Long-term treatment with the investigational oral therapy soticlestat (OV935/TAK-935) can reduce the median seizure frequency by up to 90% in adults with Lennox-Gastaut syndrome (LGS) and other developmental and epileptic encephalopathies (DEE), according to data from the ENDYMION Phase 2 trial.
Topline results are expected in the second half of 2020 from another Phase 2 study called ELEKTRA, which is testing soticlestat in children with Lennox-Gastaut and Dravet syndrome, two forms of DEE.
Soticlestat is a potent and selective inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H), and is being developed by Ovid Therapeutics in collaboration with Takeda. Blocking this enzyme is thought to reduce the activation of a neuronal signaling pathway — glutamatergic signaling via NMDA receptors — thus reducing seizure susceptibility and improving seizure control.
Soticlestat has received orphan drug designation from the U.S. Food and Drug Administration for the treatment of both Lennox-Gastaut and Dravet syndromes.
ENDYMION (NCT03635073) is an ongoing, open-label extension trial for patients who completed Ovid’s Phase 1b/2a clinical study (NCT03166215) — or the Phase 2 ELEKTRA (NCT03650452) and ARCADE (NCT03694275) trials which are both testing soticlestat’s safety and efficacy.
Enrollment is still ongoing for ELEKTRA, ARCADE, and ENDYMION at several centers in the U.S. and other countries. More information on study locations and contacts for ENDYMION can be found here. ELEKTRA information is available here. Further details on the ARCADE trial can be found here.
The findings now released by Ovid are based on the results of the first six adult patients included in ENDYMION, who had completed the previous Phase 1b/2a trial assessing the safety and tolerability of multiple doses of soticlestat in adults with DEEs.
This earlier trial showed that twice-daily oral soticlestat — given as tablets or through a gastrostomy tube — was generally well-tolerated. However, a probable drug-drug interaction was found between perampanel (sold under the brand Fycompa by Eisai) — and soticlestat. According to Ovid, these two medications should not be taken together.
The main goal of ENDYMION is to assess the long-term safety and tolerability of soticlestat over two years, and see if using the add-on therapy long-term can effectively reduce seizure frequency over time.
At the beginning of the trial, participants were started on a dose-optimization schedule until they reached a maintenance dose. Target dosing for adults is 600 mg per day (300 mg tablets, given twice a day).
Patients included in this first analysis experienced multiple seizure types, including motor seizures, and were taking various anti-epileptic medications. At the start of the trial, their seizure frequency ranged from two to 71.
Collected clinical data showed that prolonged treatment with soticlestat results in progressively fewer seizures over time. Following one to 12 weeks of treatment, the participants experienced a median reduction of 48% in seizure frequency (six patients). This improved to a median reduction of 65% after 13 to 24 weeks of treatment (six patients), and an 84% reduction after 25 to 36 weeks of treatment (six patients).
Four patients who completed 37 to 48 weeks of soticlestat treatment reduced their median seizure frequency by 90%. Three of these patients showed a reduction of 50% or more in seizure frequency.
One patient was seizure-free for 264 consecutive days, and another went 150 consecutive days without having a seizure.
In general, patients who had more seizures before starting the treatment were the ones who benefited the most from soticlestat treatment, experiencing a greater reduction in seizure frequency.
Interim data continue to demonstrate that soticlestat is safe and generally well-tolerated, with safety results consistent with previous reports. The majority of adverse events reported were mild in severity, and included upper abdominal pain, fever, bronchial wall thickening, and rales.
“While this first data cut includes a small number of patients, these initial results from ENDYMION reaffirm the potential of soticlestat to provide a tangible and durable clinical benefit for patients with DEE, a group of difficult-to-treat seizure disorders with limited therapeutic options,” Amit Rakhit, MD, Ovid’s chief medical officer and head of research and development, said in a news release.
“Specifically, we believe the sustained and progressively-improving median seizure reduction up to 90% seen in these patients is encouraging and, while early, compares favorably to other studies in different types of DEE,” he added. “We look forward to additional progress in our broad DEE clinical development program including initial data from the ARCADE study expected in [the first quarter of] 2020 and topline results from the randomized ELEKTRA study now expected in [the second half of] 2020 as a result of robust enrollment.”
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