Pitolisant Hydrochloride

As the hype around the vast medical potential of GLP-1 drugs continues unabated, another peptide is starting to make its own mark. In August, Takeda garnered FDA approval for oveporexton, a drug that mimics a vital brain protein called orexin. Orzeyful, as it's now known, is the first approved medicine that targets the underlying biology of the uncommon sleep disorder narcolepsy type 1. But experts who spoke to Fierce are virtually unanimous that orexin mimics have much broader potential than narcolepsy, with several referring to them as the “GLPs of neuroscience.” Orexin drugs coming down the pike could find use in other sleep disorders as well as in fatigue, cognition and mood—broad societal problems that present potentially massive markets. “It can have many benefits in terms of attention or arousal, essentially being more present [and] more engaged in daily life,” Luis de Lecea, Ph.D., a co-discoverer of orexin and professor of psychiatry and behavioral sciences now based at Stanford University, told Fierce. “I think it can be more effective than anything that is out there in that direction.” de Lecea was mapping the “uncharted territory” of the hypothalamus in the lab of J. Gregor Sutcliffe, Ph.D., at San Diego’s Scripps Research Institute when orexin popped out of a protein screen. Because they thought it was similar to another peptide, incretin, but was made by neurons in the hypothalamus, the team named the newfound compound hypocretin in their 1998 paper describing it. Around the same time, a group led by Masashi Yanagisawa, M.D., Ph.D., independently discovered the same peptides, but called them orexins—after the Greek word for appetite—because they thought they induced feeding. This ultimately didn’t hold up, de Lecea told Fierce, but the orexin name stuck, to his chagrin. “I don't like the name orexins because they are a bit misleading,” he said. “I still call them hypocretins.” But whatever you call them, it has since become apparent that hypothalamic peptides play a big role not just in sleep, but in all facets of alertness. These neurons in the hypothalamus are “integrators of information,” said de Lecea, who added that they take stock of the body’s sleepiness, circadian rhythm, metabolic state, emotions and more. The orexin system evaluates all this input and provides a single, binary output—either activating the brain’s alert system of molecules like norepinephrine, dopamine and serotonin, or not. “The output is like a master switch of all arousal circuits,” de Lecea said. It didn’t take long for researchers to connect this master switch to narcolepsy. In the 1990s, Emmanuel Mignot, M.D., Ph.D., completed his then-mandatory French military service in an unusual way. He traveled to Stanford to work with William Dement, M.D., Ph.D., considered the father of sleep medicine , and to test out a potential new narcolepsy drug from a French company, Mignot told Fierce. That drug eventually became the stimulant modafinil. Once in California, he began working with a group of dogs that Dement had amassed, all with narcolepsy. While narcolepsy isn’t genetic in humans, it is in dogs, and Mignot quickly became obsessed with finding the cause. “Instead of coming back to France, I decided to try to find the gene,” he recalled. “People thought I was crazy, which I was, honestly. And the best proof that I was crazy is it took me 10 years.” Mignot ultimately landed on the hypocretin-2 gene as the cause of canine narcolepsy, again around the same time as Yanagisawa’s group. Mignot and Yanagisawa shared the 2023 Breakthrough Prize in Life Sciences for their discovery. Another key moment for the field came in 2007, when de Lecea’s group found that stimulating the orexin system alone was enough to wake up sleeping mice. “To be able to demonstrate causality of these very small group of neurons, though of course in animal models—it was very clear that was going to be translated into something important in humans,” de Lecea told Fierce. Much is still unknown about the full extent of how orexin neurons connect to other brain regions, and of course it remains to be seen just how much use drugs mimicking the waking peptide will have in areas outside of sleep. But even if orexin agonists only prove useful in narcolepsy, they will still have done a great service by solving an often debilitating, overlooked disease. “Nobody cared a shit about narcolepsy when I started,” Mignot said. “These drugs make a huge difference.” Takeda’s own history with orexin also dates back to the late 1990s and the early days of the peptide's discovery. “It was that understanding of the underlying cause of the disease that spurred scientists at Takeda to try and agonize those remaining receptors,” Sarah Sheikh, head of global development at the Japanese pharma, told Fierce. “If you could stimulate those receptors, you could probably treat all the symptoms of the disease, because you were mimicking the natural system.” Stimulating the receptors is a much trickier task than inhibiting them, which was first achieved by Merck & Co.’s Belsomra in 2014 for the treatment of insomnia. Sheikh compared the receptor to a keyhole—many different shapes can potentially block access, but unlocking the receptor’s effects requires the right key. Takeda’s first attempts at key cutting proved unsuccessful, but ultimately informative, Sheikh explained. First came an intravenous formulation called danavorexton or TAK-925, which proved too inconvenient for a patient to take every day. The first potential pill, firazorexton or TAK-994, showed promising efficacy but was derailed by liver toxicity. “Unfortunately, there's no way to predict that,” Sheikh said. “You find that out in patient trials, and we did with TAK-994.” Despite the safety issues, the pill was so effective that patients asked to stay on it anyway, the Takeda exec told Fierce. This prompted the pharma to keep digging into orexin and ultimately strike gold with oveporexton. “We actually hit full throttle there,” Sheikh said. “We went from first-in-human to approval in just about five years, which is really unprecedented in neuroscience.” Takeda’s Orzeyful approval will likely fan the flames of orexin interest that first kindled back in March, when GLP-1 giant Eli Lilly announced it was paying $6.3 billion to acquire sleep specialist Centessa Pharmaceuticals. Lilly paid “a pretty hefty premium with limited data,” Danielle Brill, a biotech analyst with Truist Securities, told Fierce. With no chance of beating Takeda to the first narcolepsy type 1 approval, Lilly must have been confident “there's a bigger market to have justified the valuation,” Brill said. The bet on Centessa, followed by Takeda’s pioneering approval, is “a big validation for the bull case on this class,” Brill added, which “could have so much potential and could explode way beyond just narcolepsy.” “As you look even deeper, you can start to see orexins involved in things like inflammation; you can see them involved in things like metabolism,” Blair Jackson, the newly minted CEO of boutique neuroscience biotech Alkermes, told Fierce. “You start to realize that wakefulness as a whole is really central to our everyday living and how we feel.” But realizing these wide-ranging ambitions will require much more clinical data about orexin drugs, which currently doesn’t exist. “Their greatest potential right now is the small niche of people with hypersomnia disorders,” James Rowley, M.D., professor of medicine at Rush University in Chicago, told Fierce. Rowley, a past president of the American Academy of Sleep Medicine, suggested that most people who struggle with sleep should focus on changes in their daily lives, such as improving their sleep hygiene or getting more exercise. Instead, orexin drugs could expand into the smaller population of people with neurologic disorders who struggle with sleepiness, he suggested. Even if orexin agonists stay in the realm of narcolepsy, they will still make a tremendous impact, Rowley predicted. Narcolepsy is often thought of narrowly as a disease of excessive daytime sleepiness, but patients can also experience sudden loss of muscle tone when excited and vivid nightmares that make sleep at night hell. “All the medications we have now help reduce the sleepiness, but none restore full function,” he explained. “The data so far for these medications is that they really do restore alertness much better than the ones that we have on the market at the moment.” Though oveporexton has now crossed the finish line as Orzeyful, Takeda is keeping its pedal to the metal in an effort to stay ahead of the quickening competition. Sheikh said the company has seen positive effects on a range of symptoms in its narcolepsy trials, including mood, attention and fatigue, and Takeda also boasts an earlier-stage orexin agonist called TAK-495 in its pipeline (PDF). “We've opened up a completely new field; I'd call it a neuroscience revolution,” Sheikh said. “We intend absolutely to stay leaders in the field.” But Takeda is being chased by a surging pack of competitors, led by Lilly, who readily point out that first-in-class medicines often don’t end up being best-in-class down the line. Centessa, now operating as a subsidiary of Lilly, is aiming to get a single orexin agonist approved as a best-in-class option for three different indications: narcolepsy types 1 and 2 and idiopathic hypersomnia. “You really want one drug for three indications because there's a lot of overlap and misdiagnosis,” Centessa CEO Mario Alberto Accardi, Ph.D., told Fierce. Unlike narcolepsy type 1, patients with narcolepsy type 2 and other sleep disorders all have normal levels of orexin. Another key area for possible improvement is in dosing. Orzeyful requires two doses to keep patients awake throughout the day, and missing a dose risks sleepiness returning too early—at which point taking the drug again could keep a patient up all night. “How are you going to get to the later part of [the] day? People need to drive back home, right?” Accardi said. “Our goal is to be best-in-class from that perspective.” Lilly has experience with catching—and surpassing—its nearest competitor, having famously topped Novo Nordisk in the injectable GLP-1 market despite Novo’s substantial lead. “What Lilly brings is a tremendous amount of firepower, a tremendous amount of experience [and] of clinical development skillset,” Accardi said. The pharma’s LillyDirect platform for direct-to-consumer sales is also “extremely interesting,” he added. Dosing is top of mind for other biotechs working in the space. Alkermes has perhaps the most fleshed-out clinical trial program for its orexin agonists, called alixorexton, ALKS 7290 and ALKS 4510. Alixorexton has posted positive phase 2 data in narcolepsy type 2, and is now in late-stage development for both types of narcolepsy as well as idiopathic hypersomnia. ALKS 7290, meanwhile, has critical phase 1b data in attention deficit hyperactivity disorder (ADHD) expected in the third quarter, while ALKS 4510 is in early development for fatigue associated with neurodegenerative diseases like Parkinson’s and multiple sclerosis. Alkermes is “at the forefront” of the effort to take orexin out of sleep disorders and into broader patient populations, CEO Jackson told Fierce. The company boasts orexin options at a range of dosages as well as a split dose, he said, which he doesn’t think Takeda and Lilly can compete with yet. “If they want to go into these other indications, it's going to require other pharmacology and other assets,” he said. “They're putting a few in the clinic behind us.” To gain a foothold in the sleep world, Alkermes shelled out $2.1 billion for Avadel Pharmaceuticals in October 2025 for its approved non-orexin narcolepsy drug Lumryz. “To get into the marketplace a couple years before we're going to be there ourselves, to understand the payer environment, to understand the nursing, how to integrate with these patients, how to talk to these patients—that puts us in such a good spot,” Jackson explained. Harmony Biosciences is another upstart looking to spoil Takeda’s party with a potential best-in-class orexin agonist, though the company’s chief operating officer Peter Anastasiou told Fierce there’s room for many medicines to succeed. “No one product unlocks the value,” he said. “But rarely is the first or second or third asset the best asset, and so we believe we have, at least among the assets that are known now, the best in class.” Harmony’s orexin agonist, BP-205, stands out due to its safety profile, rapid absorption and potential for once-a-day dosing, Kumar Budur, M.D., the biotech’s chief medical and scientific officer, told Fierce. BP-205 is currently being tested in healthy volunteers, with plans for a phase 1b trial in sleep-deprived volunteers to kick off later this year before a full-throated phase 2 program in multiple central nervous system indications launches in mid-2027. To Truist’s Brill, Harmony represents a chance for a curious Big Pharma to buy its way into the orexin space. “Lilly's taking a bet that this class is going to become a big class, so it's only a matter of time until more pharma follows suit,” Brill said. “And there's not a ton of assets out there.” Harmony, which already markets a narcolepsy drug with a different mechanism called Wakix , isn’t banking on a Big Pharma to come knocking with a multibillion-dollar offer. “We can't control that,” Harmony CEO Jeffrey Dayno, M.D., told Fierce. “We build the company to grow it, and there's always, from time to time, inbound interest.” That interest will likely only increase as the orexin field continues to mature. Aside from Harmony, Alkermes, Takeda and Lilly’s Centessa, the other two most prominent orexin programs are run by Eisai and Lundbeck . This relatively small field offers plenty of room for new contenders to make plays. “A year ago, it was all about the hypersomnias,” Dayno said. “Now all of a sudden, the broader CNS potential applications are really attracting a lot of the main interest.”

iStock, Afry Harvy The FDA’s August approval of Takeda’s Orzeyful for treating the full set of narcolepsy symptoms initiated a new era in the sleep market. Takeda’s recently approved Orzeyful poses a potential threat to Jazz Pharmaceuticals’ blockbuster sleep franchise, as well as to products at companies including Alkermes and Harmony Biosciences. Yet Takeda faces threats as well, with multiple companies racing to burst through the door opened by the Orzeyful approval. There is already fierce competition in the narcolepsy space. Jazz’s Xywav and Xyrem, Alkermes’ Lumryz and Harmony’s Wakix are all FDA approved for treating cataplexy or excessive daytime sleepiness (EDS) in adults and children with narcolepsy. Revenues at Jazz’s rare sleep franchise exceeded $2 billion last year, while Wakix generated $868.5 million for Harmony. Alkermes, having acquired Lumryz in its takeover of Avadel Pharmaceuticals in February, has predicted sales of the drug could hit $335 million this year. These products face further competition from Axsome Therapeutics’ Sunosi, a former Jazz drug that generated sales of $124.8 million last year, as well as from Xyrem generics. And now, Orzeyful poses a new threat to the incumbent medications. Xywav, Xyrem and Lumryz are all based on sodium oxybate, a central nervous system depressant that the FDA approved to treat narcolepsy symptoms in 2002. Wakix, which the FDA approved in 2019, has a different mechanism of action centered on histamine, but its authorization covers the same narcolepsy symptoms as the sodium oxybate products. Orzeyful offers patients something different. How Orzeyful could disrupt the market Orzeyful is the first therapy to address the underlying cause of narcolepsy type 1 (NT1), Jefferies analysts said in an Aug. 6 note to investors. As the first therapy to directly restore orexin signaling, the drug could tackle the cataplexy and EDS treated by existing drugs, as well as the sleep paralysis, hallucinations and disrupted nighttime sleep that also affect patients with NT1. The FDA’s highlighting of Orzeyful’s effect on a spectrum of NT1 symptoms “sets up an orexin detailing message aimed squarely at the oxybate value [proposition],” Truist Securities analysts said Aug. 6 in a note to investors. Orzeyful’s efficacy is the key differentiator, Jefferies analysts said. The analysts compared Orzeyful’s effect on wakefulness, sleepiness and cataplexy favorably to data on existing narcolepsy therapies, reinforcing their view that the “restoration of orexin signaling is likely to reshape the treatment paradigm.” The FDA approved three Orzeyful doses, which Jefferies analysts said will give physicians more flexibility to tailor regimens to patients and enable dose reductions in people receiving moderate CYP3A inhibitors for other conditions. CYP3A inhibitors increase exposure to Orzeyful, which may raise the risk of adverse reactions. Use of the drug with strong CYP3A inhibitors, such as certain antifungal and HIV treatments, is contraindicated, but Jefferies analysts “see no evidence of restrictions that would materially limit prescribing.” Orzeyful’s safety profile “appears manageable,” the analysts said. The label contains no boxed warning and the product’s abuse potential is similarly manageable, the analysts added. The Drug Enforcement Administration (DEA) has yet to assign Orzeyful to a schedule. Jefferies analysts believe the data support a Schedule IV classification. Some existing narcolepsy therapies, such as Sunosi, are Schedule IV, but Xywav is in the more restrictive Schedule III. Securing a Schedule IV classification could “modestly support physician adoption and market access” for Orzeyful, Jefferies analysts said. Takeda expects to receive DEA scheduling by November, the analysts added, and will disclose pricing at that time. The analysts model a gross annual price of $142,000 per patient, benchmarked to Xywav, but believe Orzeyful’s efficacy, convenience, favorable label and manageable abuse potential could justify “a meaningful premium” over Jazz’s drug. Seeing “substantial switching potential if real-world efficacy matches clinical trial results,” the analysts assume 35% penetration of diagnosed narcolepsy patients over seven years and risk-adjusted peak sales of $1.8 billion. Truist analysts noted that Orzeyful’s label, which precludes use in narcolepsy type 2 (NT2) and children, limits “the immediate addressable overlap” to Xywav, but added that Takeda’s drug is “the leading edge of a longer-dated orexin wave of competitors” that could launch in the next few years. The wave of competitors The coming wave of orexin drug candidates includes assets in development at Alkermes, Eisai, Harmony, Kissei and Eli Lilly, the latter having recently entered the race by acquiring Centessa Pharmaceuticals for $6.3 billion upfront. Takeda is aiming to build on its early lead in the orexin field by developing TAK-360 and TAK-495 in indications including NT2 and idiopathic hypersomnia (IH), plus other conditions that cause EDS. Alkermes is among the companies studying orexin drug candidates in attention-deficit hyperactivity disorder. Lilly has hailed Centessa’s orexin candidate cleminorexton as having best-in-class potential, a claim that Harmony and Kissei have also made about their own assets. Discussing the best-in-class bar in NT1 in a Feb. 3 note to investors, Guggenheim Securities analysts predicted “an emphasis beyond [the maintenance of wakefulness test] to measurements of whole-day efficacy,” such as the Epworth sleepiness scale and weekly cataplexy rate. On those metrics, cleminorexton is best in class, the analysts said. Cleminorexton could also advance in NT2, where Guggenheim analysts noted the opportunity created by the failure of Alkermes’ alixorexton to reach the normative wakefulness threshold of 20 minutes. Sodium oxybates have set the best-in-class bar in IH, the analysts said, but have “high discontinuation rates and generally poor tolerability.” Alkermes, Lilly and Takeda are among the companies targeting IH, which Stifel analysts said in a July 19 note could be the “largest hypersomnia market opportunity for orexins.” Amid the focus on orexin, companies continue to pursue other narcolepsy targets. Axsome Therapeutics’ AXS-12, a norepinephrine reuptake inhibitor and cortical dopamine modulator, could win FDA approval in NT1 patients with cataplexy by May 1, 2027. In a July 15 note, Jefferies analysts put the chances of approval at 70% to 80% and predicted peak sales north of $300 million.