NLS Pharmaceutics Publishes New Patent for Next-Gen Dual Non-Sulfonamide Orexin Receptor Agonists

NLS Pharmaceutics Ltd., a Swiss biopharmaceutical firm in the clinical-stage, is committed to developing treatments for rare and intricate central nervous system disorders. On June 11, 2024, the company announced that Aexon Labs' latest patent application (PCT/WO2024115797) has been published by the World Intellectual Property Organization (WIPO). This patent will be utilized by NLS as part of a previously established licensing agreement with Aexon Labs.

"This patent application represents significant progress in developing a novel series of dual orexin receptor agonists aimed at treating narcolepsy and neurodegenerative diseases such as Parkinson's disease," stated Eric Konofal, MD, PhD, who serves as the Chief Scientific Officer of NLS Pharmaceutics, President of Aexon Labs, and the inventor of the Dual Orexin Receptor Agonist (DOXA) platform. "It underscores the continuous efforts of NLS to develop pioneering therapies that address critical unmet medical needs."

Key Aspects:

Innovative Dual Orexin Receptor Agonists: This new patent introduces a series of molecules, licensed from Aexon Labs, that function mainly as dual orexin receptor agonists (OX1R and OX2R). These compounds have shown efficacy in vitro and hold potential not only for alleviating narcolepsy symptoms but also for slowing the progression of neurodegenerative diseases.

Non-Sulfonamide Compounds: Unlike many existing treatments that act as orexin receptor agonists, these new non-sulfonamide derivatives could reduce the risk of side effects and adverse reactions linked with traditional sulfonamide medications. This attribute might expand their potential usage and enhance patient safety.

Mechanism of Action: The new molecules function by enhancing neurotransmitter release and protecting neuronal health through the modulation of orexin receptors (OX1R/OX2R), while integrating neuroinflammation protection via cathepsin H (CTSH) inhibition. This combined approach targets both sleep regulation and neurodegeneration, offering significant therapeutic benefits for patients.

Therapeutic Implications: CTSH is involved in proteolytic degradation and antigen presentation, affecting autoimmune responses in narcolepsy. Inhibiting CTSH could protect neuronal cells by disrupting the proteolytic pathway. When coupled with dual orexin receptor agonist action, this approach could enhance orexin signaling stability and alleviate symptoms. Neuroprotective strategies that reduce neuroinflammation and modulate immune responses could further improve therapeutic outcomes.

Focus on Narcolepsy: These compounds are primarily designed to treat narcolepsy by activating orexin pathways, crucial for maintaining wakefulness and regulating sleep patterns. This novel approach addresses the core pathology of narcolepsy, offering an effective treatment method.

Application in Neurodegenerative Diseases: Beyond narcolepsy, these multitarget molecules show promise for treating conditions like Parkinson's disease by targeting neurodegenerative processes involving OX1R and a-synuclein. This marks significant progress in developing treatments that could enhance patients' quality of life and disease outcomes.

Recent Advances and Presentations from NLS Pharmaceutics and Aexon Labs: Data presented at Sleep 2024 (Houston, June 1-5) showed limitations of selective OX2R agonists, including receptor desensitization and reduced efficacy at higher doses. Conversely, a new generation of compounds from Aexon Labs, presented at the 2024 ASCP Annual Meeting (Miami, May 27-31), targets both OX1R and OX2R and prevents the destruction of orexin cells through an inhibitory effect on CTSH. These multitarget compounds, with their broader affinity, exhibit fewer issues related to high-affinity binding and efficacy loss, suggesting a more stable pharmacological profile and better long-term outcomes.

About Narcolepsy:
Narcolepsy is a lifelong sleep disorder resulting from the autoimmune-mediated loss of 70,000-90,000 orexin-producing neurons in the hypothalamus. It is characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement (REM) sleep abnormalities, closely linked with the human leukocyte antigen HLA-DQB1*06:02. Other factors predisposing to narcolepsy include associations with polymorphisms in the T-cell receptor alpha and beta genes, which recognize antigens presented by HLA molecules, and the CTSH gene.

About NLS Pharmaceutics Ltd.:
NLS is a global development-stage biopharmaceutical company focused on discovering and developing 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 record of developing and commercializing product candidates.

About Aexon Labs, Inc.:
Aexon Labs is at the forefront of researching new compounds to address unmet needs in neurodegenerative disorders, characterized by the breakdown of neurons over time. Examples include Alzheimer's, Parkinson's, Huntington's, Narcolepsy, and Amyotrophic Lateral Sclerosis, all of which currently lack cures. Existing treatments often fail to address the root causes and may lack therapeutic effectiveness and safety. Eric Konofal, MD, PhD, serves as the President and founder of Aexon Labs. Both Dr. Konofal and Alex Zwyer, CEO of NLS Pharmaceutics, are shareholders of Aexon Labs.

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