Stoke Therapeutics, Inc. Common Stock 2026 Q3 Earnings Call

Please go ahead, sir. Good evening, and welcome to Stoke Therapeutics' third quarter 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.

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.

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 U.S. 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 multicomponent assessment of Vineland-3 data for purposes of evaluating the key secondary endpoint related to changes in cognition and behavior.

This is a positive outcome because we believe a multicomponent 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 second half of next year. Clarity on these timelines is important as we scale our organization and capabilities to deliver zorevunersen to patients following a potential U.S. approval in early 2028. 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. 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 Hoitt 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. 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 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 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 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 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.

All 162 patients enrolled in the U.S., U.K., 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 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.

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.

As Ian mentioned, for the purposes of our U.S. NDA, we plan to use a multicomponent assessment that combines four pre-specified Vineland-3 subdomains: expressive communication, receptive communication, interpersonal relationships, and personal skills. We believe the multicomponent 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 multicomponent score, we first calculate the individual treatment effect for each subdomain using a multivariate mixed model for repeat 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 the selection of Vineland subdomains.

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 to the 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 multicomponent analysis using propensity score weighting to calculate a treatment effect.