Authors :
Robert Faulkner, PhD – Harmony Biosciences
Eric Bauer, BS – Harmony Biosciences
Cathryn Faulring, RD – Harmony Biosciences
Presenting Author: Anna Jeong, MD – Harmony Biosciences
Kristen Mason, MS – Harmony Biosciences
Maju Mathews, MD – Harmony Biosciences
George Nomikos, MD, PhD – Harmony Biosciences
Amit Ray, MD – Harmony Biosciences
Grant Runyan, PhD – Harmony Biosciences
Anthony Thibodeau, BS – Harmony Biosciences
Kumar Budur, MD, MS – Harmony Biosciences
Rationale:
EPX-100 is being developed as a potential treatment for seizures in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). DS and LGS are developmental epileptic encephalopathies characterized by seizures (often drug-resistant), frequent epileptiform activity, and developmental slowing or regression. EPX-100 has been previously reported to exert its antiseizure activity through serotonin receptor agonist activity. As polypharmacy and co-administration of EPX-100 with other medications is anticipated, this study evaluated the potential of EPX-100 to act as both a victim and a perpetrator of select cytochrome P450 (CYP) enzymes (CYP3A4, CYP2B6, CYP2C19).
Methods:
This was an open-label, 3-part study in healthy, adult participants. Each part was designed as a 2-period fixed sequence, with Parts 1 and 2 involving administration of a single oral 80-mg dose of EPX-100 on Day 1 (Period 1), followed in Period 2 by either 200-mg oral itraconazole twice daily for 1 day followed by 200-mg oral itraconazole once daily for 4 days (Part 1), or 100-mg oral phenytoin 3 times daily for 14 days (Part 2). A single 80-mg EPX-100 dose was again administered on Day 5 (Part 1) or Day 14 (Part 2). Part 3 involved administration of single oral doses of 40-mg omeprazole, 2-mg midazolam, and 100-mg bupropion on Days 1, 2, and 3, respectively (Period 1). During Period 2, 80-mg twice-daily doses of EPX-100 were administered for 18 days with a single oral dose of 40-mg omeprazole, 2-mg midazolam, or 100-mg bupropion on Days 12, 14, and 15, respectively. Serial blood samples were collected on specified days and assessed for EPX‑100, its primary metabolites (M6 and M6’), and the clinical probe substrates. Statistical comparisons were performed on the ratios (combination/alone) of the least-square means of ln-transformed maximum plasma concentration, area under the plasma concentration–time curve from time zero to the last measurable concentration (AUC0-t), and extrapolated to infinity (AUCinf) values for the various analytes. Safety parameters were monitored throughout the study.Results:
Fifty-four participants were enrolled. Preliminary data indicated no drug interaction by EPX-100 on the CYP3A4 substrate (midazolam), as demonstrated by no change in the AUC of midazolam and an 18% lower AUC for its metabolite, OH-midazolam. The remaining pharmacokinetic data are pending and will be presented. EPX-100 was well tolerated during the study. All adverse events (AEs) were mild to moderate in severity with one reported as serious, which was determined to be not related to study drug.Conclusions:
The drug-drug interaction profile with EPX-100 has been evaluated, and final results will be presented. EPX-100 was generally safe and well tolerated in this study of healthy participants. Findings from this study will inform other studies of EPX‑100, including the currently enrolling ARGUS study for DS (NCT04462770) and the LIGHTHOUSE study for LGS (NCT05066217). Funding:
Harmony Biosciences, Plymouth Meeting, PA.