Slide 1: Important Information About This Document
Table of Contents Important Information About This Document This document includes scientific information about alixorexton (formerly referred to as ALKS 2680) that is intended for investors and should be read in conjunction with the press release issued, and investor presentation displayed, by the
Slide 2: Vibrance-1: Randomized Phase 2 Study of Alixorexton in Narcolepsy Type 1
Giuseppe Plazzi,1 Yves Dauvilliers,2 Ronald R. Grunstein,3 Emmanuel Mignot,4 Gert Jan Lammers,5 David T. Plante,6 Erik Buntinx,7 Rafael del Río Villegas,8 Hailu Chen,9 Alexandra Lovett,9 Craig Hopkinson,9 Bhaskar Rege,9 and Marcus Yountz9 Vibrance-1: A Randomized Phase 2 Study Evaluating Safety and
Slide 3: Financial relationship disclosures
Ineligible companies are those whose primary business is producing, marketing, selling, re-selling, or distributing health care products used by, or on patients. ◻︎ No, I HAVE NOT had a financial relationship with an ineligible company in the past 24 months. ◻︎ Yes, I HAVE had a financial relationsh
Slide 4: Orexin Receptor Agonism: Opportunity for Addressing Central Disorders of Hypersomnolence
Orexin 2 Receptor Agonism: Opportunity for Addressing Central Disorders of Hypersomnolence 1. Krahn LE, et al. Adv Ther. 2022;39(1):221-243. 2. Grunstein R, et al. Poster at SLEEP 2025 Meeting; June 8-11, 2025; Seattle, WA. IH = idiopathic hypersomnia; NT1 = narcolepsy type 1; NT2 = narcolepsy type
Slide 5: Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to Patients With NT1
Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 BC-CCI = British Columbia Cognitive Complaints Inventory; BC-CCI-E = British Columbia Cognitive Complaints Inventory – Expanded; CGI-S = Clinical Global Impression of Severity; ESS = Epwort
Slide 6: Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to Patients With NT1
Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 BC-CCI = British Columbia Cognitive Complaints Inventory; BC-CCI-E = British Columbia Cognitive Complaints Inventory – Expanded; CGI-S = Clinical Global Impression of Severity; ESS = Epwort
Slide 7: Vibrance-1 Phase 2 Study Design
Vibrance-1 Phase 2 Study: 6-Week Double-blind Period Followed by an Open-label Extension Period With Dosing Flexibility Inclusion criteria Exclusion criteria aAll patients in the open-label extension period start with 6 mg alixorexton. Dose adjustment possible (up or down) during the first 2 weeks o
Slide 8: Primary Efficacy and Secondary Endpoints
Primary Efficacy and Secondary Endpoints Were Evaluated at the End of the 6-week Double-blind Treatment Period Weekly cataplexy rate at Week 6a Change in ESS from baseline to Week 6 Primary Endpoint Change in mean sleep latency on the MWT from baseline to Week 6 Key Secondary Endpoints z z TEAEs Vit
Slide 9: Baseline Characteristics and Study Disposition
Vibrance-1 Phase 2 Study: Baseline Characteristics and Study Disposition Alixorexton once daily Placebo (N=23) 4 mg (N=23) 6 mg (N=22) 8 mg (N=24) Total (N=92) Disease Severity Mean Sleep Latency on MWT (minutes), Mean (SD) 2.8 (3.1) 3.3 (3.3) 3.4 (3.2) 2.8 (2.9) 3.1 (3.1) ESS, Mean (SD) 18.7 (2.7)
Slide 10: Most Patients had Severe Disease at Baseline
Most Patients had Severe Disease at Baseline Narcolepsy Severity Scale (NSS) Daytime sleepiness, cataplexy, hallucinations, sleep paralysis, and disturbed nighttime sleep Mild 0-14 Moderate 15-28 Severe 29-42 Very Severe 43-57 Overall Baseline NSS: 31.3 (8.6) Alixorexton once daily Placebo (N=23) 4
Slide 11: Primary Endpoint: Mean Sleep Latency on the MWT
Primary Endpoint: Mean Sleep Latency on the MWT Showed Alixorexton Achieved Normative Wakefulness at All Doses Primary Endpoint Analysis at Week 6 Alixorexton once daily Change from baseline at Week 6 (minutes)a PBO (N=23) 4 mg (N=23) 6 mg (N=22) 8 mg (N=24) LSM -0.6 21.6 23.5 25.5 (95% CI of LSM) (
Slide 12: Key Secondary Endpoint: Epworth Sleepiness Scale
Key Secondary Endpoint: Epworth Sleepiness Scale Showed Alixorexton Achieved Normative Wakefulness at All Doses aANCOVA model. Missing data were imputed using multiple imputation. 1. Johns MW, Sleep 1991; 14: 540-5. ANCOVA = analysis of covariance; CI = confidence interval; ESS = Epworth Sleepiness
Slide 13: Alixorexton Improved ESS Scores Early and Sustained Through Week 13
Alixorexton Improved ESS Scores as Early as Week 2 and Sustained the Effect Through Week 13 aThis snapshot of the open-label extension reflects data as of 1 July 2025 from the 59 patients who had completed the Week 13 visit as of that date. Not all patients had completed the open-label extension at
Slide 14: Key Secondary Endpoint: Weekly Cataplexy Rate at Week 6
Key Secondary Endpoint: WCR at Week 6 Showed Alixorexton Reduced Cataplexy Events Versus Placebo Key Secondary Endpoint Analysis Alixorexton once daily WCR at Week 6a,c PBO (N=23) 4 mg (N=23) 6 mg (N=22) 8 mg (N=24) Mean incidence rate 13.1 6.4 4.0 8.4 (95% CI of incidence rate) (7.5, 22.9) (3.6, 11
Slide 15: Many Patients on Alixorexton Experienced No Cataplexy During Week 6
Many Patients on Alixorexton Experienced No Cataplexy During Week 6 = Alixorexton Achievement of 100% cataplexy reduction during Week 6a aThe minimum number of required cataplexy diaries was 5 days weekly. PBO = placebo.
Slide 16: Alixorexton was Generally Well Tolerated
Alixorexton was Generally Well Tolerated Over 6 Weeks of Treatment aIf a patient had multiple adverse events, the highest severity is presented in summary by severity, and the highest relationship to study drug is presented in summary by relationship. bRelationship of TEAE to the drug as determined
Slide 17: Alixorexton was Generally Well Tolerated: Safety Summary
Alixorexton was Generally Well Tolerated Over 6 Weeks of Treatment Most TEAEs were mild to moderate in severity There were no serious TEAEs reported Most commonly reported TEAEs occurred within the 1st week of dosing Most insomnia events resolved within 1 week Most urinary events (pollakiuria and mi
Slide 18: Conclusions
= Conclusions Once-daily alixorexton: Demonstrated statistically significant, clinically meaningful improvements on the MWT and ESS at Week 6 compared with placebo, achieving a normative wakefulness profile at all doses tested Improvements on the ESS were observed as early as Week 2 and sustained th
Slide 19: Vibrance-1 Demonstrated Clinically Meaningful Improvements on Outcomes Important to Patients With NT1
Vibrance-1 Demonstrated Clinically Meaningful Improvements on Outcomes Important to Patients With NT1 BC-CCI = British Columbia Cognitive Complaints Inventory; BC-CCI-E = British Columbia Cognitive Complaints Inventory – Expanded; CGI-S = Clinical Global Impression of Severity; ESS = Epworth Sleepin
Slide 20: Acknowledgments
Acknowledgments The authors would like to thank: The patients Their families and caregivers Vibrance-1 investigators and their staff Funding provided by Alkermes
Slide 21: Improvement in Severity of Narcolepsy Symptoms and Fatigue With Alixorexton
Yves Dauvilliers,1 Ronald R. Grunstein,2 Emmanuel Mignot,3 Gert Jan Lammers,4 David T. Plante5 Erik Buntinx,6 Rafael del Río Villegas,7 Hailu Chen,8 Craig Hopkinson,8 Bhaskar Rege,8 Marcus Yountz,8 Michael J. Doane,8 and Giuseppe Plazzi9 Improvement in the Severity of Narcolepsy Symptoms and Fatigue
Slide 22: Financial relationship disclosures
Ineligible companies are those whose primary business is producing, marketing, selling, re-selling, or distributing health care products used by, or on patients. ◻︎ No, I HAVE NOT had a financial relationship with an ineligible company in the past 24 months. ◻︎ Yes, I HAVE had a financial relationsh
Slide 23: Effects of Alixorexton on Overall Disease Severity and Fatigue in NT1
Vibrance-1 Examined the Effects of Alixorexton on Overall Disease Severity and Fatigue in Patients With NT1 BC-CCI = British Columbia Cognitive Complaints Inventory; BC-CCI-E = British Columbia Cognitive Complaints Inventory – Expanded; CGI-S = Clinical Global Impression of Severity; ESS = Epworth S
Slide 24: Exploratory Endpoints Evaluated During Double-blind Treatment Period
0 Weeks Optional Open-label Extension 7 Weeks All patients receive alixorexton (adjusted dosinga) Exploratory Endpoints Were Evaluated During the Double-blind Treatment Period of the Vibrance-1 Phase 2 Study 4 mg Alixorexton 6 mg Alixorexton 8 mg Alixorexton Placebo 6-Week Randomized Double-Blind Tr
Slide 25: Narcolepsy Severity Scale for Clinical Trials (NSS-CT)
Narcolepsy Symptoms Excessive daytime sleepiness Cataplexy Hypnagogic/ hypnopompic hallucinations Sleep paralysis Narcolepsy Severity Scale for Clinical Trials (NSS-CT) Measures the Severity and Impact of the Core Symptoms of Narcolepsy 1. Dauvilliers Y, et al. Sleep 2020;43(6):1-11. 2. Dauvilliers
Slide 26: Alixorexton Significantly Improved Narcolepsy Symptom Severity
Alixorexton Significantly Improved Narcolepsy Symptom Severity in Patients With NT1 from Baseline to Week 6 aNSS-CT severity ratings: mild, 0-14; moderate, 15-28; severe, 29-42; very severe, 43-57. CI = confidence interval; LSM = least square means; NSS-CT = Narcolepsy Severity Scale-Clinical Trials
Slide 27: Most Patients on Alixorexton Reported Mild Narcolepsy Severity at Week 6
Most Patients on Alixorexton Reported Mild Narcolepsy Severity at Week 6 Alixorexton Baseline aValues shown within bars are rounded to the nearest whole number and may not sum to 100%. NSS-CT = Narcolepsy Severity Scale-Clinical Trials. Alixorexton Week 6
Slide 28: Clinicians Rated Patients on Alixorexton as Having Less Severe Symptoms on CGI-S
Clinicians Rated Patients on Alixorexton as Having Less Severe Symptoms on CGI-S at Week 6 Compared to Placebo and Baseline Alixorexton Baseline At week 6, all doses were significantly different from placebo (P = 0.0145 at 4 mg, P = 0.0001 at 6 mg, and P = 0.0011 at 8 mg, all nominal). aValues shown
Slide 29: Patients Reported Less Severe Disease on PGI-S at Week 6
Patients on Alixorexton Reported Less Severe Disease on PGI-S at Week 6 Compared to Placebo and Baseline A single-item, patient-reported assessment on the severity of their sleep disorder over the past 7 days on a scale of 0 to 4 PGI-S Sleep Disorder At week 6, the 6 mg and the 8 mg dose were signif
Slide 30: Fatigue Is a Persistent, Severe, and Debilitating Unmet Need in Narcolepsy
Fatigue Is a Persistent, Severe, and Debilitating Unmet Need That Impacts the Lives of Patients With Narcolepsy Most narcolepsy patients experience fatigue, which often persists even with treatment1-3 Fatigue negatively affects patients’ mental health, functional outcomes and overall quality of life
Slide 31: Alixorexton Significantly Reduced PROMIS-Fatigue Scores
Alixorexton Significantly Reduced PROMIS-Fatigue Scores from Baseline to Week 6 in Patients With NT1 Baseline Week 2 Week 4 Week 6 CI = confidence interval; LSM = least square means; PBO = placebo; PROMIS = Patient Reported Outcomes Measurement Information System; SE = standard error. Upper Limit, N
Slide 32: Patients Reported Less Fatigue on PGI-S at Week 6
Patients on Alixorexton Reported Less Fatigue on PGI-S at Week 6 Compared to Placebo and Baseline At week 6, all doses were significantly different from placebo (P = 0.0019 for the 4 mg dose, P = 0.0003 for the 6 mg dose, and P = 0.0005 for the 8 mg dose, all nominal). aValues shown within bars are
Slide 33: Conclusions
Alixorexton demonstrated statistically significant, clinically meaningful improvements on established scales: Clinician- and patient-reported severity of narcolepsy symptoms NSS-CT, PGI-S Sleep Disorder, and CGI-S Patient-reported fatigue PROMIS-Fatigue and PGI-S Fatigue Conclusions Alixorexton is t
Slide 34: Alixorexton May Address Many Clinical Needs of Patients with NT1
Alixorexton May Address Many of the Clinical Needs of Patients with NT1, Including Overall Disease Severity and Fatigue BC-CCI = British Columbia Cognitive Complaints Inventory; BC-CCI-E = British Columbia Cognitive Complaints Inventory – Expanded; CGI-S = Clinical Global Impression of Severity; ESS
Slide 35: Acknowledgments
Acknowledgments The authors would like to thank: The patients Their families and caregivers Vibrance-1 investigators and their staff Funding provided by Alkermes
Slide 36: Improvement in Patient-reported Cognitive Functioning in NT1 With Alixorexton
Giuseppe Plazzi,1 Yves Dauvilliers,2 Ronald R. Grunstein,3 Emmanuel Mignot,4 Gert Jan Lammers,5 David T. Plante,6 Erik Buntinx,7 Rafael del Río Villegas,8 Hailu Chen,9 Craig Hopkinson,9 Bhaskar Rege,9 Marcus Yountz,9 and Michael J. Doane9 Improvement in Patient-reported Cognitive Functioning in Pati
Slide 37: Financial relationship disclosures
Ineligible companies are those whose primary business is producing, marketing, selling, re-selling, or distributing health care products used by, or on patients. ◻︎ No, I HAVE NOT had a financial relationship with an ineligible company in the past 24 months. ◻︎ Yes, I HAVE had a financial relationsh
Slide 38: Effects of Alixorexton on Cognitive Impairment in Patients With NT1
Vibrance-1 Examined the Effects of Alixorexton on Cognitive Impairment in Patients With NT1 BC-CCI = British Columbia Cognitive Complaints Inventory; BC-CCI-E = British Columbia Cognitive Complaints Inventory – Expanded; CGI-S = Clinical Global Impression of Severity; ESS = Epworth Sleepiness Scale;
Slide 39: Cognitive Impairment is Among the Most Common and Disruptive Symptoms in Narcolepsy
Patients Describe Negative Impacts Across: Memory Problem Solving Attention Processing Speed Word Finding Expressing Thoughts Beyond sleepiness and cataplexy, people with narcolepsy frequently report experiencing cognitive impairment and overall “brain fog”1-3 There are negative impacts of cognitive
Slide 40: OX2R Agonism May Enhance Cognition Across Cognitive Circuitry
OX2R Agonism May Enhance Cognition by Activating Receptors Expressed Throughout Cognitive Circuitry 1. Marcus JN, et al. J Comp Neurol. 2001;435(1):6-25. 2. Sakurai T. Nat Rev Neurosci. 2007;8(3):171-181. 3. Alexandre C, et al. Curr Opin Neurobiol. 2013;23(5):752-759. 4. Sarter M, et al. Brain Res R
Slide 41: OX2R Agonism May Enhance Cognition Across Cognitive Circuitry: Attention Pathway
OX2R Agonism May Enhance Cognition by Activating Receptors Expressed Throughout Cognitive Circuitry Orexin pathway Originates in hypothalamus and engages distributed neuronal circuitry Promotes adaptive behavioral responses Attention Pathway Cortical, sensory, and basal ganglia circuitry receives or
Slide 42: Exploratory Cognition Assessments
0 Weeks Optional Open-label Extension 7 Weeks Patients received alixorexton (adjusted dosinga) Exploratory Endpoints Were Evaluated During the Double-blind Treatment Period of the Vibrance-1 Phase 2 Study 4 mg Alixorexton 6 mg Alixorexton 8 mg Alixorexton Placebo 6-Week Randomized Double-Blind Treat
Slide 43: BC-CCI Assesses Severity and Impact of Cognitive Impairment
Cognitive Impairment BC-CCI Assesses the Severity and Impact of Cognitive Impairment From the Patient’s Perspective BC-CCI = British Columbia Cognitive Complaints Inventory. Items include: Forgetfulness/memory problems Poor concentration Trouble expressing thoughts Trouble finding the right word Slo
Slide 44: Alixorexton Significantly Reduced Severity of Cognitive Impairment on the BC-CCI
Baseline Week 2 Week 4 Week 6 Alixorexton Significantly Reduced Severity of Cognitive Impairment on the BC-CCI From Baseline to Week 6 BC-CCI = British Columbia Cognitive Complaints Inventory; CI = confidence interval; LSM = least squares means; PBO = placebo; SD = standard deviation; SE = standard
Slide 45: Most Patients Reported No or Minimal Cognitive Impairment on the BC-CCI at Week 6
Most Patients on Alixorexton Reported No or Minimal Cognitive Impairment on the BC-CCI at Week 6 Alixorexton Baseline Alixorexton Week 6 aValues shown within bars are rounded to the nearest whole number and may not sum to 100%. BC-CCI = British Columbia Cognitive Complaints Inventory.
Slide 46: BC-CCI Expanded Assesses Severity and Impact of Cognitive Impairment
BC-CCI Assesses the Severity and Impact of Cognitive Impairment From the Patient’s Perspective Items include: Forgetfulness/memory problems Poor concentration Trouble expressing thoughts Trouble finding the right word Slow thinking speed Trouble figuring things out or solving problems Perceived Seve
Slide 47: Alixorexton Significantly Reduced the Impact of Cognitive Impairment
Alixorexton Significantly Reduced the Impact of Cognitive Impairment on NT1 Patients From Baseline to Week 6 Baseline Week 2 Week 4 Week 6 Change from baseline at Week 6 (Exploratory endpoint) Alixorexton once daily PBO (N=23) 4 mg (N=23) 6 mg (N=22) 8 mg (N=24) Baseline, mean (SD) 5.6 (2.5) 5.3 (2.
Slide 48: PGI-S Cognition at Week 6
PGI-S Cognition Most Patients Treated with Alixorexton Reported Mild or No Cognitive Impairment on PGI-S Cognition at Week 6 At week 6, all doses of alixorexton were significantly different from placebo (P = 0.0015 for the 4 mg dose, P = 0.0004 for the 6 mg dose, and P < 0.0001 for the 8 mg dose, al
Slide 49: Conclusions
Conclusions Alixorexton demonstrated statistically significant and clinically meaningful improvements from baseline on established measures evaluating the severity and impact of cognitive impairment in patients with NT1 BC-CCI: improvements observed on overall patient-reported outcome measure encomp
Slide 50: Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to Patients With NT1
Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 BC-CCI = British Columbia Cognitive Complaints Inventory; BC-CCI-E = British C
Slide 51: Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to Patients With NT1
Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Statistically significant, clinically meaningful improvements compared to plac
Slide 52: Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to Patients With NT1
Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Statistically significant, clinically meaningful improvements compared to plac
Slide 53: Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to Patients With NT1
Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Statistically significant, clinically meaningful improvements compared to plac
Slide 54: Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to Patients With NT1
Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Statistically significant, clinically meaningful improvements compared to plac
Slide 55: Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to Patients With NT1
Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Statistically significant, clinically meaningful improvements compared to plac
Slide 56: Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to Patients With NT1
Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Vibrance-1 Examined the Effects of Alixorexton on Measures Relevant to the Clinical Needs of Patients With NT1 Statistically significant, clinically meaningful reduction in patient-reported
Slide 57: Once-daily Alixorexton Is Being Evaluated in NT1, NT2, and IH
Once-daily Alixorexton Is Being Evaluated in NT1, NT2, and IH 1. Alkermes, Inc. NCT06358950 (Vibrance-1). https://clinicaltrials.gov/study/NCT06358950. 2. Alkermes, Inc. NCT06555783 (Vibrance-2). https://www.clinicaltrials.gov/study/NCT06555783. 3. Alkermes, Inc. NCT06843590 (Vibrance-3). https://cl
Slide 58: Acknowledgments
Acknowledgments The authors would like to thank: The patients Their families and caregivers Vibrance-1 investigators and their staff Funding provided by Alkermes