Ovid Therapeutics announced results from the ARCADE and ENDYMION studies of soticlestat (OV935/TAK-935) in patients with developmental and epileptic encephalopathies (DEEs). The Phase 2 ARCADE study is a signal-finding open-label pilot study of soticlestat in patients with CDKL5 deficiency disorder (CDD) and Dup15q syndrome (Dup15q), two highly refractory rare epilepsies that have no approved treatment options, while ENDYMION is an open-label long-term extension study with soticlestat. All patients who completed the ARCADE study opted to roll over into ENDYMION. Soticlestat is a potent, highly selective, oral, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H) being developed in collaboration with Takeda Pharmaceutical Company Limited.
Together, data from the ARCADE and ENDYMION studies show seizure frequency reduction over time. In CDD patients (n=12), median motor seizure frequency reduction was 24% during the 12-week maintenance period in the ARCADE study, increasing to a 50% reduction in the ENDYMION long-term extension study in the five CDD patients who reached nine months of continuous treatment. In Dup15q patients (n=8), there was an increase in median motor seizure frequency in the ARCADE study during the 12-week maintenance period; however, longer-term data from the four Dup15q patients who reached nine months of continuous treatment showed a 74% reduction in median motor seizure frequency. Soticlestat was generally well tolerated in both studies and continues to demonstrate a favorable safety profile. Data reported today are consistent with, and build upon, previous findings with soticlestat.
“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,” said Amit Rakhit, M.D., MBA, President and Chief Medical Officer of Ovid Therapeutics. “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. 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.”
“Anti-epileptic drugs can lose efficacy over time. Soticlestat may produce acute and long-term antiseizure effects in addition to potential improvements outside of motor seizure frequency reduction as suggested by clinical global impression scales,” said Scott Demarest, M.D., child epileptologist, Assistant Professor of Pediatrics and Neurology at the University of Colorado. “Soticlestat is emerging as a potentially valuable therapeutic option, particularly given its favorable safety profile and potential to provide a durable treatment benefit. Patients with these disorders need more options to manage their treatment-resistant seizures, and collective data from the Phase 2 ELEKTRA, ARCADE and ENDYMION studies warrant further investigation of soticlestat.”
ARCADE is a Phase 2 open-label, signal-finding pilot study designed to inform the potential for future development of soticlestat in CDD and Dup15q. The study enrolled 20 patients, ages 2 to 55 years, with refractory epileptic seizures associated with CDD (n=12) or Dup15q (n=8) and consisted of a four- to six-week screening period to establish baseline seizure frequency, followed by a 20-week treatment period, including an eight-week titration/dose optimization period and a 12-week maintenance period. Patients in the study were allowed to be on one to six concomitant anti-epileptic drugs (AEDs), with the majority of patients concomitantly treated with at least four AEDs, representing a highly refractory patient population. The primary objective of the ARCADE study was to determine percent change from baseline in motor seizure frequency during the 12-week maintenance period. Afterward, patients were offered the chance to continue soticlestat treatment in the ENDYMION open-label extension study, and all patients who completed ARCADE elected to roll over into ENDYMION.
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ENDYMION is a multi-center, open-label extension study of soticlestat in any patient who has participated in any previous soticlestat DEE clinical study, including patients with CDD, Dup15q, Dravet syndrome and Lennox-Gastaut syndrome. The primary objective of ENDYMION is to assess the long-term safety and tolerability of soticlestat in patients with DEEs and, secondarily, to evaluate the effect of soticlestat on seizure control over time.
Soticlestat is a potent, highly selective, first-in-class inhibitor of the enzyme cholesterol 24-hydroxylase (CH24H), with the potential to reduce seizure susceptibility and improve seizure control. CH24H is predominantly expressed in the brain, where it converts cholesterol into 24S-hydroxycholesterol (24HC) to adjust the homeostatic balance of brain cholesterol. 24HC is a positive allosteric modulator of the NMDA receptor and modulates glutamatergic signaling associated with epilepsy. Glutamate is one of the main neurotransmitters in the brain and has been shown to play a role in the initiation and spread of seizure activity. Recent literature indicates that CH24H is involved in over-activation of the glutamatergic pathway through modulation of the NMDA channel and that increased expression of CH24H can disrupt the reuptake of glutamate by astrocytes, resulting in epileptogenesis and neurotoxicity. Inhibition of CH24H by soticlestat reduces the neuronal levels of 24HC and may improve excitatory/inhibitory balance of NMDA channel activity.