Ovid Therapeutics‘ investigational treatment soticlestat (OV935/5/TAK935) was found to progressively reduce seizure frequency — by up to 90% — in adults with rare and hard-to-treat epilepsies, including Dravet syndrome, after one year of treatment, according to preliminary data from the ENDYMION study.
Topline results from the Phase 2 ELEKTRA study, testing soticlestat in children with Dravet syndrome and Lennox-Gastaut syndrome (LGS), are expected in the second half of 2020.
Soticlestat is a potent, highly-selective, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H), which has a major role in clearing cholesterol in the brain. 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.
In collaboration with Takeda, Ovid Therapeutics is investigating soticlestat as a new approach for treating adults and children with rare epileptic syndromes. The U.S. Food and Drug Administration (FDA) granted orphan drug designation to soticlestat for the treatment of both Dravet syndrome and LGS in December 2017.
ENDYMION (NCT03635073) is an ongoing, open-label extension trial for patients who completed Ovid’s Phase 1b/2a clinical trial (NCT03166215) — or the Phase 2 trials ELEKTRA (NCT03650452) or ARCADE (NCT03694275), both of which are also testing soticlestat. Both the ELEKTRA and ARCADE trials are still running.
Enrollment for ELEKTRA and ARCADE, as well as for ENDYMION, is ongoing at several centers in the U.S. and other countries. More information on study locations and contacts for ENDYMION can be found here. For ELEKTRA information, please go here. Further details on the ARCADE trial can be found here.
The prior Phase 1b/2a study that set the basis for ENDYMION was a 12-week, dose-escalation trial whose purpose was to characterize the safety and tolerability of multiple doses of soticlestat in adults with developmental and epileptic encephalopathies (DEE). These DEE disorders include Dravet syndrome and LGS.
That trial enrolled 18 patients and showed that twice-daily oral soticlestat — given as tablets or through a gastrostomy tube — was generally well-tolerated and acted according to its mechanism of action.
Data gained from that study also revealed that there is probably a drug-drug interaction between perampanel — sold under the brand Fycompa — and soticlestat. Given that data, these two medications should not be taken together, the company said.
The findings now released by Ovid Therapeutics are based on the results of the first six adult patients included in ENDYMION, who had completed the Phase 1b/2a trial.
The main goal of ENDYMION is to assess the long-term safety and tolerability of soticlestat over two years, and to see if prolonged add-on therapy with the treatment effectively reduces 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.
The data shows that overall, soticlestat continues to have a favorable safety profile, consistent with prior observations. The most common unwanted events were mild, and included upper abdominal pain, fever, bronchial wall thickening, and rales, which are clicking, bubbling, or rattling sounds in the lungs. One patient reported feeling nausea. No serious adverse events were observed.
Regarding efficacy, the findings suggest that prolonged treatment with soticlestat results in progressively fewer seizures over time.
At the start of the trial, the patients’ seizure frequency ranged from 2 to 71. Following 25-36 weeks of treatment, the participants experienced a median reduction of 84% in seizure frequency (six patients) and a 90% reduction following 37-48 weeks of treatment (four patients).
The two patients who spent the longest period of time seizure-free had 264 and 150 consecutive days without seizures, the researchers said.
In general, a greater reduction in seizure frequency was observed in those participants who had more seizures upon study initiation.
“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 [developmental and epileptic encephalopathies], a group of difficult-to-treat seizure disorders with limited therapeutic options,” Amit Rakhit, MD, MBA, Ovid’s chief medical officer and head of research and development, said in a press 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. We look forward to additional progress in our broad DEE clinical development program including initial data from the ARCADE study expected in Q1 [first quarter] 2020 and topline results from the randomized ELEKTRA study now expected in 2H [second half] 2020 as a result of robust enrollment,” he added.