Soticlestat Reduces Seizure Frequency in Rare Epilepsies

Amit Rakhit, MD, MBA

Results from the signal finding, phase 2, open-label ARCADE pilot study (NCT03694275) and ENDYMION long-term extension study (NCT03635073) in patients with CDKL5 deficiency disorder (CDD) and Dup15q syndrome (Dup15q) demonstrated seizure frequency reduction over time with treatment with soticlestat (Ovid Therapeutics).¹

Soticlestat, a potent, highly selective, oral, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H), showed a 24% median motor seizure frequency reduction during the 12-week maintenance period in the ARCADE study among patients with CDD (n = 12). An increase to 50% reduction was observed in the ENDYMION long-term extension study in the 5 patients with CDD who reached 9 months of continuous treatment.

Among a cohort of 8 patients with Dup15q, investigators noted an increase in median motor seizure frequency in the ARCARDE study during the 12-week maintenance period. However, longer-term data for the 4 patients with Dup15q who reached 9 months of continuous treatment showed a 74% reduction in median motor seizure frequency.

"CDD and Dup15q patients have various seizure types and are on multiple concomitant antiseizure medications per current medical practice, and yet they still lack significant control of their respective seizures,” Amit Rakhit, MD, MBA, president and chief medical officer, Ovid Therapeutics, said in a statement. “Data from ARCADE, while a small open-label study, and ENDYMION support previous findings of the early activity of soticlestat and, importantly, the longer-term ENDYMION study shows seizure frequency reduction across multiple rare epilepsies over time.

READ MORE: Multiple AED Use Lowers Risk of SUDEP, Generalized Tonic-Clonic Seizures

In the ARCADE study, 2 patients with CDD experienced a ≥50% to <75% reduction in motor seizures along with 1 patient who experienced a ≥75% reduction in motor seizures during the 20-week study period.

The overall clinical benefit was measured by the Clinical Global Impression of Change (CGI-C) and Caregiver Global Impression of Change (Care GI-C) scales. After starting treatment with soticlestat, 67% of patients with CDD were deemed markedly improved with minimal or no adverse events on the CGI-C scale.

For the Care-GI-C scale, 92% of caregivers reported improvement on soticlestat treatment at the end of the ARCADE study, with 42% reporting much or very much improved. Exit interviews from the caregiver of patients in the CDD cohort also gave insight into improvements in verbal and nonverbal communication, alertness, level of engagement, overall quality of daily functioning and caregiver-chosen domains to suggest benefits of soticlestat treatment in domains beyond seizure control.

In total, 38% of patients with Dup15q were deemed markedly improved with minimal or no adverse events (AEs) on the CGI-C scale after starting soticlestat treatment. Additionally, 50% of caregivers reported improvement on soticlestat treatment at the end of ARCARDE.

Soticlestat was generally well tolerated in both studies and continued to demonstrate a safe profile. Constipation (n = 4 of 20; 20%), rash (n = 3 of 20; 15%), and seizure (n = 3 of 20; 15%) were among the most common AEs reported. Treatment with soticlestat did not lead to any serious AEs or deaths.

ARCADE enrolled 20 patients ages 2 to 55 years and consisted of a 4- to-6-week screening period to establish baseline seizure frequency, followed by a 20-week treatment period, including an 8-week titration optimization period and a 12-week maintenance period. Patients included in the study were allowed to be on 1 to 6 concomitant anti-epileptic drugs (AEDs), with the majority of the patient population using over 4 at a time.

"Data from ARCADE and ENDYMION will help inform next development steps for the soticlestat program in CDD and Dup15q, while we prepare to discuss data from our Phase 2 ELEKTRA study in Dravet syndrome and Lennox-Gastaut syndrome with the FDA,” Rakhit added.

Ovid Therapeutics recently announced topline results from the phase 2 ELEKTRA study of soticlestat in children with Dravet syndrome (DS) or Lennox-Gastaut syndrome (LGS). Ultimately, the data were positive, suggesting that the CH24H inhibitor can reduce seizures in these patient populations.²

REFERENCES

1. Ovid Therapeutics provides soticlestat (OV935/TAK-935) results from ARCADE and ENDYMION studies showing seizure reduction in rare epilepsies. News release. New York, NY: Ovid Therapeutics. September 30, 2020. Accessed October 2, 2020. https://www.globenewswire.com/news-release/2020/09/30/2101306/0/en/Ovid-Therapeutics-Provides-Soticlestat-OV935-TAK-935-Results-from-ARCADE-and-ENDYMION-Studies-Showing-Seizure-Reduction-in-Rare-Epilepsies.html​

2. Phase 2 ELEKTRA Study of Soticlestat (TAK-935/OV935) Meets Primary Endpoint Reducing Seizure Frequency in Children with Dravet Syndrome or Lennox-Gastaut Syndrome. News release. New York, NY; Osaka, Japan. Ovid Therapeutics; Takeda Pharma. Published August 25. 2020. Accessed August 25, 2020. https://investors.ovidrx.com/news-releases/news-release-details/phase-2-elektra-study-soticlestat-tak-935ov935-meets-primary