Swiss clinical-stage biopharmaceutical company NLS Pharmaceutics Ltd announced positive data from five in vitro drug-drug interaction (DDI) studies investigating the potential for DDI of mazindol—being developed for the treatment of narcolepsy—as well as its hydrolyzed metabolite. 

NLS recently obtained Orphan Disease Designation from the US Food and Drug Administration (FDA) and the European Medicines Agency for Mazindol ER, an extended-release formulation of mazindol. Mazindol is a triple monoamine reuptake inhibitor and partial orexin-2 receptor agonist, which was used for many years to treat patients diagnosed with narcolepsy in compassionate use programs.

Based upon results from the in vitro metabolism and transporter studies, mazindol ER demonstrated very low risk for DDI and demonstrated pharmacological differentiation versus currently available medications used to treat narcolepsy, which can have significant DDI effects preventing co-administration or requiring dose adjustments, according to a release from NLS.

Typical DDI studies include cytochrome P450 (CYP), UDP glucuronosyltransferase (UGT), and transporter inhibition and induction studies to evaluate whether mazindol affects the pharmacokinetic (PK) effect of other drugs. In addition, in vitro studies are conducted with CYP and transporter substrates to evaluate whether other drugs can affect mazindol PK.

Following FDA guidelines, the in vitro DDI studies were designed to evaluate the drug interaction potential across a wide range of metabolic enzymes and transporters when co-administered with mazindol. The mazindol in vitro studies examined the following:

  • 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 and solute carrier transporter inhibition and substrate potential in cells and vesicles

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. Based on these in vitro data, it can be concluded that mazindol and the hydrolysis metabolite are not inhibitors of CYPs, UGTs, or transporters (including P-glycoprotein, breast cancer resistance protein, organic anion transporter [OAT]1, OAT3, and organic cation transporter [OCT]2), and mazindol does not induce metabolism. Therefore, 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 breast cancer resistance protein, OAT1, OAT3, and OCT2. Only the hydrolysis metabolite (but not mazindol) is a P-glycoprotein substrate; thus a clinical DDI study of mazindol is planned to quantify the potential for an increase in the hydrolyzed metabolite exposure in the presence of a P-glycoprotein inhibitor (eg, Itraconazole). Otherwise, concomitant medications are not expected to affect the PK of mazindol.

“We are pleased to have seen these positive results from our DDI in vitro study with mazindol, which further demonstrated its differentiated pharmacological and safety profile. 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,” says George Apostol, MD, MS, chief medical officer of NLS, in a release. “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.”

Beginning in July, NLS will initiate the AMAZE development program for Mazindol ER, consisting of two pivotal phase 3, randomized, double-blind, placebo-controlled, multicenter studies in the US designed to assess the safety and efficacy of mazindol in patients with narcolepsy type 1 compared to placebo. These two studies will enroll a total of 100 narcolepsy type 1 patients. 

Mazindol ER will be administered at fixed doses of three milligrams once daily for eight weeks. A 52-week open-label extension will further evaluate the long-term safety and tolerability of Mazindol ER in narcolepsy type 1 patients. Topline data from the double-blind studies are expected in late 2024.

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