Alkermes Plc · NASDAQ:ALKS
Alkermes — Investor Day (March 2021)
144 slides from Alkermes's investor day presentation, Mar 25, 2021
Slide 1: Alkermes Investor Day
March 25, 2021 Alkermes Investor Day Exhibit 99.1
Slide 2: Forward-Looking Statements and Non-GAAP Financial Information
Forward-Looking Statements and Non-GAAP Financial Information 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: the co
Slide 3: Scientific and Business Excellence: New Approaches to Creating Value
Richard Pops Chief Executive Officer Scientific and Business Excellence: Focused on New Approaches to Creating Value
Slide 4: Diversified Biopharmaceutical Company With Proven Capabilities
Diversified Biopharmaceutical Company With Proven Drug Development and Commercialization Capabilities Significant, diverse revenues driving >$1B topline and positioned for growth Proprietary commercial products that target large markets in addiction and psychiatry Additional potential revenue stream
Slide 5: Legacy R&D Strategy and Evolution
Legacy R&D Strategy Target evaluation driven by potential to add new medical value to established medications Enabled rapid advancement to late-stage development Yielded VIVITROL®, ARISTADA®, VUMERITY®, LYBALVI™* Evolution of Alkermes R&D Strategy Advanced formulation science, prodrug chemistry and
Slide 6: Evolution of Alkermes R&D Strategy: Focus & Management
Molecular design, medicinal chemistry and protein engineering expertise applied to develop novel molecules to address unmet needs in neuroscience and oncology Scientific Excellence New R&D Strategy Focus: Two areas of scientific expertise: Neuroscience and Oncology Programs with validated biology ra
Slide 7: Value Enhancement Plan: Growth, Efficiency and Profitability
Business Excellence Value Enhancement Plan: Growth, Efficiency and Profitability Value Enhancement Plan Establishes clear profitability targets Provides framework for capital allocation decisions and prioritization of investments Focuses investment on highest-ROI opportunities emerging from new R&D
Slide 8: Scientific & Business Excellence Drive Enterprise Value
Innovation-driven value creation and profitability Scientific Excellence Business Excellence Scientific & Business Excellence Drive Enterprise Value
Slide 9: Consistent With Alkermes' Purpose and Values
Consistent With Alkermes’ Purpose and Values
Slide 10: Today's Agenda
Today’s Agenda VALUE CREATION Innovation, Growth and Profitability — Blair Jackson, Executive Vice President and Chief Operating Officer ALKERMES’ NEW R&D MODEL Optimizing for Success — Craig Hopkinson, M.D., Executive Vice President and Chief Medical Officer Focus on Innovative Molecular Design — M
Slide 11: Value Creation at Alkermes: Innovation, Growth and Profitability
Blair Jackson Chief Operating Officer Value Creation at Alkermes: Innovation, Growth and Profitability
Slide 12: Strong Operational Foundation to Drive Value Creation
Strong Operational Foundation to Drive Value Creation Revenues: Diverse and positioned for growth Commitment to Profitability: Focused on organizational efficiency and cost management Capital Allocation: Focused on highest-ROI opportunities Strong Corporate Governance: Board refreshment, independenc
Slide 13: Revenues: Growing Commercial Products Serving Large Markets
Revenues: Growing Commercial Products Serving Large Markets
Slide 14: Topline Growth and Diversification Reflect Evolving Business
Topline Growth and Diversification Reflect Evolving Business * Inclusive of ARISTADA INITIO®. **VUMERITY® developed by Alkermes and licensed to Biogen.
Slide 15: Current proprietary commercial products and growth drivers
Current proprietary commercial products Proprietary candidate under FDA review; PDUFA June 1 Licensed Product (royalty & manufacturing revenue) Expected Growth Drivers Patent Life 2020 Net sales CAGR Indications Alcohol dependence (AD) Prevention of relapse to opioid dependence (OD) following opioid
Slide 16: VIVITROL: Growth in Opioid Dependence and Alcohol Dependence
VIVITROL®: Growth in Opioid Dependence and Alcohol Dependence 23% CAGR 2015-2019 COVID-19 Impact +54% +38% +31% +6% +45% VIVITROL Net Sales ($M) VIVITROL Growth in Alcohol Dependence COVID-19 interrupted 5 consecutive years of strong brand growth Alcohol dependence indication – strong source of rece
Slide 17: VIVITROL: Anticipated Recovery Following COVID-19 Disruption
VIVITROL®: Anticipated Recovery Following COVID-19 Disruption Alcohol dependence*: Resumed growth as new patient starts rebounded from pandemic lows in Q2’20 Opioid dependence*: Volumes have stabilized but continue to be impacted by COVID-19-related disruptions to the treatment landscape Reduced pat
Slide 18: ARISTADA: Strong Growth Driven by Two-Month Dose
50% CAGR ARISTADA®: Strong Growth Driven by Two-Month Dose * Inclusive of ARISTADA INITIO®; **TRx Data: IQVIA NPA data Dec R3; MOT: Months of therapy ARISTADA Net Sales* ($M) ARISTADA 1064 mg TRx MOT increased ~50% in 2020** Strong performance reflects favorable product characteristics Growth of 2-m
Slide 19: ARISTADA: Growth Outpaced aLAI Antipsychotic Market
aLAIs Branded Market Size* Annual TRx** Market Share** ~$3.5B ~2M 9% ARISTADA MOT Share ARISTADA TRx MOT Growth Rate ARISTADA®: Growth Outpaced Atypical Long-Acting Injectable (aLAI) Antipsychotic Market *Includes ARISTADA®, Abilify Maintena® (estimated sales), Invega Sustenna/Trinza®, Risperdal Con
Slide 20: LYBALVI: Potential New Revenue Driver in Oral Atypical Antipsychotic Market
Alkermes Value Proposition Drive operating leverage from established psychiatry commercial infrastructure Expected to be accretive in year 2 of launch *The brand name LYBALVI™ has been conditionally accepted by the FDA and will be confirmed upon approval. ** NDA resubmission under review following F
Slide 21: Oral Atypical Antipsychotic Markets Represent Large Opportunities
ORAL AAPs BIPOLAR I DISORDER Branded Market Size1 Annual TRx2 Market Share4 $1.5B ~15M 21% olanzapine $1.7B ~15M† 12% olanzapine ORAL AAPs SCHIZOPHRENIA* Commercial Payer %3 20% 39% ~70K treatment switches occur each month5 olanzapine NBRx growth year-over-year6 15% Oral Atypical Antipsychotic (AAP)
Slide 22: VUMERITY Growth Presents Additional Long-Term Revenue Opportunity
Novel oral fumarate for the treatment of relapsing forms of multiple sclerosis (MS) Biogen holds exclusive, worldwide license to commercialize 15% royalty to Alkermes on worldwide net sales ~$8B oral MS market* *IQVIA NPA TRx data. VUMERITY® Growth Presents Additional Long-Term Revenue Opportunity
Slide 23: Near-Term Expected Revenue Drivers
*These expectations, and the underlying assumptions and risks, are set forth in the Company’s 8-K filed with the SEC on February 11, 2021. The Company expressly disclaims any obligation to update or reaffirm these expectations. Near-Term Expected Revenue Drivers Expected 2021 Net Sales: Full indicat
Slide 24: Capital Allocation: Organizational Efficiency and Cost Management
Capital Allocation: Focused on Organizational Efficiency and Cost Management
Slide 25: Comprehensive Analysis of Operations and Cost Structure
Conducted Comprehensive Analysis of Operations and Cost Structure and Implemented Significant Changes Conducted extensive review of operations and cost structure both internally and with external advisors to identify potential areas for efficiencies and savings Completed peer benchmarking to identif
Slide 26: Disciplined Capital Allocation Supports Highest ROI Priorities
Disciplined Capital Allocation Supports Highest ROI Priorities Drive operating margins of commercial business and focus on profitability Create value through innovation and position ALKS for future growth
Slide 27: Capital Allocation: VIVITROL and ARISTADA
Disciplined Capital Allocation Supports Highest-ROI Priorities VIVITROL® Awareness and marketing campaign for alcohol dependence indication Addiction sales infrastructure ARISTADA® Drive growth through continued focus on two-month dose plus ARISTADA INITIO® Psychiatry sales infrastructure Shared com
Slide 28: Capital Allocation: LYBALVI Launch
Disciplined Capital Allocation Supports Highest-ROI Priorities Commercial Launch Complete sales force hiring Support patient access programs Commence planned marketing campaign Initiate physician outreach & payer interactions Life Cycle Management Complete early-in-illness phase 3 study Initiate pla
Slide 29: Capital Allocation: Nemvaleukin Studies
Disciplined Capital Allocation Supports Highest-ROI Priorities Initiate studies to support potential registration pathways in mucosal melanoma and platinum-resistant ovarian cancer (PROC) Continued enrollment in ARTISTRY-2 dose expansion evaluating nemvaleukin subcutaneous anti-tumor activity Contin
Slide 30: Capital Allocation: Neuroscience and Oncology Research
Disciplined Capital Allocation Supports Highest-ROI Priorities Neuroscience ALKS 1140 Complete phase 1 enabling activities Initiate phase 1 first-in-human study Initiate phase 0 biomarker study Orexin Nominate orexin candidate to the clinic Oncology IL-12 Lead candidate generation IL-18 Advance lead
Slide 31: Pairing Revenue Strength With Expense Management to Achieve Profitability Targets
Pairing Revenue Strength With Active Expense Management to Achieve Profitability Targets Plan to achieve profitability targets through active management of cost structure, adapted to revenue growth profile Profitability Targets G&A and manufacturing efficiency R&D prioritization/ cost off-sets Comme
Slide 32: Evaluation of Strategic Opportunities
Evaluation of Strategic Opportunities Monetization of non-core assets Strategic collaboration for nemvaleukin and other oncology assets Financial Operational Elements of legacy drug delivery/drug manufacturing business Platforms Intellectual property Preclinical and clinical assets outside of strate
Slide 33: Strong Corporate Governance: Board Refreshment, Independence and Oversight
Strong Corporate Governance: Board Refreshment, Independence and Oversight
Slide 34: Maintaining Strong Board of Directors and Corporate Governance
Maintaining Strong Board of Directors and Corporate Governance Board Composition and Refreshment Board skills and expertise support strategy and long-term value creation Appointed 4 new, independent directors since September 2019 New directors bring financial, operational and oncology expertise Thre
Slide 35: Board of Directors
Richard F. Pops Leadership experience and deep industry knowledge gained through >25 years in the industry Current CEO of Alkermes Board member of BIO and PhRMA Andy Wilson Experience in finance and accounting, strategic planning, investor relations and business development Former CFO of PerkinElmer
Slide 36: Diversified Biopharmaceutical Company With Proven Capabilities
Diversified Biopharmaceutical Company With Proven Drug Development and Commercialization Capabilities Significant, diverse revenues driving >$1B topline and positioned for growth Proprietary commercial products that target large markets in addiction and psychiatry Additional potential revenue stream
Slide 37: Developing New Treatments: Optimizing for Success
Craig Hopkinson Executive Vice President, R&D and Chief Medical Officer Developing New Treatments to Address Unmet Patient Need in Neuroscience and Oncology: Optimizing for Success
Slide 38: Alkermes R&D Objective
Alkermes R&D Objective Develop innovative medicines with clear value propositions relative to current and anticipated future standards of care in neuroscience and oncology Based on strong biological rationale Embodied in new molecular entities that leverage Alkermes’ advanced small molecule drug dev
Slide 39: Evolution to Novel Drug Development
Evolution to Novel Drug Development with Differentiated and Contemporary Approach Leverage advanced medicinal chemistry and protein engineering capabilities to develop novel molecular entities with strong intellectual property protection Employ integrated approach to target selection, development an
Slide 40: Integrated Approach to Target Evaluation and Portfolio Assessment
Integrated Approach to Target Evaluation and Portfolio Assessment One line sentence One line sentence One line sentence One Line Sentence One line sentence One line sentence
Slide 41: Efficient Development Designed to Expedite Go/No-Go Answers
Clinical Development Preclinical Research & Development Efficient Development Designed to Expedite Answers to Critical Go/No-Go Questions Early demonstration of preclinical proof-of-concept in disease-relevant models Thorough molecular design feasibility assessment In-depth drug metabolism, pharmaco
Slide 42: Portfolio Management and Investment Prioritization
Portfolio Management and Investment Prioritization: Data-Driven Decision Making Pre-established success criteria and stage-gates throughout development process Enables ‘quicker kills’ and de-risks overall R&D investment Cross functional, integrated governance to enable strategic decision making Exte
Slide 43: External Advisory Boards Inform R&D Planning
R&D Strategic Planning and Execution Integrates Ongoing Feedback from External Advisory Boards Dedicated neuroscience and oncology Scientific Advisory Boards comprised of leading experts in medicinal chemistry, translational medicine and academic science Offer insight into current scientific state-o
Slide 44: New R&D Approach Designed to Increase Probability of Success
Alkermes New R&D Approach is Designed to Increase the Probability of Technical, Regulatory and Commercial Success Efficiently bring important new medicines to patients Design medicines with compelling value propositions Accelerate time to data and decision milestones Establish and adhere to clear go
Slide 45: Focus on Innovative Molecular Design
Markus Haeberlein, Ph.D. Focus on Innovative Molecular Design: Harnessing Alkermes’ Scientific & Technical Capabilities Senior Vice President, Research
Slide 46: Alkermes' Expertise: Molecular Design
Alkermes’ Expertise: Molecular Design Strong biology rationale: Capabilities focused within defined scientific platforms Targets externally validated and vetted with scientific advisors Potential opportunity for first-in-class or best-in class therapies Structure/activity insight guides molecular de
Slide 47: Customized Medicinal Chemistry or Protein Engineering Approach
Customized Medicinal Chemistry or Protein Engineering Approach for Each Target
Slide 48: Purpose-Built Toolbox for Advanced Molecular Design
Sophisticated, Purpose-Built, State-of-the-Art Toolbox for Advanced Molecular Design ALKSketch Proprietary molecular design platform with on-the-fly in silico predictions
Slide 49: Scientific Platforms Serve as Foundation to R&D Strategy
Scientific Platforms Serve as the Foundation to R&D Strategy and Focus in Neuroscience and Oncology Synaptic Dysfunction Immune Modulation Oncology Neuroscience Engineered Cytokines HDAC Inhibitors Orexin Agonist
Slide 50: Synaptic Dysfunction: A Versatile Platform
Synaptic Dysfunction: A Versatile Platform Across Neurology and Psychiatry Synaptic loss is the best current pathologic correlate of cognitive decline1 Improving synaptic function is critical to slow progression and preserve cognitive and functional abilities in neurological disorders2 Targeting sy
Slide 51: Development Candidates Emerging From Neuroscience Platform
Development Candidates Emerging From Neuroscience Platform HDAC: histone deacetylase; CoREST: co-repressor of repressor element-1 silencing transcription factor
Slide 52: Immune Modulation in Oncology Based on Engineered Cytokines
Immune Modulation in Oncology Based on Engineered Cytokines Proinflammatory cytokines have pleiotropic effects and can act on every phase of the cancer immunity cycle1 Alkermes is focusing on cytokine-based therapies designed to: Increase visibility of tumor cells to immune system Increase tumor-kil
Slide 53: Portfolio of Engineered Cytokines
Immune Modulation Portfolio of Engineered Cytokines IL-18R IL-18R MYD88 IL-2Rg IL-2R STAT5 IL-12R IL-12R STAT4 IL-18 IL-2 IL-12
Slide 54: Focus and Discipline Integral to R&D Portfolio Advancement
Focus and Discipline Integral to R&D Portfolio Advancement Discovery Phase Phase 1 Phase 2 Phase 3 IND Enabling Phase Oncology Neuroscience
Slide 55: Nemvaleukin alfa: Clinical Data Updates from ARTISTRY-1 and ARTISTRY-2
Jessicca Rege, Ph.D. Vice President, Clinical Research, Oncology Nemvaleukin alfa: A Novel, Engineered Interleukin-2 (IL-2) Variant Immunotherapy Clinical Data Updates from ARTISTRY-1 and ARTISTRY-2 Trials
Slide 56: Today's Agenda
Harnessing the potential of the IL-2 pathway Advancing a differentiated IL-2 ‒ Nemvaleukin alfa (nemvaleukin) molecular design ‒ Nemvaleukin clinical development strategy Clinical data overview ‒ ARTISTRY-1 (intravenous dosing): Focus on melanoma and platinum-resistant ovarian cancer ‒ ARTISTRY-2 (s
Slide 57: IL-2 Therapy Has Proven Anti-Tumor Efficacy
IL-2 Therapy Has Proven Anti-Tumor Efficacy IL-2 is a natural regulator of the activity of lymphocytes involved in the immune response Recombinant human IL-2 as monotherapy can drive complete and durable responses in certain tumor types, but its toxicity profile significantly limits its potential br
Slide 58: Nemvaleukin Sterically Occluded From High-Affinity IL-2 Receptor
Nemvaleukin is Sterically Occluded From Binding to the High-Affinity IL-2 Receptor b a High-Affinity Receptor-bearing cell b Intermediate-Affinity Receptor-bearing cell CD8+ T cell NK cell CD122 CD132 Treg cell CD25 CD122 CD132 Suppress Immune Response Treg cells For illustrative purposes only;
Slide 59: Nemvaleukin Key Differentiation Parameters
Nemvaleukin Key Differentiation Parameters Support Broad Potential Utility Support Broad Potential Utility = Monotherapy activity observed with IV nemvaleukin in CPI- experienced patients Combination activity observed with pembrolizumab Combination activity observed with multiple agents in preclinic
Slide 60: Clinical Development Strategy Focused on Difficult to Treat Cancers
Clinical Development Strategy Focused on Difficult to Treat Cancers With Clear Unmet Need CPI-Unapproved Tumor Types CPI-Approved Tumor Types Combo with anti-PD-(L)1 Combo with anti-PD-1 PROC Addition to standard-of-care vs. New potential therapies designed to address important unmet needs where che
Slide 61: ARTISTRY-1 Intravenous Dosing Study
ARTISTRY-1 Intravenous Dosing Study
Slide 62: IV Nemvaleukin: Monotherapy Anti-Tumor Activity in Melanoma and RCC
IV Nemvaleukin: Demonstrated Monotherapy Anti-Tumor Activity in Melanoma and Renal cell Carcinoma Data cutoff March 1, 2021. *Reported after data extraction PR=partial response, RP2D = Recommended Phase 2 Dose. Dose: Nemvaleukin (IV RP2D 6 µg/kg) Monotherapy
Slide 63: ARTISTRY-1 Safety Summary
Safety profile of nemvaleukin in combination with pembrolizumab generally consistent with monotherapy profile In combination, no emerging evidence of additive toxicities to those already established for pembrolizumab alone ARTISTRY-1 Safety Summary Chills, pyrexia & fatigue are most frequently (>30%
Slide 64: Monotherapy Responses in Melanoma
Monotherapy Responses in Melanoma
Slide 65: High Unmet Needs Remain for Refractory Melanoma
High Unmet Needs Remain for Treatment of Refractory Melanoma Fifth most common type of cancer in the U.S.1 U.S. prevalence: ~100K new cases in 2020 ~7K estimated deaths in the U.S. in 2020 due to melanoma Melanoma patients with distant metastases have a 5-year survival rate of 27%2 Incidence has ris
Slide 66: ARTISTRY-1 Melanoma Monotherapy Cohort
ARTISTRY-1 Monotherapy Study Melanoma Cohort ARTISTRY-1 Nemvaleukin Melanoma Monotherapy Cohort Focused on Unmet Need Progressed on: Immune checkpoint inhibitor (e.g., anti-PD-(L)1 with or without anti-CTLA-4) Targeted agent as appropriate (e.g., BRAF inhibitor if BRAF-mut) Protocol-defined efficacy
Slide 67: Nemvaleukin Monotherapy Responses in CPI-Experienced Melanoma Patients
ARTISTRY-1: Nemvaleukin Monotherapy Responses in CPI-Experienced Melanoma Patients Preliminary data (ongoing study): Out of 28 evaluable patients (with ≥ 1 scans): Total 3 responses observed, with tumor shrinkage 2 mucosal melanoma and 1 cutaneous melanoma Majority of patients are ongoing as of Marc
Slide 68: Case Study: 67-Year-Old Male Cutaneous Melanoma Patient
ARTISTRY-1 Monotherapy Dose Expansion Cohort Case Study: 67-Year-old Male Cutaneous Melanoma Patient Started Tx: December 2020 (Remains On treatment*): Nemvaleukin monotherapy (6 µg/kg IV) Treatment-related AEs: Manageable with no dose modifications Anemia and fever, grade 2 Intermittent neutropenia
Slide 69: Nemvaleukin Monotherapy for Melanoma Advancing Toward Registration Stage
Nemvaleukin Monotherapy for Melanoma Advancing Toward Registration Stage
Slide 70: Responses in Platinum-Resistant Ovarian Cancer With Pembrolizumab
Responses in Heavily Pre-treated Platinum-Resistant Ovarian Cancer Patients in Combination with Pembrolizumab
Slide 71: High Unmet Needs Remain for Treatment of Ovarian Cancer
High Unmet Needs Remain for Treatment of Ovarian Cancer Second most common gynecological cancer1 U.S. prevalence: ~233K cases in 20172 Leading cause of gynecologic cancer-related deaths in the U.S.1 5-year survival rate for stage IV ovarian cancer of 29%3 Median overall survival (mOS) for platinum-r
Slide 72: Nemvaleukin With Pembrolizumab: Responses in Heavily Pre-treated Ovarian Cancer
ARTISTRY-1: Nemvaleukin in Combination With Pembrolizumab Responses in Heavily Pre-treated Ovarian Cancer Out of 14 patients with ≥1 scans: 4 patients experienced an objective response 1CR, 3PRs confirmed and unconfirmed 5 patients remain on study as of March 15, 2021 data cut ARTISTRY-1 Part C – Ef
Slide 73: Responses in Platinum-Resistant Ovarian Cancer
ARTISTRY-1: Nemvaleukin in Combination With Pembrolizumab Responses in Platinum-Resistant Ovarian Cancer ARTISTRY-1 Part C – Efficacy †CR due to node shrinkage to <10 mm short axis, *per RECIST criteria BEV=bevacizumab, CAP=capecitabine, CBP=carboplatin, CDDP=cisplatin, DOC=docetaxel, GEM=gemcitabin
Slide 74: Case Study: 75-Year-Old Ovarian Cancer Patient
ARTISTRY-1: Nemvaleukin in Combination With Pembrolizumab Case Study: 75-Year-Old Ovarian Cancer Patient High-Grade Serous Ovarian Cancer PD-L1 status: unknown BRCA status: wild-type Platinum-resistant ARTISTRY-1 Part C – Efficacy On-Study Tumor Shrinkage OC4 Diagnosis Prior Treatment Patient has re
Slide 75: Advancing Fast-to-Market Opportunity in PROC
Advancing Fast-to-Market Opportunity in Platinum-Resistant Ovarian Cancer (PROC) Ongoing studies designed to accumulate additional data ARTISTRY-1 Intravenous Phase 1/2 ARTISTRY-2 Subcutaneous Phase 1/2 ARTISTRY-3 Tumor Microenvironment Phase 2 ION Head and Neck Phase 2
Slide 76: Clinical Update for ARTISTRY-2: Selection of RP2D
Clinical Update for ARTISTRY-2 Selection of Recommended Phase 2 Dose (RP2D)
Slide 77: ARTISTRY-2: RP2D Determined
ARTISTRY-2: RP2D Determined SC 3 mg q7d nemvaleukin selected as recommended phase 2 dose (RP2D) for ARTISTRY-2 efficacy expansion stage Selection of RP2D based on totality of data including PK/PD, safety and efficacy during dose escalation phase Acceptable safety and tolerability profile consistent
Slide 78: Safety Profile of SC Nemvaleukin
Safety Profile of SC Nemvaleukin Consistent With Mechanism of Action and IV Nemvaleukin SC 3 mg q7d declared as RP2D based on totality of data 6 mg q21d dose may offer additional flexibility in treating certain tumor types and/or in combination settings in the future Maximum tolerated doses (MTD) fo
Slide 79: SC Nemvaleukin Induced Selective Expansion of NK and CD8+ T Cells
SC Nemvaleukin Induced Dose-Dependent, Selective Expansion of Circulating NK and CD8+ T Cells 3 mg q7d SC nemvaleukin provided greater expansion of CD8+ T cells and NK cells relative to IV nemvaleukin CD8+ T Cells Nemvaleukin Fold Change from Baseline NK Cells Nemvaleukin Fold Change from Baseline T
Slide 80: ARTISTRY-2: Phase 2 Efficacy Expansion Initiated
ARTISTRY-2: Phase 2 Efficacy Expansion Initiated Following SC RP2D Determination Phase 2: Efficacy Expansion in Solid Tumors INITIATED at RP2D Combination nemvaleukin + pembrolizumab Efficacy expansion in select solid tumors where previous responses were observed Phase 1: Dose Escalation, 6-Week Mon
Slide 81: Case Study: 69-Year-Old Female With High-Grade Serous PROC
ARTISTRY-2: Nemvaleukin in Combination With Pembrolizumab Case Study: 69-Year-Old Female With High-Grade, Serous PROC Started Tx: January 2021 (remains on treatment): Nemvaleukin (3 mg q7d) subcutaneous + pembrolizumab IV Data as of March 1, 2021 *Patient continued on therapy as of March 1, 2021; **
Slide 82: Advancing Nemvaleukin Across Key Domains
Advancing Nemvaleukin Across Key Domains Submission of data for presentation at upcoming congresses ARTISTRY-1: Updated safety and efficacy data ARTISTRY-2: Dose escalation and initial efficacy and safety data Advance ongoing studies Advance interactions with regulatory authorities Initiate studies
Slide 83: Nemvaleukin Alfa: Preclinical Research
Heather Losey, Ph.D. Nemvaleukin Alfa: Preclinical Research Paving the Clinical Development Path Sr. Director, Research Program Lead, Oncology
Slide 84: Portfolio of Engineered Cytokines
Immune Modulation Portfolio of Engineered Cytokines IL-18R IL-18R MYD88 IL-2Rg IL-2R STAT5 IL-12R IL-12R STAT4 IL-18 IL-2 IL-12
Slide 85: Immuno-oncology Goal: Activate Immune Responses to Drive Tumor Cell Death
Antigen Identification and Presentation Immune System Activation Immune Cell-mediated Tumor Cell Death Endogenous IL-2 Other Cytokines Recognition by Immune System Immuno-oncology Goal: Activate Innate and Adaptive Immune Responses to Drive Tumor Cell Death Dendritic cell presenting antigen Activate
Slide 86: Immuno-oncology Goal: Enhanced Antigen Presentation and Cell Death
Immuno-oncology Goal: Activate Innate and Adaptive Immune Responses to Drive Tumor Cell Death Enhanced Antigen Identification and Presentation, Cell Death Immune System Activation Immune Cell-mediated Tumor Cell Death Endogenous IL-2 Other Cytokines Chemotherapy Radiation Checkpoint Inhibitors Targe
Slide 87: Nemvaleukin Amplifies Immune System Activation
Immuno-oncology Goal: Activate Innate and Adaptive Immune Responses to Drive Tumor Cell Death Antigen Identification and Presentation Amplified Immune System Activation Immune Cell-mediated Tumor Cell Death Nemvaleukin Recognition by Immune System Dendritic cell presenting antigen Activation and exp
Slide 88: Nemvaleukin With Immunogenic Cell Death Agents
Immuno-oncology Goal: Activate Innate and Adaptive Immune Responses to Drive Tumor Cell Death Enhanced Antigen Identification and Presentation, Cell Death Amplified Immune System Activation Enhanced Immune Cell-mediated Tumor Cell Death Chemotherapy Radiation Checkpoint Inhibitors Targeted Agents Gr
Slide 89: Preclinical Efforts Inform the Clinical Development Strategy
Nemvaleukin: Preclinical Efforts Inform the Clinical Development Strategy Receptor selectivity Maintained potency CD8+ T cell & NK cell expansion Minimal expansion of Tregs Responses in multiple tumor types (monotherapy and in combination with anti-PD-1) Preclinical Research Monotherapy Combination
Slide 90: Agents That Induce Immunogenic Cell Death May Offer Synergy
Agents That Induce Immunogenic Cell Death (ICD) May Offer Synergistic Advantages in Combination With Nemvaleukin Agents that induce immunogenic cell death include: Immune Checkpoint Inhibitors Growth Factor Pathway Inhibitors Cytotoxic Chemotherapies / Radiation
Slide 91: Combination With Growth Factor Pathway Inhibitors
Agents That Induce Immunogenic Cell Death (ICD) May Offer Synergistic Advantages in Combination With Nemvaleukin Immune Checkpoint Inhibitors Anti-PD-1/L1 (Ongoing clinical trials) Anti-CTLA-4 Growth Factor Pathway Inhibitors Multi-tyrosine kinase inhibitors Anti-VEGF/VEGFR antibodies Cytotoxic Chem
Slide 92: Inhibition of Growth Factor Pathways Induces Immunogenic Cell Death
Inhibition of Growth Factor Pathways Induces Immunogenic Cancer Cell Death Growth factors support several mechanisms that promote cancer cell survival and metastasis1 Inhibition of tumor growth factor pathways is a validated therapeutic approach in oncology1,2 T cell mediated immune responses emergi
Slide 93: Nemvaleukin With Growth Factor Pathway Inhibitors in Mouse Tumors
Nemvaleukin in Combination With Growth Factor Pathway Inhibitors Enhanced Cancer Fighting Mechanisms in Mouse Tumors Alkermes internal data on file; *The mouse ortholog of nemvaleukin, RDB 1462, was used in mouse MC38 tumor model Combination with Growth Factor Pathway Inhibitors Nemvaleukin in combi
Slide 94: Gene Expression Effects of Nemvaleukin and Lenvatinib in Mice
Nemvaleukin in Combination With Growth Factor Pathway Inhibitors Enhanced Cancer Fighting Mechanisms in Mouse Tumors Combination with Growth Factor Pathway Inhibitors Angiogenesis gene expression Immune cytolytic activity gene expression Tumor Gene Expression in Mice Treated with Nemvaleukin* and Le
Slide 95: Nemvaleukin Enhanced Anti-Tumor Efficacy of Lenvatinib in Mouse Tumors
Nemvaleukin Enhanced the Anti-Tumor Efficacy of Lenvatinib in Mouse Tumors Combination with Growth Factor Pathway Inhibitors Nemvaleukin* in combination with either lenvatinib or lucitanib (not shown) resulted in enhanced tumor suppression and survival relative to monotherapy groups Similar results
Slide 96: Combination With Chemo / Radiation
Agents That Induce Immunogenic Cell Death (ICD) May Offer Synergistic Advantages in Combination With Nemvaleukin Immune Checkpoint Inhibitors Anti-PD-1/L1 (Ongoing clinical trials) Anti-CTLA-4 Growth Factor Pathway Inhibitors Multi-tyrosine kinase inhibitors Anti-VEGF/VEGFR antibodies Cytotoxic Chem
Slide 97: Potential Synergistic Benefits to Chemotherapy or Radiation
Exploring Nemvaleukin’s Potential Synergistic Benefits to Chemotherapy or Radiation Mediated Mechanisms Chemotherapy and radiation can have positive effects on anti-cancer immunity Both can directly induce tumor cell lysis and lead to immunogenic cancer cell death1 Chemotherapy and radiation can enh
Slide 98: Research Collaborations With Leading Institutes
Research Collaborations With Leading Institutes Explore Further Potential Clinical Utility of Nemvaleukin SOC: Standard of Care
Slide 99: Preclinical Efforts Inform the Clinical Development Strategy
Nemvaleukin: Preclinical Efforts Inform the Clinical Development Strategy Receptor selectivity Maintained potency CD8+ T cell & NK cell expansion Minimal expansion of Tregs Responses in multiple tumor types (monotherapy and in combination with anti-PD-1) Preclinical Research Monotherapy Combination
Slide 100: Tumor-Targeted Split IL-12 Fusion Protein Program
Joshua Heiber, Ph.D. Tumor-Targeted Split IL-12 Fusion Protein Program Principal Scientist, Research, Oncology
Slide 101: Portfolio of Engineered Cytokines
Immune Modulation Portfolio of Engineered Cytokines IL-18R IL-18R MYD88 IL-2Rg IL-2R STAT5 IL-12R IL-12R STAT4 IL-18 IL-2 IL-12
Slide 102: IL-12 is a Highly-Potent Proinflammatory Cytokine
IL-12 is a Highly-Potent Proinflammatory Cytokine With Diverse Anti-Tumor Effects IL-12 is a heterodimeric protein consisting of two covalently linked subunits p35 and p401 Individual components are non-functional Anti-tumor activity is driven through activation of both innate and adaptive immune co
Slide 103: IL-12 Clinical Utility Limited by Severe Toxicities
IL-12 Potential Clinical Utility Limited by Severe Toxicities Clinical evaluation limited due to severe toxicities associated with systemic exposure to IL-12 and its narrow therapeutic index1,2, 3 Systemic administration associated with the potential for rapid development of lethal inflammatory synd
Slide 104: Alkermes' Design Approach: Engineered Tumor-Targeted IL-12 Subunits
Alkermes’ Design Approach: Build Functional IL-12 in the Tumor Through Engineered Tumor-Targeted IL-12 Subunits Key design considerations and challenges: Split IL-12 to create functionally inactive subunits to be directed to the tumor microenvironment Engineer IL-12 subunits to address inherent stab
Slide 105: Tumor Site-Specific Assembly of Functional IL-12
Tumor Site-Specific Assembly of Functional IL-12 Designed to Avoid Systemic IL-12 Exposure Tumor-targeted p35 subunit Tumor-targeted p40 subunit Functional IL-12 Sequentially-timed injections of tumor-targeted subunits reduce systemic exposure to functional IL-12, thereby potentially reducing associ
Slide 106: Differential Clearance of Targeted Subunits
Preclinical Data Demonstrated Differential Clearance of Targeted Subunits to Minimize Systemic IL-12 Exposure Tumor clearance of targeted IL-12 subunits was slower than serum clearance, facilitating tumor-specific assembly Tumor and serum pharmacokinetics from PET/CT imaging of radiolabeled tumor-ta
Slide 107: Accumulation of Split IL-12 Subunits in the Tumor
Preclinical Data Demonstrated Accumulation of Tumor-Targeted Split IL-12 Subunits in the Tumor +Alkermes internal data on file; Murine CT-26 tumors in Balb/c mice; %ID/g = percent of injected dose per gram of tissue * = p<0.05, ** = p<0.01, *** = p<0.001
Slide 108: Sequential Administration Resulted in Dose-Dependent Pharmacodynamic Response
Sequential Administration of Split IL-12 Subunits Resulted in Dose-Dependent Pharmacodynamic Response in Preclinical Study Alkermes internal data on file; PBMC humanized NCG mice
Slide 109: Split IL-12: Advancing Toward Preclinical Proof-of-Concept
Tumor-Targeted Split IL-12: Advancing Toward Preclinical Proof-of-Concept and Cell Line Development
Slide 110: Neuroscience
Neuroscience
Slide 111: Selective HDAC Inhibitors in Synaptic Dysfunction
Selective HDAC Inhibitors in Synaptic Dysfunction Markus Haeberlein, Ph.D. Senior Vice President, Research
Slide 112: Alkermes' HDAC Inhibitor Portfolio
Alkermes’ HDAC Inhibitor Portfolio Introduction to synaptogenesis and synaptic dysfunction Biological rationale for the program: Established epigenetic control of synapse formation and function modulated by HDAC inhibitors Limitations of first-generation HDAC agents as CNS therapeutics Alkermes’ nov
Slide 113: Synapses Play a Vital Role in Brain Function
Synapses Play a Vital Role in Brain Function, Learning and Memory presynaptic axon dendritic spine dendrite synapse: points of communication between neurons presynaptic axon axon synaptogenesis: formation of synapses occurring throughout a healthy person's lifespan
Slide 114: Synaptopathies Span Multiple Neurological Diseases
Synaptopathies Span Multiple Neurological Diseases Independent of Underlying Pathology Many neurological disorders are characterized by synaptic pathology, which includes: Synapse loss Abnormal density of dendritic spines Aberrant synaptic signaling and plasticity Targeting the synapse may slow prog
Slide 115: Epigenetic Control of Synaptogenesis
Epigenetic Control of Synaptogenesis Knockout or inhibition of histone deacetylases, HDACs, increases the number of synapses. Conversely, overexpression reduces the number of synapses1 HDAC inhibitors function by enhancing the acetylation of histones. This opens up the chromatin and increases access
Slide 116: Class I HDACs Function in Multi-Protein Complexes
DOC1 RBBP4/7 RBBP4/7 RBBP4/7 RBBP4/7 Class I HDACs Function in Association With Multi-Protein Complexes That Determine Their Activity HDAC family consists of 18 HDAC enzymes Complexes with HDAC1/2 CoREST complex is directly involved in repression of prosynaptic genes in neuronal tissue Sin3 RERE MIE
Slide 117: Novel Chemotypes Selectively Target HDAC1/2 in CoREST Complex
Alkermes’ Novel Chemotypes Selectively Target HDAC1/2 Bound in the CoREST Complex Alkermes has designed HDAC inhibitors binding to HDAC1/2 specifically in the CoREST complex Selectivity achieved by exploiting a key pocket present in HDAC1/2 HDAC1/2 in the CoREST complex HDAC1/2 RCOR1/2/3 Fuller et a
Slide 118: Alkermes' Proprietary HDAC Inhibitors: Design Goals
Alkermes’ Proprietary HDAC Inhibitors: Design Goals
Slide 119: ALKS 1140: Novel CoREST-Selective Inhibitor Candidate
ALKS 1140: A Novel CoREST-Selective Inhibitor Candidate for the Treatment of Neurodegenerative and Neurodevelopmental Disorders
Slide 120: ALKS 1140 Achieved HDAC Compound Design Goals
ALKS 1140 Achieved Alkermes’ HDAC Compound Design Goals CSF: cerebrospinal fluid *Alkermes data on file CSF/Cplasma, unbound ratio in rat/dog/NHP = 0.6-1.5* Minimal effects in vitro and in preclinical in vivo assessments* 80-250-fold selectivity vs. other HDAC Class I complexes* Brain penetration: E
Slide 121: Rational Assessment of HDAC Inhibitors
Rational Assessment of HDAC Inhibitors via Molecular, Structural and Functional Assays Molecular Gene and/or protein modification Structural Synapse formation Functional Long-term potentiation (LTP)
Slide 122: ALKS 1140 Increased Synapse-Related Proteins and Activated Dendritic Spines
ALKS 1140 Increased Proteins Related to Number of Synapses and Activated Dendritic Spines Increase in Number of Synapses SV2A/PSD-95 coincidence Increase in Activated Dendritic Spines PSD-95/pTrk coincidence Molecular Illustration of SV2A puncta (green) in culture overlaid on MAP2 (dendrites); Alker
Slide 123: ALKS 1140 Increased Density and Persistence of Dendritic Spines
ALKS 1140 at Day 14 ALKS 1140 Increased Density and Persistence of Dendritic Spines ALKS 1140 ALKS 1140 3mg/kg/day Increased Dendritic Spine Density Persistence of Dendritic Spines Vehicle at Day 14 Vehicle Structural †p<0.1; *p<0.05; **p<0.01; Data from wild type mouse model Alkermes data on file †
Slide 124: ALKS 1140 Improved Synaptic Efficacy
ALKS 1140 Improved Synaptic Efficacy in Wild Type Mice and Restored Synaptic Function in Disease Model Ordinary one-way ANOVA, Holm Sidak post hoc Normalized last 10 min fEPSP slope (%) Long-term Potentiation in Wild Type Mice Long-term Potentiation in Transgenic Mice with Hippocampal Synaptic Defic
Slide 125: Potential Indications: Rare and Orphan Diseases
Potential Indications in Neurodegenerative and Neurodevelopmental Disorders With Cognitive Deficits Indications that share common pathophysiology of synaptic dysfunction in hippocampus with deficits in cognition Includes certain autism spectrum disorders with reduced synaptic density Initial clinica
Slide 126: ALKS 1140 Development Plan
ALKS 1140 Development Plan: Seek Early Clinical Evidence of Activity Synaptic biomarkers and neurocognitive assessments are core components of the early clinical development plan and program decision-making SAD: single-ascending dose; MAD: multiple-ascending dose; PK: pharmacokinetic; PD: pharmacody
Slide 127: HDAC Chemistry in Frontotemporal Dementia With Granulin Mutations
Leveraging Alkermes’ HDAC Chemistry Expertise in New Indications: Frontotemporal Dementia With Granulin Precursor Mutations (FTD-GRN)
Slide 128: Treatment Options Needed for FTD-GRN
Treatment Options Needed for Frontotemporal Dementia With Granulin Precursor Mutations (FTD-GRN) Frontotemporal Dementia (FTD) is caused by degeneration of the frontal and/or temporal lobes FTD patients demonstrate severe synaptic deficits1 ~60,000 people in U.S. have FTD2 No currently available the
Slide 129: HDAC Inhibitors Increased Progranulin Levels and Dendritic Spine Density
Alkermes’ HDAC Inhibitors Increased Both Progranulin Levels and Dendritic Spine Density GRN Gene Expression Human SH-SY5Y Cells 1 Gass, J., et al. Mol. Neurodeg. 2012;7(33) 2 Kleinberger, G., et al. Mol. Neurobiol. 2013;47:337-360 Progranulin Protein Human SH-SY5Y Cells Total Spine Density Wild Type
Slide 130: Alkermes' Pipeline of Selective HDAC Inhibitors
Alkermes’ Pipeline of Selective HDAC Inhibitors Target Evaluation Lead Generation Lead Optimization Clinical Development Discovery Project Start Candidate Nomination Research POC Oncology Neuroscience POC: proof-of-concept
Slide 131: Orexin Receptor Agonists for Narcolepsy and Other Sleep Disorders
Brian Raymer, Ph.D. Orexin 2 Receptor Agonists for the Treatment of Narcolepsy and Other Sleep Disorders Senior Director, Research Project Leadership and Strategy
Slide 132: Abnormal Orexin Neurotransmission in Sleep Disorders
Abnormal Neurotransmission of Orexin in the Brain Seen in Patients With Sleep Disorders Orexin, also known as hypocretin, is a neuropeptide produced in the hypothalamus Orexin controls sleep and arousal by stimulating the release of neurotransmitters that promote alertness, such as histamine, seroto
Slide 133: Narcolepsy: A Chronic Neurological Disorder
Narcolepsy: A Chronic Neurological Disorder Chronic neurological disorder characterized by daytime sleepiness and sudden transitions into sleep1 Affects ~200,000 people in U.S. and 3M people globally2 70% of narcolepsy patients have narcolepsy type 13, distinguished by: Cataplexy, a sudden muscle we
Slide 134: Orexin Receptor Agonists Present Opportunity for New Sleep Disorder Therapies
Recent Identification of Orexin 2 Receptor Agonists Presents Opportunity for New Sleep Disorder Therapies OX2R agonists may have utility as replacement therapy for low or no levels of orexin by stimulating downstream release of wake-promoting neurotransmitters Potential applicability in narcolepsy a
Slide 135: Leveraging Molecular Design Capabilities to Target Orexin Dysfunction
Leveraging Alkermes’ Molecular Design Capabilities to Target Orexin Dysfunction in Narcolepsy Working to develop a best-in-class molecule designed to: Mimic potency and performance of endogenous peptide OX2R agonist with orally-bioavailable therapy Possess favorable half-life Have PK/PD profile that
Slide 136: Design Goals: Differentiated Orexin Receptor Agonist
Design Goals: Differentiated Orexin 2 Receptor Agonist to Address Unmet Patient Needs Increased wakefulness duration Improved cataplexy control Robust Efficacy Reduced risk of heart rate and blood pressure effects seen with stimulants Favorable Tolerability Once-daily, oral medication Dose to allow
Slide 137: Lead Orexin Candidate RDC-264177 Potency Superior to Orexin Peptide
Alkermes’ Lead Orexin Candidate, RDC-264177, Demonstrated Potency Superior to Orexin Peptide in Preclinical Studies Application of RDC-264177 (‘177) induced robust concentration-dependent increases in neuronal excitability in rodent brain tissue RDC-264177 demonstrated greater potency compared to an
Slide 138: RDC-264177 Promoted Prolonged Wakefulness In Vivo
RDC-264177 Promoted Prolonged Wakefulness in Preclinical In Vivo Studies RDC-264177 via oral dosing demonstrated dose-dependent wake duration (shown by red gamma bands and dark blue theta and delta bands) PharmacoEEG: Pharmaco-electroencephalography Alkermes data on file
Slide 139: RDC-264177 Dose-Dependent Increases in Exposure and Wakefulness
RDC-264177 Demonstrated Dose-Dependent Increases in Exposure and Wakefulness Pharmacokinetics (PK) Pharmacodynamics (PD) Strong PK/PD relationship demonstrated in rat EEG model suggests potential for low human dose RDC-264177 did not adversely elevate heart rate and blood pressure in a rat hemodynam
Slide 140: RDC-264177 Increased Wakefulness and Reduced Cataplexy in Model
RDC-264177 Demonstrated Dose-Dependent Increased Wakefulness and Reduced Cataplexy in Predictive Model Mean ± SEM; One-way ANOVA * = p<0.05, *** = p<0.001 0.1 mg/kg 1 mg/kg 10 mg/kg RDC-264177 0.1 mg/kg 1 mg/kg 10 mg/kg RDC-264177 DTA mouse model of narcolepsy1,2 serves as a predictive disease model
Slide 141: Moving Forward: Potential for Differentiated Orexin Agonist
Moving Forward in Development: Potential for Meaningfully Differentiated Orexin Agonist Nomination of lead candidate, RDC-264177, planned for 2021 based on data that demonstrated potential for: Robust efficacy Convenient dosing Favorable tolerability Developing efficient clinical strategy with early
Slide 142: www.alkermes.com
www.alkermes.com
Slide 143: Appendix
Appendix
Slide 144: Alkermes plc and Subsidiaries GAAP to Non-GAAP Adjustment
Allcermes ple and Subsidiaries GAAP to Non-GAAP Adjustment: (Caaudiced) cere reconciling tons