Positive Data for Narcolepsy, Sleep Disorders, ADHD Drug


New positive data was recently released from 5 in vitro studies investigating the potential for drug-drug interaction of mazindol.



New positive data was recently released from 5 in vitro studies investigating the potential for drug-drug interaction (DDI) of mazindol, which is a triple monoamine reuptake inhibitor and partial orexin-2 agonist, as well as its hydrolyzed metabolite (M6).1 Mazindol ER is in the process of development for the treatment of narcolepsy and other sleep-wake disorders, but also has positive studies evaluating it for the treatment of adult attention deficit/hyperactivity disorder (ADHD).2

The in vitro studies were designed to evaluate the DDI potential for several metabolic enzymes and transporters when coadministered with mazindol, including:

-CYP inhibition in human liver microsomes

-CYP induction in cultured human hepatocytes

-CYP and UGT reaction phenotyping

-UGT inhibition in human liver microsomes

-ATP-binding case (ABC) and solute carrier (SLC) transporter inhibition and substrate potential in cells and vesicles

“This latest set of data reinforce that mazindol may have the potential to provide an advantage over other current treatments for patients with narcolepsy taking multiple drugs, including hormonal contraceptives, proton-pump inhibitors and anti-epileptic drugs, who are at higher risk of experiencing adverse drug interactions or even discontinuation of their medications due to those interactions,” said George Apostol, MD, MS, chief medical officer of NLS. “Based on these data, once-daily Mazindol ER shows potential to meet yet another unmet need of narcolepsy patients, in addition to its strong efficacy, fast onset of action, well demonstrated long-term safety profile, low scheduling and its unique mechanism of actions.”

Results of the in vitro perpetrator studies showed that mazindol and its hydrolysis metabolite do not have the potential to inhibit or induce the metabolism/transport of concomitant medications. Therefore, based on these data, it can be concluded that mazindol and the hydrolysis metabolite are not inhibitors of CYPs, UGTs, or transporters and mazindol does not induce metabolism. Furthermore, mazindol does not affect the PK of concomitant medications.

Results of the in vitro victim studies showed that mazindol is not metabolized by CYPs or UGTs and is not transported by BCRP, OAT1, OAT3, and OCT2. Concomitant medications are not expected to affect the PK of mazindol.

“Discussions with both physicians as well as patient advocacy groups at SLEEP 2023, the annual meeting of the American Academy of Sleep Medicine (AASM) and the Sleep Research Society (SRS), held on June 3-7, 2023, in Indianapolis, reinforced the importance a mazindol’s DDI drug profile to realize an unmet need for patients,” said Alex Zwyer, NLS chief executive officer.

The AMAZE development program for Mazindol ER will begin in July 2023. It will consist of 2 phase 3, randomized, double-blind, placebo-controlled, multicenter studies in the US meant to assess the safety and efficacy of mazindol in 100 patients with narcolepsy type 1. Doses (3 mg) of mazindol ER will be administered once daily for 8 weeks, then a 52-week open-label extension will further evaluate the long-term safety and tolerability. Data are expected in late 2024.


1. NLS Pharmaceutics announces positive safety data from in vitro CYP450 and transporter mediated drug-drug interaction studies of mazindol. FirstWord Pharma. June 14, 2023. Accessed June 15, 2023. https://firstwordpharma.com/story/5751664

2. Wigal TL, Newcorn JH, Handal N, et al. A double-blind, placebo-controlled, phase ii study to determine the efficacy, safety, tolerability and pharmacokinetics of a controlled release (CR) formulation of mazindol in adults with DSM-5 attention-deficit/hyperactivity disorder (ADHD). CNS Drugs. 2018;32(3):289-301.

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