Summary: New preclinical data on AEX-2, a first-in-class dual orexin receptor agonist, highlight its potential to treat narcolepsy, neurodegeneration, and metabolic disorders with a multi-target approach.
Key Takeaways:
- AEX-2 is a novel non-sulfonamide dual orexin receptor agonist that could offer a safer and more targeted alternative to existing orexin-based therapies.
- In preclinical models, AEX-2 increased wakefulness without excessive fragmentation, preserved REM sleep, and significantly reduced cataplexy episodes, making it a strong candidate for NT1 treatment.
- AEX-2 and AEX-41 are being explored for neurodegenerative conditions due to their engagement with the Sigma-1 receptor, which plays a role in neuroprotection and synaptic plasticity.
- The compounds may also address diabetes-related neurological disorders, given the connection between orexin signaling, metabolic regulation, and brain health.
- NLS Pharmaceutics aims to begin investigational new drug -enabling studies in 2025, with first-in-human trials expected by 2026.
- Preclinical results will be shared at the 2025 American Society for Clinical Psychopharmacology Annual Meeting.
New preclinical findings on AEX-2, a potential as a first-in-class non-sulfonamide dual orexin receptor agonist (DOXA) for narcolepsy and related neurological disorders, have been released by NLS Pharmaceutics Ltd, in collaboration with Aexon Labs Inc. According to a press release, these results build upon NLS’s multi-target neurodegenerative strategy, which also includes AEX-41, demonstrating a novel and promising approach to addressing sleep disorders, neuroinflammation, and metabolic dysfunction.
Key Preclinical Findings on AEX-2 (20 mg/kg, IP)
Recent preclinical advancements have demonstrated the multi-target potential of DOXA compounds, including AEX-41 and AEX-2, in redefining sleep-wake regulation and neuroprotection. In orexin-deficient mouse models, these compounds exhibited strong wake-promoting effects and sleep-wake cycle stabilization, reinforcing their potential as next-generation therapeutics.
Key findings include:
- Wakefulness enhancement: AEX-2 significantly increased total wake duration while maintaining a stable wake architecture, avoiding excessive fragmentation.
- REM sleep preservation: Unlike traditional stimulants, AEX-2 regulated rapid eye movement (REM) sleep dynamics, minimizing undesired suppression and sleep rebound effects.
- Reduction in cataplexy: AEX-2 effectively reduced the frequency and duration of cataplexy episodes, a crucial advancement for treating narcolepsy type 1 (NT1).
According to NLS, these data underscore the potential of AEX-2 as a safer and more targeted alternative to other orexin-based therapies in development, some of which have been hindered by safety concerns.
Beyond narcolepsy, NLS Pharmaceutics and Aexon Labs are advancing AEX-2 and AEX-41 into new therapeutic areas, leveraging their multi-target mechanisms that extend to neuroinflammatory and metabolic pathways.
- Targeting neuroinflammation: Recent discoveries highlight AEX compounds’ engagement with the Sigma-1 receptor, which plays a key role in neuroprotection, synaptic plasticity, and REM sleep regulation.
- Potential in ALS and neurodegenerative diseases: Sigma-1 receptor modulation, combined with orexin receptor activation, suggests AEX-41 may have applications in ALS and Parkinson’s disease, particularly in preserving motor function and reducing neuroinflammation.
- Addressing diabetes-associated neurological disorders: Given the link between orexin signalling, metabolic regulation, and sleep disorders, the multi-target properties of DOXA compounds such as AEX-2 and AEX-41 could provide new therapeutic avenues for diabetes-related neuropathy and cognitive decline.
Aexon Labs has played a key role in optimizing these multi-target molecules, ensuring high blood-brain barrier penetration and selective receptor affinity.
Unlocking Multi-target Potential
NLS Pharmaceutics is advancing AEX-2 and AEX-41 into investigational new drug-enabling studies in 2025, targeting first-in-human clinical trials by 2026.
Beyond dual orexin receptor activation, these compounds engage Sigma-1 receptor modulation, cathepsin inhibition, and mitochondrial regulation, reinforcing their first-in-class potential.
To validate this multi-target strategy, additional preclinical studies are underway, including an ongoing diabetes-associated neurological disorders model, potentially broadening their applications beyond sleep disorders.
“The recent preclinical findings represent a key milestone for our DOXA platform,” says Eric Konofal, MD, PhD, chief scientific officer of NLS Pharmaceutics, in a release. “These preliminary findings reinforce our commitment to developing neurodegenerative therapies that not only manage symptoms, but also address the underlying mechanisms of sleep and neurodegenerative disorders. With ongoing studies in [diabetes-associated neurological disorders], we are further expanding the potential of our multitarget approach to address metabolic dysfunction and its impact on brain health.”
Alex Zwyer, CEO of NLS Pharmaceutics, says in a release, “We are encouraged by these recent preclinical results, which showcase the unique potential of our DOXA platform. We believe these findings not only strengthen our commitment to developing transformative neurodegenerative therapies, but they also highlight the importance of addressing the underlying mechanisms associated with sleep and neurodegenerative disorders. As we continue our studies in [diabetes-associated neurological disorders], we are optimistic about expanding the therapeutic landscape of our multi-target approach.”
NLS Pharmaceutics plans to present the definitive results on AEX-2 and AEX-41 at the American Society for Clinical Psychopharmacology Annual Meeting, taking place May 27-30, 2025 in a poster presentation titled “Non-Sulfonamide Dual Orexin Receptor Agonists: Preliminary Results of AEX-41 and AEX-2 in a Mouse Model.”
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