Atypical absence seizure

SKYLINE Study in Dravet Syndrome Narrowly Missed its Primary Endpoint of Reduction in Convulsive Seizure Frequency and Showed Clinically Meaningful and Nominally Significant Effects in Multiple Key Secondary Efficacy Endpoints SKYWAY Study in Lennox-Gastaut Syndrome Missed its Primary Endpoint of Reduction in Major Motor Drop Seizures Soticlestat Showed a Consistent and Favorable Safety and Tolerability Pro Both Studies Takeda Will Move Forward to Discuss the Totality of the Data with Regulatory Authorities OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) today announced topline data from its SKYLINE and SKYWAY studies. SKYLINE (TAK-935-3001) was a multicenter, randomized, double-blind Phase 3 study that evaluated soticlestat (TAK-935) plus standard of care versus placebo plus standard of care in patients with refractory Dravet syndrome (DS).1 Soticlestat narrowly missed the primary endpoint of reduction from baseline in convulsive seizure frequency as compared to placebo (p-value = 0.06). Among the six key secondary endpoints, soticlestat showed clinically meaningful and nominally significant results in the responder rate, measures of caregiver and clinician global impression of improvement, and seizure intensity and duration scales over the 16-week treatment period (all p-values ≤ 0.008). SKYWAY (TAK-935-3002) was a multicenter, randomized, double-blind Phase 3 study that evaluated soticlestat plus standard of care versus placebo plus standard of care in patients with refractory Lennox-Gastaut syndrome (LGS).2 Soticlestat missed the novel primary endpoint of reduction from baseline in Major Motor Drop (MMD) seizure frequency as compared to placebo. In SKYLINE and SKYWAY, some pre-specified subgroups of patients also showed nominally significant treatment effects on the primary and secondary efficacy endpoints of caregiver and clinician global impression of improvement, and seizure intensity and duration scales over the 16-week treatment period. Further analyses are being conducted. Soticlestat was generally well tolerated in both SKYLINE and SKYWAY studies and demonstrated a safety pro with the findings of previous studies. “We are grateful to all the participants and their families, as well as investigators and clinical staff for their participation in these important studies,” said Sarah Sheikh, M.Sc., B.M., B.Ch., MRCP, Head, Neuroscience Therapeutic Area Unit and Head, Global Development at Takeda. “Even with currently available therapies, we know that many patients with developmental encephalopathies like DS and LGS still experience persistent unmet need across multiple dimensions, such as seizure burden and treatment tolerability. While we would have wished for more declarative results on the primary endpoints, we are encouraged by positive outcomes seen in the totality of the data and are looking forward to engaging health authorities to determine the best path forward.” In the Phase 2 study, ELEKTRA, soticlestat demonstrated a statistically significant reduction of seizures from baseline compared to placebo (p-value = 0.002) in the combined DS and LGS study population during the full treatment period.3 In the DS cohort, statistically significant reduction in convulsive seizure frequency from baseline compared to placebo (p-value = 0.0007) was also achieved.3 In a pooled analysis of SKYLINE and the DS cohort of the Phase 2 ELEKTRA study, soticlestat also showed a reduction from baseline in convulsive seizure frequency compared to placebo (p-value = 0.001). Takeda will engage with regulatory authorities to discuss the totality of the data generated by these studies to determine next steps. Takeda will also plan to present results of both Phase 3 studies at an upcoming scientific congress. Takeda is continuing to assess the financial impacts of the study results, including impairment loss for intangible assets, on the first quarter ending June 30, 2024 and will communicate as necessary in due course. About Soticlestat (TAK-935) Soticlestat (TAK-935) is an investigational, first-in-class potent and selective inhibitor of cholesterol 24-hydroxylase (CH24H), an enzyme primarily expressed in the brain that catabolizes cholesterol to 24-S hydroxycholesterol (24HC) resulting in a reduction in glutamatergic hyperexcitability.4,5 About Dravet Syndrome and Lennox-Gastaut Syndrome Dravet syndrome and Lennox-Gastaut syndrome are types of developmental and epileptic encephalopathies (DEEs), a group of rare epilepsy syndromes that typically become apparent during infancy or early childhood and are highly drug-resistant to many antiseizure medications.6,7 Individuals with DS and LGS also suffer from common non-seizure symptoms such as problems with alertness, communication and disruptive behavior.7,8 Dravet syndrome is most commonly caused by a genetic mutation in the SCN1A gene and affects approximately 1 in 15,000 to 1 in 21,000 people in the United States.7,9 Dravet syndrome is characterized by prolonged focal seizures that can evolve to convulsive tonic-clonic seizures.7 Children with Dravet syndrome experience developmental disabilities as seizures increase.7 Other common symptoms include changes in appetite, difficulty balancing and a crouched gait when walking.7 Lennox-Gastaut syndrome is estimated to affect fewer than 1 in 1,000 people in the United States.10 Lennox-Gastaut syndrome is a heterogeneous condition and characterized by several different types of seizures, most commonly atonic (drop), tonic and atypical absence seizures.6 Children with Lennox-Gastaut syndrome may also develop cognitive dysfunction, delays in reaching developmental milestones and behavioral problems.6,8 Lennox-Gastaut syndrome can be caused by a variety of underlying conditions but in some cases no cause can be identified.8 About Takeda’s SKYLINE Trial The Phase 3 SKYLINE is a global, multicenter, 1:1 randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy, safety, and tolerability of soticlestat as adjunctive therapy in pediatric and young adult subjects with Dravet syndrome. The primary endpoint was percent change from baseline in convulsive seizure frequency per 28 days in subjects receiving soticlestat as compared with placebo during the full treatment period. Key secondary endpoints included evaluation of effects on treatment response, Care GI-I (Caregiver Global Impression of Improvement), CGI-I, CGI-I Non-Seizure Symptoms, QI-Disability, CGI-I seizure intensity and duration.1 A total of 144 subjects aged 2 – 21 years were enrolled in the study. The diagnosis of Dravet syndrome was adjudicated independently by the Epilepsy Study Consortium. The study treatment period was 16 weeks including a 4-week titration period and 12 weeks maintenance period. Patients were randomized 1:1 to receive either soticlestat or matching placebo twice daily (BID) added to current antiseizure therapy administered orally or via enteral tube feeding. Soticlestat was started at 100 mg BID or weight equivalent dose for 7 days and titrated up weekly, based on tolerability, up to 300 mg BID or weight equivalent dose. Upon completion of the study, willing subjects had the option to enroll in an ongoing open-label extension study (ENDYMION 2).1,11,12 About Takeda’s SKYWAY Trial The Phase 3 SKYWAY is a global, multicenter, 1:1 randomized, double-blind, placebo-controlled, parallel group study to evaluate the efficacy, safety, and tolerability of soticlestat as adjunctive therapy in pediatric and adult subjects with Lennox-Gastaut syndrome. The primary endpoint was percent change from baseline in Major Motor Drop (MMD) seizure frequency per 28 days in subjects receiving soticlestat as compared with placebo during the full treatment period. Key secondary endpoints included evaluation of effects on treatment response, Care GI-I, CGI-I, CGI-I Non-Seizure Symptoms, QI-Disability, CGI-I seizure intensity and duration.2 A total of 270 subjects aged 2 – 55 years were enrolled in the study. The diagnosis of Lennox-Gastaut syndrome was adjudicated independently by the Epilepsy Study Consortium. The study treatment period was 16 weeks including a 4-week titration period and 12 weeks maintenance period. Patients were randomized 1:1 to receive either soticlestat or matching placebo twice daily (BID) added to current antiseizure therapy administered orally or via enteral tube feeding. Soticlestat was started at 100 mg BID or weight equivalent dose for 7 days and titrated up weekly, based on tolerability, up to 300 mg BID or weight equivalent dose. Upon completion of the study, willing subjects had the option to enroll in an open-label extension study (ENDYMION 2).2,11,12 About Takeda Takeda is focused on creating better health for people and a brighter future for the world. We aim to discover and deliver life-transforming treatments in our core therapeutic and business areas, including gastrointestinal and inflammation, rare diseases, plasma-derived therapies, oncology, neuroscience and vaccines. Together with our partners, we aim to improve the patient experience and advance a new frontier of treatment options through our dynamic and diverse pipeline. As a leading values-based, R&D-driven biopharmaceutical company headquartered in Japan, we are guided by our commitment to patients, our people and the planet. Our employees in approximately 80 countries and regions are driven by our purpose and are grounded in the values that have defined us for more than two centuries. For more information, visit . Forward-Looking Statements This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could”, “anticipates”, “estimates”, “projects” or similar expressions or the negative thereof. These forward-looking statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those expressed or implied by the forward-looking statements: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations, including global health care reforms; challenges inherent in new product development, including uncertainty of clinical success and decisions of regulatory authorities and the timing thereof; uncertainty of commercial success for new and existing products; manufacturing difficulties or delays; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the impact of health crises, like the novel coronavirus pandemic, on Takeda and its customers and suppliers, including foreign governments in countries in which Takeda operates, or on other facets of its business; the timing and impact of post-merger integration efforts with acquired companies; the ability to divest assets that are not core to Takeda’s operations and the timing of any such divestment(s); and other factors identified in Takeda’s most recent Annual Report on Form 20-F and Takeda’s other reports filed with the U.S. Securities and Exchange Commission, available on Takeda’s website at: or at . Takeda does not undertake to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results or statements of Takeda in this press release may not be indicative of, and are not an estimate, forecast, guarantee or projection of Takeda’s future results. Medical information This press release contains information about products that may not be available in all countries, or may be available under different trademarks, for different indications, in different dosages, or in different strengths. Nothing contained herein should be considered a solicitation, promotion or advertisement for any prescription drugs including the ones under development. References Soticlestat as an Add-on Therapy in Children and Young Adults With Dravet Syndrome. ClinicalTrials.gov. Published June 25, 2021. Last accessed June 14, 2024. . A Study of Soticlestat as an Add-on Therapy in Children, Teenagers, and Adults With Lennox-Gastaut Syndrome. Published June 24, 2021. Last accessed June 14, 2024. Hahn CD, Jiang Y, Villanueva V, et al. A phase 2, randomized, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of SOTICLESTAT as adjunctive therapy in pediatric patients with Dravet Syndrome or Lennox–Gastaut syndrome (elektra). Epilepsia. 2022;63(10):2671-2683. doi:10.1111/epi.17367 Nishi T, Kondo S, Miyamoto M, et al. Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice. Scientific Reports. 2020;10(1). doi:10.1038/s41598-020-74036-6 Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW. Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. Journal of Biological Chemistry. 2003;278(25):22980-22988. doi:10.1074/jbc.m303415200 Arzimanoglou A, French J, Blume WT, et al. Lennox-Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology. The Lancet Neurology. 2009;8(1):82-93. doi:10.1016/s1474-4422(08)70292-8 Anwar A, Saleem S, Patel UK, Arumaithurai K, Malik P. Dravet Syndrome: An Overview. Cureus. 2019;11(6). doi:10.7759/cureus.5006 Jahngir MU, Ahmad MQ, Jahangir M. Lennox-Gastaut Syndrome: In a Nutshell. Cureus. 2018;10(8). doi:10.7759/cureus.3134 Wu YW, Sullivan J, McDaniel SS, et al. Incidence of Dravet Syndrome in a US Population. Pediatrics. 2015;136(5):e1310-e1315. doi:10.1542/peds.2015-1807 Trevathan E, Murphy CC, Yeargin‐Allsopp M. Prevalence and descriptive epidemiology of Lennox‐Gastaut Syndrome among Atlanta Children. Epilepsia.1997;38(12):1283-1288. doi:10.1111/j.1528-1157.1997.tb00065.x A Study of Soticlestat in Adults and Children With Rare Epilepsies (Endymion 1). Published August 18, 2017. Last accessed June 14, 2024. Ovid Therapeutics Announces Positive Initial Data from Ongoing ENDYMION Open-Label Extension Trial. Published September 23, 2019. Accessed June 14, 2024. View source version on businesswire.com: Contacts Japanese Media Jun Saito jun.saito@takeda.com U.S. and International Media Rand Walton rand.walton@takeda.com Source: Takeda Pharmaceutical Company Limited View this news release online at:

Interim 2-year findings show soticlestat appeared generally safe and well tolerated, consistent with prior studiesSustained reduction in frequency of drop seizures among Lennox-Gastaut patients and convulsive seizures among Dravet patients were documented for up to two yearsSustained reductions were also seen in the frequency of all-seizures from baseline for up to 2 years across both cohortsA separate post-hoc study of the Phase 2 ELEKTRA study presented at the meeting found a reduction in median seizure frequency across multiple seizure types measured NEW YORK, April 27, 2023 (GLOBE NEWSWIRE) -- Ovid Therapeutics Inc. (NASDAQ: OVID) reports that Takeda Pharmaceuticals presented interim data at the 2023 annual meeting of the American Academy of Neurology (AAN) from ENDYMION 1, a long-term, open label extension study evaluating the effects of soticlestat on patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The findings reaffirm soticlestat was generally safe and well tolerated. Soticlestat additionally showed an encouraging median seizure reduction in both conditions. Ovid interest in soticlestat: Soticlestat is a potent highly selective, oral, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H) that is currently being studied by Takeda in two, pivotal Phase 3 trials for the potential treatment of DS and LGS, both highly refractory epilepsies. Ovid maintains a significant financial interest in soticlestat, including potential milestones payments and royalties, if soticlestat receives regulatory approval and is commercialized. Findings from the ENDYMION 1 interim analysis: The ENDYMION 1 trial was designed to assess the long-term safety and tolerability of soticlestat as an adjunctive therapy to standard treatment, in participants with developmental and epileptic encephalopathies (DEE) who participated in prior short-term efficacy and safety studies. The primary objective is to assess the incidence of treatment emergent adverse events (TEAEs) for up to eight years. The secondary endpoints include measuring the effect of soticlestat on seizure frequency, assessed as the median percentage change from baseline seizure frequency over 28 days (Session 44). The interim analysis of ENDYMION 1 presented at AAN included 47 patients with DS and 83 patients with LGS. The data cut for this analysis was May 31, 2022, with median soticlestat exposures of 80.1 (range 1.4–134.0) and 88.3 (range 1.0–178.0) weeks for DS and LGS, respectively. Key findings were: Soticlestat was generally well tolerated over a period of approximately 2 years. Approximately 78% of patients tolerated the highest dose level well (300 mg BID; weight adjusted in patients < 60kg). The majority of TEAEs were mild or moderate in severity. Drug-related TEAEs occurring in > 5% of patients were decreased appetite (10.0%), seizure (7.7%), and somnolence (7.7%). Soticlestat demonstrated a sustained reduction in frequency of convulsive (DS) and drop (LGS) seizures from baseline up to 2 years. At weeks 1–12, 49–60, and 97–108 median changes in Dravet patients’ convulsive seizures was respectively: -33.7% (n = 46); -47.8 (n = 28), -58.2 (n = 22). In LGS patients, the median change in drop seizures at weeks 1-12, 49–60, and 97–108 was respectively: -29.3% (79), -14.1% (n = 49), -36.6% (n=35). Reduction in “all seizure” frequency: At weeks 1–12, 49–60, and 97–108 median changes in all seizure frequency from baseline were –28.0% (n=46), –59.6% (n=28), and –53.4% (n=22) in DS patients, respectively, and –28.4% (n=79), –17.7% (n=49), and –27.7% (n=35) in LGS patients, respectively. Participant retention in ENDYMION: At the final efficacy assessment period presented in the interim analysis (97-108 weeks), 22 DS participants (47%) and 35 LGS participants (42%) remained in the study. It was noted that most of the data presented were collected over the COVID-19 pandemic period. At the AAN meeting, Takeda additionally presented post-hoc analysis data from the Phase 2 ELEKTRA study, which evaluated the efficacy of treatment with soticlestat by seizure type in patients with DS or LGS. In patients with DS or LGS, soticlestat was associated with a median percentage reduction from baseline in seizure frequency that was numerically superior to placebo in all but two seizure types over the full 20-week treatment period. The greatest reductions in seizure frequency from baseline over the full 20-week treatment period were observed for absence or atypical absence seizures in patients with DS and focal seizures with motor signs in patients with LGS (Poster session 11). About Soticlestat (TAK-935)Soticlestat is a potent, highly selective, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H), with the potential to reduce seizure susceptibility and improve seizure control. CH24H is predominantly expressed in the brain, where it converts cholesterol into 24S-hydroxycholesterol (24HC) to adjust the homeostatic balance of brain cholesterol. 24HC is a positive allosteric modulator of the NMDA receptor and modulates glutamatergic signaling associated with epilepsy. Glutamate is one of the main neurotransmitters in the brain and has been shown to play a role in the initiation and spread of seizure activity. Recent literature indicates that CH24H is involved in over-activation of the glutamatergic pathway through modulation of the NMDA channel and that increased expression of CH24H can disrupt the reuptake of glutamate by astrocytes, resulting in epileptogenesis and neurotoxicity. Inhibition of CH24H by soticlestat reduces the neuronal levels of 24HC and may improve excitatory/inhibitory balance of NMDA channel activity. Soticlestat is currently being evaluated by Takeda in two, pivotal, randomized, placebo-controlled trials in Lennox-Gastaut syndrome (SKYWAY) and Dravet syndrome (SKYLINE). ENDYMION Open-Label Extension Study UpdateAll patients who completed the ELEKTRA trial elected to roll over into the ENDYMION open-label extension study. The primary objective of ENDYMION is to assess the long-term safety and tolerability of soticlestat over eight years of treatment in patients with rare epilepsies and, secondarily, to evaluate the effect of soticlestat on seizure frequency over time. Data from the ELEKTRA patients who have rolled over into the ENDYMION study are supportive of results in the core study. About Dravet Syndrome and Lennox-Gastaut Syndrome Dravet syndrome and Lennox-Gastaut syndrome are types of developmental and epileptic encephalopathies (DEEs), a heterogeneous group of rare epilepsy syndromes. Dravet and Lennox-Gastaut syndrome typically become apparent during infancy or early childhood and are highly refractory to many antiseizure medications. Dravet syndrome is most commonly caused by a genetic mutation in the SCN1A gene and affects approximately 1 in 15,000 to 1 in 21,000 people in the United States. Dravet syndrome is characterized by prolonged focal seizures that can evolve to convulsive tonic-clonic seizures. Children with Dravet syndrome experience developmental disabilities as seizures increase. Other common symptoms include changes in appetite, difficulty balancing and a crouched gait when walking. Lennox-Gastaut syndrome is estimated to affect approximately 1 in 11,000 people in the United States. Lennox-Gastaut syndrome is a heterogeneous condition and characterized by several different types of seizures, most commonly atonic (drop), tonic and atypical absence seizures. Children with Lennox-Gastaut syndrome may also develop cognitive dysfunction, delays in reaching developmental milestones and behavioral problems. Lennox-Gastaut syndrome can be caused by a variety of underlying conditions, but in some cases no cause can be identified. About Ovid Therapeutics Ovid Therapeutics Inc. is a New York-based biopharmaceutical company striving to conquer seizures and brain disorders with courageous science. Ovid’s pipeline of small molecule and genetic medicines candidates seek to meaningfully improve the lives of people and families affected by epilepsies. Ovid is developing OV329, a GABA aminotransferase inhibitor, for treatment-resistant seizures; and OV350, a direct activator of the KCC2 transporter, for potential treatment of epilepsies. In addition, Ovid maintains a significant financial interest in the future regulatory development and potential commercialization of soticlestat, which Takeda is responsible for advancing globally. Soticlestat is a cholesterol 24 hydroxylase inhibitor, which is currently in Phase 3 trials for Dravet and Lennox-Gastaut syndromes. For more information about these and other Ovid research programs, please visit www.ovidrx.com. Forward-Looking Statements This press release includes certain disclosures that contain “forward-looking statements,” including, without limitation: the potential development and use of OV329, OV350 or soticlestat; and the status of Takeda’s two pivotal Phase 3 trials evaluating soticlestat for Lennox-Gastaut and Dravet syndromes. You can identify forward-looking statements because they contain words such as “anticipates,” “believes,” “expected,” “intends,” “plan,” “potential,” and “will,” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances). Forward-looking statements are based on Takeda’s current expectations and assumptions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that may differ materially from those contemplated by the forward-looking statements, which are neither statements of historical fact nor guarantees or assurances of future performance. Important factors that could cause actual results to differ materially from those in the forward-looking statements include, without limitation, uncertainties inherent in the clinical development and regulatory approval processes, the risk that Ovid may not be able to realize the intended benefits from its financial interest in soticlestat. Additional risks that could cause actual results to differ materially from those in the forward-looking statements are set forth under the caption “Risk Factors” in Ovid’s Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) on March 13, 2023, and in future filings Ovid makes with the SEC. Any forward-looking statements contained in this press release speak only as of the date hereof, and Ovid assumes no obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as otherwise required by law. Contacts Investors and Media:Meg Alexander917-943-6681malexander@ovidrx.com