ALKS-2680

— Orexin 2 Receptor Agonist ALKS 2680 Demonstrated Clinically Meaningful and Statistically Significant Improvements from Baseline in Mean Sleep Latency Compared to Placebo at All Doses Tested — — ALKS 2680 Was Generally Well Tolerated at All Doses Tested — — Vibrance-1 Phase 2 Study of ALKS 2680 in Patients With Narcolepsy Type 1 Is Ongoing — DUBLIN, June 3, 2024 /PRNewswire/ -- Alkermes plc (Nasdaq: ALKS) today announced new data from the full narcolepsy type 1 (NT1) cohort of a phase 1b, proof-of-concept study evaluating ALKS 2680, the company's novel, investigational, oral orexin 2 receptor (OX2R) agonist in development as a once-daily treatment for narcolepsy. The data are being presented at SLEEP 2024, the 38th annual meeting of the Associated Professional Sleep Societies (APSS), taking place June 1-5, 2024 in Houston. The phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of ALKS 2680 via once-daily, single, oral administration. Ten patients with NT1 were randomized1 to one of four crossover sequences in which each participant received 1 mg, 3 mg and 8 mg of ALKS 2680, and placebo, with washout periods between each treatment. Initial results from the first four patients in this NT1 cohort were previously presented at the 2023 World Sleep Congress. "Data from this phase 1b study provide evidence of a significant treatment effect of single doses of ALKS 2680 in patients with narcolepsy type 1. In addition, patients' self-reported measures of alertness further support continued clinical development of this investigational treatment, which has the potential to help address significant unmet needs for people living with excessive daytime sleepiness associated with narcolepsy," said Ron Grunstein, M.D., Ph.D., Head of Sleep and Circadian Research at the Woolcock Institute of Medical Research. Data highlights from the SLEEP poster presentation (Abstract ID 1323; Poster board 423) include: Mean Sleep Latency Over 8 Hours: In patients with NT1, treatment with ALKS 2680 demonstrated improved wakefulness compared to placebo at all doses tested, with a clear dose response. Treatment with ALKS 2680 resulted in statistically significant and clinically meaningful improvements in mean sleep latency on the Maintenance of Wakefulness Test (MWT), with a mean change from baseline versus placebo of 18.4 minutes at the 1 mg dose (p=0.0002), 22.6 minutes at the 3 mg dose (p=0.0001), and 34.0 minutes at the 8 mg dose (p≤0.0001) (least squares mean difference). Placebo treatment resulted in an approximately 1.4 minute reduction in mean sleep latency from baseline. Prior to treatment with ALKS 2680, these patients had a mean sleep latency on the MWT of approximately six minutes at baseline.2 At the 3 mg and 8 mg doses, the observed mean MWT scores over an eight-hour period post-dose were within the reported normal range for healthy individuals.3 Patient-Reported Alertness on the Karolinska Sleepiness Scale (KSS): The KSS is a subjective measure of self-reported alertness over the past five minutes, using a nine-point scale (with 1 being "extremely alert"; 9 being "extremely sleepy"; and 5 being "neither alert nor sleepy"). Change from baseline on KSS was an exploratory endpoint. ALKS 2680 demonstrated clinically meaningful, dose-dependent improvements in self-reported alertness in patients with NT1. The average self-reported score at baseline was approximately 7. ALKS 2680 showed improvements of 2 to 3 points in self-reported alertness between 1 and 8 hours, indicating clinically meaningful improvements (p<0.001 at all dose levels vs. placebo). Safety: ALKS 2680 was generally well tolerated across all doses tested in patients with NT1. Most treatment-emergent adverse events (TEAEs) were mild in severity, transient and self-resolving (with one moderate case of nausea that resolved with food intake). There were no severe adverse events (AEs). AEs observed in >1 patient and deemed to be related to study drug were insomnia,4 pollakiuria, salivary hypersecretion, decreased appetite, dizziness and nausea. There were no serious AEs (SAEs) reported or TEAEs leading to study drug discontinuation in patients with NT1. There were no drug-related, treatment-emergent, clinically meaningful changes from baseline in laboratory values at any dose. Additionally, no cardiovascular safety signals were identified in vital signs or electrocardiogram (ECG) parameters. "We're encouraged by the results of this proof-of-concept study of ALKS 2680 in patients with narcolepsy type 1. The clear dose response reinforced our design principles for this program, and we are looking forward to further characterizing the efficacy and safety of ALKS 2680 in patients with narcolepsy type 1 in the ongoing Vibrance-1 phase 2 study," said Craig Hopkinson, M.D., Chief Medical Officer and Executive Vice President, Research & Development at Alkermes. About the ALKS 2680 Phase 1 Study The phase 1 study for ALKS 2680 included single-ascending dose and multiple-ascending dose evaluations in healthy volunteers, and double-blind, crossover treatment in patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH). In the healthy volunteer phase of the study, each cohort included eight participants, six of whom were randomized to receive ALKS 2680 and two of whom received placebo. In the single-dose portion, ALKS 2680 was dosed from 1 mg to 50 mg. In the multiple-dose portion, participants received single daily doses of ALKS 2680 ranging from 3 mg to 25 mg strengths for up to 10 days. The objectives of this part of the study were to assess ALKS 2680's safety, tolerability, pharmacokinetics (PK) and pharmacodynamics. The phase 1b proof-of-concept part of the study enrolled patients with NT1 (n=10), NT2 (n=9) or IH (n=8). Following an initial two-week washout period of existing medications, patients received single doses of three active dose levels of ALKS 2680 (1 mg, 3 mg and 8 mg for NT1; 5 mg, 12 mg and 25 mg for NT2 and IH) and placebo in a randomized sequence in a four-way crossover design, with washout periods between each treatment in the sequence. The objectives were to assess safety and tolerability, and changes from baseline in average sleep latency, as measured through the Maintenance of Wakefulness Test (MWT) at each crossover period, along with plasma PK, and patient-reported measures of alertness on the Karolinska Sleepiness Scale (KSS). About ALKS 2680 ALKS 2680 is a novel, investigational, oral, selective orexin 2 receptor (OX2R) agonist in development as a once-daily treatment for narcolepsy. Orexin neuropeptides are important regulators of the sleep/wake cycle through OX2R activation, and loss of orexinergic neurons in the brain is associated with excessive daytime sleepiness and cataplexy in narcolepsy.5 ALKS 2680 was designed to address the underlying pathology of narcolepsy with the goal of improving duration of wakefulness and providing cataplexy control. Once-daily oral administration of ALKS 2680 was previously evaluated in a phase 1 study in healthy volunteers and people living with narcolepsy type 1, narcolepsy type 2 and idiopathic hypersomnia and is currently being evaluated in the Vibrance-1 phase 2 study in patients with narcolepsy type 1. About the Vibrance-1 Study Vibrance-1 is a phase 2, randomized, double-blind, dose-range-finding study evaluating the safety and efficacy of ALKS 2680 compared to placebo in patients with narcolepsy type 1. More information can be found at (identifier: NCT06358950) and (for U.S. audiences only). About Alkermes plc Alkermes plc 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 and bipolar I disorder, and a pipeline of clinical and preclinical candidates in development for neurological disorders, including narcolepsy. 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 . 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 clinical development activities for, and the potential therapeutic and commercial value of, ALKS 2680 for the treatment of narcolepsy. 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: whether ALKS 2680 could be shown to be ineffective or unsafe; whether preclinical and initial clinical results for ALKS 2680 will be predictive of results of future clinical studies or real-world results; whether future clinical trials or future stages of ongoing clinical trials for ALKS 2680 will be initiated or completed on time or at all; 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, 2023 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 . 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 Nine of 10 participants completed all 4-way randomized crossover periods. One participant withdrew from the study after receiving the initial ALKS 2680 dose due to poor venous access and inability to undergo further blood draws. 2 Patients with NT1 in the phase 1b study had baseline sleep latencies ranging from one to 15 minutes. 3 Krahn LE, Arand DL, Avidan AY, et al. Recommended protocols for the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test in adults: guidance from the American Academy of Sleep Medicine. J Clin Sleep Med. 2021;17(12):2489–2498. 4 Insomnia includes TEAE terms of insomnia and middle insomnia (i.e., difficulty maintaining sleep). 5 Nagahara T, Saitoh T, Kutsumura N, Irukayama-Tomobe Y, Ogawa Y, Kuroda D, Gouda H, Kumagai H, Fujii H, Yanagisawa M, Nagase H. Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists. J Med Chem. 2015 Oct 22;58(20):7931-7. doi: 10.1021/acs.jmedchem.5b00988. Epub 2015 Aug 26. PMID: 26267383. Alkermes Contacts: For Investors: Sandy Coombs, +1 781 609 6377 For Media: Gretchen Murphy, +1 781 609 6419 SOURCE Alkermes plc

– Late-Breaking Abstracts Containing Data From the Full Narcolepsy Type 1 Cohort From the ALKS 2680 Phase 1b Study and Vibrance-1 Phase 2 Study Design Accepted for Poster Presentations – – Findings From In-Depth Qualitative Patient Interviews on the Burden of Narcolepsy Will Also Be Presented – DUBLIN, May 28, 2024 /PRNewswire/ -- Alkermes plc (Nasdaq: ALKS) today announced plans to present three posters related to ALKS 2680 at SLEEP 2024, the 38th annual meeting of the Associated Professional Sleep Societies (APSS), taking place June 1-5, 2024 in Houston. ALKS 2680 is the company's novel, investigational, oral orexin 2 receptor (OX2R) agonist in development as a once-daily treatment for narcolepsy. The company will present two posters during a late-breaking abstract session: Data from the full cohort (n=10)1 of patients with narcolepsy type 1 (NT1) from the phase 1b, proof-of-concept study evaluating single dose oral administration of ALKS 2680. Safety results and pharmacodynamic efficacy assessments evaluating objective (Maintenance of Wakefulness Test [MWT]) and subjective patient-reported (Karolinska Sleepiness Scale [KSS]) measures of sleepiness will be presented. Study design and methods for the Vibrance-1 study, a recently initiated phase 2 clinical trial evaluating the safety and efficacy of ALKS 2680 compared to placebo in patients with NT1. In addition, findings from in-depth, qualitative interviews with patients with NT1 (n=12) and narcolepsy type 2 (NT2) (n=10) will be presented. During the 60-minute interviews, participants described the impact and burden of disease on many facets of their lives, including work and school activities, mental health, activities of daily living and relationships. "We have made significant progress in the ALKS 2680 program in the last year, including generating proof-of-concept data that validated our design hypothesis and enabled us to initiate our Vibrance-1 phase 2 study in patients with narcolepsy type 1," said Craig Hopkinson, M.D., Chief Medical Officer and Executive Vice President, Research & Development at Alkermes. "We are excited to present data from the full narcolepsy type 1 cohort from our phase 1b study and qualitative findings that bring to light new insights from patients that demonstrate the breadth of impacts narcolepsy can have on patients' lives. We look forward to engaging with the sleep community at this important scientific meeting." Details of Alkermes' presentations at SLEEP 2024 are as follows: "Safety and Pharmacodynamic Effects of the Orexin 2 Receptor Agonist ALKS 2680 in Patients with Narcolepsy Type 1: A First-in-Human Phase 1 Study" Abstract ID: 1323 Poster Board Number: 423 Presenter: Ron Grunstein, M.D., Ph.D., Head of Sleep and Circadian Research at the Woolcock Institute of Medical Research Presentation Date: The poster will be presented on Tuesday, June 4, 2024 from 10:00–10:45 a.m. CT, during session P-31. "Vibrance-1: Study Design and Methods for a Phase 2, Randomized, Placebo-Controlled, Parallel Group Study Evaluating the Safety and Efficacy of ALKS 2680 in Patients With Narcolepsy Type 1" Abstract ID: 1363 Poster Board Number: 462 Presenter: David T. Plante, M.D., Ph.D., Associate Professor of Psychiatry at the University of Wisconsin-Madison Presentation Date: The poster will be presented on Tuesday, June 4, 2024 from 11:00–11:45 a.m. CT, during session P-31. "The Burden of Living with Narcolepsy: Patient Perspectives from In-Depth Qualitative Interviews" Abstract ID: 673 Poster Board Number: 302 Presenter: Michael J. Doane, Ph.D., Alkermes Presentation Date: The poster will be presented on Wednesday, June 5, 2024 from 11:00–11:45 a.m. CT, during session P-42. About ALKS 2680 ALKS 2680 is a novel, investigational, oral, selective orexin 2 receptor (OX2R) agonist in development as a once-daily treatment for narcolepsy. Orexin neuropeptides are important regulators of the sleep/wake cycle through OX2R activation, and loss of orexinergic neurons in the brain is associated with excessive daytime sleepiness and cataplexy in narcolepsy.2 ALKS 2680 was designed to address the underlying pathology of narcolepsy with the goal of improving duration of wakefulness and providing cataplexy control. Once-daily oral administration of ALKS 2680 was previously evaluated in a phase 1 study in healthy volunteers and people living with narcolepsy type 1, narcolepsy type 2 and idiopathic hypersomnia and is currently being evaluated in a phase 2 study in patients with narcolepsy type 1. About the Vibrance-1 Study Vibrance-1 is a phase 2, randomized, double-blind, dose-range-finding study evaluating the safety and efficacy of ALKS 2680 compared to placebo in patients with narcolepsy type 1. More information can be found at (identifier: NCT06358950) and (for U.S. audiences only). About Alkermes plc Alkermes plc 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 and bipolar I disorder, and a pipeline of clinical and preclinical candidates in development for neurological disorders, including narcolepsy. 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 . Alkermes Contacts: For Investors: Sandy Coombs, +1 781 609 6377 For Media: Gretchen Murphy, +1 781 609 6419 SOURCE Alkermes plc