NLS Pharmaceutics Reports Promising Preclinical Data for New Narcolepsy Treatment

NLS Pharmaceutics Ltd. (NASDAQ:NLSP) (NASDAQ:NLSPW) (NLS), a biopharmaceutical firm, has recently shared promising preclinical data from its dual orexin receptor agonist (DOXA) platform. The focus is on AEX-41 and AEX-2, two groundbreaking non-sulfonamide DOXAs, which target orexin-1 (OX1R) and orexin-2 (OX2R) receptors while also inhibiting cathepsins. Cathepsins are crucial in various physiological processes and present a novel therapeutic strategy for narcolepsy and other neurological conditions.

The preclinical study, which began in October 2024 at the Centre for Neuroscience Research of Lyon, revealed noteworthy findings. One key result was improved wakefulness and sleep architecture in orexin knockout mice. When administered orally at 40 mg/kg, AEX-41 significantly increased wakefulness and reduced REM sleep duration, which is essential for managing narcolepsy's core symptoms.

Moreover, the efficacy of AEX-41 paralleled that of sulfonamide-derivative selective OX2R agonists under similar conditions, suggesting its potential as a versatile alternative for broader therapeutic applications. Its dual-action mechanism, targeting both orexin receptors and inhibiting Cathepsin H (CTSH), could impact not only sleep-wake regulation but also underlying neurodegenerative processes.

In 2025, NLS plans to expand its research to explore the effects of CTSH inhibition in animal models of neuroinflammation, a significant factor in the progression of neurodegenerative diseases. An Investigational New Drug (IND) application is planned for 2026-2027 to support this new area of research.

Dr. Eric Konofal, Chief Scientific Officer of NLS and the inventor of the DOXA platform, remarked on the transformative approach of AEX-41 in treating narcolepsy. By targeting both orexin receptors and cathepsins, the goal is to offer both symptomatic relief and potential disease modification, a significant advancement over current therapies. Additionally, due to the broad mechanism of cathepsins, the DOXA platform may complement Kadimastem's pipeline, particularly in diabetes, which is often linked with sleep-wake regulation issues such as insomnia, and in amyotrophic lateral sclerosis (ALS).

NLS continues to advance the development of AEX-41 and AEX-2, with plans to further assess their safety and efficacy in clinical settings. Beyond narcolepsy, the company is investigating their potential use in other neurodegenerative disorders, including ALS, leveraging their unique dual-targeting mechanism.

Narcolepsy, a lifelong sleep disorder, is caused by the autoimmune-mediated loss of 70,000-90,000 orexin-producing neurons in the hypothalamus. It is marked by excessive daytime sleepiness, cataplexy, and rapid eye movement sleep abnormalities, and is closely associated with the human leukocyte antigen HLA-DQB1*06:02. Other risk factors include polymorphisms in the T-cell receptor alpha and beta genes, which recognize antigens presented by HLA molecules, and the CTSH gene.

NLS Pharmaceutics Ltd. is a global biopharmaceutical company focused on developing innovative therapies for rare and complex central nervous system disorders. With a strong pipeline targeting narcolepsy, idiopathic hypersomnia, and neurodegenerative diseases, NLS is dedicated to addressing unmet medical needs.