Slide 1: Alkermes Orexin Portfolio Strategy Review
Alkermes Orexin Portfolio Strategy Review October 9, 2024
Slide 2: Forward-Looking Statements
Forward-Looking Statements Note Regarding Forward-Looking Statements Certain statements set forth in this presentation 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:
Slide 3: Alkermes Orexin Portfolio Strategy Session
Alkermes Orexin Portfolio Strategy Session Craig Hopkinson, M.D. Executive Vice President & Chief Medical Officer © 2024 Alkermes. All rights reserved.
Slide 4: Alkermes Orexin Portfolio Strategy: Data-driven Progression
Alkermes Orexin Portfolio Strategy: Data-driven Progression Orexin 2 Receptor Pathway Central Disorders of Project Saturn Hypersomnolence Expansion Program Regulator of the sleep/wake cycle • Narcolepsy type 1 Exploring conditions • Narcolepsy type 2 characterized Downstream by fatigue, cognition, a
Slide 5: Today's Agenda
Today’s Agenda Advanced Molecular Design Principles to ALKS 2680 Dose Selection and Harness Orexin Mechanism Orexin Portfolio Expansion Strategy Brian Raymer, Ph.D. Bhaskar Rege, Ph.D. Exec. Director, Project Leadership & Strategy SVP, Pharmaceutical and Early Stage Development ALKS 2680: Differenti
Slide 6: Advanced Molecular Design Principles to Harness the Potential of the Orexin Mechanism
Advanced Molecular Design Principles to Harness the Potential of the Orexin Mechanism Brian Raymer, Ph.D. Executive Director, Project Leadership and Strategy © 2024 Alkermes. All rights reserved.
Slide 7: Utilizing Advanced Molecular Design Principles to Harness the Broad Potential of the Orexin Mechanism
Utilizing Advanced Molecular Design Principles to Harness the Broad Potential of the Orexin Mechanism • Orexins, also known as hypocretins, are neuropeptides produced in the hypothalamus • Based on orexin’s role in regulating the sleep-wake cycle, initial drug development for the orexin 2 receptor
Slide 8: Orexin Receptor Pathways and Neurotransmission
Orexin 2 Receptor Pathways and Neurotransmission • Orexin neurons project from the Cortex hypothalamus into multiple brain regions and modulate an array of downstream neurotransmitters Sensory Processing • These neurons exert central control of wakefulness PFC Cg • Pathways modulated by orexin may T
Slide 9: Orexin Receptor (OX2R) is a Transmembrane G-Protein Coupled Receptor
Orexin 2 Receptor (OX2R) is a Transmembrane G-Protein Coupled Receptor Stimulated by Orexin Peptides Inactive OX2R Orexin-B (Fragment) Derived from PDB ID: 5WQC Crystal structure of 9aa orexin B fragment bound to OX2R 9 © 2024 Alkermes. All rights reserved.
Slide 10: Orexin Receptor Does Not Signal Downstream in the Inactive State
Orexin 2 Receptor Does Not Signal Downstream in the Inactive State Inactive OX2R Derived from PDB ID: 5WQC 10 © 2024 Alkermes. All rights reserved.
Slide 11: Orexin Peptides Activate the Receptor and Initiate a Broad Signaling Cascade
Orexin Peptides Activate the Receptor and Initiate a Broad Signaling Cascade Active OX2R • In the active state, receptor signaling is “on" ‒ Downstream cellular (neuron) signaling and neurotransmitter release facilitated by movement of transmembrane regions and release of G proteins activation Cryst
Slide 12: Understanding the Peptide Interaction is Key to Replicating Activation
Understanding the Peptide Interaction is Key to Replicating Activation With a Small Molecule Key Activator Interactions Active OX2R Hydrophobic interactions Hydrogen F227 bond Q134 Q134 Y317 H350 movement activation activation 12 © 2024 Alkermes. All rights reserved.
Slide 13: Numerous Challenges in Replicating the Orexin Peptide in a Small Molecule
Numerous Challenges in Replicating the Orexin Peptide in a Small Molecule Balancing complex Potency Selectivity and often competing critical variables is key to designing small Metabolic profile Oral bioavailability molecule orexin 2 receptor agonists Pharmacokinetic Brain penetration profile 13 © 2
Slide 14: Pharmacokinetic Profile Impacts Key Safety and Efficacy Features
Pharmacokinetic (PK) Profile Impacts Key Safety and Efficacy Features PK objective: • Mimic natural sleep/wake cycle with once-daily, Plasma/Brain Concentration oral dosing • High potency to allow for low overall doses and exposures Efficacious Concentration First Indication (NT1) Time For illustrat
Slide 15: Magnitude and Duration of Pharmacodynamic Effect Determined by PK Profile
Magnitude and Duration of Pharmacodynamic Effect Determined by Pharmacokinetic Profile PK objective: • Dose-dependent, proportional increase in Plasma/Brain Concentration AUC with lower-than- proportional increase in Cmax Efficacious Concentration First Indication (NT1) Duration at Dose A Duration a
Slide 16: Efficacious Concentrations and Required Doses May Differ by Indication
Efficacious Concentrations and Required Doses May Differ by Indication Tolerability Limit PK objective: • Dosing flexibility to accommodate NT1, NT2 Plasma/Brain Concentration and IH as well as variability in patient profiles Efficacious Concentration Other Indications (NT2/IH) • Wide therapeutic wi
Slide 17: ALKS 2680 Design Reflects Key Pharmacokinetic Features
ALKS 2680 Design Reflects Key Pharmacokinetic Features Tolerability Limit ALKS 2680 design objective • Mimic natural sleep/wake cycle Plasma/Brain Concentration with once-daily, oral dosing Efficacious • High potency to allow for low Concentration Other overall doses and exposures Indications (NT2/I
Slide 18: Utilizing Advanced Molecular Design Principles to Harness the Broad Potential of the Orexin Mechanism
Utilizing Advanced Molecular Design Principles to Harness the Broad Potential of the Orexin Mechanism • Orexin neuropeptides are key regulators of wakefulness and work in a diurnal manner • In addition to wakefulness, the orexin pathway may benefit additional symptomatic domains such as fatigue, moo
Slide 19: ALKS 2680: Differentiated Orexin Receptor Agonist Advancing in Phase 2 in NT1, NT2 and IH
ALKS 2680: Differentiated Orexin 2 Receptor Agonist Advancing in Phase 2 in NT1, NT2 and IH Julie Himes, M.D. Senior Vice President, Clinical Development NT1: Narcolepsy type 1; NT2: Narcolepsy type 2; IH: Idiopathic hypersomnia © 2024 Alkermes. All rights reserved.
Slide 20: Symptom Commonality Across Sleep Disorders Results in Diagnostic Challenges
Symptom Commonality Across Sleep Disorders Results in Diagnostic Challenges Common Symptoms in Narcolepsy Type 1, Narcolepsy Type 2 and Idiopathic Hypersomnia Symptoms NT1 NT2 IH Excessive daytime sleepiness (EDS) Sleep-onset REM periods (SOREMP) Cataplexy Disrupted nighttime sleep Needed naps: shor
Slide 21: ALKS 2680: Investigational Oral Orexin Receptor Agonist
ALKS 2680: Investigational Oral Orexin 2 Receptor Agonist for the Treatment of Narcolepsy and Idiopathic Hypersomnia 2024 Clinical Program Status ALKS 2680 is a highly potent, selective OX2R agonist • ≥10-fold more potent than orexin Aa • Phase 1 single ascending dose and multiple ascending dose stu
Slide 22: Phase 1b: Randomized, Double-Blind, PBO-Controlled Study of ALKS 2680
Phase 1b: Randomized, Double-Blind, PBO-Controlled Study of ALKS 2680 in Patients With NT1, NT2 and IH Provides Proof-of-Concept ≥14-day Assessment washout (Days -2 to 9) Placebo ALKS 2680 ALKS 2680 ALKS 2680 Patient 1:1:1:1 Safety screening ALKS 2680 Placebo ALKS 2680 ALKS 2680 follow-up Baseline a
Slide 23: Phase 1b: ALKS 2680 Generally Well-Tolerated at all Doses Tested
Phase 1b: ALKS 2680 Generally Well-Tolerated at all Doses Tested in NT1, NT2 and IH • Most TEAEs were mild in severity and transient • No deaths, serious TEAEs, severe TEAEs, or TEAEs leading to discontinuation • Treatment-related TEAEs* reported in >1 subject in each population listed below: ◦ NT1
Slide 24: Phase 1b: Meaningful, Consistent and Dose-Dependent Effect on Wakefulness
Phase 1b: Results Demonstrated Meaningful, Consistent and Dose-Dependent Effect on Wakefulness in NT1, NT2 & IH Patients Absolute Mean Sleep Latency on Maintenance of Wakefulness Test (MWT) - Mean SE Narcolepsy Type 1 (n = 10) Narcolepsy Type 2 (n = 9) Idiopathic Hypersomnia (n = 8) 40 30 Minutes
Slide 25: Phase 1b: Patient Data Support Advancement and Dose Selection in Phase 2
Phase 1b: ALKS 2680 Patient Data Support Advancement and Dose Selection in Phase 2 in NT1, NT2 and IH • Tested a range of doses to explore dose response for each patient population • Generally safe and well tolerated with no treatment related discontinuations • Statistically significant and clinical
Slide 26: Phase 2 Clinical Program Evaluating Once-Daily Administration of ALKS 2680
Phase 2 Clinical Program Evaluating Once-Daily Administration of ALKS 2680 Across a Range of Patient Populations Double-blind treatment ALKS 2680 dose 1 Randomization ALKS 2680 dose 2 Initial Safety Washout Open-label extension screening follow-up ALKS 2680 dose 3 With dose adjustment option Placebo
Slide 27: Phase 2 Clinical Program Evaluating Once-Daily Administration of ALKS 2680
Phase 2 Clinical Program Evaluating Once-Daily Administration of ALKS 2680 Across a Range of Patient Populations Double-blind treatment ALKS 2680 dose 1 Randomization ALKS 2680 dose 2 Initial Safety Washout Open-label extension screening follow-up ALKS 2680 dose 3 With dose adjustment option Placebo
Slide 28: Evaluating the Impact of ALKS 2680 on Symptoms and Outcomes Important to Patients
Evaluating the Impact of ALKS 2680 on Symptoms and Outcomes Important to Patients in Phase 2 Impact on excessive daytime sleepiness Productivity at work Frequency, location and impact of Difficulty driving, being active cataplexy (NT1 only) Impact on self-care and usual activities Hallmark Symptoms
Slide 29: Phase 1 Data Support Rapid Advancement of ALKS 2680 Into Phase 2
Phase 1 Data Support Rapid Advancement of ALKS 2680 Into Phase 2 in Multiple Indications Patient data underscore unique Executing comprehensive profile of ALKS 2680 clinical program • Clinically meaningful, statistically significant and dose- • Advancing phase 2 program: dependent effect on wakefuln
Slide 30: Narcolepsy and Idiopathic Hypersomnia: Insights into Prevalence and Patient Experiences
Narcolepsy and Idiopathic Hypersomnia: Insights into Prevalence and Patient Experiences Charlie Pak, Ph.D. Vice President, New Product Planning © 2024 Alkermes. All rights reserved.
Slide 31: Narcolepsy and IH Prevalence
Narcolepsy and IH Prevalence
Slide 32: Narcolepsy and IH Affect People Around the World
Narcolepsy and IH Affect People Around the World Narcolepsy (Types 1 & 2) and Idiopathic Hypersomnia (IH) affect people around the world 32 © 2024 Alkermes. All rights reserved.
Slide 33: Narcolepsy and Idiopathic Hypersomnia in the U.S.
Narcolepsy and Idiopathic Hypersomnia in the U.S. Narcolepsy prevalence 200,000a 100,000b diagnosed Idiopathic Hypersomnia 40,000 diagnosedc aNarcolepsy Network Fast Facts bCohen et al., Sleep Med 43:14 (2018) and Longstreth et al., Sleep Med 10:422 (2009) prevalence rates applied to U.S. population
Slide 34: Recent Data Show Shift Toward Higher Prevalence of Narcolepsy Type 2 vs. Type 1
Recent Literature and Data Demonstrate Shift Toward Higher Prevalence of Narcolepsy Type 2 vs. Type 1 2002 2009 2018 2023 Silber et al. Longstreth et al. Cohen et al. Ohayon et al. Sleepa Sleep Medicineb Sleep Medicinec Sleep Medicined 2019 2024 Sheer et al. Alkermes Sleepe claims data on file NT1:N
Slide 35: Approved Narcolepsy Treatments Generate Net Sales > $2.5B in the U.S.
Approved Narcolepsy Treatments Generate Net Sales > $2.5B in the U.S. Narcolepsy Drug Sales in U.S. $3,000 FDA-Approved Medicines (ar)modafinil (ar)modafinil $2,500 WAKIX® (pitolisant) $2,000 Annual Sales ($M) SUNOSI® (solriamfetol) $1,500 LUMRYZ™ (sodium oxybate) ER $1,000 XYWAV® (Ca, Mg, Na, K oxy
Slide 36: Patient Experiences
Patient Experiences
Slide 37: High Unmet Patient Need Remains Despite Available Treatments
High Unmet Patient Need Remains Despite Available Treatments A recent survey was conducted in the United States with the aim of sharing patients’ perspectives on the treatment of narcolepsy with the US Food and Drug Administration (FDA). It included over 1,000 people with narcolepsy…95% of responder
Slide 38: Patients Adapt Lifestyle By Prioritizing Where and When Energy is Exerted
Patients Adapt Lifestyle By Prioritizing Where and When Energy is Exerted Maslow’s Hierarchy of Needsa Self-Actualization: Desire to become the most that one can be People living with narcolepsy and IH focus energy toward basic life Esteem: Respect, self-esteem, status, recognition, necessities and
Slide 39: Narcolepsy and IH Symptoms May Impact Many Facets of Life
Narcolepsy and IH Symptoms May Impact Many Facets of Life Career/job choices Academic pursuits Living situations Social engagements, friendships, romantic relationships Ability to be a caregiver Daily accommodations: Naps, coffee, etc. Source: Qualitative primary market research studies with narcole
Slide 40: Narcolepsy and IH Symptoms Can Severely Impact Daily Activities
Narcolepsy and IH Symptoms Can Severely Impact Daily Activities • Car accident “I was at work one day, and I fell asleep holding a piece of industrial glass Safety • Mishandling / dropping heavy items and I dropped it and it almost cut my artery in my neck.” – NT1 patient • Losing focus while watchi
Slide 41: Patients Identify Multiple Areas of Unmet Needs Despite Current Therapies
Patients Identify Multiple Areas of Unmet Needs Despite Current Therapies Symptom control Disease modifying Non-stimulant “I would be alert and… I wouldn’t “I wish there was an option for my sleep “On stimulants, I'm fearful that I am hurting constantly feel like I need to take a nap, disorder that
Slide 42: Patient Needs Integrated into Development Strategy
Patient Needs Integrated into Development Strategy Science Clinical / Clinical Trial Treatment Regulatory Design Patient Insights 42 © 2024 Alkermes. All rights reserved.
Slide 43: Data-Driven Decision Making: ALKS 2680 Dose Selection and Orexin Portfolio Expansion Strategy
Data-Driven Decision Making: ALKS 2680 Dose Selection and Orexin Portfolio Expansion Strategy Bhaskar Rege, Ph.D. Senior Vice President, Pharmaceutical and Early-Stage Development © 2024 Alkermes. All rights reserved.
Slide 44: Alkermes' Data-Driven Approach to Decision Making Across Our Orexin Portfolio
Alkermes’ Data-Driven Approach to Decision Making Across Our Orexin Portfolio Data-Driven ALKS 2680 phase 2 Decision clinical dose selection Making Project Saturn: Orexin Portfolio Expansion Strategy 44 © 2024 Alkermes. All rights reserved.
Slide 45: Synthesis of Multiple Data Inputs Improves Clinical Decision Making
Synthesis of Multiple Data Inputs Improves Clinical Decision Making Pharmaco- Experimental Integrated Data Statistical Decision Studies Analysis Models 45 © 2024 Alkermes. All rights reserved.
Slide 46: Preclinical: Integrated Analysis for Translatable Data and Phase 1 Dose Selection
Preclinical: Integrated Analysis Designed to Deliver Highly Translatable Data and Enable Efficient Phase 1 Dose Selection Pharmaco- Experimental Integrated Data Statistical Decision Studies Analysis Models DTA model Wakefulness Exposure Predicted human Preclinical qEEG qEEG Dose selection: response
Slide 47: Clinical: Data Intensive Phase 1 Program Designed to Deliver Early POC
Clinical: Data Intensive Phase 1 Program Designed to Efficiently Deliver Early POC in Patients and Inform Phase 2 Dose Selection Pharmaco- Experimental Integrated Data Statistical Decision Studies Analysis Models Phase 0 SDHV, NT1, NT2 MWT, study feasibility Population PK Phase 1 SAD qEEG, PK & Safe
Slide 48: Model Outputs Enable Data-Driven Dose Selection
Model Outputs Enable Data-Driven Dose Selection Simulated Population-Based Probability Estimates to Achieve Target Profile by Dose 100% 1.0 Efficacy Target Probability 0% 0.0 0 2 4 6 8 10 12 14 16 18 For illustrative purposes only. Does not represent actual data. Dose 48 © 2024 Alkermes. All rights
Slide 49: Model Outputs Enable Data-Driven Dose Selection
Model Outputs Enable Data-Driven Dose Selection Simulated Population-Based Probability Estimates to Achieve Target Profile by Dose Phase 2 Dose Range 100% 1.0 Phase 2 Dose Efficacy Selection Objective Target • Maximize probability of achievingprobability Maximize efficacy target ofwhile minimizing a
Slide 50: Project Saturn: Opportunity to Apply Orexin Mechanism Across Neurology and Psychiatry
Project Saturn: Opportunity to Apply Orexin Mechanism Across a Range of Indications in Neurology and Psychiatry Orexin 2 Receptor Agonism Direct Orexin Pharmacology Expanded Orexin Polypharmacology Disorders with known Disease areas which Disease areas where the orexin mechanism in orexin deficits c
Slide 51: Orexin Receptor Pathways and Neurotransmission
Orexin 2 Receptor Pathways and Neurotransmission • Orexin neurons project from the Cortex hypothalamus into multiple brain regions and modulate an array of downstream neurotransmitters Sensory Processing • These neurons exert central control of wakefulness PFC Cg • Pathways modulated by orexin may T
Slide 52: Basic Anatomy and Neurocircuitry in Preclinical Models Similar to Humans
Basic Anatomy and Neurocircuitry in Preclinical Models Similar to Humans Cg mPFC DR NB CeA VTA LC PIR Acb ARH TMN Rat brain mPFC: medial prefrontal cortex; Cg: cingulate gyrus; Acb: nucleus accumbens; NB: nucleus basalis of Meynert; ARH: arcuate nucleus of the hypothalamus; CeA: central nucleus of t
Slide 53: Alkermes OX2R Molecules Dose-Dependently Engaged Circuits
Alkermes OX2R Molecules Dose-Dependently Engaged Circuits Associated With Wakefulness, Fatigue, Mood & Cognition/Attention Cg **** **** mPFC DR **** **** **** **** NB ** **** CeA VTA LC PIR ** **** Acb **** **** **** **** **** **** ARH TMN **** **** **** **** Percent Change in Brain Region Rat brain
Slide 54: Neurocircuitry Activated by Alkermes OX2R Agonist Increased Key Neurotransmitters
Neurocircuitry Activated by Alkermes OX2R Agonist Increased Key Neurotransmitters Neurotransmitter Profile Following Acute, Oral Dosing of ALKS OX2R Agonist (Vehicle Subtracted) 100% 80% * mPFC **** **** 60% * * 40% Acb *** **** **** 20% * 0% Prefrontal Cortex Nucleus Accumbens Percent Change in Bra
Slide 55: Orexin Receptor Agonist Pathway May Have Potential Applicability in Broad Range of Indications
Orexin 2 Receptor Agonist Pathway May Have Potential Applicability in Broad Range of Indications Select disease states which intersect across aspects of wakefulness, fatigue, mood and cognition Neurology • Attention-deficit/hyperactivity disorder • Multiple sclerosis fatigue • Parkinson’s disease Ps
Slide 56: Advancing Multiple Orexin Development Candidates
Advancing Multiple Orexin Development Candidates With Unique Opportunities for Treatment of Neurology & Psychiatry Disorders Next Planned Discovery Preclinical Phase 1 Phase 2 Phase 3 Milestone ALKS 2680 Narcolepsy Type 1 Phase 2 data H2 2025 Narcolepsy Type 2 Phase 2 data H2 2025 Idiopathic Hyperso
Slide 57: Executing a Rigorous Development Plan to Evaluate Potential Opportunities
Executing a Rigorous Development Plan to Evaluate Potential Opportunities Assessment of Brain Wave Activity Measure of Neurotransmitters • Translational measure of • Quantitative measure of pharmacological engagement pharmacological additivity, synergy • Gold standard for assessing sleep- or interf
Slide 58: Multidimensional, Translational Preclinical Research to Identify New Clinical Opportunities
Utilizing Multidimensional, Translational Preclinical Research to Identify New Clinical Opportunities for Orexin 2 Receptor Agonists Julie Brooks, Ph.D. Director, CNS Disorders © 2024 Alkermes. All rights reserved.
Slide 59: Executing a Rigorous Development Plan to Evaluate Potential Opportunities
Executing a Rigorous Development Plan to Evaluate Potential Opportunities Assessment of Brain Wave Activity Measure of Neurotransmitters • Translational measure of • Quantitative measure of pharmacological engagement pharmacological additivity, synergy • Gold standard for assessing sleep- or interf
Slide 60: Preclinical Pharmacology Strategy in Mood and Stress Disorders
Preclinical Pharmacology Strategy in Mood and Stress Disorders Measures of Cortical Serotonin • Measurement of prefrontal cortical serotonin neurotransmission to assess impact of pharmacological interventions • Deficits in prefrontal cortical serotonin Microdialysis neurotransmission contribute to s
Slide 61: Chronic Social Defeat Model Induces Robust Depressive-like Phenotype
Chronic Social Defeat Model Induces Robust Depressive-like Phenotype Chronic Social Defeat Stress Social Preference (SP) Test (repeated across 10 days) Consistently induces enduring physiological and behavioral Reliably measures social interaction by calculating time phenotypes similar to depression
Slide 62: Chronic Social Defeat Model Approximates Individual Variability in Stress Response
Chronic Social Defeat Model Approximates Individual Variability in Stress Response Observed in Humans Exposure to chronic social defeat leads to two types of Social preference score (%) 400 behavioral responses in the social preference test: Resilient Behavior 300 Resilient mice maintain social inte
Slide 63: Susceptible Mice Received Therapeutic Intervention and Were Assessed
Susceptible Mice Received Therapeutic Intervention and Were Assessed for Restoration of Resilient Behavior Baseline Post Dosing Chronic Social Defeat Stress (10 days) SP Test Treatment Period (14 days) SP Test • Ketamine: single dose on day 1 • Fluoxetine: daily dosing for 14 days • ALKS orexin 2 re
Slide 64: Clinically Efficacious Antidepressants Demonstrated Effect in Susceptible Mice
Clinically Efficacious Antidepressants Demonstrated Effect in Susceptible Mice Social Preference Performance in Susceptible Mice *** Social preference score (%) 300 Social Preference Assay demonstrated sensitivity to ** FDA-approved agents with different mechanisms: * * 200 • Fluoxetine: FDA-approve
Slide 65: Orexin Receptor Agonist Exhibited Antidepressant-like Effects
Orexin 2 Receptor Agonist Exhibited Antidepressant-like Effects in Chronic Social Defeat Model Social Preference Performance in Susceptible Mice *** Social preference score (%) 300 Social Preference Assay demonstrated sensitivity to ** FDA-approved agents with different mechanisms: * * 200 • Fluoxet
Slide 66: Microdialysis Enables Quantitative Measurement of Prefrontal Cortical Serotonin
Microdialysis Enables Quantitative Measurement of Prefrontal Cortical Serotonin Illustration of Cortical Microdialysis • Deficits in serotonin neurotransmission contribute to symptoms of depression • Many treatments for mood disorders restore serotonin neurotransmission • Symptom domains of interest
Slide 67: SSRI Significantly Elevated Prefrontal Cortical Serotonin
SSRI Significantly Elevated Prefrontal Cortical Serotonin Prefrontal Cortical Serotonin *** • Acute administration of SSRI 350 significantly elevated prefrontal 300 cortical serotonin 250 % Baseline 200 150 100 50 0 -90 -60 -30 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Dosing Time (min) Veh
Slide 68: Orexin Receptor Agonist Enhanced SSRI-induced Increase in Prefrontal Cortical Serotonin
Orexin 2 Receptor Agonist Enhanced SSRI-induced Increase in Prefrontal Cortical Serotonin Prefrontal Cortical Serotonin **** *** • Acute administration of SSRI 350 significantly elevated prefrontal 300 cortical serotonin 250 % Baseline 200 • Co-administration of Alkermes 150 orexin 2 receptor agonis
Slide 69: Mood and Stress Data Summary
Mood and Stress Data Summary Preclinical models with strong predictive validity provide translational value and enable decision making Monotherapy: • Chronic Social Defeat Model data suggested antidepressant-like effects of orexin 2 receptor agonist Polypharmacology: • Early evidence that co-adminis
Slide 70: Preclinical Pharmacology Strategy in Attention and Impulsivity Disorders
Preclinical Pharmacology Strategy in Attention and Impulsivity Disorders Measures of Cortical Acetylcholine • Measurement of cortical acetylcholine neurotransmission to assess impact of pharmacological interventions • Acetylcholine neurotransmission plays a key role in information processing, Microd
Slide 71: 5-Choice Serial Reaction Time Task Measures Impulsivity and Attention
5-Choice Serial Reaction Time Task Measures Impulsivity and Attention in Translational Model Task Trial Phases and Potential Outcomes Measure of Impulse Control Premature nose-poke responses: Based on number of instances subject fails to withhold response until after light stimulus is presented Meas
Slide 72: Shortened Intertrial Time Impairs Attentional Task Performance in Subgroup of Rats
Shortened Intertrial Time Increases Task Cadence Leading to Impaired Attentional Task Performance in a Subgroup of Rats Short Intertrial Time • Shortening the 5-Choice Serial Reaction 120 Time Task intertrial time decreases High Performers Total Trials Completed attentional performance and task 100
Slide 73: Orexin Receptor Agonist Improved Task Engagement in Low Performer Rats
Orexin 2 Receptor Agonist Improved Task Engagement in Low Performer Rats Low Performer Rats in the 5-Choice Serial Reaction Time Task • Alkermes orexin 2 receptor agonist 120 significantly increased the number of trials Total Trials Completed * completed by low performer rats under 100 Vehicle the s
Slide 74: Improved Task Performance Maintained When Combined With Non-stimulant Treatment
Improved Task Performance Following Orexin 2 Receptor Activation was Maintained When Combined With Non-stimulant Treatment Low Performer Rats in the 5-Choice Serial Reaction Time Task • Alkermes orexin 2 receptor agonist 120 significantly increased the number of trials Total Trials Completed * compl
Slide 75: 5-Choice Serial Reaction Time Task Measures Impulsivity and Attention
5-Choice Serial Reaction Time Task Measures Impulsivity and Attention in Translational Model Task Trial Phases and Potential Outcomes Measure of Impulse Control Premature nose-poke responses: Based on number of instances subject fails to withhold response until after light stimulus is presented Meas
Slide 76: Long Intertrial Time Increases Impulsivity in a Subgroup of Rats
Long Intertrial Time Slows Task Cadence Leading to Increased Impulsivity in a Subgroup of Rats Long Intertrial Time • Extending the 5-Choice Serial Reaction 100 High Impulsive Time Task intertrial time leads to an Premature Responses (#) Low Impulsive increase in impulsivity in a subset of rats 80 (
Slide 77: Orexin Receptor Agonist Decreased Impulsivity in High Impulsive Rats
Orexin 2 Receptor Agonist Decreased Impulsivity in High Impulsive Rats High Impulsive Rats in 5-Choice Serial Reaction Time Task • Alkermes orexin 2 receptor agonist 100 Vehicle significantly lowered the number of Premature Responses (#) OX2R impulsive premature responses made 80 by high impulsive r
Slide 78: Orexin Agonist Maintained Impulse Control Efficacy of Non-stimulant Treatment
Orexin 2 Receptor Agonist Maintained Impulse Control Efficacy of Non-stimulant Treatment in High Impulsive Rats High Impulsive Rats in 5-Choice Serial Reaction Time Task • ADHD non-stimulant treatment 100 Vehicle significantly lowered the number of Premature Responses (#) OX2R impulsive premature re
Slide 79: Microdialysis Enables Quantitative Measurement of Prefrontal Cortical Acetylcholine
Microdialysis Enables Quantitative Measurement of Prefrontal Cortical Acetylcholine Illustration of Cortical Microdialysis • Acetylcholine neurotransmission plays a key role in information processing, attention and arousal • Enhancing acetylcholine neurotransmission contributes to effective attenti
Slide 80: Orexin Receptor Agonist Significantly Increased Prefrontal Cortical Acetylcholine Release
Orexin 2 Receptor Agonist Significantly Increased Prefrontal Cortical Acetylcholine Release Prefrontal Cortical Acetylcholine *** • Alkermes orexin 2 receptor agonist 500 significantly increased prefrontal 400 cortical acetylcholine % Baseline 300 200 100 0 -90 -60 -30 0 30 60 90 120 150 180 210 240
Slide 81: ADHD Non-stimulant Treatment Significantly Increased Prefrontal Cortical Acetylcholine Release
ADHD Non-stimulant Treatment Significantly Increased Prefrontal Cortical Acetylcholine Release Prefrontal Cortical Acetylcholine ** *** • Alkermes orexin 2 receptor agonist 500 significantly increased prefrontal 400 cortical acetylcholine % Baseline 300 • ADHD non-stimulant treatment 200 significant
Slide 82: Prolonged Elevation of Prefrontal Cortical Acetylcholine With Co-administration
Prolonged Elevation of Prefrontal Cortical Acetylcholine Observed Following Co-administration of OX2R Agonist and ADHD Non-stimulant Treatment Prefrontal Cortical Acetylcholine **** ** *** • Alkermes orexin 2 receptor agonist 600 significantly increased prefrontal 500 # cortical acetylcholine % Base
Slide 83: Attention and Impulsivity Data Summary
Attention and Impulsivity Data Summary Preclinical models with strong predictive validity provide translational value and enable decision making Monotherapy: • 5-Choice Serial Reaction Time Task data suggest orexin 2 receptor agonist improved measures of attention and task engagement and decreased b
Slide 84: Validated Preclinical Models Provide Translational Value and Enable Data-driven Decision Making
Validated Preclinical Models Provide Translational Value and Enable Data-driven Decision Making • Orexin 2 receptor agonist demonstrated significant effects across prefrontal cortical neurotransmission, cortical arousal, and symptom-relevant behavioral assays • Orexin pharmacology coupled with crede
Slide 85: © 2024 Alkermes. All rights reserved.
© 2024 Alkermes. All rights reserved.