank you to everyone joining us this evening. There's been a busy quarter at Stoke. Tonight, we will discuss our recent progress, including an update on the advancement of patients through key time points in the EMPRA Phase 3 registrational study of Zoriva Nursen.

Speaker #3: Our recent discussion with the FDA related to our NDA planning and the latest on our commercial readiness activities. I'll start with some highlights from our Phase 3 study.

Speaker #3: To date, approximately 110 of the 162 enrolled patients have completed their week 28 visit. This is the time point at which data for the primary endpoint of changing major motor seizure frequency is captured.

Speaker #3: Approximately 20 patients have also completed their week 52 visit, marking the end of the study treatment period and the time point at which key secondary endpoint data will be captured.

Ian Smith: All of these patients are continuing into the open-label portion of the study. Notably, there have been no treatment discontinuations to date. Barry will provide some additional metrics and context in a few moments. Next, I will highlight our recent interaction with the FDA that gave us the opportunity to discuss our five years of clinical data for zorevunersen, including our phase I, II, and OLE studies, and to align on key aspects of our planned 2027 US NDA submission. We were pleased with the agency's engagement, responsiveness, and interest in zorevunersen. An important outcome of our meeting was the FDA's willingness to accept a multi-component assessment of Vineland-3 data for purposes of evaluating the key secondary endpoint related to changes in cognition and behavior.

Speaker #3: All of these patients are continuing into the open-label portion of the study. Notably, there have been no treatment discontinuations to date. Barry will provide some additional metrics and context in a few moments.

Speaker #3: Next, I will highlight our recent interaction with the FDA, which gave us the opportunity to discuss our five years of clinical data for Zoriva Nursen.

Speaker #3: Including our Phase 1, Phase 2, and OLE studies, and to align on key aspects of our planned 2027 US NDA submission. We were pleased with the agency's engagement, responsiveness, and interest in Zoriva Nursen, and an important outcome of our meeting was the FDA's willingness to accept a multi-component assessment of Violent 3 data for purposes of evaluating the key secondary endpoint related to changes in cognition and behavior.

Ian Smith: This is a positive outcome because we believe a multi-component approach acknowledges the complexity of the disease and the fact that each patient's experience with Dravet syndrome is different, especially when it comes to impacts on cognition and behavior. Coming out of the discussion, we are reiterating our timelines for a data readout in Q3 2027, followed by a planned NDA submission in the H2 of next year. Clarity on these timelines is important as we scale our organization and capabilities to deliver zorevunersen to patients following a potential US approval in early 2028.

Speaker #3: This is a positive outcome because we believe a multi-component approach acknowledges the complexity of the disease and the fact that each patient's experience with drug-based syndrome is different.

Speaker #3: Especially when it comes to impacts on cognition and behavior. Following the discussion, we are reiterating our timelines for a data readout in Q3 2027, followed by a planned NDA submission in the second half of the following year.

Speaker #3: Clarity on these timelines is important as we scale our organization and capabilities to deliver Zoriva Nursen to patients, following a potential US approval in early 2028.

Ian Smith: Our medical affairs team has done an incredible job over the past two years establishing a foundation of awareness and understanding of Dravet syndrome and the data to support the disease-modifying potential of zorevunersen. We are continuing to expand our educational efforts, moving to reach more clinicians and other stakeholders, including payers, with the recent addition of our field market access team. We continue to learn as much as we can about Dravet syndrome and the opportunity through ongoing research. These efforts have given us additional confidence in the addressable patient population and are guiding our organizational build. At the same time, the field is continuing to evolve, and we see growing awareness of the needs of patients with Dravet syndrome and other genetic epilepsies.

Speaker #3: Our Medical Affairs team has done an incredible job over the past two years, establishing a foundation of awareness and understanding of drug-based syndrome, and the data to support the disease-modifying potential of Zoriva Nursen.

Speaker #3: We are continuing to expand our educational efforts moving to reach more clinicians and other stakeholders, including payers, with the recent addition of our field market access team.

Speaker #3: We continue to learn as much as we can about drug-based syndrome and the opportunity through ongoing research. These efforts have given us additional confidence in the addressable patient population and are guiding our organizational build.

Speaker #3: At the same time, the field is continuing to evolve and we see growing awareness of the needs of patients with drug-based syndrome and other genetic epilepsies.

Ian Smith: We are encouraged by the actions of stakeholder organizations such as American Epilepsy Society's Presidential Task Force on preparing for disease-modifying therapies and education and advocacy related to the need for genetic testing. Jason will share more on these efforts in a few minutes. We see haploinsufficient diseases as a clear and unique opportunity for our platform, which is why we are excited to advance STK-002. Autosomal dominant optic atrophy, or simply ADOA, is a rare genetic disease that is primarily caused by a haploinsufficiency that results in 50% of functional protein production. STK-002 is designed to increase naturally occurring, fully functional OPA1 protein production to address the underlying cause of this disease. In addition to our preclinical data, recent data from the field supports the potential of the OPA1-targeting hypothesis.

Speaker #3: We are encouraged by the actions of stakeholder organizations, such as the American Epilepsy Society's Presidential Task Force, on preparing for disease-modifying therapies and education and advocacy related to the need for genetic testing.

Speaker #3: Jason will share more on these efforts in a few minutes. We see haploinsufficient diseases as a clear and unique opportunity for our platform. Which is why we are excited to advance STK002.

Speaker #3: Autosomal dominant optic atrophy, or simply ADOA, is a rare genetic disease that is primarily caused by a haploinsufficiency, resulting in 50% of functional protein production.

Speaker #3: SDK002 is designed to increase naturally occurring fully functional OPA1 protein production to address the underlying cause of this disease. In addition to our preclinical data, recent data from the field supports the potential of the OPA1 targeting hypothesis.

Ian Smith: Dosing is now underway in the third cohort of our phase I OSPREY study, and we expect to initiate the fourth dose cohort in early 2027. Initial safety and efficacy data are anticipated in the H1 of next year, which will inform future development. As we expand our research efforts, we will continue to focus on severe genetic diseases driven by haploinsufficiency with an emphasis on the CNS, given our experience in Dravet syndrome. With that, I would summarize by saying that Stoke has made great progress throughout 2026, and we are well-positioned heading into the end of this year. With that, I will turn the call over to Barry.

Speaker #3: Dosing is now underway in the third cohort of our Phase 1 Osprey study, and we expect to initiate the fourth dose cohort in early 2027.

Speaker #3: Initial safety and efficacy data are anticipated in the first half of next year, which will inform future development. As we expand our research efforts, we will continue to focus on severe genetic diseases.

Speaker #3: Driven by haploinsufficiency, with an emphasis on the CNS given our experience in drug-based syndromes. With that, I would summarize by saying that Stoke has made great progress throughout 2026, and we are well positioned heading into the end of this year.

Speaker #3: With that, I will turn the call over to Barry.

Barry Ticho: Thank you, Ian. I will start by expanding on our phase III progress that Ian mentioned. EMPEROR is a global, double-blind, sham-controlled phase III study of zorevunersen in patients with Dravet syndrome. The study is designed as a 52-week treatment period in which patients receive two loading doses plus two maintenance doses of either zorevunersen or a sham, followed by an open-label extension period in which all patients receive zorevunersen. The primary endpoint is percent change from baseline in log transformed major motor seizure frequency at week 28. All secondary endpoints are measured at week 52. To protect the integrity of the study, we will not review or analyze any data until all patients reach week 52. The study is progressing very well.

Speaker #2: Thank you, Ian. I'll start by expanding on our Phase 3 progress that Ian mentioned. EMPRA is a global double-blind sham-controlled Phase 3 study of Zoriva Nursen in patients with drug-based syndrome.

Speaker #2: The study is designed as a 52-week treatment period in which patients receive two loading doses plus two maintenance doses of either Zoriva Nursen or sham, followed by an open-label extension period in which all patients receive Zoriva Nursen.

Speaker #2: The primary endpoint is percent change from baseline in log-transformed major motor seizure frequency at week 28. All secondary endpoints are measured at week 52.

Speaker #2: To protect the integrity of the study, we will not review or analyze any data until all patients reach week 52. The study is progressing very well.

Barry Ticho: All 162 patients enrolled in the US, UK, and Japan are through week 8 of the study, which means that they have received either the two loading doses of 70 milligrams of zorevunersen or a sham. Approximately 130 patients are through week 24, and therefore have only one of the four doses left in the 52-week treatment period. Approximately 110 patients have also completed their week 28 visit, the time point at which the primary endpoint of change in major motor seizure frequency is measured. Approximately 65 patients are through week 40 and have therefore received all four doses of zorevunersen or sham. Approximately 20 patients have reached the end of the 52-week treatment period. All of these patients are continuing into the open-label extension period. No patients have discontinued treatment in EMPEROR. When we originally designed EMPEROR, we set an enrollment target of 150 patients.

Speaker #2: All 162 patients enrolled in the US, UK, and Japan are through week 8 of the study, which means that they have received either the two loading doses of 70 milligrams of Zoriva Nursen or sham.

Speaker #2: Approximately 130 patients are through week 24 and therefore have only one of the four doses left in the 52-week treatment period. Approximately 110 patients have also completed their week 28 visit, the time point at which the primary endpoint of change in major motor seizure frequency is measured.

Speaker #2: Approximately 65 patients are through week 40 and have therefore received all four doses of Zoriva Nursen or sham. Approximately 20 patients have reached the end of the 52-week treatment period.

Speaker #2: All of these patients are continuing into the open-label extension period. No patients have discontinued treatment in EMPRA. When we originally designed EMPRA, we set an enrollment target of 150 patients.

Barry Ticho: This was based on a goal of 128 evaluable patients at the end of the study with an assumed 15% discontinuation rate. We ultimately enrolled 162 patients, and as I mentioned, there have been no discontinuations to date. These metrics reflect a well-designed trial, the need for better treatments, and a deeply committed community of investigators, site teams, and caregivers. The primary endpoint of EMPEROR is change in major motor seizure frequency at week 28. There is no doubt that anti-seizure medications are providing benefit for patients. Even still, seizure control remains the number one goal for new treatments. Demonstrating a disease-modifying impact on cognition and behavior is expected to take longer, which accounts for the year-long treatment period and evaluation of the Vineland results at week 52.

Speaker #2: This was based on a goal of 128 evaluable patients at the end of the study, with an assumed 15% discontinuation rate. We ultimately enrolled 162 patients, and as I mentioned, there have been no discontinuations to date.

Speaker #2: These metrics reflect a well-designed trial, the need for better treatments, and a deeply committed community of investigators, site teams, and caregivers. The primary endpoint of EMPRA is change in major motor seizure frequency at week 28.

Speaker #2: There's no doubt that anti-seizure medicines are providing benefit for patients. Even still, seizure control remains the number one goal for new treatments. Demonstrating a disease-modifying impact on cognition and behavior is expected to take longer which accounts for the year-long treatment period and evaluation of the final results at week 52.

Barry Ticho: As Ian mentioned, for the purposes of our US NDA, we plan to use a multi-component assessment that combines four pre-specified Vineland-3 subdomains, expressive communication, receptive communication, interpersonal relationships, and personal skills. We believe the multi-component assessment is the most appropriate way to evaluate changes in cognition and behavior due to the variability in how the disease affects patients. To generate a multi-component score, we first calculate the individual treatment effect for each subdomain using a multivariate mixed model for repeated measures, or MMRM. We then average all four scores to produce a single number that reflects the overall treatment effect. I will show you what that looks like in a minute. Before I do that, I want to remind you of an analysis that we performed back in 2024 to inform the design of the phase III study, and specifically to help us prioritize a selection of Vineland subdomains.

Speaker #2: As Ian mentioned, for the purposes of our US NDA, we plan to use a multi-component assessment that combines four pre-specified vitamin 3 subdomains. Expressive communication, receptive communication, interpersonal relationships, and personal skills.

Speaker #2: We believe the multi-component assessment is the most appropriate way to evaluate changes in cognition and behavior, due to the variability in how the disease affects patients.

Speaker #2: To generate a multi-component score, we first calculate the individual treatment effect for each subdomain using a multivariate mixed model for repeated measures, or MMRM.

Speaker #2: We then average all four scores to produce a single number that reflects the overall treatment effect. I'll show you what that looks like in a minute.

Speaker #2: Before I do that, I want to remind you of an analysis that we performed back in 2024 to inform the design of the Phase 3 study.

Speaker #2: And specifically, to help us prioritize the selection of vitamin subdomains. On the left side, you see data from a subset of patients treated in our Phase 1, 2, and OLE studies.

Barry Ticho: On the left side, you see data from a subset of patients treated in our phase I, II, and OLE studies. These patients received a total cumulative dose of zorevunersen that was consistent with our plans for phase III. On the right, you see data from patients followed in our natural history study whose baseline characteristics were matched in treated patient population. Week 68 was used for these analyses because it was the most proximal to a 52-week study design when accounting for the pause in dosing between the last phase I, II dose and the first OLE dose. Selection of these subdomains was further supported by feedback from clinicians and caregivers. Now, with an additional 2 years of data, and in light of our recent discussion with the FDA, we generated a multi-component analysis using propensity score weighting to calculate a treatment effect.

Speaker #2: These patients received a total cumulative dose of Zoriva Nursen that was consistent with our plans for Phase 3. On the right, you see data from patients followed in our natural history study whose baseline characteristics were matched to the treated patient population.

Speaker #2: Week 68 was used for these analyses because it was the most proximal to a 52-week study design when accounting for the pause in dosing between the last Phase 1/2 dose and the first OLE dose.

Speaker #2: Selection of these subdomains was further supported by feedback from clinicians and caregivers. Now, with an additional two years of data, and in light of our recent discussion with the FDA, we generated a multi-component analysis using propensity score weighting to calculate a treatment effect.

Barry Ticho: Use of propensity score weighting mimics randomization by adjusting for baseline differences between treated and natural history groups. This is the closest we can come to replicating a randomized trial. This analysis demonstrates the overall treatment effect across the 4 subdomains using a multi-component average, as well as the contributions of each of the 4 selected subdomains. Even with small numbers of patients, a highly statistically significant multi-component score was demonstrated. With 5 years of clinical data, an assumption of 150 evaluable patients, and the change to a multi-component assessment of the Vineland-3 for our US NDA, we have run a calculation of the minimum treatment effect to achieve a P value of 0.05 to 0.01.

Speaker #2: The use of propensity score weighting mimics randomization by adjusting for baseline differences between treated and natural history groups. This is the closest we can come to replicating a randomized trial.

Speaker #2: This analysis demonstrates the overall treatment effect across the four subdomains using a multi-component average as well as the contributions of each of the four selected subdomains.

Speaker #2: Even with a small number of patients, a highly statistically significant multi-component score was demonstrated. With five years of clinical data, an assumption of 150 evaluable patients, and the change to a multi-component assessment of the vitamin 3 for our US NDA, we have run a calculation of the minimum treatment effect to achieve a p-value of 0.05 to 0.01.

Barry Ticho: The study has 90% power to detect a treatment difference between treatment arms of 46% to 53% relative reduction in seizure frequency at a two-sided significance level of 0.05 to 0.01 respectively at weeks 28 and week 52. For the second key secondary endpoint measured by Vineland-3, the study has 90% power to detect a treatment difference of approximately 1.8 to 2.1 raw score points in the multi-component assessment at week 52, using the same two-sided significant levels of 0.05 to 0.01 respectively. We are often asked to explain the real-world meaning of these Vineland scores. What I can say is that even small changes can have meaningful impacts for patients and their families. This has been documented in the literature and is evident in the video case study that was included as supplemental to our data published in the New England Journal of Medicine earlier this year.

Speaker #2: The study has 90% power to detect a treatment difference between treatment arms of 46% to 53% relative reduction in seizure frequency at a two-sided significance level of 0.05 to 0.01, respectively, at weeks 28 and week 52.

Speaker #2: For the second key secondary endpoint, measured by vitamin 3, the study has 90% power to detect a treatment difference of approximately 1.8 to 2.1 raw score points in the multi-component assessment at week 52.

Speaker #2: Using the same two-sided significance levels of 0.05 to 0.01 respectively. We are often asked to explain the real-world meaning of these vitamin scores. What I can say is that even small changes can have meaningful impacts for patients and their families.

Speaker #2: This has been documented in the literature and is evident in the video case study that was included as supplemental to our data published in the New England Journal of Medicine earlier this year.

Barry Ticho: We will continue to keep you updated as we progress the study, and we look forward to our data readout in Q3 of next year. Let me turn to our second clinical stage program, STK-002. Momentum and awareness of this program are increasing. Earlier this month at the American Academy of Ophthalmology annual meeting, our teams delivered 2 presentations of data that support the potential of STK-002 as a disease-modifying treatment for ADOA. ADOA is a rare genetic disease that leads to progressive degeneration of the optic nerve and vision loss starting in the first decade of life. It is the most common inherited optic nerve disorder, affecting approximately 13,000 in the US, UK, EU4, and Denmark. The majority of cases are caused by mutations in one copy of the OPA1 gene, resulting in haploinsufficiency and reduced functional OPA1 protein.

Speaker #2: We will continue to keep you updated as we progress the study, and we look forward to our data readout in Q3 of next year.

Speaker #2: Let me turn to our second clinical stage program, STK002. Momentum and awareness of this program are increasing. Earlier this month, at the American Academy of Ophthalmology annual meeting, our teams delivered two presentations of data that support the potential of STK002 as a disease-modifying treatment for ADLA.

Speaker #2: ADLA is a rare genetic disease that leads to progressive degeneration of the optic nerve and vision loss, starting in the first decade of life.

Speaker #2: It is the most common inherited optic nerve disorder affecting approximately 13,000 in the US, UK, EU4, and Denmark. The majority of cases are caused by mutations in one copy of the OPA1 gene.

Speaker #2: Resulting in haploinsufficiency and reduced functional OPA1 protein. Approximately half of people living with ADLA will progress to legal blindness. There are currently no approved treatments for ADLA.

Barry Ticho: Approximately half of people living with ADOA will progress to legal blindness. There are currently no approved treatments for ADOA. STK-002 is designed to increase OPA1 protein expression with the aim of improving vision in people with ADOA. We are encouraged by our preclinical data, as well as emerging data from the field, demonstrating that upregulation of OPA1 protein has disease-modifying potential. In ADOA patient-derived cells with different OPA1 variants, STK-002 significantly increased OPA1 protein expression and improved mitochondrial function compared with healthy controls. On the next slide, you see that after a single intravitreal dose in non-human primates, STK-002 was also shown to reach retinal ganglion cells and increase retinal OPA1 protein. On the left side, staining shows STK-002 in red in retinal ganglion cells with increased signal correlating with increased dose.

Speaker #2: STK002 is designed to increase OPA1 protein expression with the aim of improving vision in people with ADLA. We are encouraged by our preclinical data, as well as emerging data from the field, demonstrating that upregulation of OPA1 protein has disease-modifying potential.

Speaker #2: In ADLA patient-derived cells with different OPA1 variants, STK002 significantly increased OPA1 protein expression and improved mitochondrial function compared with healthy controls. On the next slide, you see that after a single intravitreal dose in non-human primates, STK002 was also shown to reach retinal ganglia cells and increase retinal OPA1 protein.

Speaker #2: On the left side, staining shows STK002 in red in retinal ganglion cells, with increased signal correlating with increased dose. In the center, immunofluorescence staining with an OPA1 antibody, again in red, shows an increase in OPA1 protein in the retinal ganglion cell layer.

Barry Ticho: In the center, immunofluorescence staining with an OPA1 antibody, again in red, shows an increase in OPA1 protein in the retinal ganglion cell layer. OPA1 protein levels increased at all doses by week 4 by 44% to 47% at the 0.3 milligram and 1 milligram doses respectively. The phase I OSPREY study in people with ADOA is ongoing in the UK and Europe. The study aims primarily to evaluate the safety, tolerability, and exposure of single ascending doses of STK-002 following a standard dose escalation design. OSPREY will also assess clinical activity, including changes in visual function and patient quality of life, as well as retinal mitochondrial dysfunction. Data from our natural history study show higher levels of mitochondrial stress strongly correlate with decreased visual acuity.

Speaker #2: OPA1 protein levels increased at all doses by week 4 by 44 to 47% at the 0.3 milligram and 1 milligram doses respectively. The phase 1 Osprey study in people with ADLA is ongoing in the UK and Europe.

Speaker #2: The study aims primarily to evaluate the safety, tolerability, and exposure of single ascending doses of STK002 following a standard dose escalation design. Osprey will also assess clinical activity, including changes in visual function and patient quality of life, as well as retinal mitochondrial dysfunction.

Speaker #2: Data from our natural history study show higher levels of mitochondrial stress strongly correlate with decreased visual acuity. Osprey is designed to provide clinical proof of concept by testing whether increasing OPA1 protein expression with STK002 translates into measurable effects on visual function in patients with ADLA.

Barry Ticho: OSPREY is designed to provide clinical proof of concept by testing whether increasing OPA1 protein expression with STK-002 translates into measurable effects on visual function in patients with ADOA. The study is progressing well. We recently completed dosing of the first 2 cohorts of patients, and dosing the third cohort is underway, with completion expected by year-end. Subject to ongoing safety assessments, we expect to begin dosing of the fourth cohort in early 2027. We expect cohorts 3 and 4 to reach dose levels that may produce measurable effects on visual function. Initial safety and efficacy data from these higher dose cohorts are expected in the first H1 2027. With that, I will turn the call over to Jason.

Speaker #2: The study is progressing well. We recently completed dosing of the first two cohorts of patients, and dosing of the third cohort is underway, with completion expected by year-end.

Speaker #2: Subject to ongoing safety assessments, we expect to begin dosing of the fourth cohort in early 2027. We expect cohorts 3 and 4 to reach dose levels that may produce measurable effects on visual function.

Speaker #2: Initial safety and efficacy data from these higher dose cohorts are expected in the first half of 2027. With that, I will turn the call over to Jason.

Jason Hoitt: Thank you, Barry. Shifting back to Dravet, I will start by sharing an overview of the patient population. While we have shared these data previously, our latest market research continues to validate our assumptions and strengthen our confidence in the numbers. There are an estimated 38,000 patients with Dravet syndrome across the 7 major markets where we are running the EMPEROR study, the US, UK, EU 4, and Japan, including approximately 16,000 in the US alone. Of those 16,000 in the US, we estimate 6,000 are under the age of 25 and likely under the care of a pediatric provider. These are the patients who would be immediately addressable at the time of a potential US launch. Pediatric neurologists and epileptologists tend to follow the field closely and are typically the most well-informed about the disease and current treatment options.

Speaker #1: Thank you, Barry. Shifting back to Dravet, I'll start by sharing an overview of the patient population. While we've shared these data previously, our latest market research continues to validate our assumptions and strengthen our confidence in the numbers.

Speaker #1: There are an estimated 38,000 patients with Dravet syndrome across the seven major markets where we're running the EMPEROR study: the US, UK, EU4, and Japan.

Speaker #1: Including approximately 16,000 in the US alone. Of those 16,000 in the US, we estimate 6,000 are under the age of 25 and likely under the care of a pediatric provider.

Speaker #1: These are the patients who would be immediately addressable at the time of a potential US launch. Pediatric neurologists and epileptologists tend to follow the field closely and are typically the most well-informed about the disease and current treatment options.

Jason Hoitt: An ICD-10 code was established in 2020 and is used to track confirmed Dravet diagnoses. With the increasing awareness of Dravet syndrome and the importance of genetic testing, we are seeing 40 to 50 new patients entering these claims databases every month, equating to 500 to 600 every year, including newly identified younger patients and older patients finally arriving at a diagnosis. As a result, we anticipate the total number of immediately addressable patients to increase between now and the time of launch. We are confident that we know where 80% of the 6,000 immediately addressable patients are being cared for today. In the US, the Dravet population is highly concentrated around centers of excellence and other key treatment centers. Approximately half of identified US patients are cared for by the top 50 sites.

Speaker #1: The ICD-10 code was established in 2020 and is used to track confirmed Dravet diagnoses. With the increasing awareness of Dravet syndrome and the importance of genetic testing, we're seeing 40 to 50 new patients entering these claims databases every month, equating to 500 to 600 every year.

Speaker #1: Including newly identified younger patients, and older patients finally arriving at a diagnosis. As a result, we anticipate the total number of immediately addressable patients to increase between now and the time of launch.

Speaker #1: We're confident that we know where 80% of the 6,000 immediately addressable patients are being cared for today. In the US, the Dravet population is highly concentrated around centers of excellence and other key treatment centers.

Speaker #1: Approximately half of identified U.S. patients are cared for by the top 50 sites. All 50 of those sites are experienced in administering intrathecal medicines, and over half of these sites have participated in a Zoriva nursing study.

Jason Hoitt: All 50 of those sites are experienced in administering intrathecal medicines, and over half of these sites have participated in a zorevunersen study. There is a high level of awareness of zorevunersen in anticipation for the phase III readout and potential approval. The Dravet community has been involved in this program since its earliest days, and sites are anticipating strong demand upon a potential US approval. Several of the top treatment centers have proactively reached out to us asking what they can do to be ready to deliver zorevunersen. Our teams are beginning to engage with sites to help them prepare the infrastructure protocols and staff expertise necessary to administer zorevunersen with appropriate capacity. The Dravet community has been waiting years for a medicine like zorevunersen. Our job is to do everything we can to ensure they do not have to wait a day longer than they need to.

Speaker #1: There's a high level of awareness of Zoriva nursing in anticipation for the phase 3 readout and potential approval. The Dravet community has been involved in this program since its earliest days and sites are anticipating strong demand upon a potential US approval.

Speaker #1: Several of the top treatment centers have proactively reached out to us asking what they can do to be ready to deliver Zoriva nursing. Our teams are beginning to engage with sites to help them prepare the infrastructure protocols and staff expertise necessary to administer Zoriva nursing with appropriate capacity.

Speaker #1: The Dravet community has been waiting years for a medicine like Zoriva. Our job is to do everything we can to ensure they don't have to wait a day longer than they need to.

Jason Hoitt: To that end, we are adding resources and capabilities with an emphasis on people who have launched high science new medicines, particularly for rare genetic diseases, and are committed to delivering excellence in patient care and overall experience. Our head of patient services recently joined Stoke, and she is in the initial stages of designing a patient support program that reflects the unique needs of this patient community and enables timely access. Our goal is to make the process between prescription and treatment as simple and easy as possible. Co-creation sessions with caregivers, clinicians, and office administrators are underway to design a program that meets their needs. On the payer side, we recently deployed our payer account team, who will start their educational efforts with medical directors at insurers across the country.

Speaker #1: To that end, we're adding resources and capabilities with an emphasis on people who have launched high science new medicines, particularly for rare genetic diseases, and are committed to delivering excellence in patient care and overall experience.

Speaker #1: Our head of patient services recently joined Stoke and she's in the initial stages of designing a patient support program that reflects the unique needs of this patient community and enables timely access.

Speaker #1: Our goal is to make the process between prescription and treatment as simple and easy as possible. Co-creation sessions with caregivers, clinicians, and office administrators are underway to design a program that meets their needs.

Speaker #1: On the payer side, we recently deployed our payer account team, who will start their educational efforts with medical directors at insurers across the country.

Jason Hoitt: These educational efforts build upon the years-long effort of our medical affairs team, who have supported our clinical teams and have done an exceptional job of education and awareness with healthcare providers and treating physicians around the world. Our latest HCP market research shows a high conviction in the data and in the disease-modifying potential of zorevunersen. We are also making progress among the broader neurology community, who may be less familiar with the latest advances in the treatment of Dravet syndrome. We are very encouraged by the growing awareness and interest we experienced at the recent Child Neurology Society meeting.

Speaker #1: These educational efforts build upon the years-long effort of our medical affairs team, who have supported our clinical teams and have done an exceptional job of education and awareness with healthcare providers and treating physicians around the world.

Speaker #1: Our latest HCP market research shows a high conviction in the data and in the disease-modifying potential of Zoriva nursing. We're also making progress among the broader neurology community who may be less familiar with the latest advances in the treatment of Dravet syndrome.

Speaker #1: We are very encouraged by the growing awareness and interest we experienced at the recent Child Neurology Society meeting. As recently as three years ago, very few people at this meeting knew about Dravet, Zoriva nursing, or Stoke.

Jason Hoitt: As recently as three years ago, very few people at this meeting knew about Dravet, zorevunersen, or Stoke. Today, there is a far greater appreciation among general neurologists and epileptologists for the genetic drivers of Dravet syndrome and the reclassification of genetic epilepsies as DEEs. The ability to genetically diagnose these diseases is also prompting physicians and medical societies to rethink the treatment paradigm. One such example is the American Epilepsy Society's new presidential task force on disease-modifying therapies. The intent behind this new initiative is to prepare those who treat these diseases for the arrival of genetically targeted treatments. We are encouraged by initiatives like this one, which complement the work we are doing, signaling a shared commitment to improve outcomes for patients and recognition of the potential for a new class of medicines.

Speaker #1: Today, there's far greater appreciation among general neurologists and epileptologists for the genetic drivers of Dravet syndrome, and the reclassification of genetic epilepsies as DEEs.

Speaker #1: The ability to genetically diagnose these diseases is also prompting physicians and medical societies to rethink the treatment paradigm. One such example is the American Epilepsy Society's new Presidential Task Force on disease-modifying therapies.

Speaker #1: The intent behind this new initiative is to prepare those who treat these diseases for the arrival of genetically targeted treatments. We're encouraged by initiatives like this one, which complement the work we're doing, signaling a shared commitment to improve outcomes for patients and recognition of the potential for a new class of medicines.

Jason Hoitt: Beyond our educational efforts, we are preparing to initiate two additional clinical studies of zorevunersen by the end of this year. This includes a study in adult patients, which is intended to support access and reimbursement, as well as a study in infants and toddlers. The primary objective of these studies is to evaluate the safety of zorevunersen in these populations. These are not registrational studies. Consistent with our Breakthrough Therapy designation, we believe we can achieve a broad label without an upper age limit. Taken together, the strength of the clinical package, the continued positive feedback from payers and providers, and how we are preparing our organization and the treating community, give us confidence that we will be able to deliver zorevunersen to families quickly at the time of a potential US launch in early 2028. With that, I will turn it over to Thomas.

Speaker #1: Beyond our educational efforts, we're preparing to initiate two additional clinical studies of Zoriva by the end of this year. This includes a study in adult patients, which is intended to support access and reimbursement, as well as a study in infants and toddlers.

Speaker #1: The primary objective of these studies is to evaluate the safety of Zoriva dosing in these populations. These are not registrational studies. Consistent with our breakthrough therapy designation, we believe we can achieve a broad label without an upper age limit.

Speaker #1: Taken together, the strength of the clinical package, the continued positive feedback from payers and providers, and how we're preparing our organization and the treating community give us confidence that we'll be able to deliver Zoriva nursing to families quickly at the time of a potential US launch in early 2028.

Speaker #1: With that, I'll turn it over to Thomas.

Thomas Leggett: Thank you, Jason. I will remind you that full financial results can be found in today's press release and our 10-Q that we file next week. Today, I will focus on the strength of our balance sheet position. We ended the quarter with $358.8 million in cash equivalents, and marketable securities. This excludes restricted cash of $3.2 million. Our net loss for the three months ended 30 September was $73.6 million, which include $11 million of non-cash stock-based compensation expense. Our priorities at Stoke have not changed. Advancing our phase III study of zorevunersen, preparing the organization for potential US commercialization, and investing in our pipeline while maintaining a strong financial position. Along with the reimbursement we received from Biogen for zorevunersen-related expenses and a potential development milestone payment, we expect our cash position to fund our operations into early 2028. Thank you.

Speaker #2: Thank you, Jason. I will remind you that full financial results can be found in today's press release and our 10Q that we filed next week.

Speaker #2: Today, I will focus on the strength of our balance sheet position. We ended the quarter with $358.8 million in cash, cash equivalents, and marketable securities.

Speaker #2: This excludes restricted cash of $3.2 million. Our net loss for the three months ended September 30 with $73.6 million, which include $11 million of non-cash stock-based compensation expense.

Speaker #2: Our priorities at Stoke have not changed. Advancing our phase 3 study of Zoriva nursing, preparing the organization for potential US commercialization, and investing in our pipeline while maintaining a strong financial position.

Speaker #2: Along with the reimbursement we received from Biogen for Zoriva nursing-related expenses and a potential development milestone payment, we expect our cash position to fund our operations into early 2028.

Speaker #2: Thank you. I will now ask for the line to be open for Q&A.

Thomas Leggett: I will now ask for the line to be opened for Q&A.

Operator: Thank you. Ladies and gentlemen, to ask a question at this time, you will need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, simply press star 11 again. Please stand by while we compile the Q&A roster. Our first question coming from the line of Kevin Helfrich with Goldman Sachs. Your line is now open.

Speaker #3: Thank you. Ladies and gentlemen, to ask a question at this time, you will need to press star 11 on your telephone and wait for your name to be announced.

Speaker #3: Do we draw your question simply press star 11 again? Please stand by while we compile the Q&A roster. And our first question coming from the lineup, Kevin Strang with Goldman Sachs.

Speaker #3: He is now open.

Kevin Helfrich: Great, thanks. Just a question on the design for EMPEROR in terms of data quality monitoring. Can you walk us through how you designed the trial with that in mind in terms of the Vineland-3 subdomain scores, how you could consistently collect that across different time points, across different sites? That would be helpful. As just a brief follow-up on the multicomponent analysis plan that you have in place now, are there any meaningful differences between this plan with the FDA and what you have planned in Europe? Thanks.

Kevin Strang: Great, thanks. Just a question on the design for EMPEROR in terms of data quality monitoring. Can you walk us through how you designed the trial with that in mind in terms of the Vineland-3 subdomain scores, how you could consistently collect that across different time points, across different sites? That would be helpful. As just a brief follow-up on the multicomponent analysis plan that you have in place now, are there any meaningful differences between this plan with the FDA and what you have planned in Europe? Thanks.

Speaker #4: Great. Thanks. Just a question on the design for Emperor in terms of data quality monitoring. Can you walk us through how you design the trial with that in mind in terms of the violin 3 subdomains cores?

Speaker #4: How could you consistently collect that across different time points and across different sites? That would be helpful. And then, as just a brief follow-up, on the multi-component analysis plan that you have in place now, are there any meaningful differences between this plan with the FDA and what you have planned in Europe?

Speaker #4: Thanks.

Barry Ticho: Thanks, Kevin, for the question. This is Barry. The collection of the data for the Vineland in the study is vitally important. What we have put into place are several measures. One important one is that there is a trained central rater who collects all the data and puts together the scores, so that is uniformity across all the different sites. Second is that we encourage the same family member to be the reporter on the questionnaire. At every time that the questionnaire is asked, it's the same person giving the response. We also do have an internal spokesperson who is reviewing on nearly a daily basis to make sure that the Vineland tests are being collected and done appropriately at every site.

Speaker #2: Thanks, Kevin, for the question. This is very so the collection of the data for the violin in the study is vitally important. And so what we have put into place are several measures one important one is that there is a trained central rater who collects all the data and puts together the scores.

Speaker #2: So that is uniformity across all the different sites. Second is that we encourage the same family member to be the reporter on the questionnaire.

Speaker #2: So at every time that the questionnaires ask, it's the same person giving the response. And then we also do have an internal spokesperson who is reviewing, on nearly a daily basis, to make sure that the violin tests are being collected and done appropriately.

Speaker #2: At every site.

Ian Smith: Kevin, it's Ian here. I'll take the US versus Europe question. Correct, I'm sure we'll talk about it more on this call. The MC4, as we call it now. That's for the US, but in Europe, they still have what's called a net treatment benefit for individual Vineland subdomains, and there are five of them. In a similar way that we had before we got to the MC4. Biogen is in control of that filing in Europe, and we'll wait to see how they proceed with those authorities overseas.

Speaker #4: And Kevin, it's Ian here. I'll take the U.S. versus Europe question. Correct, and I'm sure we'll talk about it more on this call. The MC4, as we call it now, that's for the U.S.

Speaker #4: But in Europe, they still have what's called a net treatment benefit for individual VIOMED subdomains, and there's five of them. In a similar way, we had before we got to the MC4, Biogen is in control of that filing in Europe.

Speaker #4: And we'll wait to see how they proceed with those authorities overseas. Great. Thank you.

Kevin Helfrich: Great. Thank you.

Kevin Strang: Great. Thank you.

Operator: Thank you. Our next question in queue coming from the line of Laura Chico with Wedbush. Your line is now open.

Speaker #3: Thank you. Our next question in queue coming from the lineup, Laura Chick with Bush. She is now open.

Laura Chico: Good afternoon. Thank you very much for taking the question. Just two for me. Following the interactions with the FDA, I am wondering if you could elaborate if there has been any change on the potential for an advisory committee meeting. How have the expectations there changed? Just a point of clarification, what remaining areas need to be resolved prior to the rolling submission? I am sorry, one last one for Barry Ticho, perhaps. You recently presented some data at the CNS meeting on the OLE data. Could you just remind us on how the protocol there handles discontinuations of preexisting ASMs? I guess maybe to say it differently, I am trying to remember whether patients are coming off some of their baseline ASMs when they were on at study entry. Thanks.

Speaker #5: Good afternoon. Thank you very much for taking the question. Just two for me. I guess following the interactions with the FDA, I'm wondering if you could elaborate if there's been any change on the potential for an advisory committee meeting?

Speaker #5: How have the expectations there changed? And just to point a clarification, what remaining areas need to be resolved prior to the rolling submission? And I'm sorry, last one last one for Barry, perhaps.

Speaker #5: You recently presented some data at the CNS meeting on the OLE data. Could you just remind us on how the protocol there handles discontinuations of pre-existing ASMs?

Speaker #5: I guess maybe set it differently. I'm trying to remember whether patients are coming off some of their baseline ASMs when they were what they were on at study entry.

Speaker #5: Thanks.

Ian Smith: Laura, I will take the first two, and then Barry Ticho can take the question regarding maybe a change in medicines or ASM medicines through to week 28. Firstly, adcom. We do not anticipate an adcom. There was absolutely no discussion relating to an adcom when we had our FDA interaction a month or so ago. As far as submitting data for the NDA, we anticipate submitting data throughout H1 2027 with a completion of the submission in H2 2027. What we want to do is we want to submit that data to give the FDA the option to review early. There are no guarantees they will review early until they actually confirm that they are doing a rolling review. We will await that. But we will be submitting the data to the FDA to give them the option.

Speaker #2: So Laura, I will take the first two and then Barry can take the question regarding maybe a change in medicines or ASM medicines through to week 28.

Speaker #2: And so, firstly, ADCOM—we don't anticipate an ADCOM. There was absolutely no discussion relating to an ADCOM when we had our FDA interaction a month or so ago.

Speaker #2: As far as submitting data for the NDA, we anticipate submitting data throughout the first half of 2027, with completion of the submission in the second half of 2027.

Speaker #2: And yeah, what we want to do is submit that data to give the FDA the option to review early. There's no guarantee they will review early until they actually confirm that they're doing a rolling review, so we will await that.

Speaker #2: But we will be submitting the data to the FDA to give them the option. And we'll be continuing to work with the FDA to talk about the importance of what our medicine has shown, basically through our phase one, two, and our OLE data.

Ian Smith: And we will be continuing to work with the FDA to talk about the importance of what our medicine has shown, basically through our phase I, II, and our OLE data. And we have had multiple meetings outside just this meeting with the FDA to show the importance of our data and the urgent need to move fast through our submission and potentially through our approval. Barry, do you want to talk about how we treat change in ASM medicines through week 28?

Speaker #2: And we've had multiple meetings outside just this meeting with the FDA to show the importance of our data and the urgent need to move fast through our submission and potentially through our approval.

Speaker #2: Then Barry, do you want to talk about how we treat change in ASM medicines through week 28?

Barry Ticho: Sure. Thanks, Laura, for the question. So the background anti-seizure medications, the patients are monitored for the first 6 weeks before treatment with the background anti-seizure medications kept stable, and then they are supposed to stay stable through at least the first 6 months to the week 28 endpoint. And again, the background medications are continued, so any effects that we are going to see with zorevunersen will be on top of the baseline anti-seizure medications that they are already on. This is the way we saw in phase I, II, that the improvements that we saw in terms of, or the reductions that we saw in seizures, seizure frequency, were on top of background standard of care anti-seizure medications.

Speaker #1: Sure. Thanks, Laura, for the question. For background anti-seizure medications, the patients are monitored for the first six weeks before treatment, with the background anti-seizure medications kept stable.

Speaker #1: And then they're supposed to stay stable through at least the first six months to the week 28 endpoint. And again, the background medications are continued so any effects that we're going to see with rivaroxaban will be on top of the baseline anti-seizure medications that they're already on.

Speaker #1: This is the way we saw in phase one, two, that the improvements that we saw in terms of or the reductions that we saw in seizures seizure frequency were on top of background standard of care anti-seizure medications.

Ian Smith: Laura, could I just also add, it is a great question. One actually Barry and I frequently talk about. And I want to remind everyone that there is an 8-week screen period before you come into the EMPEROR study. That 8-week screen period, there is a number of things, but one of the things it does is it allows you to assess that these patients are already on a stable background of medicines. And so when they enter the study, whether they go into sham or active drug arm, they are on a stable background of anti-seizure medicine. So we would anticipate there to be small changes in terms of anti-seizure medicines. But there probably will be changes and we will assess week 28, and we will look at the data with and without the changes of those background seizure medicines.

Speaker #2: Laura, could I just also

Speaker #4: also add it's a great question. One actually Barry and I frequently talk about. And that I want to remind everyone that there is an eight-week screen period before you come into the EMPER study.

Speaker #4: That eight-week screen period there's a number of things, but one of it one of the things it does is it allows you to assess that these patients are already on a stable background of medicines.

Speaker #4: And so when they enter the study, whether they're going to SHAM or ACTIF drug arm, they're on a stable background of anti-seizure medicines. So we would anticipate that to be small changes in terms of anti-seizure medicines and but there probably will be changes and we will assess week 28 and we'll look at the data with and without the changes of those background seizure medicines.

Laura Chico: Thank you very much.

Speaker #5: Thank you very much.

Operator: Thank you. Our next question in queue coming from the line of Pete Stavropoulos with Cantor Fitzgerald. Your line is now open.

Speaker #3: Thank you. Our next question in queue coming from the lineup, Pizza Fabulous with Cancer Fitzgerald. He is now open.

Pete Stavropoulos: Hello, Ian and team. Congrats on the progress and thanks for taking our questions. Couple from me. For the Vineland-3 subdomains, you showed a very impressive forest plot compared to natural history. You mentioned on the call that even small changes can be meaningful. Just help us understand what those treatment effects sort of translate to with examples. Also that was also at 18 months. What gives you confidence that the one-year time point is sufficient to capture differences between the two different arms under the current multicomponent assessment of the four pre-specified subdomains?

Speaker #6: Hello Ian and team. Congrats on the progress, and thanks for taking our questions. A couple from me. For the Violin three subdomains, you showed a very impressive forest plot compared to natural history.

Speaker #6: You mentioned on the call that even small changes can be meaningful. Just help us understand what those treatment effects sort of translate to with examples.

Speaker #6: Also, that was also at 18 months. What gives you confidence that the one-year time point is sufficient to cap the differences between the two different arms?

Speaker #6: Under the current multi-component assessment of the forest, pre-specified subdomains.

Barry Ticho: Pete, this is Barry. Thanks for that question. Very important. When we look at the treatment effect of the Vineland changes, we know that even small changes can be reflected and impact on the families. We have heard that from many families. The measures of the Vineland are scores of zero, one, and two, for instance. That means that a score of zero would mean for a particular activity, that child would never do that, and a score of one would be usually. If you ask the question, for instance, does the child respond to their own name or be able to say their own name? Those are questions.

Speaker #1: Yeah, Pete, this is Barry. Thanks for that question. Very important. So when we look at the treatment effect, or the Vaillon changes, we know that even small changes can be reflected as impactful and can have an impact on the families.

Speaker #1: And we've heard that from many families. The measures of the Vineland are scores of 0, 1, and 2, for instance. And the so that means that a score of 0 would mean for a particular activity that child would never do that.

Speaker #1: And a score of 1 would be usually. So if you ask the question, for instance, does the child respond to their own name or be able to say their own name, those are questions.

Barry Ticho: If you can imagine a child never being able to say their own name as opposed to sometimes being able to say their own name, that is a change of one point, which, as you can imagine, is quite meaningful for a family. Another would be following a simple instruction of one action. Again, zero being they never can do that, or one meaning they can. As you can imagine, these are effects that are having a huge impact both on the quality of life of the child as well as the family.

Speaker #1: If you can imagine a child never being able to say their own name as opposed to sometimes being able to say their own name, that's a change of one point, which, as you can imagine, is quite meaningful for a family.

Speaker #1: Another would be following a simple instruction of one action. Again, 0 being they never can do that or 1 meaning they can't. So as you can imagine, these are effects that are having a huge impact both on the quality of life of the child as well as the family.

Ian Smith: Pete, I will just add to that. I am not sure how familiar people are with Vineland-3. To be honest, it sits on my desk. I look at it most days of the week, and I look at the questions, and as Barry gives some good examples. But it also includes things like, do you recognize your name? Never, you get a zero. Sometimes you get a one. Usually you get a two. That is how it works. There is a long list of these type of questions that you add up into it in terms of total score at baseline. You then do it at week 52 in our study, and same questions, and you add it all up. Let us say there is a total score of 150 at baseline, but then you would get a total score of 154. That would be four Vineland points, four extra points.

Speaker #4: Pete, I'll just add to that. I'm not sure how familiar people are with violin three. To be honest, it sits on my desk. I look at it most days of the week.

Speaker #4: And I look at the questions, and as Barry gives some good examples, but it also includes things like: Do you recognize your name? Never.

Speaker #4: You get a 0. Sometimes you get a 1. Usually, you get a 2. And that's how it works. And there's a long list of these type of questions that you add up into it in terms of total score.

Ian Smith: Usually you get a two. That is how it works. There is a long list of these type of questions that you add up into it in terms of total score at baseline. You then do it at week 52 in our study, and same questions, and you add it all up. Let us say there is a total score of 150 at baseline, but then you would get a total score of 154. That would be four Vineland points, four extra points.

Speaker #4: At baseline, you then do it at week 52 in our study and same questions and you add it all up. Let's say there's a total score of 150, but then at baseline, but then you'd get a total score of 154.

Speaker #4: That would be four violin points, four extra points. That would be what's maybe the drug is contributing towards. So that's how the scoring works.

Ian Smith: That would be what maybe the drug is contributing towards. So that is how the scoring works. To Barry's point, you shift somebody that never does something to a patient that does something sometimes, that is a one-point score, and therefore meaningful. I would advise people to take a look at the Vineland scoring or the questions, and you will get a good feel for the type of questions that are asked. As far as your question regarding the 12-month, yes, we did put up the forest plot for the 18-month data. Interestingly, what we are trying to show here is that I would start with saying, when you take the basket of endpoints approach, you have multiple ways to measure disease modification. Contrast that to a hierarchical assessment of individual Vineland domains.

Speaker #4: And so to Barry's point, you shift a somebody that never does something to a patient that does something sometimes that's a one-point score. And therefore, meaningful.

Speaker #4: And I would advise people to take a look at the violin scoring or the questions and you'll get a good feel for the type of questions that are asked.

Speaker #4: As far as your question regarding the 12-month and so yes, we did put up the forest plot for the 18-month data. Interestingly, what we were trying to show here is that I would start with saying when you take the basket of endpoints approach, you have multiple ways to measure disease modification.

Speaker #4: And contrast that to a hierarchical assessment of individual violin domains there is sometimes a little bit of a lottery there if you can hit the first one so you can go to the second one and hit the second one to go to the third one.

Ian Smith: There is sometimes a little bit of a lottery there if you can hit the first one, so you can go to the second one and hit the second one to go to the third one. With the multi-component assessment, we remove that hierarchical assessment, the need for hierarchical assessment. What you are doing is you are assessing four domains equally as a basket to get an average score. That is a much better way in a disease that manifests itself with multiple comorbidities that frankly do manifest at different variations within each patient. What it also does, which is a really nice outcome, it is a statistical outcome, but because you have got more valuable data, you are measuring an end point four times. You actually get more powering. You asked about the 12-month data and scoring if we ran the same assessment. We did.

Speaker #4: With the multi-component assessment, we remove that hierarchical assessment, the need for hierarchical assessment. And what you're doing is you're assessing four domains equally as a basket to get an average score.

Speaker #4: And that's a much better way in a disease that manifests itself with multiple comorbidities that frankly do manifest at different variations within each patient.

Speaker #4: What it also does, which is a really nice outcome, it's a statistical outcome, but because you've got more valuable data, you're measuring an endpoint four times.

Speaker #4: You actually get more powering. And you asked about the 12-month data and scoring if we ran the same assessment. We did. And interestingly, in those four domains, we missed p-values on three out of the four.

Ian Smith: Interestingly, in those four domains, we missed key values on three out of the four, but we hit one out of the four. Overall, our MC4 score, so our multi-component score, achieved an overall P value of less than 0.001. Just to give you an idea of how much it enhances the powering, because you have got more valuable data and you are assessing four endpoints equally. Now, those three endpoints that missed, they did have trends, and they were close to 0.05, so understand that. There was one that was below 0.05. But overall, the MC4 P value was 0.001 or 0.01, sorry. So less than.

Speaker #4: But we hit one out of the four. Overall, our MC4 score, so our multi-component score achieved an overall p-value of less than 0.001. Just to give you an idea of how much it enhances the powering because you've got more valuable data and you're assessing four endpoints equally.

Speaker #4: Now, those three endpoints that missed they did have trends and they were close to 0.05. So understand that. And that was one that was below 0.05.

Speaker #4: But overall, the MC4 p-value was 0.001 or 0.01, sorry. So less than. And so what we're trying to show here is that we've enhanced the powering of the study, but as a principle, it's enhanced and it's more appropriate of how to measure the cognition and behavioral benefits our medicine may be providing to these patients because it is a basket approach.

Ian Smith: And so what we are trying to show here is that we have enhanced the powering of the study, but as a principle, it is enhanced and it is more appropriate of how to measure the cognition and behavioral benefits our medicine may be providing to these patients because it is a basket approach.

Pete Stavropoulos: Well, thanks very much, Ian, and congratulations again on the progress and looking forward to the data.

Speaker #6: All right. Well, thanks very much, Ian, and congratulations again on the progress. Looking forward to the data.

Pete Stavropoulos: Well, thanks very much, Ian, and congratulations again on the progress and looking forward to the data.

Ian Smith: Thanks, Pete.

Speaker #4: Thanks, Pete.

Operator: Thank you. Our next question coming from the line of Andrew Tsai with Jefferies. Your line is now open.

Speaker #5: Thank you. Our next question coming from the line of Andrew Simon with Jeffrey. CLN is now open.

[Analyst] (Jefferies): Hey, guys. Congrats on all the great execution. This is John on for Andrew. Thanks so much for taking our question. Earlier this week, your partner, Biogen, made a comment about how they think differentiation and differential pricing, especially for ex-US, as far as revenue, is going to have an impact on cognition. Just curious how you guys think about their comments and whether there is an alignment on the underlying value proposition. Thanks.

Speaker #7: Hey, guys. Congrats on all the great execution. This is John on for Andrew. Thanks so much for taking our question. So earlier this week, your partner Biogen made a comment about how they think differentiation and differential pricing, especially for XUS, is for the revenue soon to have an impact on cognition.

Speaker #7: So just curious how you guys think about their comments and whether there is an alignment on the underlying value proposition. Thanks.

Ian Smith: Well, I think Biogen can give you their best answer. I do not mean to speak for Biogen. But I have been involved with rare disease, genetic diseases, and readouts in the single-payer markets within Europe, for example, which is what I think you are asking about, John. I will tell you that it is more challenging in those markets than it is in the US. In the US, I would say the approach, and I am very comfortable talking about the US because those are our territories. But in the US, it is about the totality of the data. We have been sharing 4-year OLE data, New England Journal of Medicine, various peer-reviewed presentations with the payers, and they understand the value of the medicine. Jason will probably comment on that later.

Speaker #4: Well, I think Biogen can give you their best answer and so I don't mean to speak for Biogen. But I've been involved with rare disease genetic diseases and readouts in the single-payer markets within Europe, for example, which is what I think you're asking about, John.

Speaker #4: I will tell you that it is more challenging in those markets than it is in the US. And in the US, I would say the approach and it was very comfortable talking about the US because that's our those are our territories.

Speaker #4: But in the US, it is about the totality of the data. And we've been sharing four-year OLE data, New England Journal of Medicine, various peer-reviewed presentations with the payers.

Speaker #4: And they understand the value of the medicine. And Jason will probably comment on that later. Whereas in the EU, for example, they do hold you closer to the label in terms of valuing a medicine, and they have a whole scoring system in certain countries.

Ian Smith: Whereas in the EU, for example, they do hold you closer to the label in terms of valuing a medicine. They have a whole scoring system in certain countries. But overall, it is more challenging over there. But Biogen should be able to provide you more understanding of that. But it is more challenging in Europe.

Speaker #4: But overall, it is more challenging over there. But Biogen should be able to provide you more understanding of that. But it is more challenging in Europe.

[Analyst] (Jefferies): Thanks so much. Then maybe just one quick follow-up, if I may. I was curious, besides the Vineland-3 adjustment in the recent FDA meeting, what other topics may have come up in the meeting with the FDA? Or was Vineland-3 the main focus? Thanks.

Speaker #7: Thanks so much. And then maybe just one quick follow-up if I may. I was curious, besides the Vineland 3 adjustment and the recent FDA meeting, what other topics may have come up in the meeting with the FDA?

Speaker #7: Or was Vineland 3 kind of the main focus? Thanks.

Ian Smith: There was a few other things. I think Vineland-3, getting to the multicomponent 4 assessment was the priority focus. The submission of data to the NDA was important. There was also, we did ask the question regarding the OLE data, the four-year OLE data, which will be five-year OLE data by the time that we submit our data. We asked them whether that can be included in the label, and we got a clear answer from them, which is it will be a review issue, which is a good answer for us. This is a chronically dosed medicine and by the time we file, we are going to have five years' worth of data to show how these children may have compounded benefits year one to year two to year three to year four to year five. We believe that is important.

Speaker #4: There was a few other things. I think Vineland 3 getting to the multi-component 4 assessment was the priority focus. The submission of data to the NDA was important.

Speaker #4: And there was also we did ask the question regarding the OLE data, the four-year OLE data, which will be five-year OLE data by the time that we submit our data.

Speaker #4: We asked them whether that can be included in the label. And we got a clear answer from them, which is it will be a review issue.

Speaker #4: Which is a good answer for us. And this is a chronically dosed medicine. By the time we file, we're going to have five years' worth of data.

Speaker #4: To show how these children may have compounded benefits year one to year two to year three to year four to year five. And we believe that's important.

Ian Smith: The regulations for labeling is that you put clinical study data on the label that is supportive of an understanding of the benefits a medicine may provide. Overall, the interaction with the FDA is always a great opportunity to continue to educate on our medicine. That is where we started with the OLE data because it is a chronic disease, and we are dosing a chronic medicine. We have come a long way with the FDA over the last two years, and I think that was one of the reasons it drove the outcome to the multicomponent assessment, where we are assessing cognition and behavior on a basket of endpoints now.

Speaker #4: And the regulations for labeling is that you put clinical study data on the label that is supportive of an understanding of the benefits that a medicine may provide.

Speaker #4: Overall, the interaction with the FDA is always a great opportunity to continue to educate on our medicine. And that's where we started with the OLE data because it is a chronic disease and it would dosing a chronic medicine.

Speaker #4: And we've come a long way with the FDA over the last two years. And I think that was one of the reasons it drove the outcome to the multi-component assessment where we're assessing cognition and behavior on a basket of endpoints now.

[Analyst] (Jefferies): Understood. Thanks so much, and congrats again on all the progress.

Speaker #7: Understood. Thanks so much. And congrats again on all the progress.

Ian Smith: Thank you.

Speaker #4: Thank you.

Operator: Thank you. Our next question in queue, coming from the line of Sumant Kulkarni with Canaccord. Your line is now open.

Speaker #5: Thank you. Our next question in the queue is coming from the line of Suman Kulkarni with Canaccord. The line is now open.

Sumant Kulkarni: Good afternoon. Thanks for taking our questions. This is again related to the Vineland scale and the multicomponent assessment used as a key secondary endpoint. Does the relative contribution of the subdomain to the average score assume importance, and would high deviations from the mean on subdomains make a difference to being able to support a disease-modifying claim on the label? I guess asked another way, would an average that meets the definition of clinical relevance still be viewed that way if one or two subdomains drive most of the difference, even if the others may take away from the effect?

Speaker #6: Good afternoon. Thanks for taking our questions. This is again related to the Vineland scale and the multi-component assessment used as a key secondary endpoint.

Speaker #6: Does a relative contribution of a subdomain to the average score assume importance and would high deviations from the mean on subdomains make a difference to being able to support a disease-modifying claim on the label?

Speaker #6: I guess asked another way, would an average that meets the definition of clinical relevance still be viewed that way if one or two subdomains drive most of the difference, even if the others may take away from the effect?

Ian Smith: Thanks for the question, Sumant. The way it does work is, I will keep this simple, which is you do assess equally each subdomain. So there are four subdomains you assess equally. Let us say you score a three, a three, a two, and a two. Make the numbers easy. Divide that by four, and that gives you an MC4 score of 2.5. That is what you then assess the p-value. One of the things I want to be very clear on, what we are trying to help you with these forest plots that we have showed today. That 2.5, if you score it, because you are assessing Vineland four different ways and you have got more valuable data, you get more power to that score.

Speaker #4: Thanks for the question, Suman. The way it does work and I'll keep this simple. Which is you do assess equally each subdomain. So there's four subdomains you assess equally.

Speaker #4: Let's say you score a 3, a 3, 2, and a 2. Make the numbers easy. Divide that by 4 and that gives you a multiple MC4 score of 2 and a half.

Speaker #4: That's what you then assess the p-value. One of the things I want to be very clear on what we're trying to help you with these forest plots that we've showed today that 2 and a half if you score it because you're assessing Vineland four different ways and you've got more valuable data, you get more power to that score.

Ian Smith: That is why when I referred to the 12-month or even the 18-month scoring of MC4, that we got a lower p-value than we did in any individual domain. So what it really translates to is you could miss on one of the domains in terms of a p-value, but still achieve a significantly low p-value of potentially 0.01, as we saw on the 12-month data. I will just take this opportunity. When I say we missed on one on the 12-month data, I want to be clear, and Barry was in his remarks earlier on this call. The 12-month data was suboptimal dose. There was a six to seven-month gap in dosing, and they did not get the level of dosing that we are dosing in our phase III.

Speaker #4: And that's why, when I referred to the 12-month or even the 18-month scoring of MC4, we got a lower p-value than we did in any individual domain.

Speaker #4: And so, what it really translates to is you could miss on one of the domains, in terms of a p-value, but still achieve a significantly low p-value, potentially 0.01.

Speaker #4: As we saw on the 12-month data. And I'll just take this opportunity, when I say we missed on one on the 12-month data, I want to be clear and Barry was in his remarks earlier on this call.

Speaker #4: The 12-month data was suboptimal dosed. There was a 6 to 7-month gap in dosing. And they did not get the level of dosing that we're dosing in our phase three.

Ian Smith: I do want to remind people of that, but I am giving you the example that we still hit a very low p-value, less than 0.01, even on the 12-month data. It is a simple kind of average, but because you have got more valuable data, you get greater power.

Speaker #4: So I do want to remind people of that. But I'm giving you the example: we still hit a very low p-value—less than 0.01—even on the 12-month data.

Speaker #4: So, it is a simple kind of average. But because you've got more valuable data, you get greater powering.

Barry Ticho: I will just add, Sumant. This is Barry. What Ian was talking about also, the 12-month data, those were the relatively small number of patients, quite small number of patients. So obviously we are going to have more. Addressing your question a little bit more specifically, of the four subdomains, there is no one that is more important than the other when we do this calculation. The other thing, the advantage of doing this multi-component is that it smooths out the variability and the differences between the different subdomains. So even if there is one that is extreme, extremely high, for instance, or extremely low, the multi-component will take that into account and average it out.

Speaker #2: And I'll just add, Suman, this is Barry. So again, what Ian was talking about also, the 12-month data, those were the relatively small number of patients, quite small number of patients.

Speaker #2: So obviously, we're going to have more. Addressing your specifically, there is no the four subdomains, there is no one that is more important than the other.

Speaker #2: When we do this calculation, and the other thing that the advantage of doing this multi-component is that it smooths out the variability and the differences between the different subdomains.

Speaker #2: So even if there is one that is extreme—extremely high, for instance, or extremely low—the multi-component will take that into account and average it out.

Sumant Kulkarni: Got it. Thank you.

Speaker #6: Got it. Thank you.

Operator: Thank you. Our next question coming from the line of Yaron Werber with TD Cowen. Your line is now open.

Speaker #5: Thank you. Our next question is coming from the line of your own work with TD Cowen. CLN is now open.

Yaron Werber: Great. Thanks so much, and really nice progress. Barry, on the last point on the MMRM is a big deal on the composite, right? Because essentially it uses the entire curve in every visit. You are not just doing baseline against the end. As you mentioned, it really helps reduce heterogeneity and ultimately really boosts the power. Also, I believe that when you use MMRM, the way you handle dropouts is you do not have to impute. Can you comment on that? Also, the second question, are you doing the MMRM, the multiplicity at the same time, or is each score still hierarchical of the four domains? Thank you.

Speaker #7: Great, thanks so much. And really nice progress point. The MMRM is a big deal on the composite, right? Because essentially, it uses the entire curve and every visit.

Speaker #7: You're not just doing baseline against the end. And as you mentioned, it really helps reduce heterogeneity and ultimately really boost the power. And also, I believe that when you use MMRN, you're not the way you handle dropouts is you don't have to impute.

Speaker #7: Can you comment on that? And also, the second question, are you doing the MMRN the multiplicity at the same time or is each score still hierarchical of the four domains?

Speaker #7: Thank you.

Barry Ticho: Yaron, thanks. This is Barry. As far as the MMRM, yes, we are using the MMRM for the Vineland. The advantage of that is that it takes into account all of the data collected up to that time point. So as you mentioned, it is not just at week 52. So we do have a collection of the Vineland, for instance, at 6 months in the study. So that would be combined with the data that we have at the 52-week endpoint, and it does allow then for any missing data, and could then impute for missing data or take that into account. As far as the hierarchy, the multi-component endpoint will be assessed as all four of the sub-domains together. So there is no need to put together any hierarchy.

Speaker #2: Barry, thanks. This is Barry. So as far as the MMRM, yes, we're using the MMRN for the Vineland. And the advantage of that is that it takes into account all of the data collected up to that time point.

Speaker #2: So as you mentioned, it's not just at week 52. So we do have a collection of the Vineland, for instance, at six months in the study.

Speaker #2: So that would be combined with the data that we have at the 52-week. Endpoint. And it does allow then for any missing data and could then impute for missing data or take that into account.

Speaker #2: As far as the hierarchy, the multi-component endpoint will be assessed as all four of the subdomains together, so there is no need to put together any hierarchy.

Barry Ticho: That was part of what we had in agreement with FDA, that we can measure just that as a second key endpoint. We will just use the multi-component and not have to do any ranking of the sub-domains. So that obviously is an advantage in terms of having power for that endpoint.

Speaker #2: And that was part of what we had an agreement with FDA, that we can measure just that as the key, as the second key endpoint.

Speaker #2: We will just use the multi-component and not have to do any ranking of the subdomains. So that obviously is an advantage in terms of having power for that endpoint.

Yaron Werber: Thank you. Super useful.

Speaker #7: Thank you. Super useful.

Operator: Thank you. Our next question in queue coming from the line of Joseph Stringer with Needham. Your line is now open.

Speaker #5: Thank you. Our next question in the queue is coming from the line of Joseph Stringer with Needham. CLN is now open.

Joseph Stringer: Hi, thanks for taking our question. Just a follow-up question on the statistical analysis. Given the change to the MC4R analysis from the individual component, can you speak to how this affects the alpha allocation? Does this change the split across the primary endpoint, the week 28 endpoint, and the seizure endpoint at week 52 in this new MC4 assessment?

Speaker #2: Hi. Thanks for taking our question. Just a follow-up question on the statistical analysis just given the change to the MC4R analysis from the individual component.

Speaker #2: Can you speak to how this affects the alpha allocation? Does this change the split across the primary endpoint, the week 28 endpoint, and the seizure endpoint at week 52 in this new MC4 excuse me, MC4 assessment?

Ian Smith: Joe, it's Ian. I think Barry referred to these endpoints and how they're measured, the primary, given this change with MC4. In the prepared remarks, we gave you the updated powering. Let me just remind you of that. Firstly, we do have more patients that are being retained in this study than we initially anticipated. Just to remind you of the initial expectations, we thought this would be a 150-patient study with potentially a 15% dropout. That gave us an estimate of needing 128 patients to power the study. If we bring it all the way forward, as of today, we've got 162 patients in the study, of which zero dropouts and 110 of those are already through the primary endpoint.

Speaker #4: So Joe, did see it. I think Barry referred to these endpoints and how they're measured, the primary given this change with MC4. In the prepared remarks, we gave you the updated powering and so let me just remind you of that.

Speaker #4: Firstly, we do have more patients that are being retained in this study than we initially anticipated. Just to remind you of the initial expectations, we thought this would be a 150-patient study with a potentially a 15% dropout.

Speaker #4: That gave you as an estimate to needing 128 patients to power the study. If we bring it all the way forward, as of today, we've got 162 patients in the study.

Speaker #4: Of which zero dropouts and 110 of those are already through the primary endpoint. So we believe there is going to be more valuable patients.

Ian Smith: We believe there is going to be more evaluable patients, and what we showed you today is we're making an assumption, that's all it is, but maybe there's going to be 150 evaluable patients. Assuming there's 150 evaluable patients, and with this new assessment, we anticipate that we need a 46% to 53% treatment effect for seizure reductions just to achieve P values of 0.05 or 0.1. For that Vineland endpoint, it's now 1.8 to 2.1 to achieve a P value of 0.05 to 0.01. So the evaluable patients that are still in the study and this change has really enhanced the overall powering of the study. But I do want to continue to kind of echo, I'll say, or repeat, the real benefit here is this is a disease with many comorbidities, and they evolve at different rates within different patients.

Speaker #4: And what we showed you today is we were making an assumption. That's all it is. But maybe there's going to be 150 of valuable patients.

Speaker #4: Assuming there's 150 of valuable patients and with this new assessments, we anticipate that we need a 46 to 53% treatment effect for seizure reductions just to achieve p-values of 0.05 or 0.1.

Speaker #4: And for that Vineland endpoint, it's now 1.8 to 2.1 to achieve a p-value of 0.05 to 0.01. So it has the valuable patients that are still in the study and this change has really enhanced the overall powering of the study, but I do want to continue to kind of echo I will say or repeat the real benefit here is this is a disease with many comorbidities.

Speaker #4: And the evolve at different rates within different patients. And so being able to measure these endpoints in a basket approach is the real win here because that's the way you should be measuring disease modification.

Ian Smith: And so being able to measure these endpoints in a basket approach is the real win here, because that's the way you should be measuring disease modification.

Barry Ticho: And I'll just add, Joe, to your question, in terms of split, there is no alpha split. So the seizure reduction at 28 weeks is the primary endpoint. 52-week seizure reduction is the first secondary, and the Vineland is the second secondary. So alpha is not split between those.

Speaker #2: And I'll just add, Joe, to your question, in terms of split, there is no alpha split. So the seizure reduction at 28 weeks is the primary endpoint.

Speaker #2: 52-week seizure reduction is the first secondary. And the Vineland is the second secondary. And so alpha is not split between those.

Operator: Thank you. Our next question in queue coming from the line of Jessica Fye with JPMorgan. Your line is now open.

Speaker #5: Thank you. Our next question in queue coming from the line of Jessica Pye with JP Morgan. CLN is now open.

Jessica Fye: Hey, guys. Good afternoon. Thanks for taking my question. I was curious, what do experts tell you is a clinically meaningful drop in seizures?

Speaker #6: Hey, guys. Good afternoon. Thanks for taking my question. I was curious, what do experts tell you is a clinically meaningful drop in seizures?

Ian Smith: Clinically meaningful drop in seizures? Actually, Jason, why don't you take that? You spend a lot of time in the field.

Speaker #4: Clinically meaningful drop in seizures? Actually, Jason, why don't you take that. I'm going to spend a lot of time in the field.

Jason Hoitt: Yeah, it's a great question, Jess. When we talk to healthcare providers in market research, I think the first thing they talk about when you talk about what the unmet need is in Dravet, it is the persistent seizure burden that exists today with the anti-seizure medications, and the strong desire to ultimately get as close as possible, if not to seizure freedom itself. So any additional reduction in seizures on top of the best standard of care medicines is considered an advance. But I think most are expecting something in the neighborhood of 40% to 50% additional reduction over what you would see in the control arm.

Speaker #2: Yeah. It's a great question, Jess. When we talk to healthcare providers and market research, I think the first thing they talk about when you talk about what the unmet need is in Dravet it is the persistent seizure burden that exists today with the anti-seizure medicines.

Speaker #2: And the desire, the strong desire to ultimately get as close as possible, if not to seizure freedom itself. And so any additional reduction in seizures on top of the best standard of care medicines is considered an advance.

Speaker #2: But I think most are expecting something in the neighborhood of 40 to 50 percent additional reduction over what you would see in the control arm.

Jessica Fye: To be clear, is that an expectation for the trial, or is the threshold for clinical meaningfulness really 40%?

Speaker #6: And to be clear, is that an expectation for the trial or is this the threshold for clinical meaningfulness really 40%?

Jason Hoitt: It's more what their expectation is of a disease-modifying treatment versus clinically meaningful. I think if you ask them what's clinically meaningful, fewer seizures is always clinically meaningful relative to more seizures.

Speaker #2: It's more about what their expectation is of a disease-modifying treatment versus what's clinically meaningful. I think if you ask them what's clinically meaningful, fewer seizures is always clinically meaningful relative to more seizures.

Jessica Fye: Okay. Just the last one from me. Is success in EMPEROR defined by achieving stat sig with a P value less than 0.05 or less than 0.01?

Speaker #6: Okay. And just the last one for me. Is success in Emperor defined by achieving stat sig with a p-value less than 0.05 or less than 0.01?

Barry Ticho: Yes, this is Barry Ticho. The answer is 0.05. This is a standard assessment that we have put into the protocol so that 0.05 for the primary as well as the key secondaries would be statistically significant.

Speaker #2: No, Jess, this is Barry. Yeah. The answer is 0.05. So this is a standard assessment that we have put into the protocol so that 0.05 for the primary as well as the key secondaries would be statistically significant.

Jessica Fye: Great. Thank you.

Speaker #6: Great. Thank you.

Operator: Thank you. Our next question coming from the line of Marc Goodman with Leerink. Your line is now open.

Speaker #5: Thank you. Our next question comes from the line of Mark Goodman with Lyric. Mark, your line is now open.

Marc Goodman: Yeah. Did the comment around the 5-year data being a review issue, did that refer to if the study just misses, then the FDA would consider the longer-term 5-year data a review issue? Is that what you were saying?

Speaker #7: Yeah. The comment around the five-year data being a review issue, did that refer to if the study just misses then the FDA would consider the longer-term five-year data a review issue?

Speaker #7: Is that what you were saying?

Ian Smith: When it comes to misses, it always depends on how close you are on the miss. It is always a discussion. There are many drugs that have had P values that miss on the 0.05 but have been close. When you take into the totality of the primary and secondary endpoints and tertiary endpoints, you can absolutely have a discussion with the FDA. I do feel as though we are in a good position with the OLE data, which will be 5 years of OLE data, or effectively 6 years of OLE data by the time we file. It does put you in a good position. But we did not discuss, Marc, with them about missing.

Speaker #4: When it comes to misses, it always depends on how close you are on the miss. And it's always a discussion. I mean, there's many drugs that have had p-values that miss on the 0.05 but have been close, and when you take into account the totality of the primary and secondary endpoints and tertiary endpoints, you can absolutely have a discussion with the FDA.

Speaker #4: I do feel as though we're in a good position with the OLE data, which will be five years of OLE data, or effectively six years of OLE data by the time we file and so it does put you in a good position.

Speaker #4: But we didn't discuss Mark, we didn't discuss with them about missing. It was more of a it was more of an education of the disease.

Marc Goodman: Right.

Ian Smith: It was more of an education of the disease, and we started there, just as we did this time last year when we asked if they would support an NDA submission on the basis of the OLE in phase I data. This continuous education, certainly over the last 2 years, has really brought the FDA forward to be in a really good spot of understanding the disease and how our medicine affects that disease. It will be the totality of the data that will drive the label.

Speaker #4: And we started there just as we did this time last year, when we asked if they would support an NDA submission on the basis of the OLE in phase one data.

Speaker #4: And this continuous education certainly over the last two years has really brought the FDA forward to be in a really good spot of understanding the disease and how our medicine affects that disease and so it will be the totality of the data that will drive the label.

Marc Goodman: I guess, Ian, one of the other analysts was asking about at the FDA meeting, and you mentioned three things, and the third thing was they asked about the 4-year data, and you talked about the 5-year data, and you said it was a review issue. What did you mean exactly?

Speaker #7: I guess, Ian, one of the other analysts was asking about the FDA meeting, and you mentioned three things. The third thing was that they asked about the four-year data, and you talked about the five-year data, saying it was a review issue.

Speaker #7: What did you mean exactly when you said it would be a review issue? Referring to the five-year data serving as what?

Ian Smith: Yeah

Marc Goodman: when you said it would be a review issue? Referring to the five-year data serving as what?

Ian Smith: Yeah

Marc Goodman: when you said it would be a review issue? Referring to the five-year data serving as what?

Ian Smith: Oh, okay. Yes. Thanks for clarifying, Marc. When you go to the FDA, the process is you submit a briefing book. That briefing book has questions in it. One of the questions that we put in that briefing book specifically was, would you support putting the OLE data within our label? Section 14, it's known as. But would you support putting that data in our label if we were to have approval? As you probably know, the FDA doesn't say yes at this point in time. But they did say it would be a review issue, which is a very clear answer, which is

Speaker #4: Oh, okay. Yes. Thanks for clarifying, Mark. So when you go to the FDA, the process is you submit a briefing book. That briefing book has questions in it.

Speaker #4: One of the questions that we put in that briefing book specifically was: Would you support putting the OLE data within our label—Section 14, it's known as—but would you support putting that data in our label if we would have to have approval?

Speaker #4: And as you probably know, the FDA doesn't say "yes" at this point in time, but they did say it would be a review issue, which is a very clear answer.

Marc Goodman: Yeah

Ian Smith: it's the totality of data. And so

Speaker #4: It's the totality of data. And so that's what I meant by it would be a review issue.

Marc Goodman: Right

Ian Smith: that's what I meant by it being a review issue.

Marc Goodman: Got it. Secondly, just to be clear on this MC4, it can be positive even if the benefit is concentrated in one or two subdomains, the way you have described it, right? So that discussion is, you have had that with FDA. If you hit your Vineland secondary endpoint with the P value, you are going to be good, right? Even if it is driven by one or two of these subdomains. Is that fair to say?

Speaker #7: Got it. And then just secondly, just to be clear on this MC4, it can be positive even if the benefit is concentrated in one or two subdomains, the way you've described it, right?

Speaker #7: So that discussion is you've had that with the FDA. If you hit your Vinland secondary endpoint with the p-value you're going to be good, right?

Speaker #7: Even if it's driven by one or two of these subdomains. Is that fair to say?

Ian Smith: That is correct. They have actually gone far with us in the discussion to advise us that they would like to see it as a forest plot because they want to understand what drives the MC4 score. The example you just gave, Marc Goodman, is a good one where you make the example where you say you miss or you get a zero in one of the domains. If you hit on the others, yes, as long as you hit your P value on MC4, yes, acceptable.

Speaker #4: That is correct. They've actually gone as far with us in the discussion to advise us that they would like to see it as a forest plot because they want to understand what drives the MC4 score.

Speaker #4: So the example you just gave, Mark, is a good one, where you made the example that you miss or you get a zero in one of the domains. But if you hit on the others, yes, as long as you hit your p-value on MC4, yes, that's acceptable.

Marc Goodman: Thank you.

Speaker #7: Thank you.

Operator: Thank you. Our next question in queue coming from the line of Rudy Li with Wolfe Research. Your line is now open.

Speaker #5: Thank you. Our next question in queue coming from the line of Rudy Lee with Move Research. CLN is now open.

Rudy Li: Hey, thanks for taking my question. Maybe a question for Barry Ticho. For upcoming ADOA readouts in H1, what is the bar for visual retinal benefits to support your dosing selection? I mean, making sure you are reaching the therapeutic levels. Are you measuring OPA1 protein levels, and do you need further dose-finding studies before a pivotal? Thanks.

Speaker #8: Hey, thanks for taking my question. Maybe a question for Barry. For upcoming ADOA readout in first half, so what is the bar for visual retinal benefits to support your dosing selection?

Speaker #8: I mean, making sure you're reaching the therapeutic levels. Are you measuring OPA1 protein levels and do you need further dose reading study before a pivotal?

Speaker #8: Thanks.

Barry Ticho: Yeah, Rudy, thanks for the question. Yeah, so the ADOA program is a very important program for us, and we do have quite a bit of preclinical data and data from the field that supports the premise that increasing OPA1 protein levels in the cell can have a beneficial effect and potentially even improve vision in ADOA patients. So the phase I study is designed primarily as a safety study, which will be an important readout, but we are also looking at visual acuity as well as a biomarker measure of mitochondrial function. So those will be important endpoints for us to analyze in terms of the decision to make to go forward. But again, improvement in vision would be something that we would be looking for as well as the safety effects.

Speaker #2: Yeah, Rudy, thanks for the question. Yeah. So the ADOA program is a very important program for us. And we do have quite a bit of preclinical data and data from the field that supports the premise that increasing opioid-1 protein levels in the cell can have a beneficial effect and potentially even improve vision in ADOA patients.

Speaker #2: So the phase one study is designed primarily as a safety study, which will be an important readout, but we are also looking at visual acuity as well as a biomarker measure of mitochondrial function.

Speaker #2: So those will be important endpoints for us to analyze in terms of the decision to make to go forward. But again, improvement in vision would be something that we would be looking for as well as the safety effects.

Rudy Li: Yeah. So it sounds like you need another dose-ranging study to determine the right dose moving forward. Is that fair?

Speaker #8: Good. So it sounds like you need another dose-reading study to determine the right dose moving forward. Is that fair?

Barry Ticho: I would say that we will wait and see what the data are. We are considering different ways to potentially accelerate the program because this is a disease where the patients, there is no approved medicine for these patients. Patients are progressively losing vision. So there is a tremendous amount of interest, both on the part of the patient advocates as well as the clinicians to see this sort of medicine. So we are going to look for the way that we can most quickly get the medicine to the patients. To your other question, in terms of the OPA1 protein level, that is not something we are measuring, but as I mentioned, we have this biomarker for mitochondrial function. So that would be an important way that we could look at the basis for the mechanism of action of the medicine.

Speaker #2: I would say that we'll wait and see what the data are. We are considering different ways to potentially accelerate the program because this is a disease where the patients—there is no approved medicine for these patients.

Speaker #2: And patients are progressively losing vision and so there's a tremendous amount of interest both on the part of the patient advocates as well as the clinicians to see this sort of medicine.

Speaker #2: So we're going to look for the way that we can most quickly get the medicine to the patients. And it's the other question—in terms of the OPA1 protein level, that's not something we're measuring, but as I mentioned, we have this biomarker for mitochondrial function.

Speaker #2: So that would be an important way that we could look at the basis for the mechanism of action of the medicine.

Rudy Li: Very helpful. Thank you.

Speaker #8: Very helpful. Thank you.

Operator: Thank you. Our next question coming from the line of Yatin Suneja with Guggenheim. Your line is now open.

Speaker #5: Thank you. Our next question coming from the line of Yatin Sinija with Guggenheim. CLN is now open.

Yatin Suneja: Hey, guys. Thank you for taking my question. Maybe just one more on ADOA. Could you maybe articulate for us a little bit more on what the learnings were from the first two cohorts? Then how would you characterize the concept later this year? So that is the first part. Then the second is on the spend side. Could you maybe also comment on how should I model the spend in Q4 and in 2027? Any sort of color you guys could provide would be great. Thank you.

Speaker #8: Hey, guys. Thank you for taking my question. Maybe just one more on ADOA. Could you maybe articulate for us a little bit more on what the learnings were from the first two cohorts, and then how would you characterize the concept later this year?

Speaker #8: So that's first part. And then the second is on the spend side. Could you maybe also comment on how should I model the spend in 4Q and in 2027?

Speaker #8: Any sort of color you guys could provide would be great. Thank you.

Barry Ticho: Yatin, thanks for that important question. This is Barry. In terms of progressing the study, as I mentioned before, the primary endpoint is safety. We do have a safety monitoring committee that reviews the results, and they did review the results of the first two cohorts. So that recommendation to move forward to the third cohort was part of the safety review.

Speaker #4: So Yatin, thanks for that important question. This is very in terms of progressing the study, as I mentioned before, the primary endpoint is safety.

Speaker #4: We do have a safety monitoring committee that reviews the results. And they did review the results of the first two cohorts. And so that recommendation to move forward to the third cohort was part of the safety review.

Ian Smith: I would just add, Yatin, to what Barry is saying. As we move into the third and fourth cohort at doses of 0.3 milligrams and 0.5 milligrams, we are starting to move into the therapeutic dosing level. That is why we anticipate seeing safety and efficacy results in H1 2027. Tommy?

Speaker #8: Now, just to add, Yatin, to what Barry is saying, as we move into the third and fourth cohort, the doses of 0.3 milligrams and 0.5 milligrams, we are starting to move into the therapeutic dosing level.

Speaker #8: And that's why we anticipate seeing safety and efficacy results in the first half of 2027. And Tommy.

Thomas Leggett: Yatin, this is Tommy here. Thanks for the question. Just to get you straight there in terms of how to guide forward to Q4 2026, I think you should look at Q3 2026. You saw the increase we saw quarter-to-quarter, and I think you could assume a similar number going forward.

Speaker #2: And Yatin, this is Tommy here. Thanks for the question. Just to help you just to get you straight there in terms of how to guide forward to Q4 2026, I think you should look at Q3 2026.

Speaker #2: You saw the increase we saw quarter-to-quarter. I think you could assume a similar number going forward.

Operator: Thank you. I am showing no further question. I will now turn the call back over to Ian Smith for any closing comments.

Speaker #5: Thank you. And I'm showing over the question. I'll now turn the call back over to Ian Smith for any closing comments.

Ian Smith: Oh, thank you. I just want to thank everybody for their time tonight. We approach this call thanking for submitting questions to us beforehand. It gives us good clarity. Fortunately, we were in position to help you understand this technical analysis of the primary and secondary endpoints and the powering of the study. All very important and all very good questions. So we appreciate your time and your patience of listening to us, and look forward to catching up with you very soon. Thank you.

Speaker #4: Oh, thank you. I just want to thank everybody for their time tonight. We appreciate you joining this call. Thank you for submitting questions to us beforehand; it gives us good clarity, fortunately.

Speaker #4: We were in a position to help you understand this technical analysis of the primary and secondary endpoints, and the powering of the study. All very important, and all very good questions.

Speaker #4: So I appreciate your time and your patience of listening to us. And I look forward to catching up with you very soon. Thank you.

Operator: Ladies and gentlemen, that does end our conference for today. Thank you for your participation. You may now disconnect.