Efficacy, Safety and Tolerability of Soticlestat (TAK-935/OV935) as an Adjunctive Therapy in Patients with 15q Duplication Syndrome (Dup15q) or Cyclin-Dependent Kinase-Like 5 Deficiency Disorder (CDD) in a Signal-Finding Phase 2 Study (ARCADE)
Scott Demarest1, Shafali Jeste2, Nitin Agarwal3, Dimitrios Arkilo4, Peter B. Forgacs5, Mahnaz Asgharnejad4, Ying Yan5, Ronald Thibert6
1Pediatrics and Neurology, University of Colorado School of Medicine, 2UCLA, 3Pediatric Epilepsy, Minnesota Epilepsy Group, 4Takeda Pharmaceutical Company Limited, 5Ovid Therapeutics Inc, 6MassGeneral Hospital for Children, Massachusetts General Hospital
Objective:

To characterize efficacy and safety of soticlestat (TAK-935/OV935) in patients with Dup15q or CDD in ARCADE (NCT03694275).

Background:

Dup15q and CDD are rare, treatment-resistant epilepsies. Soticlestat is a highly selective first-in-class inhibitor of cholesterol 24-hydroxylase with efficacy supported by preclinical and clinical studies.

Design/Methods:

Phase 2, open label signal-finding study. Inclusion criteria: age 2–55 years; 1–6 antiseizure medications; ≥3 motor seizures during 4-week baseline period. Treatment periods: 20‑week total (8-week dose-optimization, 12-week maintenance). Maximum dose: soticlestat 600mg/day (weight-based dosing for patients <60Kg). Primary endpoint: median percent change from baseline in motor seizure frequency during maintenance period. Safety outcome: incidence of treatment-emergent adverse events (TEAEs).

Results:

Twenty patients (dup15q, n=8; CDD, n=12) were enrolled in ARCADE (mean age, 10.7 years; 60% female). Primary outcome results showed median percent seizure frequency of +11.7% (Dup15q cohort) and -23.6% (CDD cohort) from baseline in motor seizure frequency during the maintenance period. The median change from baseline over the 20 weeks of treatment was +13.4% (Dup15q cohort) and –13.6% (CDD cohort). There were two early terminations during ARCADE. Nineteen ARCADE patients (95%) experienced TEAEs (mild, n=15 [75%]; moderate, n=10 (50%]; severe, n=3 [15%]). Serious TEAEs were reported by 3 patients (15%); none considered to be drug-related. The caregiver global impression of change scale demonstrated improvement in 11/12 (91.6%) CDD patients and 3/6 (50%) Dup15q patients. The clinician global impression of change scale demonstrated improvement in 8/12 (66.6%) CDD patients and 2/6 (33.3%) Dup15q patients. Long-term data are presented separately.

Conclusions:

Results from the open-label ARCADE show a signal for seizure reduction in CDD but not in Dup15q patients, with positive trend in global impression scales for both syndromes. Overall, soticlestat was well tolerated in this study.

Study funded by Takeda Pharmaceutical Company Limited and Ovid Therapeutics Inc.