Soticlestat Decreases Motor Frequency in CDKL5 Deficiency Disorder, With Benefits in Dup15q Syndrome

Scott Demarest, MD, MSCS

Data from the phase 2 ARCADE study (NCT03694275), a pilot trial of soticlestat (Takeda Pharmaceuticals) showed that when used as an adjuvant, treatment with the agent was associated with a decrease in motor seizure frequency in patients with CDKL5 deficiency disorder (CDD) and a decrease in all seizure frequency among both CDD and Chromosome 15q duplication (Dup15q) syndrome groups observed.

Also known as TAK-935, administration of the therapy during the 12-week maintenance period was associated with a median change from baseline in motor seizure frequency of +11.7% in the Dup15q syndrome group and –23.6% in the CDD group. The increase observed in the Dup15q syndrome group was "most likely due to the older age of this cohort," the study investigators noted. In addition, safety findings from the study were consistent with previous studies, with no new safety signals identified.

Led by Scott Demarest, MD, MSCS, neurologist and clinical director of precision medicine, Children’s Hospital Colorado, and assistant professor of pediatrics-neurology, University of Colorado, the modified-intent-to-treat (mITT) population included 20 participants who received at least 1 dose of soticlestat and had at least 1 efficacy assessment. The open-label trial included pediatric and adult patients between 2 and 55 years of age who experienced at least 3 motor seizures in the 3 months before screening and at baseline.

The mITT population comprised of 8 individuals with Dup15q syndrome and 12 with CDD who were on a 20-week treatment period that consisted of a dose-optimization period and a 12-week maintenance phase. The median age of patients with Dup15q syndrome was 13.5 years (range, 9-27), and the median age of patients with CDD was 5.5 years (range, 2-17). At baseline, both groups exhibited a wide variety of seizure types in addition to motor seizures. Most patients were taking more than 1 antiseizure medication (ASM), with 13 (65%) taking at least 3.

During the maintenance period and full 20-week treatment period, respectively, the Dup15q syndrome group showed median changes in motor seizure frequency of +11.7% and 13.4%; however, this group showed median changes in all seizure frequency—motor and nonmotor—of –23.4% and –18.2% during these time periods. Patients in the CDD group showed median changes of –30.5% and –26.0% in seizure frequency during the maintenance and full treatment periods, respectively.

Investigators noted that the improvement in seizure frequency seen in the CDD group during the maintenance period (–23.6%) was similar to that observed in a recent trial of ganaxolone (Ztalmy; Marinus Pharmaceuticals), which became the first ASM approved specifically for the treatment of CDD in March 2022. In the CDD group, during the maintenance period, 1 patient (9.1%) experienced a reduction in motor seizure frequency of at least 75%, 3 patients (27.3%) experienced reductions of at least 50%, and 5 (45.5%) experienced reductions of at least 25%.

Global functioning, assessed through the Clinical Global Impression-Clinician (CGI-C) score, was improved in half of the patients with Dup15q syndrome at the final visit. For the CDD group, improvements in CGI-C and Care GI-C scores relative to baseline were observed in 66.7% and 91.7% of patients, respectively. Pharmacodynamic activity of soticlestat was also observed in the study, as plasma 24HC levels were decreased by 73.3% and 82.0% of patients with Dup15q syndrome and CDD, respectively.

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Most of the cohort (95%; n = 19) reported treatment-emergent adverse events (TEAEs); although, most were mild (75%; n = 15) or moderate (45%; n = 9) in severity. None of the mild or moderate TEAEs in either of the groups led to study discontinuation. Three patients (25%) with CDD reported severe TEAEs of constipation, asthenia, respiratory syncytial virus bronchiolitis, and seizure. Of these, constipation, asthenia, and seizure, were considered treatment related. No severe TEAEs were reported in the Dup15q syndrome group.

In total, 13 patients (65%) reported TEAEs that were considered drug-related by the investigator, none of which were considered serious or led to study discontinuation. Additionally, the percentage of absence seizure-free days remained unchanged from baseline, with a median of 100% for both treatment groups and in both study periods.

Soticlestat, still an investigational agent, has shown to have benefit in other rare epilepsies such as Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The notable phase 2 ELEKTRA study (NCT03650452) comprised of patients with DS (n = 51) and LGS (n = 88) achieved its primary end point, with a combined placebo-adjusted median reduction in seizure frequency of 30.21 for soticlestat-treated patients during the maintenance period (P = .0008). During this period, investigators observed placebo-adjusted median reductions in convulsive and drop seizure frequencies of 50.00% in patients with DS (P = .0002) and 17.08% in patients with LGS (P = 1160).²

REFERENCES
1. Demarest S, Jeste S, Agarwal N, et al. Efficacy, safety, and tolerability of soticlestat as adjunctive therapy for the treatment of seizures in patients with Dup15q syndrome or CDKL5 deficiency disorder in an open-label signal-finding phase 2 study (ARCADE). Epilep & Behav. 2023;142:109173. Doi:10.1016/j.yebeh.2023.109173
2. Hahn CD, Jiang Y, Villanueva V, et al. A phase 2, 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; 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.epub 2022.