Over a 6-month open-label extension period, mazindol ER was found to be safe, with patients demonstrating significant decreases in number of weekly cataplexy episodes and improvements in daytime sleepiness.
In newly announced, long-term findings from an open-label extension study (OLE), NLS Pharmaceuticals’ lead product candidate, Quilience, an extended-release formulation of mazindol, showed improvement in patients with narcolepsy who remained on treatment through the double-blind phase and among those who crossed over from placebo.
Of the 60 patients who completed the randomized controlled double-blind phase 2 trial (NCT05055024), 52 (87%) enrolled into the OLE, where they received mazindol extended-release (ER) for an additional 6 months as a once-daily, monotherapy. Mazindol, a triple monoamine reuptake inhibitor and partial orexin-2 receptor agonist, has been mainly used as an appetite suppressant, but also to treat narcolepsy in compassionate use programs.
For patients treated with mazindol ER in the double-blind period, this group saw an additional improvement of 0.8 (standard deviation [SD], 2.86) points in excessive daytime sleepiness on the Epworth Sleepiness Scale (ESS). At the conclusion of the OLE, the mean ESS for this group reached 8.9 (SD, 6.12), considerably low scores that were typical for individuals without narcolepsy. The therapy was also shown to be safe and well tolerated, with no unexpected adverse events (AEs) throughout the combined studies.
"The open label extension study further validates the safety and tolerability seen in the DB Phase 2 trial, while demonstrating further efficacy gains with longer treatment duration, beyond the original 4 weeks of DB treatment,” George Apostol, MD, chief medical officer, NLS Pharmaceuticals, said in a statement.1 "These data, along with numerous preclinical studies conducted this year, show the potential for Mazindol ER as a once-daily monotherapy to meet the unmet needs of current narcolepsy patients. We look forward to sharing the full data set from the final OLE results along with our Phase 2 clinical trial in Indianapolis at SLEEP 2023, a conference hosted by the American Academy of Sleep Medicine (AASM), this June."
From baseline of the double-blind period to month 6 in the OLE, patients on mazindol ER saw ESS scores decline by approximately 10.2 (SD, 5.83) points, with maximum efficacy observed at approximately 2 months of treatment and sustained throughout the rest of the OLE duration. Additionally, those who switched from placebo to mazindol ER in the OLE saw improvement in ESS scores, declining to levels comparable to those who remained on treatment throughout the entirely of the OLE.
Following treatment with mazindol ER, patients with narcolepsy type 1 saw the mean number of weekly cataplexy episodes decrease from 16.6 (SD, 10.96) to 2.9 (SD, 4.30). During the 6-month OLE, the mean weekly cataplexy episodes for these patients remained relatively stable in the 2 to 4 range through week 24. At 8 weeks of treatment in the OLE phase, patients who crossed over from placebo achieved mean weekly cataplexy episodes of 3.8 (SD, 7.05), down from the approximate 10.3 (SD, 12.11) at the end of the 4-week double-blind period. For both groups, the mean reduction in weekly cataplexy episodes was more than 80% from the double-blind study baseline.
In the study, there were a small handful of patients with narcolepsy type 1 who achieved 0 weekly cataplexy episodes throughout the OLE, including 1 patient who went from nearly 11 weekly episodes to 0 by the end of the OLE. Dry mouth, COVID-19, constipation, urinary tract infection, and nausea were the most frequent AEs, with no treatment-related serious AEs recorded in the study.
Looking forward, a phase 3 program for mazindol ER is expected to begin in mid-2023 following the end of a phase 2 meeting with the FDA, which is scheduled in the first quarter of 2023.