Alixorexton

– Alixorexton Demonstrated Statistically Significant and Clinically Meaningful Improvements in Wakefulness and Cataplexy – – At All Doses Tested, Alixorexton Demonstrated Clinically Meaningful Improvements in Patient-Reported Outcomes Related to Disease Severity, Fatigue, Cognition and Health-Related Quality of Life – – Alixorexton Was Generally Well Tolerated at All Doses Tested – DUBLIN--(BUSINESS WIRE)--Aug. 24, 2026-- Alkermes plc (Nasdaq: ALKS) today announced the publication of data from the Vibrance‑1 phase 2 study of alixorexton in adults with narcolepsy type 1 (NT1) in The Lancet Neurology. Alixorexton is a novel, investigational, oral, selective orexin 2 receptor (OX2R) agonist in development for the treatment of NT1, narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH). Based on the positive results demonstrated by alixorexton in the phase 2 Vibrance Studies in NT1 and NT2, Alkermes has initiated the Brilliance Studies, a global phase 3 program evaluating once-daily and split dose regimens of alixorexton in adults with NT1 and NT2. The phase 2 Vibrance-1 study was conducted in 92 adults with NT1 and included a six-week, randomized, placebo-controlled, double-blind period followed by an optional seven-week open-label extension. As previously announced, treatment with once-daily alixorexton led to statistically significant improvements from baseline versus placebo in both objective and subjective measures of excessive daytime sleepiness, as measured by the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS)1, respectively. All dose groups (4 mg, 6 mg and 8 mg) achieved mean sleep latency values within the normative range on the MWT (i.e., ≥20 minutes) and ESS (a score of ≤10) at week six. Weekly cataplexy rate2 was significantly decreased versus placebo in the 6 mg alixorexton group. Alixorexton also demonstrated clinically meaningful improvements on exploratory patient-reported endpoints assessing overall disease severity, fatigue, cognition and health-related quality of life. Alixorexton treatment was generally well tolerated, with most treatment-emergent adverse events (TEAEs) being mild to moderate in severity, and no serious TEAEs. “The data published in The Lancet Neurology highlight the robust efficacy of once-daily doses of alixorexton in patients with narcolepsy type 1 across measures of wakefulness and excessive daytime sleepiness. Along with a generally well-tolerated profile, alixorexton demonstrated improvements across a broad range of symptoms that affect daily functioning, including cataplexy, overall disease severity, cognition and fatigue. These data are a substantial contribution to the evidence base supporting the potential of orexin 2 receptor agonists to transform the treatment of narcolepsy and the utility of a range of doses to address the individual needs of people living with NT1,” said Giuseppe Plazzi, M.D., Ph.D., Neurologist, Director of the Narcolepsy Center at the IRCCS of the Neurological Sciences of Bologna and Professor of Childhood Neuropsychiatry at the University of Modena and Reggio Emilia. “In the Vibrance-1 study, alixorexton demonstrated substantial and clinically meaningful benefits across multiple dimensions of narcolepsy type 1,” said Craig Hopkinson, M.D. (MBChB), Chief Medical Officer and Executive Vice President, Research & Development at Alkermes. “The totality of evidence generated across the Vibrance phase 2 program in narcolepsy has reinforced our confidence in alixorexton’s potential to meaningfully impact the lives of people living with narcolepsy type 1 and type 2. These findings highlight the potential of alixorexton to address a broad range of symptoms that continue to burden patients despite currently available therapies. With the global Brilliance phase 3 program now underway in both narcolepsy type 1 and type 2, we are excited to continue advancing alixorexton in this next stage of development.” About the Vibrance-1 Phase 2 Study (NCT06358950) Vibrance-1 was a phase 2, randomized, double-blind, dose-range-finding, placebo-controlled study evaluating the safety and efficacy of alixorexton in adults with narcolepsy type 1 (NT1). Participants (n=92) were randomized to receive one of three doses of alixorexton (4 mg, 6 mg or 8 mg) or placebo to be taken once-daily for six weeks. The primary endpoint assessed whether participants taking alixorexton experienced an improvement in wakefulness compared to participants taking placebo, as measured by the change from baseline in mean sleep latency on the Maintenance of Wakefulness Test (MWT) at week six. Secondary endpoints included change from baseline in Epworth Sleepiness Scale (ESS) score at week six, mean weekly cataplexy rate (WCR) at week six2, and incidence of adverse events. The study also included a number of exploratory patient-reported outcome measures, which evaluated the effect of alixorexton on participants’ disease severity, fatigue and cognition. All participants in the double-blind portion of the study were eligible to continue to a seven-week open-label safety extension portion of the study, followed by a long-term safety study. About Alixorexton Alixorexton (formerly referred to as ALKS 2680) is a novel, investigational, oral, selective orexin 2 receptor (OX2R) agonist in development for the treatment of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH). Orexin, a neuropeptide produced in the lateral hypothalamus, is considered to be the master regulator of wakefulness due to its activation of multiple, downstream wake-promoting pathways that project widely throughout the brain.3 Targeting the orexin system may address excessive daytime sleepiness across hypersomnolence disorders, whether or not deficient orexin signaling is the underlying cause of disease.4 Alixorexton is currently being evaluated in the phase 3 Brilliance Studies in patients with NT1 and NT2, and in the phase 2 Vibrance-3 study in patients with IH. The U.S. Food and Drug Administration (FDA) has granted alixorexton Breakthrough Therapy designation for the treatment of NT1 and Orphan Drug Designation (ODD) for the treatment of IH. The European Commission has granted ODD to alixorexton for the treatment of narcolepsy. About Alkermes plc Alkermes plc (Nasdaq: ALKS), a mid-cap growth and value equity, is a global biopharmaceutical company that seeks to develop innovative medicines in the field of neuroscience. The company has a portfolio of proprietary commercial products for the treatment of alcohol dependence, opioid dependence, schizophrenia, bipolar I disorder and narcolepsy. Alkermes’ pipeline includes late-stage clinical candidates in development for narcolepsy and idiopathic hypersomnia, and orexin 2 receptor agonists in early clinical development for other neurological disorders, including attention-deficit hyperactivity disorder (ADHD) and fatigue associated with multiple sclerosis and Parkinson’s disease. Headquartered in Ireland, Alkermes also has a corporate office and research and development center in Massachusetts and a manufacturing facility in Ohio. For more information, please visit Alkermes’ website at www.alkermes.com. Note Regarding Forward-Looking Statements Certain statements set forth in this press release constitute “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, but not limited to, statements concerning: the potential therapeutic and commercial value of alixorexton. The company cautions that forward-looking statements are inherently uncertain. Although the company believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, the forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those expressed or implied in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: clinical study results for alixorexton may not be predictive of results of future stages of ongoing clinical studies, future clinical studies or real-world results; clinical studies for alixorexton may not be initiated or completed on expected timelines or at all; alixorexton may be shown to be ineffective or unsafe; the FDA may not agree with the company’s regulatory strategies or components of its development program for alixorexton, including clinical trial designs, conduct and methodologies; potential changes in the cost, scope and duration of the alixorexton development program; and those risks and uncertainties described under the heading “Risk Factors” in the company’s Annual Report on Form 10-K for the year ended Dec. 31, 2025 and in subsequent filings made by the company with the U.S. Securities and Exchange Commission (SEC), which are available on the SEC’s website at www.sec.gov. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Except as required by law, the company disclaims any intention or responsibility for updating or revising any forward-looking statements contained in this press release. 1 ESS: 8-item self-administered questionnaire that measures severity of excessive daytime sleepiness across multiple conditions over the past 7 days (≤10 = normative). 2 Weekly cataplexy rate was derived at Week 6 from patients’ cataplexy diaries over Weeks 5 and 6. 3 Buysse, D. Diagnosis and assessment of sleep and circadian rhythm disorders. Journal of Psychiatric Practice. 2005; 11(2):102-115 4 Ten-Blanco M, Flores A, Cristino L, Pereda-Perez I. Targeting the orexin/hypocretin system for the treatment of neuropsychiatric and neurodegenerative diseases: From animal to clinical studies. Frontiers in Neuroendocrinology. 2023;69(101066). https://www.sciencedirect.com/science/article/pii/S0091302223000146 View source version on businesswire.com: https://www.businesswire.com/news/home/20260824378408/en/ Alkermes Contacts: For Investors: Sandy Coombs, +1 781 609 6377 For Media: Gretchen Murphy, +1 781 609 6419 Source: Alkermes plc

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.”