As the first orexin-2 receptor agonist for narcolepsy nears FDA approval, a preclinical compound shows promise for its higher potency.
By Sree Roy
Summary: The preclinical profile of a Harmony Biosciences’ drug candidate positions it as a potentially versatile orexin-2 receptor agonist across central disorders of hypersomnolence, according to new data presented at SLEEP 2025.
Takeda is on track to be the first to bring an orexin-2 receptor agonist to market in the United States, with its lead drug candidate TAK-861 aimed at treating narcolepsy type 1. However, new data presented at SLEEP 2025 suggest that a more potent orexin-2 receptor agonist could eventually surpass Takeda’s candidate in prescriptions. A higher-potency compound may effectively treat not only narcolepsy type 1, but also narcolepsy type 2 and idiopathic hypersomnia—without triggering deleterious side effects.
Potency matters, says Kumar Budur, MD, MS, chief medical and scientific officer at Harmony Biosciences. At SLEEP, he presented a poster on BP1.15205, Harmony’s orexin-2 receptor agonist candidate, reporting that it produces significant wake-promoting and cataplexy-suppressing effects in a dose-dependent manner. It also showed potential for once-daily oral dosing.
Potency, he says, is “one of the main factors that went into our interest in BP1.15205.” Harmony is sub-licensing the compound for the United States and Latin America from Bioprojet (which, in turn, is licensing it from Teijin Pharma Ltd in Japan). “This particular compound continues to be the most potent orexin receptor agonist based on all the publicly disclosed data from other companies,” Budur says.
Emerging data, as interpreted by Budur, show incremental dose increases are needed for efficacy as hypersomnolence moves from narcolepsy type 1 (NT1) to narcolepsy type 2 (NT2) to idiopathic hypersomnia. “Some of the competitors in this space have noticed that as they go higher on the dose, they have some dose-limiting side effects, and in some cases, they are not able to stay dose proportional,” he says. “Having the most potent receptor agonist gives us the dosing flexibility at which we can target all three central disorders of hypersomnolence: NT1, NT2, and idiopathic hypersomnia.”
How the Compound Impacted Mice with Narcolepsy
A study by Teijin used the standard transgenic mouse model of narcolepsy type 1. Mice are predominantly nocturnal—sleeping during the day, while being awake, alert, and scuttling around at night. Except for these transgenic mice with narcolepsy—they remain sleepy during the night when they should be awake, similar to humans with narcolepsy.
The investigators gave a single oral dose of BP1.15205 to the transgenic mice at the beginning of the 12-hour dark period of a 24-hour light/dark cycle—that is, when the narcoleptic mice should be awake but struggled to do so. “It showed that at very low doses, BP1.15205 was able to keep these mice awake, increased their sleep latency, and more importantly, we also saw dose-proportionality as the dose was increased,” Budur says. The increase in time awake was exactly what the investigators expected to happen with a potent orexin-2 receptor agonist. (The study was not designed to look at the mice’s normal sleep period.)
BP1.15205 By the Numbers
Harmony highlighted specific new data it wants the sleep subspecialty to know about the preclinical studies of BP1.15205:
In Vitro Orexin Receptor Functional Studies:
- BP1.15205 is a highly potent agonist at OX2R receptors: EC50 = 0.015 nM.
- BP1.15205 is highly selective for human OX2R receptors: >600-fold selectivity over human OX1R receptors.
- Minimal interspecies difference in agonist functional properties was observed between human and mouse orexin-2 receptors.
In Vivo Pharmacology Studies:
- Single oral dose administration of BP1.15205 in transgenic mice at the beginning of the 12-hour dark period of a 24-hour light/dark cycle 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, respectfully, as compared to vehicle-treated animals.
- Significant and dose-dependent decreases in the total number and duration of cataplexy-like episodes were measured following single dose, oral administration of BP1.15205 beginning at 1 mg/kg, as compared to vehicle.
BP1.15205 Safety Profile
Also at SLEEP, Harmony released data from its three-month Good Laboratory Practice toxicity study in mice and dogs. The study revealed no concerning adverse events and supports a favorable safety and tolerability profile. No adverse events or biochemical changes were observed following a three-month treatment period at doses up to 300 mg/kg a day, pending histopathology data. “The hematological and biochemical findings were clean. There was nothing from a safety perspective,” Budur says.
Next Up: Human Studies
A first-in-human study for BP1.15205 is planned for the second half of this year, with topline data anticipated in 2026. Harmony will also file an Investigational New Drug application for BP1.15205 with the Food and Drug Administration.
“This is a new class of innovative drugs for patients with central disorders of hypersomnolence, so we are very excited about it,” Budur says. “[BP1.15205] could potentially—and I want to emphasize potentially—be the best-in-class drug. We will continue to pursue our compound and see how the field evolves. And hopefully we’ll be able to make a difference in patients’ lives.”
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