The experimental framework is designed to explore the therapeutic potential of two first-in-class non-sulfonamide dual orexin receptor agonists using a validated orexin knockout mouse model of narcolepsy.

Summary: NLS Pharmaceutics Ltd is investigating two novel dual orexin receptor agonists (DOXAs), AEX-41 and AEX-2, in a preclinical study to assess their potential for treating narcolepsy. The research, conducted at the Centre for Neuroscience Research of Lyon, focuses on promoting wakefulness, enhancing sleep quality, and reducing cataplexy in an orexin knockout mouse model. By targeting both orexin-1 (OX1R) and orexin-2 (OX2R) receptors, along with inhibiting cathepsins, these compounds aim to outperform existing selective OX2R agonists. Initial results are anticipated by early December, with potential future applications in other neurological conditions.

Key Takeaways:

Dual Orexin Targeting for Enhanced Outcomes: AEX-41 and AEX-2 target both OX1R and OX2R receptors, potentially providing superior wakefulness and sleep stability compared to selective OX2R agonists.
Study Approach: The preclinical study uses EEG/EMG monitoring in narcoleptic mice to evaluate the impact on wakefulness, sleep architecture, and cataplexy suppression, with rigorous testing under both normal and stress conditions.
Broader Neurotherapeutic Potential: Beyond narcolepsy, NLS plans to explore the application of its dual orexin receptor agonist platform in treating other neurodegenerative diseases like amyotrophic lateral sclerosis.

NLS Pharmaceutics Ltd, a Swiss clinical-stage biopharmaceutical company focused on the discovery and development of innovative therapies for patients with rare and complex central nervous system disorders, provided insights into the preclinical program evaluating its dual orexin receptor agonist (DOXA) platform.

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. This approach aims to address the unmet therapeutic needs in narcolepsy and related neurological disorders.

The ongoing studies are conducted at the Centre for Neuroscience Research of Lyon, an institution specializing in sleep and neurological research. The experimental framework is designed to explore the therapeutic potential of AEX compounds using an international validated orexin knockout mouse model of narcolepsy.

Key elements of the study include:

Study Objectives:
- Promote Wakefulness: Evaluate the impact of AEX compounds on maintaining wakefulness in narcoleptic mice.
- Enhance Sleep Quality: Assess improvements in sleep architecture and stability.
- Suppress Cataplexy Attacks: Measure reductions in the frequency and severity of cataplexy, a hallmark symptom of narcolepsy.
Methodology:
The study leverages EEG/EMG technology to monitor brain activity and muscle tone, providing precise data on wakefulness, non-rapid eye movement (NREM), and rapid eye movement (REM) sleep phases. Post-surgical recovery is followed by controlled drug administration, ensuring accurate measurement of the compound’s efficacy.
Experimental Design:
The study aims to evaluate the potential superiority of AEX compounds over existing therapies through a two-part approach:
- Part 1: Direct evaluation of AEX compounds performance on key metrics such as sustained wakefulness and improved sleep architecture.
- Part 2: Assessment of compound efficacy under challenging stress conditions, including sleep deprivation, to test the robustness and durability of their effects.

Anticipated Superiority Over Selective OX2R Agonists

While existing selective OX2R agonists have demonstrated efficacy in managing narcolepsy symptoms, DOXA are expected to surpass these benchmarks. By engaging both OX1R and OX2R receptors and addressing broader neurological pathways, AEX-41 and AEX-2 offer the potential for enhanced therapeutic outcomes, including greater wakefulness stability and improved sleep quality under real-world conditions.

“Our preclinical program reflects our commitment to redefining the treatment landscape for narcolepsy and related disorders. The advanced study design and methodology we’ve implemented aim to demonstrate not only the efficacy of our compounds but their potential superiority in addressing both symptoms and underlying disease mechanisms,” says Eric Konofal, MD, PhD, chief scientific officer of NLS, in a release.

First results from the ongoing study are expected to be shared in early December. The company’s broader development plans include exploring the application of its DOXA platform also in other neurodegenerative conditions, such as amyotrophic lateral sclerosis.