Takeda Pharmaceuticals kicked down the door to a new market last month when it scored an FDA nod for Orzeyful — the first orexin agonist drug approved for Type 1 narcolepsy. But the orexin field is just starting to take shape and competitors are close behind.
Orexins, neuropeptides secreted by neurons in the hypothalamus, are implicated in a host of vital functions, making them a tantalizing target for drug developers. Clinical data from narcolepsy trials have already demonstrated that boosting orexins can improve narcolepsy symptoms like excessive sleepiness. What else could activating these receptors do? Theories abound that orexins could play a role in a wide range of CNS conditions, many of which lack approved treatments.
“This conversation has gotten really exciting about broader CNS indications … and has come up in relation to areas like cognition, fatigue, ADHD, mood, etc.,” Dr. Jeff Dayno, CEO of Harmony Biosciences, which is developing an orexin candidate, said. “We see a very large opportunity, both in terms of unmet needs for patients, as well as the large market opportunities.”
So far, orexin agonist drug developers have focused their research on narcolepsy, an indication with therapeutic gaps and relatively easier outcomes to measure. While Takeda crossed the regulatory finish line first, it may not have the market to itself for long.
Commercial-stage Alkermes has developed a global phase 3 program testing its candidate alixorexton in Type 1 and Type 2 narcolepsy. The drug is also in phase 2 for idiopathic hypersomnia. Winning in multiple indications could give Alkermes a broader reach in narcolepsy, but it’s not alone in that approach.
Eli Lilly staked a claim to the orexin space when it agreed in March to acquire Centessa Pharmaceuticals — and its mid-stage orexin pipeline built around the same three indications — for about $6.3 billion upfront. That deal closed in June.
While Harmony is trailing the pack with its orexin candidate, which is still in early-stage development, the company is banking on the strong potency of its treatment as being key to carving out a niche.
In its most recent earnings report, Harmony disclosed that topline single-ascending-dose phase 1 data for its orexin agonist BP-205 demonstrated a favorable safety and tolerability profile. BP-205 also showcased the potential for once-a-day dosing, which could be a critical frontier in orexin drug development.
“BP-205, to date, is the most potent orexin receptor agonist in clinical development. We are talking about a potency of 0.015 nanomolars,” Dr. Kumar Budur, Harmony’s executive vice president, chief medical and scientific officer, said of the candidate’s potency. “Just for comparison, [Orzeyful] has a potency of 2.5 nanomolars. Basically, BP-205 is 160 times more potent than [Orzeyful].”
Alkermes is also targeting once-a-day dosing with alixorexton. Takeda’s Orzeyful, by contrast, was approved to be taken twice daily.
BP-205’s safety profile could also set it apart.
“To the extent we can extrapolate the data from the single-ascending-dose study, the emerging safety and tolerability profile is very encouraging,” Dayno said.
Early signals indicate that BP-205 is rapidly absorbed, Budur said, a feature that could be an advantage in CNS conditions where patients are looking for immediate symptom relief.
“Rapid acting is extremely helpful in conditions like ADHD for example,” Budur said.
Building off its track record
Harmony has already made its mark on the narcolepsy market. Its first-in-class narcolepsy drug Wakix, which targets the histamine H3 receptor, won its initial approval in 2019 for excessive daytime sleepiness and has since expanded its label to include cataplexy and pediatric patients.
Although Wakix is Harmony’s only approved product, the company is guiding that it will cross the blockbuster threshold this year, Dayno said. The drug netted over $261 million in net product revenue in the second quarter — a 30% jump over the same period in 2025.
For now, Wakix is giving Harmony all the financial cushion it needs to develop its clinical programs, Dayno said, which include other narcolepsy candidates and drugs aimed at multiple types of epilepsy.
Harmony has long maintained a focus on the rare neurological diseases and Dayno acknowledged that if BP-205 eventually succeeds in indications outside of narcolepsy, it could transform the company into an enterprise targeting larger patient populations. But its experience in the sleep/wakefulness space would aid that transition, Dayno said.
“What we feel we are building, if we look long term, is a leading patient-focused CNS company with multiple franchise assets,” Dayno said.
For now though, Harmony hasn’t disclosed which indications it plans to target with BP-205. The company said it plans to initiate two phase 2 studies for the candidate by mid-2027 in “multiple CNS indications.”
And as Harmony contemplates its clinical future, what would be the holy grail for its orexin drug? For Budur, there are multiple therapeutic areas where he’d love to see orexins put to use.
“Cognition, mood and fatigue … these are all the indications that have really, really high unmet needs. For example, fatigue. There are no good medicines to treat fatigue today,” he said. “So wherever it goes, wherever it is successful, I think that will be a huge benefit from a patient perspective.”
