NLS Pharmaceutics Ltd. a Swiss clinical-stage biopharmaceutical company dedicated to developing therapies for rare and complex central nervous system disorders, is proud to announce the launch of a preclinical program evaluating Mazindol ER (Extended-Release) as a novel treatment for fentanyl dependence. Fentanyl dependence is a major global health crisis and was recently declared a national public health emergency by the new Trump administration. In 2023, the CDC reported 105,007 drug overdose deaths with 90% involving synthetic opioids like fentanyl.

"The opioid epidemic, and specifically the rise of fentanyl dependence, presents an urgent medical need for innovative, non-opioid treatment approaches," said Alex Zwyer, Chief Executive Officer of NLS. "We are committed to exploring the unique pharmacological profile of Mazindol, which targets multiple neurotransmitter systems implicated in opioid addiction. This preclinical program represents an important step in developing a potentially transformative therapy."

Highlights of the Preclinical Program

Mazindol, a tetracyclic compound with a distinct pharmacological profile, has shown potential in mitigating opioid dependence by acting on multiple neurotransmitter pathways, including:

• 5-HT1A receptor modulation: Regulates mood, anxiety, and reward pathways, addressing psychological aspects of opioid withdrawal.
• Mu-opioid receptor ("MOP") interaction: Provides partial modulation of opioid effects, potentially reducing cravings and withdrawal symptoms without reinforcing addiction.
• Orexin-2 receptor ("OX2R") partial agonist: Aids in restoring sleep-wake cycles and enhancing cognitive stability, which are significantly disrupted during opioid withdrawal.
• Scientific Rationale
• Fentanyl, a synthetic opioid that is up to 50 times more potent than heroin, has driven a global health crisis due to its high abuse potential and severe withdrawal symptoms. Traditional treatments, such as methadone and buprenorphine, often come with limitations, including risk of dependence and regulatory hurdles.

Mazindol ER offers a potential non-opioid alternative, addressing the underlying neurochemical imbalances associated with fentanyl addiction while supporting recovery through its multimodal action on neurotransmitter systems. The sustained-release formulation provides a long-acting therapeutic effect, improving patient compliance and minimizing withdrawal-related disruptions.

Mechanism of Action of Mazindol ER

Mazindol's unique pharmacodynamic properties position it as a promising candidate for opioid dependence treatment. Its mechanisms include:

• Inhibition of dopamine and norepinephrine transporters, restoring neurochemical balance and reducing cravings.
• 5-HT1A receptor modulation, potentially alleviating anxiety and depressive symptoms associated with withdrawal.
• MOP agonist activity, which may help mitigate opioid withdrawal symptoms while preventing full opioid reinforcement.
• Partial OX2R agonist activity, aiding in circadian rhythm regulation and reducing the impact of opioid-induced sleep disturbances.

Preclinical Study Objectives and Next Steps

The preclinical study, designated Study KO-943, will focus on:

• Evaluating the safety and efficacy of Mazindol ER in fentanyl dependence models.
• Assessing pharmacokinetics and pharmacodynamics in opioid-exposed subjects.
• Exploring the impact of Mazindol ER on craving reduction, withdrawal mitigation, and cognitive performance.
• The study is expected to be completed within 12-18 months. Upon successful results, NLS will potentially seek regulatory pathways to advance to clinical development.

"We believe that Mazindol ER could offer a paradigm shift in opioid addiction treatment," added Dr. Konofal, M.D./PhD, Chief Scientific Officer of NLSP. "Our stepwise development plan prioritizes early-stage investment to generate critical data that will pave the way for larger-scale studies and potential commercialization opportunities."

Existing Patent Portfolio

NLS Pharmaceutics has secured several patents supporting the development of Mazindol ER:

• United States Patent No. 11,207,271: Covers oral formulations containing immediate-release and sustained-release layers of mazindol and their use in treating attention deficit disorders ("ADHD") as well as sleep disorders.
• United States Patent No. 11,596,622: Granted for the use of Mazindol ER in the treatment of heroin dependence, providing a new therapeutic strategy for opioid use disorder.
• These patents strengthen the Company's intellectual property position and support the ongoing development of Mazindol ER for various indications.

About NLS:

NLS is a global development-stage biopharmaceutical company, working with a network of world-class partners and internationally recognized scientists, focused on the discovery and development of innovative therapies for patients with rare and complex central nervous system disorders who have unmet medical needs. Headquartered in Switzerland and founded in 2015, NLS is led by an experienced management team with a track record of developing and commercializing product candidates.

NLS has recently filed a Registration Statement on Form F-4 with the U.S. Securities and Exchange Commission (the "SEC"), outlining the details of the proposed merger between NLS and Kadimastem (the "Merger"). Kadimastem is a leading clinical stage cell therapy company, developing "off-the-shelf", proprietary cell products including human pancreatic islet-like cells capable of secreting insulin to generate an innovative treatment intended for the potential cure of type 1 diabetes.

Following the Merger, NLS and Kadimastem expect to continue developing NLS's promising, first-in class Dual Orexin Agonist platform within the combined company. The remaining NLS assets are expected to be divested subject to a contingent value rights agreement, the proceeds of which will be distributed entirely to the current shareholders of NLS. For more information, please visit www.nlspharma.com.

About Kadimastem:

Kadimastem is a clinical stage cell therapy company, developing "off-the-shelf", allogeneic, proprietary cell products based on its technology platform for the expansion and differentiation of Human Embryonic Stem Cells (hESCs) into functional cells. AstroRx®, the company's lead product, is an astrocyte cell therapy in clinical development for the treatment for ALS and in pre-clinical studies for other neurodegenerative indications.

IsletRx is the company's treatment for diabetes. IsletRx is comprised of functional pancreatic islet cells producing and releasing insulin and glucagon, intended to treat and potentially cure patients with insulin-dependent diabetes. Kadimastem was founded by Professor Michel Revel, Chief Scientific Officer of Kadimastem and Professor Emeritus of Molecular Genetics at the Weizmann Institute of Science. Professor Revel received the Israel Prize for the invention and development of Rebif®, a multiple sclerosis blockbuster drug sold worldwide.

Contacts:

NLS Contacts:

InvestorRelations@nls-pharma.com
www.nlspharma.com

Kadimastem Contacts:

Sarah Bazak, Investors relations
s.bazak@kadimastem.com
www.kadimastem.com

Source: prnewswire.com

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