Ovid Therapeutics Announces Positive Initial Data from Ongoing ENDYMION Open-Label Extension Trial of Soticlestat in People with Rare Epilepsies
Sustained and Progressively-Improving Median Seizure Frequency Reduction Reaching 84-90% with Prolonged Treatment of Soticlestat in this Difficult-to-Treat Patient Population
Soticlestat Continues to Advance in Rare Epilepsies; Initial Data from Phase 2 ARCADE Trial Anticipated in Q1 2020 and Data from ELEKTRA Trial Now Anticipated in 2H 2020 Due to Robust Enrollment
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This initial data from the ENDYMION open-label extension trial is from patients who previously completed Ovid’s 12-week Phase 1b/2a clinical trial of soticlestat in adults with DEE. At 12 weeks, safety and tolerability observations with soticlestat in the ENDYMION study were consistent with the completed Phase 1b/2a clinical trial. Furthermore, longer-term data from ENDYMION out to 48 weeks suggest increased seizure reduction with prolonged treatment of soticlestat in this difficult-to-treat, adult patient population with various types of DEE. Median seizure frequency reductions were 84% following 25-36 weeks (n=6) and 90% following 37-48 weeks (n=4) of treatment. In addition, the longest seizure-free durations experienced by two different patients were 264 consecutive days and 150 consecutive days, respectively.
“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, a group of difficult-to-treat seizure disorders with limited therapeutic options,” said
ENDYMION Study Design
ENDYMION is a prospective, multi-center, open-label extension study of soticlestat in patients with DEE who have participated in a previous soticlestat clinical study. The primary objective of ENDYMION is to assess the long-term safety and tolerability of soticlestat over two years of treatment in patients with rare epilepsies and secondarily, to evaluate the effect of soticlestat on seizure frequency over time.
Upon completion of a previous soticlestat clinical study, patients have the option to enroll in the open-label ENDYMION study with titration up to maintenance dose.
Patient Baseline Demographics
ENDYMION initially enrolled 7 patients who previously completed the 12-week Phase 1b/2a clinical trial of soticlestat in adults with DEE. Patients entering the trial experienced multiple seizure types, including motor seizures. Patients were on a number of anti-epileptic medications. The patient population was highly-heterogeneous and was not enriched for any specific condition and patients were each diagnosed with one of multiple DEEs. One patient enrolled into ENDYMION prior to the completion of the Phase 1b/2a clinical trial and was on concomitant perampanel. This patient was withdrawn from ENDYMION and data is not reported for this patient. Thus, the primary analysis reported today consists of 6 patients.
These 6 patients were re-baselined for seizure frequency due to a lag period ranging from 6 to 52 weeks between their completion of the Phase 1b/2a adult DEE study and the initiation of the ENDYMION study.
Seizure Frequency Reduction Results
Overall, findings suggest that prolonged treatment with soticlestat leads to increased seizure frequency reduction and is consistent with the believed mechanism of action of soticlestat.
Table 1: % Reduction from Baseline in Seizure Frequency
| Weeks 1-12 |
|Weeks 13-24 |
|Weeks 25-36 |
|Weeks 37-48 |
|Overall median % reduction in seizure frequency from baseline||48%||65%||84%||90%|
|% of patients with ≥50% reduction in seizure frequency from baseline||50%||50%||67%||75%|
|*two patients have not yet completed 48 weeks of dosing|
Patient baseline seizure frequency ranged from 2 to 71 (median=11.5). In general, a greater reduction in seizure frequency was observed in those with higher baseline seizure frequency. In terms of overall seizure free interval during treatment, one patient experienced 264 consecutive days and one patient experienced 150 consecutive days without a seizure.
In addition to the 6 patients from the Phase 1b/2a adult DEE study included in this data analysis, all patients who have completed the ARCADE and ELEKTRA studies to date have rolled over into ENDYMION. Data from patients who have completed the ARCADE study are not included in today’s analysis due to their limited treatment duration in the ENDYMION study. Data from patients previously treated in the ELEKTRA study are not included in today’s analysis due to the ongoing study being double-blinded and placebo-controlled. Ovid looks forward to reporting initial data from the ARCADE trial in Q1 2020 as previously guided. As a result of robust enrollment, Ovid now expects to report topline results from the ELEKTRA trial in 2H 2020.
Overall, safety findings are consistent with prior observations in the 12-week Phase 1b/2a adult DEE study. Soticlestat continues to show a favorable safety and tolerability profile. The majority of adverse events (AEs) were mild and comparable with those from the Phase 1b/2a adult DEE study. Specifically, AE’s that occurred included upper abdominal pain, pyrexia, bronchial wall thickening, and rales. There was one treatment-related AE of nausea. No serious adverse events (SAEs) were observed.
About the Ongoing ARCADE and ELEKTRA Trials
Beyond the ENDYMION open-label extension study, Ovid and Takeda are also conducting the Phase 2 ARCADE and ELEKTRA trials in pediatric DEE patient populations. Upon the completion of the ARCADE and ELEKTRA trials, patients are eligible to enroll in the ENDYMION open-label extension study.
ARCADE is a Phase 2, multi-center, open-label, pilot study that will evaluate the treatment of soticlestat in approximately 30 patients, aged 2 to 35 years old, with refractory epileptic seizures associated with CDKL5 Deficiency Disorder (CDD) or Dup15q syndrome. This study consists of a four to six-week screening period to establish baseline seizure frequency followed by a 20-week treatment period. The primary endpoint is the change in motor seizure frequency in patients treated with soticlestat by disorder. Initial data is expected in Q1 2020.
ELEKTRA is an international Phase 2, multi-center, randomized, double-blind, placebo-controlled study that will evaluate the treatment of soticlestat in approximately 126 pediatric patients, aged 2 to 17 years, with epileptic seizures associated with Dravet syndrome or Lennox-Gastaut syndrome (LGS). The study consists of a four to six-week screening period to establish baseline seizure frequency followed by a 20-week treatment period. The primary endpoint is the change from baseline in seizure frequency in patients treated with soticlestat compared to placebo by disorder. Topline results are expected in 2H 2020.
About Developmental and Epileptic Encephalopathies (DEE)
The International League Against Epilepsy (ILAE) defines an epileptic encephalopathy as a condition in which "the epileptiform EEG abnormalities themselves are believed to contribute to a progressive disturbance in cerebral function." These epilepsies cause significant morbidities for patients beyond what might be expected from the known underlying pathology alone and can worsen over time. Developmental and epileptic encephalopathies typically present early in life and are often associated with severe cognitive and developmental impairment in addition to frequent treatment-resistant seizures throughout the person's lifetime. These disorders vary in age of onset, developmental outcomes, etiologies, neuropsychological deficits, electroencephalographic (EEG) patterns, seizure types, and prognosis.
Despite the availability of medicines for epilepsy, there are few approved therapies for DEE and for several types there are no approved therapies. Novel therapies are needed as current therapies fail to alter the course of the disease or address co-morbidities, and many patients suffer from resistant seizures despite treatment with multiple anti-epileptic drugs (AEDs).
Soticlestat (OV935/TAK-935) 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 potentiates 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.
To Ovid’s knowledge, soticlestat is the only molecule with this mechanism of action in clinical development as an AED.
About the Ovid/Takeda Collaboration
Ovid and Takeda entered into a global development and commercialization collaboration in
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