Clinical Improvements in Cataplexy Seen Through Mazindol Extended-Release Treatment

Richard Bogan, MD

Findings from the phase 2 POLARIS study (NCT04923594) showed that treatment with mazindol extended-release (ER; NLS Pharmaceutics), a partial orexin receptor agonist and triple monoamine reuptake inhibitor, resulted in significant improvements of cataplexy severity and sleepiness in both conditions as rated by both clinicians and participants.¹

Presented at the 2023 SLEEP Annual Meeting, held June 3-7, in Indiana, Indianapolis, the double-blind, placebo-controlled trial featured 67 individuals with narcolepsy who received mazindol ER or placebo for 4 weeks. Those on active treatment initially received 2 mg dosed orally, once daily for 1 week; followed by 3 mg dosed orally, once daily for up to 3 weeks (total of 4 weeks).

Led by Richard Bogan, MD, medical director, SleepMed, South Carolina, the analysis focused on between-group differences in Clinician Global Impression-Severity (CGI-S) and Patient Global Impression-Severity (PGI-S) for cataplexy severity and excessive daytime sleepiness, respectively. Both scales had 5 levels of severity: none, mild, moderate, severe, or very severe. Among the 67 participants in the analysis, 33.3% and 35.3% of those on mazindol ER and placebo, respectively, had narcolepsy type 1.

Following treatment with mazindol ER, patients saw statistically significant improvement in both CGI-S – Sleepiness (d = –0.7; P = .016) and CGI-S – Cataplexy (d = –0.8; P = .020). For context, the mean CGI-S ­– Cataplexy and CGI-S ­– Sleepiness at baseline was approximately 3.7 and 3.4, respectively. Similarly, at the end of the double-blind period, the active treated group showed clinically and statistically significant improvements vs placebo in both PGI-S ­– Sleepiness (d = –0.8; P = .007) and PGI-S – Cataplexy (d = –0.8; P = .023).

Earlier this year, the 6-month, open-label extension (OLE) study (NCT05055024) of POLARIS was completed, with results that continued to highlight mazindol’s impact on narcolepsy. Of the 60 patients who completed the double-blind phase 2 trial, 52 (87%) enrolled into the OLE, where they received mazindol ER for an additional 6 months as a once-daily, monotherapy. For those treated with active drug in the double-blind period, this group saw an additional improvement of 0.8 (SD, 2.86) points in excessive daytime sleepiness on the Epworth Sleepiness Scale (ESS).²

At the conclusion of the OLE, the mean ESS for mazindol-treated participants 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 throughout the combined studies.

READ MORE: Findings Reveal Protective, Risk Factors Associated With Insomnia in Adults

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.

Shortly over a month ago, in early May, the FDA provided authorization to NLS Pharmaceutics to proceed with its phase 3 AMAZE program of mazindol ER in patients with narcolepsy. The program will encompass 2, double-blind phase 3 trials, comprised of 50 individuals each, to assess the efficacy and safety of mazindol ER over an 8-week treatment period. Those who completed these studies will be offered participation in a 12-month OLE.³

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REFERENCES
1. Bogan R, Stern T, Corser B, et al. Clinician and patient global impression in a phase 2 study of mazindol (NLS-1021) in adults with narcolepsy type 1 and type 2. Presented at: 2023 SLEEP Annual Meeting; June 3-7; Indiana, Indianapolis. Abstract 05782.
2. NLS Pharmaceutics announces open label extension study six-month data for Quilience® (Mazindol ER) in the treatment of narcolepsy type 1 and 2. News release. NLS Pharmaceutics. March 27, 2023. Accessed June 12, 2023. https://finance.yahoo.com/news/nls-pharmaceutics-announces-open-label-123000913.html
3. NLS Pharmaceutics receives green light from the US FDA to proceed with phase 3 clinical trial program (AMAZE) for Quilience (Mazindol ER) for the treatment of narcolepsy. News release. May 2, 2023. Accessed June 12, 2023. https://www.accesswire.com/752432/NLS-Pharmaceutics-Receives-Green-Light-from-the-US-FDA-to-Proceed-with-Phase-3-Clinical-Program-AMAZE-for-QuilienceR-Mazindol-ER-for-the-Treatment-of-Narcolepsy