Summary: NLS Pharmaceutics has shared preclinical findings on its dual orexin receptor agonist (DOXA) platform, which targets both orexin receptors (OX1R and OX2R) and cathepsins, offering a novel approach for treating narcolepsy and potentially other neurological disorders. The two lead candidates, AEX-41 and AEX-2, demonstrated promising results in animal models, including improved wakefulness, enhanced sleep architecture, and potential neuroprotective benefits. These findings pave the way for expanded research into neurodegenerative diseases and an Investigational New Drug (IND) application in 2026-2027.
Key Takeaways:
- Dual Mechanism of Action: AEX-41 and AEX-2 combine orexin receptor targeting with cathepsin inhibition, offering both symptomatic relief for narcolepsy and potential disease-modifying effects for neurodegenerative disorders.
- Promising Preclinical Results: In animal models, AEX-41 improved wakefulness and reduced REM sleep duration, showing comparable efficacy to selective orexin receptor agonists and highlighting its potential for broader therapeutic use.
- Future Applications: NLS plans to expand research to explore the role of cathepsin inhibition in neuroinflammation and neurodegeneration, with the aim of applying this platform to conditions like amyotrophic lateral sclerosis and diabetes-associated sleep-wake dysregulation.
NLS Pharmaceutics Ltd shared preclinical data demonstrating the potential of its dual orexin receptor agonist (DOXA) platform for the treatment of narcolepsy and neurological disorders.
AEX-41 and AEX-2, two first-in-class non-sulfonamide DOXAs, are designed to target both orexin-1 (OX1R) and orexin-2 (OX2R) receptors while concurrently inhibiting cathepsins. Cathepsins play significant roles in a variety of physiological processes and may offer a novel therapeutic approach for narcolepsy and other neurological disorders.
Key Preclinical Results
The ongoing preclinical study, initiated in October at the Centre for Neuroscience Research of Lyon, a neuroscience research center in Europe, produced the following data:
- Improved Wakefulness and Sleep Architecture: In orexin knockout mice, AEX-41 (administered orally at 40 mg/kg) demonstrated a significant increase in wakefulness and a reduction in REM sleep duration. These effects are crucial for managing the core symptoms of narcolepsy.
- Comparable Efficacy to Selective OX2R Agonists: The efficacy of AEX-41 was comparable to sulfonamide-derivative selective OX2R agonists under similar experimental conditions, highlighting its potential as a versatile alternative for broader therapeutic application.
- Multi-Pathway Potential: By targeting both orexin receptors and Cathepsin H inhibition activity, AEX-41 offers a dual-action mechanism that could address not only sleep-wake regulation but also underlying neurodegenerative processes.
Starting in 2025, NLS plans to expand its research to investigate the impact on Cathepsin H in animal models of neuroinflammation, a key factor in the progression of neurodegenerative diseases. An Investigational New Drug application is planned for 2026-2027 to support this new avenue of study.
“The dual mechanism of AEX-41 marks a transformative approach in treating narcolepsy. By simultaneously targeting orexin receptors and cathepsins, we aim to provide both symptomatic relief and disease-modifying potential- which would be an advancement over current therapies,” says Eric Konofal, MD, PhD, chief scientific officer of NLS and inventor of the DOXA platform, in a release. “In addition, based on cathepsins broad mechanism of action, we believe the DOXA platform may hold significant synergies with Kadimastem’s pipeline, especially in the areas of diabetes, which is often associated with sleep-wake dysregulation manifesting as insomnia, as well as amyotrophic lateral sclerosis. ″
NLS is actively advancing the development of AEX-41 and AEX-2, with plans to further evaluate their safety and efficacy in clinical settings. Beyond narcolepsy, the company is exploring their potential application in other neurodegenerative disorders, including amyotrophic lateral sclerosis, leveraging their dual-targeting mechanism.
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