NLS Pharmaceutics Ltd. a Swiss clinical-stage biopharmaceutical company focused on developing innovative therapies for central nervous system (CNS) disorders, today announced positive results from Study KO-943, a preclinical investigation evaluating the efficacy of Mazindol in mitigating fentanyl-induced conditioned place preference (CPP) in mice. The study, conducted by Key-Obs SAS, a leading preclinical CRO, provides evidence that Mazindol may offer a novel, non-opioid approach for the treatment of fentanyl use disorder — a condition contributing to over 75% of opioid-related overdose deaths in the United States.

As the United States continues to battle the devastating effects of the fentanyl epidemic — now the leading cause of death for Americans aged 18–45 — the urgency for effective, non-opioid treatment options has never been greater. Addressing the crisis has become a renewed national priority, underscored by continued federal initiatives to combat the opioid epidemic and renewed efforts to thwart the flow of illegal opioids into the country. The U.S. opioid and broader substance use disorder treatment market, valued at over $35 billion in 2021, is projected to exceed $60 billion by 2029, driven by the immediate demand for safer, more effective alternatives to traditional opioid-based therapies.

Study Design and Key Findings

Study KO-943 utilized a validated CPP paradigm in C57BL/6J mice to measure the rewarding properties of fentanyl and the modulatory effects of Mazindol. Mice were divided into four groups: vehicle control, fentanyl-only (0.1 mg/kg, s.c.), and fentanyl with Mazindol co-treatment (0.25 mg/kg or 0.5 mg/kg, i.p.). The primary outcome measured was the change in time spent in the drug-paired compartment after conditioning.

• Fentanyl significantly increased place preference (p ≤ 0.05 vs. vehicle), confirming its potent rewarding effect.
• Mazindol at 0.5 mg/kg significantly reduced fentanyl-induced CPP (p ≤ 0.05; p ≤ 0.01 vs. fentanyl-only), bringing behavior close to baseline.
• The 0.25 mg/kg dose showed a trend toward reduction, indicating a dose-dependent effect.

"We believe that these data provide compelling evidence of the multi-target potential of Mazindol to address the opioid crisis through a novel mechanism of action," said Dr. Eric Konofal, MD, PhD, Chief Scientific Officer of NLS Pharmaceutics. "By targeting key pathways—including partial mu-opioid receptor (MOP) agonism, serotonin 5-HT1A modulation, and orexin-2 receptor (OX2R) activity—Mazindol offers a robust and differentiated approach to reduce both opioid reward and withdrawal symptoms without the dependence risk associated with substitution therapies. Importantly, these findings further support the superior potential efficacy profile of Mazindol as already demonstrated in certain ADHD populations."

This development comes after the company recently raised up to $3 million and signed a $25 million committed equity facility agreement as part of the planned strategic merger with Kadimastem Ltd. This funding will enable the merged company to develop Kadimastem cell therapy clinical assets and to continue the development of the NLS assets that will remain post-merger, including:

• Assets to remain with the merged company (NucelX): DOXA platform (Dual Orexin Receptor Agonist).
• Assets to be allocated to the CVR: Mazindol ER, NLS-4, NLS-8, NLS-11, NLS-12.

Mechanism of Action

Mazindol is a pan-monoamine reuptake inhibitor with additional pharmacological effects:

• Partial mu-opioid receptor (MOP) modulation – to reduce withdrawal symptoms without reinforcing effects.
• 5-HT1A receptor interaction – to regulate mood, stress, and pain pathways during withdrawal.
• OX2R activity – to promote wakefulness and reduce sedation.

 This unique multi-target profile positions Mazindol as a differentiated and potentially safer alternative to current opioid substitution therapies.

 "We believe these compelling preclinical findings represent a significant milestone in our strategic expansion into substance use disorders," said Alex Zwyer, Chief Executive Officer of NLS Pharmaceutics. "The ability of Mazindol ER to blunt the rewarding effects of fentanyl highlights its potential as a treatment for those with substance use disorders."

 

Source: prnewswire.com

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