Harmony Biosciences Holdings has unveiled promising preclinical data for BP1.15205, an investigational orexin 2 receptor (OX2R) agonist that demonstrated significant therapeutic potential for narcolepsy type 1 and other central disorders of hypersomnolence. The data, presented at the 39th Annual Meeting of the Associated Professional Sleep Societies (APSS) in Seattle, positions BP1.15205 as a potentially best-in-class treatment option.
Robust Preclinical Efficacy Data
The preclinical studies revealed BP1.15205's exceptional potency and selectivity profile. In vitro orexin receptor functional studies demonstrated that BP1.15205 is a highly potent agonist at OX2R receptors with an EC50 of 0.015 nM and exhibits >600-fold selectivity for human OX2R receptors over human OX1R receptors.
In vivo pharmacology studies using a standard transgenic mouse model of narcolepsy showed dose-dependent therapeutic effects. Single oral dose administration of BP1.15205 at the beginning of the 12-hour dark period produced significant and dose-dependent increases in total wakefulness time and sleep latency at every dose tested, beginning at 0.03 and 0.1 mg/kg respectively, compared to vehicle-treated animals.
The compound also demonstrated significant cataplexy-suppressing effects, with dose-dependent decreases in both the total number and duration of cataplexy-like episodes following single dose oral administration beginning at 1 mg/kg compared to vehicle.
Favorable Safety and ADME Profile
BP1.15205 exhibited promising absorption, distribution, metabolism, and excretion (ADME) properties with oral bioavailability and potential for once-daily dosing. The compound's safety profile was evaluated in a 3-month GLP toxicology study conducted in two species, which revealed no concerning adverse events or biochemical changes at doses up to 300 mg/kg/day, pending histopathology data.
"We are encouraged by the robust preclinical data being presented at SLEEP, highlighting BP1.15205 as a potentially best-in-class OX2R agonist," said Kumar Budur, MD, MS, Chief Medical and Scientific Officer at Harmony Biosciences. "BP1.15205 is a new and unique chemical scaffold optimized for high potency that demonstrated statistically significant wake-promoting effects at very low doses administered orally in the standard transgenic mouse model."
Clinical Development Timeline
Harmony Biosciences is advancing BP1.15205 toward clinical development with regulatory submissions planned in both Europe and the United States. An Investigational Medicinal Product Dossier (IMPD) application with the European Medicines Agency (EMA) is being completed, while an Investigational New Drug (IND) application will be filed with the U.S. Food and Drug Administration (FDA).
A first-in-human study is planned to begin in the second half of 2025, with topline clinical data anticipated in 2026. The low-dose efficacy observed in preclinical studies suggests potential for dosing flexibility that could treat all three central disorders of hypersomnolence while maintaining an optimized benefit-risk profile.
Addressing Significant Unmet Medical Need
Narcolepsy affects approximately 170,000 Americans and is characterized by excessive daytime sleepiness (EDS) and cataplexy as its cardinal symptoms, along with other manifestations of REM sleep dysregulation including hallucinations and sleep paralysis. The disease is primarily caused by the loss of hypocretin/orexin, a neuropeptide that supports sleep-wake state stability.
The condition typically manifests in adolescence or young adulthood and affects men and women equally. However, proper diagnosis can take up to a decade, highlighting the significant unmet medical need in this patient population.
"We are very excited to advance our potentially best-in-class OX2R program and support the strategic expansion of our sleep-wake franchise," Budur added. "We are dedicated to investigating this potential new solution further with the hope of bringing a novel treatment to market that can help even more people with narcolepsy and other central disorders of hypersomnolence."
