KP1077 Shows Promise as Potential Treatment for Idiopathic Insomnia in Phase 2 Trial

Author(s):

After 5 weeks of open-label treatment, KP1077-treated patients showed mild adverse events that were typical for a central nervous system stimulant.

Christopher Drake, PhD, FAASM, DBSM

Data from a phase 2, double-blind, placebo-controlled, randomized-withdrawal, dose-optimizing trial (NCT05668754) showed that KP1077 (Zevra Therapeutics), an investigational agent, was well tolerated in patients with idiopathic hypersomnia (IH), with meaningful improvements in efficacy outcomes. The company previously announced that the results of the secondary efficacy end points were supportive of initiating a phase 3 trial of KP1077.¹

Presented at the 2024 SLEEP Annual Meeting, held June 1-5, in Houston, Texas, the objectives of the study were to assess the safety (primary end point) and efficacy of KP1077 in patients with IH. KP1077 (serdexmethylphenidate or SDX) is Zevra’s proprietary prodrug of d-methylphenidate (d-MPH) and its sole active pharmaceutical ingredient (API).

Patients entered the study in a 5-week open-label titration period where they received possible doses of 80, 160, 240, and 320 mg/day of SDX. Led by Rene A. Braeckman, PhD, senior vice president of Clinical Development at Zevra, patients were randomized to receive their daily dose either once per day (just before going to sleep) or twice per day (half the daily dose just before going to sleep and half shortly after awakening). Following the titration period, patients in each group were randomized to placebo or continued KP1077 during a 2-week double-blind withdrawal period.

Investigators completed an interim analysis when 22 patients completed the study, with results showing that KP1077 was well-tolerated for both treatments and all dose levels. Overall, the most common adverse events (AEs) observed were insomnia, headache, and nausea, all typical for a central nervous stimulant. Most of these were mild, not leading to early discontinuation from the study.

After 5 weeks of open-label treatment, mean total Epworth Sleepiness Scale scores decreased by 9 points while on KP1077. In addition, the study showed meaningful clinical improvements in scores of IH Severity Scale, Sleep Inertia Visual Analog Scale, and Brain Fog Severity Scale. Of note, the study, a proof-of-concept trial, was not powered to demonstrate statistical significance. These data, part of which were previously announced in March, will help design a potentially pivotal phase 3 trial of KP1077 in patients with IH.²

At the time of the initial data announcement, Christopher Drake, PhD, FAASM, DBSM, principal investigator for the study, said in a statement.² "Zevra’s Phase 2 trial evaluating KP1077 as a treatment for IH demonstrated clinically meaningful impact and encouraging outcomes on both clinical safety and efficacy. During the open-label dose titration period, patients showed robust improvements in IH symptom severity, including excessive daytime sleepiness that were maintained during the double-blind withdrawal period. At the end of the study, patients randomized into the KP1077 treatment group also demonstrated improvements in patient reported IH specific outcomes."

SDX, the sole active pharmaceutical ingredient in KP1077, was previously assessed in an exploratory phase 1 trial assessing cardiovascular safety. The open-label trial enrolled 15 volunteers, with each randomly receiving a series of 4 oral treatments in a crossover design: single doses of 80 mg and 200 mg of SDX, 2 doses of 40 mg of immediate-release Ritalin separated 5 hours between dosing, and a single dose of 80 mg of Ritalin LA, with each dosing period spaced at least 7 days apart.³

Maximal plasma concentrations (Cmax) of d-MPH were similar for both Ritalin treatments that were administered at equal doses of 80 mg. The d-MPH Cmax values for both SDX treatments were dose proportional with the Cmax of 200 mg SDX being approximately half of the values for Ritalin. Total plasma exposure to d-MPH was highest in the 200 mg SDX treatment group due to the extended-release profile that is unique to the prodrug, which produced prolonged exposure to d-MPH compared to both Ritalin treatment groups.

To date, the only approved drug for IH is Jazz Pharmaceuticals’ JZP-258, a combination of calcium, magnesium, potassium, and sodium oxybates; however, there are several other agents currently in the clinical pipeline.⁴

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REFERENCES
1. Braeckman R, Drake C, Gallo D, Vaughn B, AbdelFattah I. Safety and efficacy of KP1077 in a phase 2, double-blind, randomized trial in patients with idiopathic hypersomnia. Presented at: 2024 SLEEP Annual Meeting; June 1-5; Houston, TX.
2. Zevra Therapeutics announces top-line data from the phase 2 clinical trial of KP1077 for idiopathic hypersomnia. News release. March 26, 2024. Accessed June 1, 2024. https://investors.zevra.com/news-releases/news-release-details/zevra-therapeutics-announces-top-line-data-phase-2-clinical
3. KemPharm announces positive topline data from phase 1 clinical trial evaluating cardiovascular safety of serdexmethylphenidate (SDX). News release. KemPharm. September 28, 2022. Accessed June 1, 2024. https://investors.kempharm.com/news-releases/news-release-details/kempharm-announces-positive-topline-data-phase-1-clinical-trial
4. Jazz Pharmaceuticals Announces U.S. FDA Approval of Xywav® (calcium, magnesium, potassium, and sodium oxybates) Oral Solution for Idiopathic Hypersomnia in Adults. News release. Jazz Pharmaceuticals. August 12, 2021. Accessed June 1, 2024. https://www.prnewswire.com/news-releases/jazz-pharmaceuticals-announces-us-fda-approval-of-xywav-calcium-magnesium-potassium-and-sodium-oxybates-oral-solution-for-idiopathic-hypersomnia-in-adults-301354616.html