Agios Pharmaceuticals, Inc. · NASDAQ:AGIO
Agios Pharmaceuticals — Investor Day (October 2014)
130 slides from Agios Pharmaceuticals's investor day presentation, Oct 15, 2014
Slide 1: 2014 Research & Development Day
October 15, 2014 Exhibit 99.1 Agios Pharmaceuticals 2014 Research & Development Day
Slide 2: Today's agenda
Today’s agenda Time Topic Presenter 8:30 - 9:00 a.m. Registration & Breakfast 9:00 - 9:20 a.m. Welcome and Company Overview David Schenkein, M.D., CEO Cancer Metabolism: IDH-Mutant Inhibitors 9:20 – 9:45 a.m. AG-221 and AG-120 Discovery & Research Scott Biller, Ph.D., CSO 9:45 – 10:05 a.m. Overview
Slide 3: Cautionary Note Regarding Forward-Looking Statements
Cautionary Note Regarding Forward-Looking Statements This “2014 Research & Development Day” presentation and various remarks we make during this presentation contain forward-looking statements of Agios Pharmaceuticals, Inc. within the meaning of The Private Securities Litigation Reform Act of 1995,
Slide 4: Building a Great Multi-Product Biopharmaceutical Company
October 15, 2014 David Schenkein, M.D., Chief Executive Officer Building a Great Multi-Product Biopharmaceutical Company
Slide 5: Driven By Clear Corporate Vision and Values
Driven By Clear Corporate Vision and Values VISION Agios is passionately committed to the fundamental transformation of patients’ lives through scientific leadership in the field of cancer metabolism and rare genetic disorders of metabolism
Slide 6: Building a Great Multi-Product Biopharmaceutical Company
Building a Great Multi-Product Biopharmaceutical Company Created three first-in-class molecules Proof of concept for AG-221 Data for AG-120 and AG-348 later this year ~110 employees, OSOP culture Strong financial position Celgene partnership In just six years:
Slide 7: Guiding Principles
Guiding Principles Follow the science and do what is right for patients Maintain a culture of incisive decision-making driven by deep scientific interrogation, edge, and respectful irreverence Foster collaborative and synergistic spirit that includes all employees regardless of function or level Lev
Slide 8: Agios' Approach to R&D
Agios’ Approach to R&D Decisions Based on Science and Impact on Patients Research Leader in dysregulated metabolism of cancer and RGDs Novel, first-in-class medicines Incentivize scientists to take smart risks, challenge dogmas and strive for answers Responder identification necessary to validate a
Slide 9: Novel First-in-Class Portfolio: Precision Medicine Approach
Novel First-in-Class Portfolio: Precision Medicine Approach Research Clinical Development Hematologic Malignancies Hematologic Malignancies Solid Tumors PK Deficiency Primary Commercial Rights Development Programs AG-221 (IDH2m inhibitor) AG-120 (IDH1m inhibitor) AG-348 (Pyruvate kinase (R) Activato
Slide 10: What You'll Come Away With Today
What You’ll Come Away With Today More confidence that we are leading the disruptive field of dysregulated metabolism in cancer and in our novel approach to rare genetic diseases Our commitment to remaining a research driven company with world class clinical development and eventually commercial capa
Slide 11: Clinical Pipeline Progress: Building Momentum
Clinical Pipeline Progress: Building Momentum Remaining 2014 Potential Product Milestones 2014 Product Milestones Achieved Healthy volunteer data at ASH 2014 Initiate Ph 2 in PK deficiency patients by early 2015 AG - AG - AG - AG - AG - AG - Ph 1 heme data at EORTC/AACR (Nov. 19) Clear POC Initiated
Slide 12: Today's Speakers
Today’s Speakers Eyal Attar, M.D. Medical Director Sam Agresta, M.D. VP, Head of Clinical Development Scott Biller, Ph.D. Chief Scientific Officer Chris Bowden, M.D. Chief Medical Officer
Slide 13: Agios Leadership Team Here Today
Agios Leadership Team Here Today Duncan Higgons Chief Operating Officer John Evans IDH Portfolio Executive, VP BusinessDevelopment Glenn Goddard SVP, Finance Michael Su, Ph.D. SVP, Research & Development Min Wang, Ph.D., J.D. VP, Legal Affairs Marion Dorsch, Ph.D. VP, Biology
Slide 14: Building a Great Multi-Product Biopharmaceutical Company
October 15, 2014 David Schenkein, M.D., Chief Executive Officer Building a Great Multi-Product Biopharmaceutical Company
Slide 15: Cancer Metabolism at Agios: The Discovery of Mutant IDH Inhibitors
Cancer Metabolism at Agios: The Discovery of Mutant IDH Inhibitors Scott Biller, Ph.D., Chief Scientific Officer
Slide 16: Today's Key Points
Today’s Key Points Breakthrough work on IDH mutations - the 2-HG story: - Discovered that IDH mutations cause a metabolic gain of function - Determined IDH inhibitors reverse the block in normal cell differentiation caused by 2-HG Developed first investigational medicines to treat IDH mutant cancers
Slide 17: Leveraging Our Scientific Competencies: The Engine
Leveraging Our Scientific Competencies: “The Engine” Three first-in-class investigational medicines with deep pipeline Cancer Metabolism 100’s of novel targets Genetic- or metabolic-biomarker defined patients Rare Genetic Disorders of Metabolism Agios Core Capabilities “Disruptive Science” >600 gene
Slide 18: Core Capabilities in Dysregulated Metabolism
Core Capabilities in Dysregulated Metabolism Metabolic Enzyme Drug Discovery Unlocking dysregulated metabolism - Expertise in metabolism adds a new dimension to “systems biology” approach - Unique technology platform allows deep interrogation of metabolism - High level of integration across expertis
Slide 19: Flux biochemistry enables groundbreaking metabolic insights
VS. Flux biochemistry enables Agios to make groundbreaking metabolic insights Deep Understanding of Metabolic Pathways Drives Development of Transformational Medicines Metabolic Flux Analysis Enabled by C and N labeled nutrients and informatics Static view Flux Biochemistry How many metabolites exis
Slide 20: Metabolome: Untapped Opportunity For Novel Therapeutic Targets
Metabolome: Untapped Opportunity For Novel Therapeutic Targets Combining the metabolome and genome provide insight into metabolic vulnerabilities Mutations in metabolic genes or metabolic regulators Tumor specific isoforms Deletions in metabolic regulators Fusions of metabolic genes
Slide 21: Integrated Approach to Metabolic Target Discovery
Integrated Approach to Metabolic Target Discovery Identify targets with “locked-in” metabolic vulnerabilities in tumors Genetic Screens Metabolomic Screens Fold Change (genotype A vs B) Cancer Genomics
Slide 22: High Bar for Novel Targets
High Bar for Novel Targets Requirements for oncology drug discovery programs … leading to higher probability of success Cancer dependency demonstrated in vivo Precision Medicine Patient selection strategy in place Robust chemical starting points High confidence in being able to drug the target We kn
Slide 23: First-in-Class Cancer Metabolism Portfolio
First-in-Class Cancer Metabolism Portfolio Cancer Metabolism Portfolio Research Clinical Development Hematologic Malignancies Hematologic Malignancies Solid Tumors Development Programs AG-221 (IDH2m inhibitor) AG-120 (IDH1m inhibitor) Research Programs Cancer Metabolism Multiple Novel Targets Multip
Slide 24: Isocitrate Dehydrogenase (IDH) 1/2 Mutations in Cancer
Isocitrate Dehydrogenase (IDH) 1/2 Mutations in Cancer Cytoplasm Mitochondria Parsons et al, Science mutations in IDH2 also described (R172) Subsequently, IDH1 (R132) and IDH2 (R172 and R140Q) mutations found across multiple tumor types. Recurrent point mutations found at a single residue in one all
Slide 25: A Surprising Biochemical Observation: mIDH1 generates and consumes NADPH
A Surprising Biochemical Observation: m IDH1 enzyme generates and then consumes NADPH NADP+ NADPH + CO2 NADP + Isocitrate Time (sec) Source: Dang L et al. Nature 2009 IDH1
Slide 26: Metabolism Platform Identifies 2-Hydroxyglutarate in IDH Mutant Cells
Agios Metabolism Platform Identifies 2-Hydroxyglutarate at High Levels in IDH Mutant Cancer Cells Metabolic mystery solved! Unbiased metabolomic study compared IDH1 wt to IDH1 mutant expressing cells Levels for 850 species were compared across samples Only three species were found to be elevated in
Slide 27: IDH Mutation as a Gain of Function in Cancer
IDH Mutation as a Gain of Function in Cancer: IDH m IDH 2-HG as an Oncometabolite Normal isocitrate KG isocitrate KG Tumor suppressor loss-of-function Source: Dang L et al. Nature 2009
Slide 28: IDH Mutation as a Gain of Function in Cancer
IDH Mutation as a Gain of Function in Cancer: IDH m IDH mIDH IDH 2-HG as an Oncometabolite Normal isocitrate KG isocitrate KG Tumor suppressor loss-of-function Metabolic Insight Oncogene isocitrate KG 2-HG gain-of-function Source: Dang L et al. Nature 2009
Slide 29: 2-Hydroxyglutarate, an Excellent Biomarker
2HG 2-Hydroxyglutarate, an Excellent Biomarker: A Surrogate for Treatment Effect & Clinical Benefit SPECIFIC MEASURABLE CAN BE IMAGED Brain Tumor Samples AML Blood Samples Glu GABA MRI / MRS *Linda Liau / UCLA *S. Gross/JEM 2HG
Slide 30: How does 2-HG drive tumors? A Novel Mechanism
How does 2-HG drive tumors? A Novel Mechanism Differentiation Proliferation Apoptosis Resistance Angiogenesis Migration Differentiation Proliferation Apoptosis Resistance Angiogenesis Migration -KG Dependent Dioxygenases Histone demethylases DNA demethylases Prolyl hydroxylases Collagen hydroxylases
Slide 31: 2-HG Induces a Block of Differentiation
Current Model: 2-HG Induces a Block of Differentiation via Epigenetic Chromatin Remodeling DNA and Histone Demethylases IDH mt-IDH 1. Hypermethylation 2. Modulation of gene expression Oncogene isocitrate KG Leukemic Blasts Cells Blocked Differentiation 2-HG 2-HG
Slide 32: Mutant IDH Inhibitors Reverse the Block in Differentiation
Current Model: Mutant IDH Inhibitors Reverse the Block in Differentiation DNA and Histone Demethylases IDH IDHm Inhibitor mt-IDH Active Demethylation Oncogene isocitrate 2-HG Differentiated Myeloid Cells Release of Blocked Differentiation
Slide 33: AG-221: A First-in-Class Inhibitor of Mutant IDH2
AG-221: A First-in-Class Inhibitor of Mutant IDH2 Potent and reversible inhibitor of IDH2m (R140Q>172K) - Cellular IC = 12 nM (R140Q) Selective against off-targets Orally bioavailable, long half-life Induces differentiation in IDH2m primary human AML ex vivo Differentiation of human IDH2m AML ex viv
Slide 34: AG-221 Promotes Survival in Primary Human Leukemia Model
AG-221 Promotes Survival in Primary Human Leukemia Model Relapsed AML with IDH2 R140Q/FLT3-ITD/DNMT3AR882H/NPM1c/CEBPa insertion Source: Wang, ASH 2013 poster: AG-221 offers a survival advantage in a primary human IDH2 mutant AML xenograft model
Slide 35: AG-221 Induces Differentiation in Primary Human Leukemia Model
AG-221 Induces Differentiation in Primary Human Leukemia Model Naïve mice Ara-C (2mpk) Vehicle 5 mpk AG-221 15 mpk AG-221 45 mpk AG-221 Bone Marrow Differential Counts • 100% blast cells • No granules • Very little cytoplasm • Nuclei have neoplastic lobation • More mature cell forms • Nuclear latera
Slide 36: AG-120: A First-in-Class Inhibitor of Mutant IDH1
AG-120: A First-in-Class Inhibitor of Mutant IDH1 Potent and reversible inhibitor of all IDH1 mutants - Cellular IC = 8 – 20 nM Selective against off-targets Orally bioavailable, long half-life Induces differentiation in IDH1m primary human AML ex vivo AG-120 and 2-HG Concentration Profiles 50 mg/kg
Slide 37: Normal Hepatocyte Progenitor Differentiation
Normal Hepatocyte Progenitor Differentiation Source: Adapted from N. Bardessy et al, Cell Cycle, in press Progenitor Bile Duct Hepatocyte Cholangiocyte Normal Differentiation HNF4
Slide 38: Block in Hepatocyte Progenitor Differentiation Leads to Cholangiocarcinoma
Block in Hepatocyte Progenitor Differentiation Leads to Cholangiocarcinoma Source: Adapted from N. Bardessy et al, Cell Cycle, in press Progenitor Cholangiocarcinoma Oval Cell Expansion IDH Mutant Progenitor Bile Duct Hepatocyte Cholangiocyte Normal Differentiation HNF4 HNF4 2-HG 2-HG Blocks Differe
Slide 39: IDH Mutations Drive Tumorigenesis in Cholangiocarcinoma Mouse Model
IDH Mutations Drive Tumorigenesis in a Mouse Model of Intrahepatic Cholangiocarcinoma Source: Saha et al, Nature, July 2014 Induction of differentiation along the hepatocyte lineage with Agios IDH1m inhibitor AGI-5027 Repression of hepatocyte marker HNF-4 Induction of hepatocyte marker HNF-4
Slide 40: IDH1m Inhibitor Blocks Tumor Growth in Glioma Model
IDH1m Inhibitor Blocks Tumor Growth in a Primary Human Glioma Model Source: Rohle et al, Science, 2013 2-HG Levels Tumor growth inhibition observed in subcutaneous neurosphere glioma model with IDH1m inhibitor AGI-5198 • Induction of apoptosis indicated via Ki67 staining 150 450 0.0 0.5 1.0 1.5 4.0
Slide 41: IDH1m Inhibitor Reverses Epigenetic Changes and Induces Differentiation
IDH1m Inhibitor Reverses Epigenetic Changes and Induces Differentiation H3K9Me3 IHC 450 mpk Vehicle Source: Rohle et al, Science, 2013 H3K9Me3 Levels Expression of Differentiation Markers Mechanism in glioma model is consistent with reversal of hypermethylation and induction of differentiation Vehic
Slide 42: Summary
Summary We have developed a platform approach to the disruptive field of cancer metabolism Agios scientists discovered a novel gain of function with IDH mutations in cancer Oncometabolite 2-HG is a tumor driver and an excellent biomarker AG-221 (IDH2m inhibitor) and AG-120 (IDH1m inhibitor) potently
Slide 43: Acute Myeloid Leukemia (AML) and Other IDH-Mutant Diseases
October 15, 2014 Acute Myeloid Leukemia (AML) and Other IDH-Mutant Diseases Eyal C. Attar, M.D., Medical Director
Slide 44: Patients are Inspiring
Patients are Inspiring Source: Singh H and others and Attar E, Blood Cancer Journal, 2013.
Slide 45: Today's Key Points
Today’s Key Points Acute Myeloid Leukemia (AML) - Most common leukemia in adults - Poor/limited prognosis - Few treatment options, with no improvements in decades - Molecular mutations are used in prognosis and treatment IDH inhibitors have the potential to: - Change the treatment paradigm - Establi
Slide 46: AML is a Devastating Blood Cancer
AML is a Devastating Blood Cancer Leukemia • RBCs decrease • Patient health declines
Slide 47: ~18K New AML Cases in the U.S. Each Year and Growing
~18K New AML Cases in the U.S. Each Year and Growing Due to Aging Population Forecasted U.S Incidence of AML Age-Specific U.S. Incidence of AML Annual incidence of AML in the US is expected to increase by ~24% over the next 10 years (~ 2% CAGR) 18.9 19.2 19.6 20.0 20.4 20.8 21.2 21.7 22.1 22.5 23.0
Slide 48: AML Incidence and Mortality Remain Unchanged for >35 Years
AML Incidence and Mortality Remain Unchanged for >35 Years Due to Lack of Impactful Treatments AML U.S. Incidence and Mortality, 1975-2010 * Case rate mortality per year assumes incidence & mortality occur s in same year and does not take into account modest changes in incidence Sources: American Ca
Slide 49: AML Diagnosis Requires Bone Marrow and Blood Tests
AML Diagnosis Requires Bone Marrow and Blood Tests Morphology Cytogenetics Molecular
Slide 50: Molecular Mutations are Important in Prognosis and Treatment
Molecular Mutations are Important in Prognosis and Treatment Prognosis Age Cytogenetics Molecular mutations Comorbidities > 60 years old (most patients) < 60 years old (better prognosis) • Diabetes • Cardiovascular disease Three groups: NPM1 FLT3 CEBPA IDH1 and IDH2 TET2 TP53 1. Good 2. Intermediate
Slide 51: Treatment Remains Unchanged With Limited Options
Untreated AML ~18,860 pts Treatment Remains Unchanged With Limited Options Does the Patient Have APML ? Age, Perf Status, Comorbidities ~60-70% ~30-40% NO ~89% (~17K pts) ~10-12K pts Unfit for Induction Chemotherapy ~5-7K pts Relapse Sources: market research Differentiation Therapy Fit for Induction
Slide 52: Case Study: Low Intensity Treatments Carry Significant Burden
Case Study: Even Low Intensity Treatments Carry Significant Burden and Result in Poor Outcomes Transfusion requirements 72-year-old male Retired, enjoys spending time with his wife and being outdoors Felt increasingly tired for 3 months and red “spots” on his lower legs for last 2 weeks Referred to
Slide 53: Case Study: Intensive Treatments Have Limited Success
Case Study: Intensive Treatments Carry Significant Burden and Have Limited Success • 62-year-old male • Admitted to local hospital with fever, cough, sputum production • Pneumonia and low blood counts • Hematologist diagnosed AML • After a week of antibiotics, leukemia therapy was initiated Inductio
Slide 54: Case Study: Relapsed AML Has Limited Treatment Options
Case Study: Relapsed AML has Limited Treatment Options with Poor Chance of Success • 63-year-old male • 1 year after completing induction, consolidation, transplant - Developed low blood counts - Recurrent AML diagnosed 6 week hospitalization Hair loss Mouth sores Fevers Transfusions Stable disease
Slide 55: Goal: To Change the Treatment Paradigm for AML
Goal: To Change the Treatment Paradigm for AML Chemotherapy Stem Cell Transplantation (select eligible patients) AML IDHm+ AML IDHm inhibitor Potential to establish a new foundation in AML care
Slide 56: IDH Represents a Novel Target for Precision Medicine
IDH Represents a Novel Target for Precision Medicine Found in approximately 20% of AML Occur early in the disease Result in elevated 2-HG levels Elevated 2-HG modifies proteins that turn genes on and off Mutations in IDH
Slide 57: AML with IDH Mutations Demonstrate Elevated 2-HG
AML with IDH Mutations Demonstrate Elevated 2-HG AML Source: Fathi AT, et al., Blood, 2012 IDH1/2 wild type IDH1/2 mutant
Slide 58: IDH Mutations Also Found in MDS, NHL and Solid Tumors
IDH Mutations Also Found in MDS, NHL and Range of Solid Tumors Indication % IDHm IDH1m IDH2m * * Includes “basket” of emerging unconfirmed indications. Low grade glioma & 2 ary GBM 68-74 Chondrosarcoma 40-52 Acute Myeloid Leukemia (AML) 6-10 MDS/MPN Intrahepatic Cholangiocarcinoma 11-24 Ollier/Maffu
Slide 59: Tumors with IDH Mutations Demonstrate Elevated 2-HG
Tumors with IDH Mutations Demonstrate Elevated 2-HG Cholangiocarcinoma Glioma Source: Borger D R et al. Clin Cancer Res 2014;20:1884-1890; Source: Choi C et al. Nature Medicine 1012; 18, 624–629 Tumor Control
Slide 60: IDH Mutations Observed in Hematologic Malignancies
IDH Mutations Observed in Hematologic Malignancies AML MDS Non-Hodgkin Lymphoma Bone marrow Bone marrow AITL Incidence (cases/year US) 18K 15K 1.4K Prevalence (US) 25K >60K 3K IDH1m frequency 6-10% 3% ND IDH2m frequency 9-13% 3-6% 30% Treatment Options Chemotherapy Stem cell transplant Chemotherapy
Slide 61: IDH Mutations Observed in Solid Tumors With Limited Treatment Options
IDH Mutations Observed in Solid Tumors With Limited Treatment Options Gliomas Cholangiocarcinoma Chondrosarcoma Multiple sources, including market research and SEER. Estimates will continue to evolve with additional future data *excludes primary GBM Low grade and 2ary GBM Bile ducts Cartilage Incide
Slide 62: Points to Remember
Points to Remember AML - poor prognosis and high morbidity - no new treatments for > 35 years - 5-year survival rates* • ~38% adults < 65 years • ~5% adults >= 65 years IDH mutations: - found in approximately 20% of adults with AML - result in elevated 2-HG IDH mutations are also found in MDS, NHL,
Slide 63: IDH-Mutant Inhibitors Clinical Development Strategy
October 15, 2014 IDH-Mutant Inhibitors Clinical Development Strategy – Early Clinical Evidence Chris Bowden, M.D., Chief Medical Officer
Slide 64: Today's Key Points
Today’s Key Points Focus on genetically defined patient populations Precision medicine approach may provide higher probability and shorter development timelines Early AG-221 Phase 1 results support potential rapid development Advancing AG-221 and AG-120 in a broad range of tumor types
Slide 65: IDH1m and IDH2m: Distinct Genetically Defined Populations
Indication % IDHm IDH1m IDH2m IDH1m and IDH2m: Distinct Genetically Defined Populations * * Includes “basket” of emerging unconfirmed indications. Low grade glioma & 2 ary GBM 68-74 Chondrosarcoma 40-52 Acute Myeloid Leukemia (AML) 6-10 MDS/MPN Intrahepatic Cholangiocarcinoma 11-24 Ollier/Maffucci O
Slide 66: Phase I Trials for AG-221 and AG-120
Phase I Trials for AG-221 and AG-120 Leading the Clinical Development of IDH Inhibitors Study start AG-221 AML + Heme malignancies Solid Tumors March September October AG-120 AG-221 (planned 4Q) AG-120 AG-221 expansion
Slide 67: IDH Inhibitors: AML Clinical Development Paradigms
IDH Inhibitors: AML Clinical Development Paradigms Acute Myeloid Leukemia (AML) Precision Magnitude Diagnostically Defined Population Demonstrate Clinical Benefit IDH1m+ AML IDHm+ AML IDH2m+ AML Efficacy Decrease disease morbidity Safety and convenience
Slide 68: AG-221: Phase 1 Data Presented at EHA, June 2014
AG-221: Phase 1 Data Presented at European Hematology Association (EHA), June 14, 2014 AN UPDATE OF THE CLINICAL SAFETY AND ACTIVITY IN A PHASE I TRIAL OF AG-221, A FIRST IN CLASS, POTENT INHIBITOR OF THE IDH2-MUTANT PROTEIN, IN PATIENTS WITH IDH2 MUTANT POSITIVE ADVANCED HEMATOLOGIC MALIGNANCIES Ey
Slide 69: AG-221 Phase 1 Early Data: Efficacy and Response
AG-221 Phase 1 Early Data: Efficacy and Response Measured by IWG Criteria per Investigator Data Presented at European Hematology Association (EHA) on June 14, 2014 CR = Complete Response CRp = Complete Response, Incomplete Platelet Recovery CRi = Complete Response, Incomplete Hematologic Recovery PR
Slide 70: AG-221 Summary of Objective Responses
C2 C3 C4 C5 C6 C7 AG-221 Phase 1 Early Data: Summary of Objective Responses (as of May 23, 2014 data cut ) Data Presented at European Hematology Association (EHA) on June 14, 2014 C1 CR CRp CR PR PR CRp PR CR PR CR* CR PR CRi CR** Bone Fracture, Death Unrelated Neutrophil counts increase by C1D15. C
Slide 71: AG-221: Evidence of Cell Differentiation
AG-221: Evidence of Cell Differentiation Leading to Potential Paradigm Shift in Treatment Data Presented at European Hematology Association (EHA) on 6/14/2014
Slide 72: AG-221: Cellular Differentiation Leads to a CR
AG-221: Cellular Differentiation Leads to a CR Data Presented at AACR, April 2014 C1D15 bone marrow demonstrates unique differentiation effect of AG-221 therapy CR=complete response; C1D15=Cycle 1, Day 15; C3D1=Cycle 3, Day 1; C4D1=Cycle 4, Day 1. Stein EM et al. (2014) Clinical safety and activity
Slide 73: AG-221 Most Common Side Effects
AG-221 Phase 1 Early Data: Most Common Side Effects Data Presented at European Hematology Association (EHA) on June 14, 2014 Total Subjects* (N=18) n (%) Total Subjects* (N=18) n (%) MedDRA Preferred Term: Grade 1 or 2 Grade All Events Nausea 4 (22.2) 4 (22.2) Pyrexia 4 (22.2) 4 (22.2) Thrombocytope
Slide 74: AG-221 Phase I Trial in AML & Other Heme Malignancies
AG-221 Phase I Trial in AML & Other Heme Malignancies Ongoing Dose Escalation Phase 1 ASH 2014 Initiated October Expansion Cohorts Advanced Heme Malignancies
Slide 75: Dose Selected for Start of Expansion Cohorts
Ongoing Dose Escalation Dose Selected for Start of Expansion Cohorts: Multiple Factors Considered Phase 1 Initiated October Safety-dose limiting toxicity, dose modifications, chronic toxicity Pharmacokinetics-exposure, half-life, variability Pharmacodynamics-2-HG reduction Clinical activity: remissi
Slide 76: AG-221 Phase I Expansion Cohorts
AG-221: Phase I Expansion Cohorts: Homogenous patient populations Ongoing Dose Escalation Phase 1 Initiated October AG-221: Four Expansion Cohorts Cohort 2 R/R AML <60 yrs n=25 Cohort 4 Basket Heme n=25 Cohort 3 AML –decline SOC chemotherapy n=25 Cohort 1 R/R AML yrs (transplant ineligible) n=25 Dos
Slide 77: AG-221 Clinical Development Considerations: Speed and Breadth
BREADTH AG-221 Clinical Development Considerations SPEED Ongoing Dose Escalation Phase 1 Initiated October Relapsed/Refractory AML Front-Line | Unfit Patients Maintenance (Post BM Transplant) Front-Line | Fit Patients ASH 2014 Additional heme malignancies (e.g. MDS) Potential Future Directions in Co
Slide 78: Potential Endpoints for Regulatory Approval
Potential Endpoints for Regulatory Approval in Heme and Solid Tumor Cancers with an IDH Mutation U.S. Regulatory Approval Global Regulatory Approval Accelerated Pathway: - Response rates - Duration of response - Reduction in transfusions & Infections Standard Pathway: Potential Regulatory Pathways P
Slide 79: Untreated AML Clinical Setting Landscape
Untreated AML - (no APML) ~ 17K pts Clinical Setting Landscape Fit for Induction Chemotherapy Unfit for Induction Chemotherapy Age/ Comorbidities ~10% Age 80+; poor status; severe comorbidities Consolidation HSCT ~40% Success Age/MRD/ Cytogenetics Refractory High Low or Intermediate Induction and Co
Slide 80: AG-120: Potent & Selective Inhibitor of IDH1 Mutations
AG-120: Potent & Selective Inhibitor of IDH1 Mutations Current Status Potential Future Directions in Collaboration with Celgene Expansion Studies Full Development • Current Status: Two Phase 1 studies initiated in March 2014 • What’s new: Early data from Phase Heme at EORTC/AACR in November Multiple
Slide 81: IDH Inhibitors as Potential Foundation of Therapy
IDH Inhibitors as Potential Foundation of Therapy for IDH Mutant Cancers Keys to Success in Clinical Development Early Development - IDH mutation positive patients only - Partner with research for strong correlative science Speed - Data driven expansion cohorts - High unmet medical need populations
Slide 82: IDH-Mutant Inhibitors Clinical Development Strategy
October 15, 2014 IDH-Mutant Inhibitors Clinical Development Strategy – Early Clinical Evidence Chris Bowden, M.D., Chief Medical Officer
Slide 83: Rare Genetic Disorders of Metabolism: PK Deficiency and AG-348
October 15, 2014 Rare Genetic Disorders of Metabolism: Pyruvate Kinase Deficiency and PKR Activator, AG-348 Scott Biller, Ph.D., Chief Scientific Officer
Slide 84: Today's Key Points
Today’s Key Points By leveraging our scientific excellence in cellular metabolism, we have defined a transformative approach to small molecule therapies for rare genetic disorders AG-348, our first RGD therapy: - is an allosteric activator of pyruvate kinase - corrects the metabolic dysregulation in
Slide 85: Rare Genetic Disorders of Metabolism
Rare Genetic Disorders of Metabolism >1900’s >1980’s-00’s >2010’s Archibald Garrod Novel Agios approach to rare genetic disorders of metabolism : Identify optimal intervention points in dysregulated metabolic pathways Correct metabolic defect using small molecules - Potential to correct brain phenot
Slide 86: Scientific Approach to Rare Genetic Disorders of Metabolism
Scientific Approach to Rare Genetic Disorders of Metabolism Severe clinical presentation Potential to be transformative High unmet need Amenable to SM approach Agios rare genetic disorders of metabolism portfolio Detailed Mutational & structural analysis Biology/clinica l feasibility Monogenic Disea
Slide 87: Agios Approach to Correct Metabolic Pathway Defects
Agios Approach to Correct Metabolic Pathway Defects Metabolite A pool Metabolite B pool Metabolite C pool Enzyme 1 Enzyme 2* (mutant)
Slide 88: Agios Approach to Correct Metabolic Pathway Defects
Metabolite B pool Metabolite C pool Metabolite A pool Agios Approach to Correct Metabolic Pathway Defects Alternative Pathway Pathway modulation: Reduce toxic metabolites or bypass metabolic defect by targeting upstream/adjacent pathway Allosteric modulation: Restore metabolic flow by directly modul
Slide 89: Pyruvate Kinase Deficiency: Rare Hematological Genetic Disorder
Pyruvate Kinase (PK) Deficiency: Rare Hematological Genetic Disorder Disease Characteristics Agios’ Therapeutic Approach Caused by >160 hypomorphic mutations in PKR Autosomal recessive disorder characterized by chronic hemolytic anemia Poor prognosis - Presents in infancy or childhood with severe he
Slide 90: Red Blood Cells are Highly Dependent on Glycolysis
Glycolysis Glycolysis ATP ATP PKR mPKR Red Blood Cells are Highly Dependent on Glycolysis for ATP Generation Normal Red Cell PK Deficient Red Cell Glycolysis Glycolysis ATP ATP PKR mPKR PKR mutations lead to low pyruvate kinase activity and ATP levels Low ATP levels result in decreased red cell life
Slide 91: AG-348 Restores PKR Activity and Corrects the Metabolic Deficiency
Glycolysis Glycolysis ATP mPKR + AG 348 AG-348 Restores PKR Activity and Corrects the Metabolic Deficiency PK Deficient Red Cell PK Deficient Red Cell + AG-348 mPKR ATP Glycolysis Glycolysis ATP mPKR + AG 348 mPKR ATP
Slide 92: agios
2 agios R510 = RAGOW Rasew R4s6W"
Slide 93: AG-348 Increases Catalytic Efficiency and Improves Stability of Mutant Enzymes
AG-348 activates PKR WT and nearly all PKR mutant enzymes tested AG-348 increases the thermal stability of unstable mutant enzymes AG-348 Increases Catalytic Efficiency and Improves Stability of Mutant Enzymes Enzyme thermal stability of the most common unstable mutant R510Q AG-348 activates 10 of 1
Slide 94: >= agios
>= agios
Slide 95: Slide 95
Slide 96: PK Deficient Red Cells Have Metabolic Defects Causing Chronic Hemolysis
PK Deficient Red Cells Have Metabolic Defects That Result in Chronic Hemolysis ` ` WT PKR Mutant PKR Glucose 1,3-DPG 3-PG PEP Pyruvate PKR 2,3-DPG ATP Glucose 1,3-DPG 3-PG PEP Pyruvate mPKR ATP WT PKD 2,3-DPG ATP 2,3-DPG Source: Kung, ASH poster 2013 2,3-DPG levels are elevated and ATP levels reduce
Slide 97: AG-348 Restores Metabolite Levels in PK Deficient Patient Blood
AG-348 Restores Metabolite Levels in PK Deficient Patient Blood to That of Normal Red Cells ` Patient A (R510Q/G511R) Glucose 1,3-DPG 3-PG PEP Pyruvate PKR 2,3-DPG ATP AG-348 Patient B (R486W/D390N) Patient C (A495V/E241stop) 2,3-DPG ATP PKR Activity DMSO AG-348 (2 uM) Source: Kung, ASH poster 2013
Slide 98: AG-348 Activates WT PKR in Preclinical Models
AG-348 Activates WT PKR and Effects Metabolite Biomarkers in Preclinical Models WT Mouse single dose WT Mouse 13 doses (BID) Dose-dependent increase in ATP levels and decrease in 2,3-DPG levels seen in mice dosed BID with AG-348 - Single dose results in 2,3-DPG response but minimal ATP response - Mu
Slide 99: AG-348 Increases Glycolytic Flux in Preclinical Models
AG-348 Increases Glycolytic Flux in Preclinical Models 1.8-fold increase in glycolytic flux upon AG-348 treatment in wt mice time (min) DMSO AG-348 13 C labeled Unlabeled +AG-348 13 C labeled Unlabeled Vehicle Source: Agios internal research
Slide 100: Robust Suite of Metabolic Biomarkers in Place
Robust Suite of Metabolic Biomarkers in Place for Healthy Volunteer and Patient Trials ` Pharmacodynamic Biomarkers Glucose FBP 1,3-DPG 3-PG PEP Pyruvate PKR 2,3-DPG ATP AG-348 Ex Vivo PKR Activity Assay ATP & 2,3-DPG levels Glycolytic Flux Source: Kung, ASH poster 2013
Slide 101: Summary
Summary AG-348 Profile Potent activator of PKR mutant and wild-type enzymes Excellent pharmaceutical properties, oral dosing Functions by increasing catalytic efficiency and stabilizing unstable mutant proteins Corrects the metabolic phenotype in blood from multiple PK deficient patients Biomarkers
Slide 102: Rare Genetic Disorders of Metabolism: PK Deficiency and AG-348
October 15, 2014 Rare Genetic Disorders of Metabolism: Pyruvate Kinase Deficiency and PKR Activator, AG-348 Scott Biller, Ph.D., Chief Scientific Officer
Slide 103: PKR Program: Disease Background & Clinical Development Strategy
October 15, 2014 Sam Agresta, MD, MPH & TM VP, Head of Clinical Development Pyruvate Kinase-R (PKR) Program Disease Background & Clinical Development Strategy
Slide 104: Today's Key Takeaways
Today’s Key Takeaways University of Milan Stanford PK deficiency is a serious disease with life- long hemolytic anemia Current therapy is supportive and does not address underlying disease AG-348 targets mutated enzyme which drives pathogenesis Natural history and clinical evaluation of AG-348 is un
Slide 105: Pyruvate Kinase Deficiency: A Destructive Red Blood Cell Disease
Pyruvate Kinase (PK) Deficiency A Destructive Red Blood Cell Disease Disease Pathophysiology Disease Overview Source: Zanella. Blood Rev. 2007; 21(4):217;, Blood and Bone Marrow Pathology; Wintrobe’s Clinical Hematology; Physician Interviews; Market Research . Description • Rare genetic disease ofte
Slide 106: Disease Progression from Infants to Adults
Disease Progression from Infants to Adults Splenectomy Jaundice Iron Overload Pyruvate kinase deficiency is the most common enzyme abnormality of the glycolytic pathway
Slide 107: Majority of Patients Have Moderate to Severe Disease
Majority of Patients Have Moderate to Severe Disease Adult and Pediatric Diagnosed PK Deficiency Population Source: Physician Interviews; Zanella. Blood Rev. 2007; 21(4):217; Market Research Hb: Hemoglobin. Mild (20 – 30%) Moderate (20 – 30%) Severe (40 – 50%) Description • Transfusion typically req
Slide 108: PK Deficiency Diagnosis Requires Many Steps to Confirm
PK Deficiency Diagnosis Currently Requires Many Steps to Confirm Evaluation for Hemolytic Anemia Evaluation for PK Deficiency Sources: Wintrobe’s Clinical Hematology; Physician Interviews; Market Research Step Key Details • Initial symptoms of anemia may include pallor, fatigue, weakness, or reduced
Slide 109: Distribution of Patient Age at Time of Diagnosis
Distribution of Patient Age at Time of Diagnosis Majority of Patients are Diagnosed due to Symptoms Pediatric ~50% Adult ~40% Pediatric 1 Month – 18 years Adult > 18 years Description • Seek diagnosis due to inability to function with current level of anemia • Diagnosis occurs when growth and activi
Slide 110: Estimated PK Deficiency Patient Population
Estimated PK Deficiency Patient Population (U.S. and EU5) Similar to Other Rare Genetic Diseases, PK Deficiency is Largely Undiagnosed Diagnosed Patients (~2.4 K) Total U.S. and EU5 Population (~32 K) Availability of a therapy may increase awareness and willingness to diagnose patients Estimate Sour
Slide 111: PK Deficiency is an Inherited Disease
PK Deficiency is an Inherited Disease Autosomal recessive inheritance - More than 160 different causative mutations have been identified Most affected individuals are compound heterozygous for two different mutant alleles Acquired PK deficiency rarely occurs as a result of acute leukemia, pre-leukem
Slide 112: Clinical Presentation and Morbidity
Clinical Presentation and Morbidity PK deficiency results in severe and systemic disease throughout life Source: Segel et al, 2011 Death in utero from hydrops fetalis Transfusion-requiring anemia (Can be life threatening) Pallor, icterus, and splenomegaly Hepatosplenomegaly Pigmented (bilirubin) gal
Slide 113: Clinical Data in Patients with PK Deficiency
Clinical Data in 61 Patients with PK Deficiency Median Age at Diagnosis 16 yrs (1 day- 65 yrs) Source: Zanella et al, 2005 Anemia Jaundice Splenomegaly 90% 70% 81% Splenectomy 30% Neonatal Jaundice 59% Exchange Transfusion 45% Median number of Transfusions 15 (1 100) 65% exchange transfusion newborn
Slide 114: Transfusion Requirements in an Infant with PK Deficiency
Transfusion Requirements in an Infant with PK Deficiency Source: Smiers et al, 2007
Slide 115: Splenectomy Offers Minimal Disease Impact
Splenectomy Offers Minimal Disease Impact Spleen intact Spleen removed Source: Zanella et al. 2005 Normal level •
Slide 116: Extra-Medullary Hematopoiesis
Extra-Medullary Hematopoiesis Abnormal bone marrow production Source: Pratt et al. 2005 60 year old woman with PK Deficiency with spinal cord compression
Slide 117: Iron Overload Impacts Mortality
Iron Overload Impacts Mortality Liver Pathology Clinical Symptoms Iron Deposition in the Liver Source: Morton et al. 2011 Normal Portal and Central Veins No Signs of Fibrosis
Slide 118: AG-348: Clinical Development
AG-348: Clinical Development Current: Supportive only Future: Targeting enzyme defect AG-348 Bone Marrow Transplant Transfusion Iron chelation and Phototherapy Lifelong Antibiotics Chole- cystectomy Folic acid Splenectom y
Slide 119: Agios Approach to PK Deficiency
Agios Approach to PK Deficiency Clinical Trials • Healthy Volunteer Studies • Phase 2 Trial in Patients Biology & Chemistry • PKR Protein Interactions and Biologic Effect • Pharmacodynamic Correlates Disease Understanding • Natural History Study • Translational Research with Disease Experts
Slide 120: PK Deficiency Natural History Study
PK Deficiency Natural History Study Designed to Inform Registration Path Understanding the Disease & Identifying Patients and Treatment Centers Study will capture retrospective and prospective clinical data, annual quality of life measures, and genetic diagnostic information Study Design Longitudina
Slide 121: Natural History Study has Identified Global Treatment Centers
Natural History Study has Identified Global Treatment Centers - Does not include 3 sites open in Canada As of September 2014: 23 sites open >50 patients enrolled 12 additional global sites identified
Slide 122: AG-348: Clinical Development Status
AG-348: Clinical Development Status Status Today Single ascending dose study in healthy volunteers Dosing completed; met primary endpoint Multiple ascending dose study in healthy volunteers ongoing Met primary endpoint Phase 2 start-up activity initiated Expect to enroll by early 2015 Data from heal
Slide 123: AG-348 Clinical Development Status
AG-348 Clinical Development Status Current Status Potential Future Directions Phase 1 Phase 2 to Late Development Single ascending dose (SAD) escalation (Healthy Volunteer Clinical Studies) Study Designs Multiple ascending dose (MAD) escalation Randomized double blind placebo controlled trials Singl
Slide 124: Potential Phase 2 Study Considerations
Phase 2 Study Considerations Potential Open-label Global (US, EU) Single-Arm Phase 2 AG-348 Treatment End of Treatment Treatment: - Dose/Schedule decided by healthy volunteer studies Clinical endpoints: - Safety - Efficacy • Hemoglobin: stabilization and/or increase • Transfusion frequency and amoun
Slide 125: Potential Regulatory Endpoints for Approval
Potential Regulatory Endpoints for Approval PILOT (Phase II) TRIUMPH (Phase III) SHEPHERD (Phase III) Soliris® (Eculizumab) in PNH may provide regulatory precedent Key clinical endpoints: - Reduction in transfusion(s) - Avoid splenectomy - Change in hemoglobin - QOL assessments Patient Enrollment 11
Slide 126: AG-348: Potential Benefit Across All PK Deficiency Patients
AG-348: Potential Benefit Across All of PK Deficiency Patients Potential Addressable Population Expansion Patients with >4 Annual Transfusions Source: Market Research • Patients receiving transfusions suffer from anemia, poor QOL, and potentially severe adverse events • Although rarely transfused, u
Slide 127: Summary
Summary Potential for AG-348 to be first medicine to target underlying defect P K deficiency is a serious disease with life - long hemolytic anemia Current therapy is supportive and does not address underlying disease AG-348 targets mutated enzyme which drives pathogenesis Natural history and clinic
Slide 128: PKR Program: Disease Background & Clinical Development Strategy
October 15, 2014 Sam Agresta, MD, MPH & TM VP, Head of Clinical Development Pyruvate Kinase-R (PKR) Program Disease Background & Clinical Development Strategy
Slide 129: Closing Remarks & Q&A
October 15, 2014 David Schenkein, M.D., Chief Executive Officer Closing Remarks & Q&A
Slide 130: Clinical Pipeline Progress: Building Momentum
Clinical Pipeline Progress: Building Momentum Remaining 2014 Potential Product Milestones 2014 Product Milestones Achieved Healthy volunteer data at ASH 2014 Initiate Ph 2 in PK deficiency patients by early 2015 AG - AG - AG - AG - AG - AG - Ph 1 heme data at EORTC/AACR (Nov. 19) Clear POC Initiated