The agreement grants NLS Pharmaceutics global rights to non-sulfonamide orexin-1/orexin-2 receptor agonists, with potential applications in narcolepsy and idiopathic hypersomnia.

Swiss biopharmaceutical company NLS Pharmaceutics Ltd announced an exclusive worldwide license agreement with Aexon Labs Inc, a US-based biotech firm, to acquire global development and commercialization rights to Aexon’s dual orexin receptor agonists platform. 

These novel compounds are potent oral agents targeting both orexin-1 (OX1R) and orexin-2 receptors (OX2R) as agonists, with potential applications in narcolepsy, idiopathic hypersomnia, and α-Synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, all of which involve cathepsins.

“The license agreement highlights the transformative potential of these revolutionary chemical compounds compared to first-generation sulfa derivatives, selective OX2R agonists,” says Eric Konofal, MD, PhD, who works under a part-time consulting agreement for NLS as its chief scientific officer and who is also president of Aexon, in a release. “These compounds have focused solely on the role of orexin-2 receptors in treating the symptomatology of narcolepsy. Emerging scientific insights suggest a broader range of complex mechanisms at play in the pathophysiology of tetrad narcolepsy.”

One compound in particular has shown encouraging outcomes in preliminary in vitro experiments. Its dual mechanism of action involves acting as agonist for OX1R and OX2R, while concurrently serving as an inhibitor for cathepsin H (CTSH), showcasing its potential to meet medical needs.

Orexin receptor pathways play vital regulatory roles in many physiological processes, and studies have shown that orexin receptor pathways are involved in pathological processes of neurological diseases such as narcolepsy, depression, ischemic stroke, drug addiction, and Alzheimer’s disease.

“By simultaneously targeting the potential benefits of a compound acting as both a dual agonist of orexin receptors and an inhibitor of CTSH for the treatment of narcolepsy, we combine the agonist effect on orexin-1 and orexin-2 receptors, which have been shown to improve wakefulness and reduce cataplexy, with the prospective benefits of CTSH inhibition,” says Konofal in a release. “Such inhibition is theorized to be able to influence immune responses via HLA-DQB1 and the processing of proteins related to the pathogenesis of narcolepsy. This double dual-action strategy could offer a comprehensive treatment modality for narcolepsy, addressing both symptom management and the underlying causes of the disease.”

Subject to obtaining sufficient funds, Aexon plans to conduct proof-of-concept studies in animals and phase 1 first-in-human clinical development starting in early 2025. Preliminary findings will be unveiled at the 2024 ASCP Annual Meeting (Miami, Fla, May 28 – 31).

NLS co-founder and CEO Alexander Zwyer says in a release, “I believe acquiring rights to this innovative platform, which includes more than 300 compounds, represents a bridge from current to future treatments for sleep and neurodegenerative disorders. The addition of these new compounds to our existing pipeline—Mazindol ER for narcolepsy, NLS-4 for idiopathic hypersomnia, long-COVID, and chronic fatigue syndrome, and NLS-11 for Kleine-Levin Syndrome and neurodegenerative diseases—will significantly enhance and bolster our central disorders of hypersomnolence franchise.”

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