Phase 3 Argus Interim Data Support Safety of EPX-100 as Adjunctive Therapy for Dravet Syndrome

Kumar Budur, MD, MS

Interim safety and tolerability results from the phase 3 Argus clinical trial (NCT04462770) showed that investigational EPX-100 (Harmony Biosciences) was safe and generally tolerated in patients with Dravet syndrome (DS), further supporting the agent’s development in this patient population.¹

Presented at the 36^th International Epilepsy Congress, held August 30-September 3, in Lisbon, Portugal, 100% of the 24-patient cohort who completed the 16-week double-blind, placebo-controlled phase entered the open-label extension (OLE). In total, 139 treatment-emergent adverse events (TEAEs) were recorded in 21 patients (87.5%), of which 28 (33.3%) were deemed related to EPX-100. Upper respiratory tract infection, found in 13.7% of treated patients, was the most common TEAE, followed by generalized tonic-clonic seizure (7.9%), pyrexia (7.2%), and change in seizure presentation (6.5%).

Argus, a multicenter study with sites across North America, United Kingdom, and Europe, consists of a 16-week double-blind period, followed by a 156-week OLE. In the latest data update, most patients were on drug for at least 6 months to 1 year (n = 10; 41.7%), while slightly fewer patients had between 1 and 2 years of exposure (n = 6; 25%). The remaining patients had treatment exposure for between 3-6 months (n = 3; 12.5%) and between 1-3 months (n = 5; 20.8%).

The trial, led by Kumar Budur, MD, MS, chief medical officer at Harmony, and others, aims to test efficacy and safety of EPX-100, otherwise known as clemizole hydrochloride, as an adjunctive therapy in children and adults with DS. Investigators use mean percent change in 28-day countable motor seizure frequency (CMS-28) during the titration and maintenance phases as the primary efficacy end point, while secondary end points include proportion of patients with at least a 50% reduction, number of countable motor seizure-free days, and Clinician Global Impression (CGI) scores.

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EPX-100, which remains in phase 3 settings for Lennox-Gastaut syndrome (LGS) as well, is an orally administered liquid therapy that acts on central 5-hydroxytryptamine receptors to modulate serotonin signaling. The agent’s development leveraged scn1 mutant zebrafish, which closely replicate the SCN1A loss-of-function mutation and clinical features seen in most patients with DS.

Additional data from the IEC poster revealed that 10 serious AEs were reported in 5 patients, 1 of which was deemed possibly related to the study treatment. There were no deaths in the study, and only 1 treatment discontinuation, which stemmed from an AE that was possibly related to EPX-100. Of note, there were 6 events of somnolence or lethargy reported in the OLE.

Argus, which will continue through the coming years, includes only those with DS who were not adequately controlled by previous antiseizure medications. Patients in the study are positive for SCN1A gene mutation, had at least 4 countable motor seizure per 4-week baseline period, and were on a stable regimen of antiepileptic drugs for at least 30 days prior to their first visit. The trial prohibits the concurrent use of fenfluramine, those with drugs known to interfere with EPX-100, and individuals who’ve been recently exposed or plan to participate in another drug or device trial.

Prior to Argus, EPX-100 was previously assessed in a phase 1 study of adult healthy volunteers aged 24-50 years old. The early-stage trial enrolled 24 patients, testing escalating single and multiple oral doses (20-80 mg/kg/day) of EPX-100 vs placebo over a 12-week treatment period. Overall, the drug was found to be well-tolerated, with no reported clinically significant AEs, and drowsiness/grogginess only observed in the highest dose, which was consistent with evidence of EPX-100 crossing the blood brain barrier.²

REFERENCES
1. Ray A, Nomikos G, Rapchak KD, et al. Argus: A Phase 3 Study of EPX-100 (Clemizole Hydrochloride) as Adjunctive Therapy in Patients with Dravet Syndrome. Presented at: International Epilepsy Congress; August 30-Sept 3; Lisbon, Portugal.
2. Rao L, Masuoka L, Lee H, Baraban S. EPX-100 as an Adjunctive Therapy in Dravet Syndrome: Phase 1 and Phase 2 Randomized, Double-blind, Placebo-controlled Trials. Presented at: 2022 AES Annual Meeting; ABSTRACT 2.244