Slides
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Kasumi Arakawa Professor of Anesthesiology, Pain, and Perioperative Medicine Director of the FACE Lab University of Kansas Medical Center Joy Chambers-Grundy Professor of Brain Science Chair of the Chambers-Grundy Center for Transformative Neuroscience Clinical Professor of Neurology UNLV Department of Brain Health Clinical Associate Professor of Psychiatry SUNY Upstate Medical University Professor of Psychiatry & Behavioral Neuroscience Chief Research Officer and Director of Psychopharmacology Research at the Lindner Center of Hope University of Cincinnati Professor of Neurology Director of the Sleep-Wake Disorders Center at the Montefiore Medical Center Albert Einstein College of Medicine Vice President at the New England Institute for Neurology Professor of Neurology Geisel School of Medicine at Dartmouth
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Stewart J. Tepper, MD | | | Geisel School of Medicine at Dartmouth Andrea Chadwick, MD, MSc, FASA | | University of Kansas Medical Center Michael Thorpy, MD | | Albert Einstein College of Medicine Herriot Tabuteau, MD | | Axsome
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Chief Executive Officer
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is to develop and deliver transformative medicines for the hundreds of millions of people impacted by central nervous system conditions At Axsome, we are defining the future of clinical practice in brain health
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Obstructive sleep apnea Narcolepsy Migraine Fibromyalgia Shift work disorder Depression Alzheimer’s disease agitation Smoking cessation ADHD Binge eating disorder
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Develop first-in-class or best-in-class medicines Enabled by clinical research and regulatory innovation Deliver novel mechanisms of action Apply precision-based approaches in novel, underserved indications Leverage our deep expertise in neuroscience
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• • • • • •
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• • • • • •
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• • • • • • •
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Major depressive disorder Alzheimer’s disease agitation Smoking cessation ADHD Binge eating disorder MDD with EDS EDS in narcolepsy or OSA Migraine Narcolepsy Fibromyalgia Shift work disorder AXS-05 (dextromethorphan-bupropion) Solriamfetol AXS-12 (reboxetine) AXS-14 (esreboxetine) Solriamfetol
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3 5 6 7 10 >$16B peak sales potential Issued patents extending out to early 2040s >150M patients
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We are defining the future of clinical practice in brain health
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Joy Chambers-Grundy Professor of Brain Science Chair of Chambers-Grundy Center for Transformative Neuroscience Clinical Professor of Neurology UNLV Department of Brain Health
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β
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7M 14M
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Excessive motor activity behaviors • • • • • • • • • • • • • • • • • • • • • • • • • Verbal aggression behaviors Physical aggression behaviors Agitation encompasses three broadly defined symptom domains including both non-aggressive and aggressive behaviors3,4 Mild Moderate-to-severe Severe
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29 203 • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 1 2 3 4 5 6 7 CMAI total score Individual agitated behavior scores Cohen-Mansfield Agitation Inventory (CMAI)
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Accelerated Earlier higher risk Increased Greater Increased Greater Poor Agitation in patients with Alzheimer’s disease is associated with1-3:
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Agitation affects the majority of patients with Alzheimer’s disease and is one of the most troubling and consequential aspects of Alzheimer’s disease for patients and caregivers 1,2 Current pharmacologic treatments are primarily off- label medications: • • Limitations of off-label medications: • • • Only 1 FDA-approved agent, an atypical antipsychotic
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ADVANCE-1 ADVANCE-2 ACCORD-1 ACCORD-2 Phase 2/3 (N=366) Phase 3 (N=408) Phase 3 (N=108) Phase 3 (N=167) Primary endpoint: Primary endpoint: Primary endpoint: Relapse criteria: Primary endpoint: Relapse criteria:
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Rapid and substantial Significantly greater percentage low and similar CMAI total score Week
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-36% -43% -48% -29% -32% -38% Week 2 Week 3 Week 5 CMAI total score
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Number of patients (%) AXS-05 (n=159) Placebo (n=158)
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CMAI total score
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Number of patients (%) AXS-05 (n=82) Placebo (n=84)
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Hazard ratio (95% CI) 0.275 p-value Weeks from randomization Probability of freedom from relapse (%)
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7.5% 25.9% AXS-05 Placebo Patients with agitation relapse (%)
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22% 40% 61% 79% 93% Week 1 Week 2 Week 4 Week 6 Month 2 Percent of responders (CMAI ≥ 30%)
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Number of patients (%) AXS-05 (n=53) Placebo (n=54) Most common TEAEs (≥5% in AXS-05 group)
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Hazard ratio (95% CI) 0.276 p-value Weeks from randomization Probability of freedom from relapse (%)
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8.4% 28.6% AXS-05 Placebo Patients with agitation relapse (%)
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47% 54% 66% 69% 71% 75% Week 1 Week 2 Week 4 Week 6 Month 2 Month 6 Percent of responders (CMAI ≥ 30%)
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13.3% 39.3% AXS-05 Placebo CGI-S Alzheimer’s disease Hazard ratio (95% CI) p-value
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Number of patients (%) AXS-05 (n=82) Placebo (n=84) Most common TEAEs (≥3% in AXS-05 group)
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Number of patients (%) AXS-05 (n=456) Most common TEAEs (≥3%)
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ADVANCE-1 ADVANCE-2 ACCORD-1 ACCORD-2 Phase 2/3 (N=366) Phase 3 (N=408) Phase 3 (N=108) Phase 3 (N=167) Achieved primary endpoint: Primary endpoint: Achieved primary endpoint: Achieved primary endpoint:
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Low discontinuation rate No deaths reported Not associated with common AEs Consistent long-term safety
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Senior Vice President, Medical Affairs
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Substantial health consequences of smoking include increased risk of developing 2: • • • •
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Need for new and effective treatment options: • •
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α β α β α β α α β α β α
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Nicotine infusions per session Dextromethorphan (mg/kg)
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Clinical Associate Professor of Psychiatry SUNY Upstate Medical University
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Adult ADHD is associated with increased risk of developing other psychiatric disorders1 Prevalence of comorbid psychiatric disorders in adults with ADHD2 3x 4x 2x Up to 55% Up to 84% Up to 80% Up to 72%
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• • • • • • • • • • • • 70% 17% 13% Adults 20% 47% 33% Norepinephrine modulators Off-label medicationsAlpha2 agonists • • • • • • • • • • • Dopamine-norepinephrine modulators Limitations of currently available treatment options: Stimulants Non-stimulants 30% Children and adolescents
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LS mean change from baseline (SE)
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CGI-S score LS mean change from baseline
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-18.7 -17.7 -17.1 -16.3 ~16* -15.5 -14.1 -12.5 -10.6 -9.7 Change from baseline in AISRS total score
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• • • •
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39% 41% 45% 32% 38% 33% 31% 27% 33% 35% 23% 26% 25% 27% 12% 9% 10% 9% 12% 8% 4% Percent of patients 33% 52% 49% 36% 53% 35% 32% 25% 40% 40% 27% 34% 26% 26% 8% 13% 9% 9% 20% 10% 6% Percent of patients In a cross-sectional study of 117 MDD patients, sleepiness and impairment in wakefulness and energy were common symptoms in patients who responded to their antidepressant therapy across different self-rated measures1
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Sleepiness symptoms before and after SSRI treatment in patients who responded but did not remit by Week 121 Sleepiness symptoms before and after SSRI treatment in patients who remitted by Week 122 33.6% Persistent, 20.3% Treatment- emergent, 13.1% Percentage of SSRI responders Sleepiness (Hypersomnia) symptoms 33.4% 32.8% Persistent, 14.5% Treatment- emergent, 9.5% Percentage of SSRI responders Sleepiness (Hypersomnia) symptoms 24.0%
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• • • In a cross-sectional study of 252 patients with MDD1: In a cross-sectional study of 70 patients with MDD2:
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-18.8 MADRS total score
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37% 17% 'Very Much Improved' PGI-I score
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Professor of Psychiatry & Behavioral Neuroscience Chief Research Officer and Director of Psychopharmacology Research, Lindner Center of HOPE University of Cincinnati
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Recurrent episodes of binge eating • ▪ ▪ • • ▪ ▪ ▪ ▪ ▪ • • • Associated behaviors and emotional responses Additional characteristics DSM-5 criteria for BED
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28% 44% 12-month Lifetime Percent of patients • • • •
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• •
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Professor of Neurology Director of Sleep-Wake Disorders Center, Montefiore Medical Center Albert Einstein College of Medicine
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• •
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7% 10% 38% 42% 47% 53% Other (daytime) Other (nighttime) Antidepressants Stimulants Oxybates WPAs 15% 16% 21% WPA + Stimulant Oxybate + Stimulant WPA + Oxybate
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of patients reported discontinuing at least one medication due to:
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Disrupted nighttime sleep1 Cataplexy1 Cognitive impairment3 Excessive daytime sleepiness2 Percent of patients with persistent symptoms while on treatment
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Cataplexy is a burden on my day-to-day life Cataplexy burdens my social life Falling down embarrasses me Cataplexy burdens my professional life (e.g. career, school) Suffering from slurred speech embarrasses me
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CONCERT SYMPHONY ENCORE Phase 2 (N=21) Phase 3 (N=90) Phase 3 (OLP N=68; RWP N=42) Primary endpoint: Primary endpoint: Primary endpoint:
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Rate ratio* Weekly cataplexy attacks (median)
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6.5% 24.4% 22.7% 31.0% 33.3% 0.0% 4.5% 11.6% 9.3% 9.5% Percent of remitters
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-1.8 -0.9 CGI-S for EDS score
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0.7 1.6 PlaceboAXS-12 FOSQ-10 Cognitive Function Items
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57.1% 33.3% AXS-12 Placebo Percent of patients 40.5% 16.7% AXS-12 Placebo Percent of patients Patients achieving clinical response for both cataplexy and EDS at Week 51 Patients achieving clinical response for both cataplexy and cognitive function at Week 52
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-1.60 -0.87 CGI-S total score ±
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Weekly cataplexy attacks (median) SYMPHONY ENCORE open-label period All patients treated with AXS-12 in open-label period
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1.32 10.29 Weekly cataplexy attacks
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52.6% 14.3% Placebo AXS-12 NSAQ Ability to Concentrate score
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52.6% 16.7% Placebo AXS-12 PGI-C narcolepsy score
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Kasumi Arakawa Professor of Anesthesiology, Pain, and Perioperative Medicine Director of Fibromyalgia and Centralized Pain Exploration (FACE) Lab University of Kansas Medical Center
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• • • •
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• • • •
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Fatigue Impact on daily life • • • • • • • • Widespread pain
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Fibromyalgia management requires a multidisciplinary and patient-centric approach including both pharmacological and non-pharmacological interventions1,2 Commonly prescribed pharmacological interventions include a wide variety of medications2,3: • • Limitations of current treatments: • • •
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• • • • • • • • • • • • •
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Weekly mean pain score Week Week Week
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-3.9 -7.3 -6.9 -5.7 Week 2 -6.8 -11.9 -11.1 -9.4 Week 6 -7.1 -12.1 -11.2 -8.9 Week 10 FIQ total score -6.2 -13.3 -12.9 -10.1 Week 14
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-0.7 -1.4 -1.3 -1.0 Week 14 -1.1 -1.5 -1.4 -1.1 Week 10 -1.0 -1.3 -1.4 -1.2 Week 6 -0.6 -1.0 -0.9 -0.7 Week 2 mGFI total score
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Weekly mean pain score Week
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FIQ total score
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-0.6 -1.3 Week 8 mGFI total score
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Vice President of the New England Institute for Neurology and Headache Professor of Neurology Geisel School of Medicine at Dartmouth
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Time Course of CGRP, PGE2 in Migraine Concentration Time from migraine onset (hours) Peaks at 2 hours and remains elevated for up to 6 hours CGRP Peaks at 1 hour and tends to decrease with time PGE2
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reduced pain signal transmission reversed vasodilation reduced neuroinflammation central sensitization improves the absorption • •
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Time (hours) PGE2CGRP Mean Meloxicam Concentration (ng/mL) Mean Rizatriptan Concentration (pg/mL)
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N=302 N=1594 N=96
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36.9% 24.4% SYMBRAVO Placebo 43.9% 26.7% SYMBRAVO Placebo Pain freedom at 2 hours MBS freedom at 2 hours 32.6% 16.3% SYMBRAVO Placebo 19.9% 6.7% SYMBRAVO Placebo Percent of patients Percent of patients
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16.1% 11.2% 8.8% 5.3% SYMBRAVO MoSEIC Rizatriptan MoSEIC Meloxicam Placebo Percent of patients 22.7% 12.6% SYMBRAVO Placebo Percent of patients
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43.5% 35.1% 34.7% 23.0% Placebo MoSEIC Meloxicam MoSEIC Rizatriptan SYMBRAVO 42.2% 15.3% Placebo SYMBRAVO Percent of patients Percent of patients
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Pain freedom at 2 hours MBS freedom at 2 hours 17.2% 0.0% SYMBRAVO Placebo 28.6% 11.1% SYMBRAVO Placebo Percent of patients with menstrual migraine 57.1% 33.1% SYMBRAVO Placebo 37.9% 6.3% SYMBRAVO Placebo Percent of patients with menstrual migraine
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Pain freedom at 2 hours MBS freedom at 2 hours 19.0% 6.8% SYMBRAVO Placebo 36.4% 15.7% SYMBRAVO Placebo Percent of patients with morning migraine 40.5% 26.0% SYMBRAVO Placebo 47.3% 25.5% SYMBRAVO Placebo Percent of patients with morning migraine
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Low incidence of adverse events No discontinuations due to adverse events SYMBRAVO was well tolerated in patients with mild, moderate, and severe migraine pain:
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2.8 5.2 Oral CGRP inhibitor treatment period SYMBRAVO treatment period Mean mTOQ-4 total score 1.0% 16.7% 11.5% 26.0% 47.9% 47.9% 51.0% 63.5% 2-hour pain freedom Sustained pain freedom Ability to return to normal activities Ability to plan daily activities Percent of patients 2-hour pain freedoma Sustained pain freedomb Ability to return to normal activitiesc Ability to plan daily activitiesd
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Major depressive disorder Alzheimer’s disease agitation Smoking cessation ADHD Binge eating disorder MDD with EDS EDS in narcolepsy or OSA Migraine Narcolepsy Fibromyalgia Shift work disorder AXS-05 (dextromethorphan-bupropion) Solriamfetol AXS-12 (reboxetine) AXS-14 (esreboxetine) Solriamfetol
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3 5 6 7 10 >$16B peak sales potential >600 issued patents extending out to early 2040s >150M patients
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Thank you Thank you