A NOVEL DISEASE-MODIFYING STRATEGY FOR NARCOLEPSY TYPE 1 – PRECLINICAL RATIONALE AND DEVELOPMENT ROADMAP FOR THE DOXA PLATFORM

Narcolepsy type 1 (NT1) is a chronic, orphan neurological disorder caused by autoimmune-mediated destruction of orexin-producing neurons in the lateral hypothalamus, leading to profound orexin deficiency (CSF orexin-A ≤110 pg/mL), cataplexy, excessive daytime sleepiness (EDS), REM sleep dysregulation, and fragmented sleep-wake cycles. Current therapies, including OX2R-selective agonists (TAK-861, ALKS-2680, ORX750), provide symptomatic relief but suffer from receptor desensitization, high insomnia rates (up to 65%), incomplete REM control, and no impact on the underlying neurodegeneration. DOXA (Dual Orexin Receptor Agonists) platform—introduces first-in-class non-sulfonamide compounds (AEX-41, AEX-2) that restore orexin signaling more physiologically than OX2R-only molecules. Preclinical data in the ORX-KO mouse model demonstrate that AEX compounds (e.g. AEX-41 at 40 mg/kg PO) achieves 90.9% cataplexy reduction (p < 0.001), 73% wakefulness increase over 60 min (p < 0.005), and significant sleep architecture improvement (REM duration –10%, SWS transitions –15%, p < 0.05). These preclinical results outperform OX2R-selective benchmarks in animal models and support dual agonist OX1R/OX2R as a superior symptomatic strategy. To address the core neurodegenerative pathology, we propose proof-of-concept (PoC) studies in Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) models. In α-synuclein A53T transgenic mice (PD model), we plan to evaluate whether Cathepsin H (CTSH) of AEX-41 inhibitory activity can enhance α-synuclein clearance. In the B6-hTDP43wt×A315T transgenic model (Thy1-driven human TDP-43 WT/A315T mutation, ALS model), we aim to explore potential modulation of TDP-43 pathology, neuroinflammation, and motor neuron survival. These studies are proposed PoC investigations and have not yet been performed. Succinctly, a hybrid pharmacology approach combining DOXA (dual OX1R/OX2R agonist with CTSH inhibition) with regenerative cell therapy (e.g., AstroRx – hESC-derived astrocytes) could be explored in ALS models: DOXA would enhance neuronal signaling and reduce inflammation, while AstroRx would provide trophic support and glutamate clearance, potentially offering synergistic neuroprotection. These hybrid concepts are at the hypothesis stage and will be tested in future preclinical work. The development roadmap includes: 1. Formulation optimization of AEX-41 and AEX-2 to achieve robust oral bioavailability ( > 70%) and support chronic daily dosing in NT1 patients, with focus on solubility enhancement, metabolic stability, and CNS penetration. 2. Proposed PoC studies in Parkinson’s disease (PD) models using α-synuclein A53T transgenic mice to explore the neuroprotective effects of AEX-41, including reduction of α-synuclein aggregation, and motor/non-motor symptom amelioration via CTSH inhibition and dual orexin signaling. 3. Proposed PoC studies in amyotrophic lateral sclerosis (ALS) models using the B6hTDP43wt×A315T transgenic model (Thy1-driven human TDP-43 WT/A315T mutation) to investigate the potential of AEX compounds (e.g., AEX-2) to modulate TDP-43 pathology, reduce neuroinflammation, and slow motor neuron loss. 4. Diabetes PoC Study Plan – db/db and STZ-Induced Mouse models, using AEX-2 and AEX24 to evaluate insulin sensitization, β-cell rescue, glucose tolerance, and metabolic recovery in type 2 diabetes models. 5. Advancement of the Next-Gen AEX series (e.g., AEX-635, AEX-609, AEX-23, AEX-24) for broader CNS applications, including enhanced CTSH inhibition, sigma-1 receptor modulation, and improved selectivity profiles for NT1, PD, ALS, and other neurodegenerative conditions. 6. Comprehensive ADME-Tox profiling (absorption, distribution, metabolism, excretion, and toxicity) in multiple species, including CYP inhibition assessment, reactive metabolite screening, and GLP-compliant toxicology to support future clinical development. This DOXA strategy represents a potential paradigm shift from purely symptomatic to neuroprotective treatment, offering both rapid symptom relief and the prospect of slowing neurodegeneration in NT1, PD, ALS, and metabolic disorders. Early clinical translation of this approach could significantly improve long-term outcomes for patients with narcolepsy type 1 and related neurodegenerative conditions.