October 15, 2014 Agios Pharmaceuticals 2014 Research & Development Day Exhibit 99.1 |
2 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 of AML and Other IDH-Mutant Diseases Eyal Attar, M.D., Medical Director 10:05 – 10:30 a.m. Clinical Development Strategy – Early Clinical Evidence Chris Bowden, M.D., CMO 10:30 - 10:45 a.m. Break (15 min) Rare Genetic Disorders of Metabolism: Pyruvate Kinase-R (PKR) 10:45 – 11:15 a.m. AG-348, Discovery & Research Scott Biller, Ph.D. 11:15 – 11:35 a.m. PK Deficiency Disease and Clinical Development Sam Agresta, M.D., VP, Head, Clinical Development 11:35 a.m. – 12:00 p.m. Closing Remarks & Q&A David Schenkein, M.D. 12:00 – 1:00 p.m. Lunch Agios’ Leadership Team |
3 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, including statements regarding Agios’ expectations and beliefs about its business, plans and prospects. The words “believe”, “expect”, “could”, “should”, “will”, “would”, “may”, ”plan”, “intend”, “anticipate” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. The forward-looking statements contained in this presentation and in remarks made during this presentation are subject to important risks and uncertainties that may cause actual events or results to differ materially from Agios’ current expectations and beliefs, including risks and uncertainties relating to: Agios’ ability to successfully commence and complete preclinical and clinical development of its product candidates; results of preclinical studies and clinical trials; Agios’ ability to maintain its collaboration with Celgene on acceptable terms; the content and timing of decisions made by regulatory authorities, investigational review boards and publication review bodies; unplanned cash requirements and expenditures; competitive factors; Agios’ ability to obtain, maintain and enforce intellectual property protection; Agios’ capital requirements and need for funding; and general economic and market conditions. These and other risks are described under the caption “Risk Factors” in Agios’ most recent Quarterly Report on Form 10-Q, which is on file with the SEC, and in other filings that Agios may make with the SEC in the future. Any forward-looking statements contained in this presentation or in remarks made during this presentation speak only as of the date hereof, and Agios expressly disclaims any obligation to update any forward- looking statements, whether as a result of new information, future events or, except as required by law. Cautionary Note Regarding Forward-Looking Statements |
October 15, 2014 David Schenkein, M.D., Chief Executive Officer Building a Great Multi-Product Biopharmaceutical Company |
5 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 Driven By Clear Corporate Vision and Values 5 |
6 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: |
7 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 Leverage deep strategic relationships with our academic and commercial partners to improve the quality of our discovery and development efforts |
8 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 target Make molecules that have the properties with potential to go all the way Development Patient safety first Precision medicine from 1 st trial Invest heavily in translational medicine Challenge and change the standards of care Partner with regulatory agencies and advocacy groups early Agios’ Approach to R&D Decisions Based on Science and Impact on Patients |
9 Novel First-in-Class Portfolio: Precision Medicine Approach Research Clinical Development Primary Commercial Rights Development Programs AG-221 (IDH2m inhibitor) AG-120 (IDH1m inhibitor) AG-348 (Pyruvate kinase (R) Activator) Research Programs Cancer Metabolism Rare Genetic Disorders of Metabolism (Multiple Novel Targets) (Multiple Monogenic Diseases) US Rts ex-US Rts Phase 1 Studies Hematologic Malignancies Hematologic Malignancies Solid Tumors Phase 1 Studies PK Deficiency Phase 1 HV Studies |
10 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 capabilities Our vision to build one of the next great independent multi-product companies Our passion to help patients and a better understanding of the underserved diseases where we are focused |
11 Clinical Pipeline Progress: Building Momentum Healthy volunteer data at ASH 2014 Initiate Ph 2 in PK deficiency patients by early 2015 AG - 221 AG - 120 AG - 348 Remaining 2014 Potential Product Milestones 2014 Product Milestones Achieved AG - 221 AG - 120 AG - 348 Ph 1 heme data at EORTC/AACR (Nov. 19) Clear POC Initiated expansion cohorts Fast Track & Orphan Drug Designations in US Completed SAD study; Met primary endpoint in SAD & MAD studies Two Phase 1 trials ( IDH1m+ heme and solid tumors) initiated and enrolling well Additional Phase 1 data at ASH 2014 On track to initiate trial in IDH2m+ solid tumors |
12 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 |
13 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 |
October 15, 2014 David Schenkein, M.D., Chief Executive Officer Building a Great Multi-Product Biopharmaceutical Company |
Cancer Metabolism at Agios: The Discovery of Mutant IDH Inhibitors Scott Biller, Ph.D., Chief Scientific Officer |
16 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 Amazing team of scientists and cutting edge discovery engine |
17 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 genetic diseases Orphan market opportunities Significant unmet need |
18 Core Capabilities in Dysregulated Metabolism 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 expertise areas Rapid translation to clinical proof of concept - Precision medicine: guided by genomic and metabolic biomarkers - Early POC in well-defined patient populations to demonstrate clinical benefit: Higher probability of success Faster development track Genetically-Defined Patient Populations Metabolic Enzyme Drug Discovery Biochemistry Metabolism Genomics Cell Biology |
19 Metabolic Flux Analysis Enabled by 13 C and 15 N labeled nutrients and informatics Static view Flux Biochemistry How many metabolites exist in a single point at a given moment in time? How quickly are metabolites moving along enzymatic pathways? Which enzyme is the “Achilles heel” for a disease? VS. High Throughput Mass Spec Analysis Cell Culture In house Vivarium Patient Samples Flux biochemistry enables Agios to make groundbreaking metabolic insights Deep Understanding of Metabolic Pathways Drives Development of Transformational Medicines |
20 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 |
Genetic Screens Metabolomic Screens Fold Change (genotype A vs B) Cancer Genomics Integrated Approach to Metabolic Target Discovery Identify targets with “locked-in” metabolic vulnerabilities in tumors 21 |
22 High Bar for Novel Targets Cancer dependency demonstrated in vivo Precision Medicine Requirements for oncology drug discovery programs Patient selection strategy in place Robust chemical starting points High confidence in being able to drug the target We know which patients to treat using genetic and metabolic biomarkers The tumor cares … leading to higher probability of success |
23 First-in-Class Cancer Metabolism Portfolio Cancer Metabolism Portfolio Research Clinical Development Development Programs AG-221 (IDH2m inhibitor) AG-120 (IDH1m inhibitor) Research Programs Cancer Metabolism Multiple Novel Targets Multiple Phase 1 Studies Hematologic Malignancies Hematologic Malignancies Solid Tumors Phase 1 Studies |
24 Parsons et al, Science 2008 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 allele of IDH1 or IDH2 Always retains one WT allele and expresses WT protein Isocitrate Dehydrogenase (IDH) 1/2 Mutations in Cancer Cytoplasm Mitochondria : Recurrent IDH1 mutations (R132) identified in glioma. Low frequency |
25 A Surprising Biochemical Observation: NADP+ NADPH + CO2 NADP + Isocitrate Time (sec) Source: Dang L et al. Nature 2009 IDH1 mIDH1 enzyme generates and then consumes NADPH |
26 Agios Metabolism Platform Identifies 2-Hydroxyglutarate at High Levels in IDH Mutant Cancer Cells 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 mutant cells… all converge on 2-HG A B A 146.50 m/z 149.50 11.50 14.00 time m/z 147.0299 (expected 147.0299, C5H7O5) C WT signal intensity 2-Hydroxyglutarate (2-HG) Metabolic mystery solved! mIDH NADPH |
27 IDH Mutation as a Gain of Function in Cancer: Normal IDH isocitrate KG mIDH isocitrate KG Tumor suppressor loss-of-function Source: Dang L et al. Nature 2009 2-HG as an Oncometabolite |
28 IDH Mutation as a Gain of Function in Cancer: Normal IDH isocitrate KG mIDH isocitrate KG Tumor suppressor loss-of-function Metabolic Insight Oncogene isocitrate KG 2-HG mIDH gain-of-function IDH Source: Dang L et al. Nature 2009 2-HG as an Oncometabolite |
29 SPECIFIC MEASURABLE CAN BE IMAGED Brain Tumor Samples AML Blood Samples Glu GABA 2HG MRI / MRS *Linda Liau / UCLA 2-Hydroxyglutarate, an Excellent Biomarker: A Surrogate for Treatment Effect & Clinical Benefit *S. Gross/JEM 2HG |
30 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 |
Current Model: 2-HG Induces a Block of Differentiation via Epigenetic Chromatin Remodeling DNA and Histone Demethylases 1. Hypermethylation 2. Modulation of gene expression Oncogene isocitrate KG IDH Leukemic Blasts Cells Blocked Differentiation mt-IDH 31 2-HG 2-HG |
Current Model: Mutant IDH Inhibitors Reverse the Block in Differentiation DNA and Histone Demethylases Active Demethylation Oncogene isocitrate 2-HG IDH IDHm Inhibitor Differentiated Myeloid Cells Release of Blocked Differentiation mt-IDH 32 |
33 Potent and reversible inhibitor of IDH2m (R140Q>172K) - Cellular IC 50 = 12 nM (R140Q) Selective against off-targets Orally bioavailable, long half-life Induces differentiation in IDH2m primary human AML ex vivo AG-221: A First-in-Class Inhibitor of Mutant IDH2 Differentiation of human IDH2m AML ex vivo 9 Day Treatment with AG-221 AG-221 and 2-HG Concentration Profiles 25 and 50 mg/kg single oral dose Potently lowers 2-HG levels in R140Q xenograft models following a single oral dose Source: K. Yen, ASH 2013 |
34 AG-221 Promotes Survival in Primary Human Leukemia Model Source: Wang, ASH 2013 poster: AG-221 offers a survival advantage in a primary human IDH2 mutant AML xenograft model Relapsed AML with IDH2 R140Q/FLT3-ITD/DNMT3AR882H/NPM1c/CEBPa insertion |
35 AG-221 Induces Differentiation in Primary Human Leukemia Model 0 20 40 60 80 100 120 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 lateralization • Eosinophilic cytoplasm • Coarse chromatin Mitotic Blast Neutrophil Source: Wang, ASH 2013 poster: AG-221 offers a survival advantage in a primary human IDH2 mutant AML xenograft model |
36 Potent and reversible inhibitor of all IDH1 mutants - Cellular IC 50 = 8 – 20 nM Selective against off-targets Orally bioavailable, long half-life Induces differentiation in IDH1m primary human AML ex vivo AG-120: A First-in-Class Inhibitor of Mutant IDH1 AG-120 and 2-HG Concentration Profiles 50 mg/kg single oral dose Potently lowers 2-HG levels in IDH1m+ xenograft models following a single oral dose Differentiation of human IDH1m AML ex vivo 6 Day Treatment with AG-120 0 200000 400000 600000 800000 1000000 1200000 1.0 10.0 100.0 1000.0 10000.0 0.0 20.0 40.0 60.0 Time (hr) AG-120-50 mpk (single dose) 2HG (single dose) 2HG baseline (vehicle) |
37 Normal Hepatocyte Progenitor Differentiation Source: Adapted from N. Bardessy et al, Cell Cycle, in press Progenitor Bile Duct Hepatocyte Cholangiocyte Normal Differentiation HNF4 |
38 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 Differentiation |
39 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 |
40 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 4.5 5.0 5.5 6.0 6.5 AGI-5198 [mg/kg] VEHICLE AGI-198 450 mg/kg/d AGI-5198 150 mg/kg/d Ki67 IHC - |
41 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 IDH1m Inhibitor Reverses Epigenetic Changes and Induces Differentiation Vehicle 150 mpk A GI-5198 450 mpk AGI-5198 |
42 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 inhibit 2-HG production in IDHm cells and preclinical models IDH mutations induce a block in differentiation in both hematological and solid tumors - The block in differentiation can be relieved by lowering 2-HG with an IDHm inhibitor |
October 15, 2014 Acute Myeloid Leukemia (AML) and Other IDH-Mutant Diseases Eyal C. Attar, M.D., Medical Director |
Patients are Inspiring Source: Singh H and others and Attar E, Blood Cancer Journal, 2013. 2 |
3 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 - Establish new foundations of care IDH mutations exist in solid tumors and present opportunities beyond AML |
4 AML is a Devastating Blood Cancer Leukemia • RBCs decrease • Patient health declines |
5 ~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 0 5 10 15 20 25 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2 1 0 1 1 1 1 1 1 2 2 3 5 7 10 15 20 23 23 0 5 10 15 20 25 Sources: Datamonitor 2014; American Cancer Society; Leukemia and Lymphoma Society |
6 AML Incidence and Mortality Remain Unchanged for >35 Years Due to Lack of Impactful Treatments * Case rate mortality per year assumes incidence & mortality occurs in same year and does not take into account modest changes in incidence Sources: American Cancer Society; Leukemia & Lymphoma Society AML U.S. Incidence and Mortality, 1975-2010 0 1 2 3 4 5 Incidence Mortality |
7 AML Diagnosis Requires Bone Marrow and Blood Tests Morphology Cytogenetics Molecular |
8 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 3. Poor |
9 Untreated AML ~18,860 pts 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 Treatment Remains Unchanged With Limited Options Differentiation Therapy Fit for Induction Chemotherapy YES ~11% (~2K pts) |
10 Case Study: Even Low Intensity Treatments Carry Significant Burden and Result in Poor Outcomes 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 a hematologist, diagnosed with AML Transfusion requirements Patients’ health 10.5 months Outpatient azacitidine X 6 cycles 10 |
11 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 Induction chemotherapy 6 wk hospitalization Hair loss Mouth sores Fevers Transfusions Consolidation chemotherapy Stem cell transplant 4 wk hospitalization Near-fatal central line infection Fevers Transfusions 4 wk hospitalization Fevers Transfusions Immunosuppressive medications to prevent GVHD 5 months |
12 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 for 2 months Returned to clinic 2X/week for transfusions Hospitalized for fever No remission Progressive leukemia 4 months types of patients enrolled in AG-221 study Re-induction chemotherapy Outpatient clinical trial |
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 13 |
14 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 |
15 AML with IDH Mutations Demonstrate Elevated 2-HG Source: Fathi AT, et al., Blood, 2012 AML IDH1/2 wild type IDH1/2 mutant |
16 IDH Mutations Also Found in MDS, NHL and Range of Solid Tumors Indication % IDHm Low grade glioma & 2 ary GBM 68-74 Chondrosarcoma 40-52 Acute Myeloid Leukemia (AML) 6-10 MDS/MPN 3 Intrahepatic Cholangiocarcinoma 11-24 Ollier/Maffucci 80 Others* (colon, melanoma, lung, prostate) 1-3 Acute Myeloid Leukemia (AML) 9-13 MDS/MPN 3-6 Angio-immunoblastic NHL 30 Intrahepatic Cholangiocarcinoma 2-6 Giant Cell Tumor of the Bone 80 D2HG Aciduria 100 Others* (melanoma, glioma) 3-5 IDH1m IDH2m Based on literature analysis. Estimates will continue to evolve with additional future data. ** Includes “basket” of emerging unconfirmed indications. |
Tumors with IDH Mutations Demonstrate Elevated 2-HG Cholangiocarcinoma Source: Borger D R et al. Clin Cancer Res 2014;20:1884-1890; Glioma Source: Choi C et al. Nature Medicine 1012; 18, 624–629 Tumor Control 17 |
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 Stem cell transplant Chemotherapy, XRT Stem cell transplant 5-year overall survival 20-25% ~30% ~36% Multiple sources, including market research and SEER. Estimates will continue to evolve with additional future data 18 |
IDH Mutations Observed in Solid Tumors With Limited Treatment Options Multiple sources, including market research and SEER. Estimates will continue to evolve with additional future data *excludes primary GBM Gliomas Cholangiocarcinoma Chondrosarcoma Low grade and 2ary GBM Bile ducts Cartilage Incidence (cases/year US) 5K 2K – 4K 700-1000 Prevalence (US) 24K 5K -- IDH1m frequency 68-74% 11-24% 40-52% IDH2m frequency 3-5% 2-6% 6-11% Treatment Options Surgery, XRT Chemotherapy Surgery, Chemotherapy Liver transplantation Surgery, XRT Chemotherapy 5-year overall survival ~32– 68%* ~9% ~10-90% 19 |
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, and solid tumors There is a tremendous need for a safe and effective targeted molecular medicine for these patients *Source: SEER data 20 |
IDH-Mutant Inhibitors Clinical Development Strategy – Early Clinical Evidence October 15, 2014 Chris Bowden, M.D., Chief Medical Officer |
22 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 |
Indication % IDHm Low grade glioma & 2 ary GBM 68-74 Chondrosarcoma 40-52 Acute Myeloid Leukemia (AML) 6-10 MDS/MPN 3 Intrahepatic Cholangiocarcinoma 11-24 Ollier/Maffucci 80 Others* (colon, melanoma, lung, prostate) 1-3 Acute Myeloid Leukemia (AML) 9-13 MDS/MPN 3-6 Angio-immunoblastic NHL 30 Intrahepatic Cholangiocarcinoma 2-6 Giant Cell Tumor of the Bone 80 D2HG Aciduria 100 Others* (melanoma, glioma) 3-5 IDH1m IDH2m IDH1m and IDH2m: Distinct Genetically Defined Populations 23 Based on literature analysis. Estimates will continue to evolve with additional future data. ** Includes “basket” of emerging unconfirmed indications. |
Phase I Trials for AG-221 and AG-120 Leading the Clinical Development of IDH Inhibitors AG-221 AML + Heme malignancies Solid Tumors 2014 March 2013 September 2014 October Study start AG-120 AG-221 (planned 4Q) AG-120 AG-221 expansion 24 |
IDH Inhibitors: AML Clinical Development Paradigms Diagnostically Defined Population Demonstrate Clinical Benefit Acute Myeloid Leukemia (AML) IDH1m+ AML IDHm+ AML IDH2m+ AML Precision Magnitude Efficacy Decrease disease morbidity Safety and convenience 25 |
26 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 Eytan M. Stein 1 , Martin S. Tallman 1 , Daniel A. Pollyea 2 , Ian W. Flinn 3 , Amir T. Fathi 4 , Richard M. Stone 5 , Ross L. Levine 1 , Samuel Agresta 6 , Hua Yang 6 , Bin Fan 6 , Kate Yen 6 , Stéphane de Botton 7 1 Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York; 2 University of Colorado Cancer Center, Aurora, CO; 3 Sarah Cannon Research Institute, Nashville, TN; 4 Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; 5 Dana-Farber Cancer Institute, Boston, MA; 6 Agios Pharmaceuticals, Cambridge, MA; 7 Institut Gustave Roussy, Villejuif, France |
27 CR = Complete Response CRp = Complete Response, Incomplete Platelet Recovery CRi = Complete Response, Incomplete Hematologic Recovery PR = Partial Response (>50% Decrease in Bone Marrow Blasts) 30 mg BID N=7 50 mg BID N=7 75 mg BID N=6 100 mg QD N=5 100 mg BID N=5 150 mg QD N=5 Total N=35 CR 2 3 - 1 - - 6 CRp 1 - - - 1 - 2 CRi - 1 - - - - 1 PR 1 1 1 - 1 1 a 5 SD - 1 2 1 - 1 5 PD - 1 1 3 1 - 6 b ORR 4/4 5/7 1/4 1/5 2/3 1/2 14/25 NE 3 - 2 - 2 3 d 10 a PR at C1D15 b 3 Subjects with Clinical PD/Clinical Deterioration (No Day 28 Marrow Assessment). c Subjects did not have a Day 28 Marrow Assessment (Off Study). d Subjects on study (<28 days at data cut). SD = Stable Disease PD = Progressive Disease NE = Not Evaluable ORR = CR + CRp + CRi + PR 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 Note: Based on unaudited data from live clinical database c c c |
28 C2 C3 C4 C5 C6 C7 Bone Fracture, Death Unrelated Neutrophil counts increase by C1D15. Counts are in normal range by C2D15 in responders. 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 30 MG BID 50 MG BID 75 MG BID 100 MG QD 100 MG BID 150 MG QD Transplant CR CRp CR PR PR CRp PR CR PR CR* CR PR CRi CR** On Study Off Study Response Bone Marrow *Bone marrow blasts 7% at C51. Dose escalated to 75 mg BID on study in CR, **Bone marrow blast increase to 11% at C3D1. Dose escalated to 75 mg BID. On study Note: Based on unaudited data from live clinical database |
AG-221: Evidence of Cell Differentiation Leading to Potential Paradigm Shift in Treatment Data Presented at European Hematology Association (EHA) on 6/14/2014 29 |
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. 30 Stein EM et al. (2014) 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. |
Total Subjects* (N=18) n (%) MedDRA Preferred Term: Grade 1 or 2 Grade 3 All Events Nausea 4 (22.2) 0 4 (22.2) Pyrexia 4 (22.2) 0 4 (22.2) Thrombocytopenia 1 (5.6) 3 (16.7) 4 (22.2) Anemia 2 (11.1) 1 (5.6) 3 (16.7) Dizziness 3 (16.7) 0 3 (16.7) Febrile neutropenia 0 3 (16.7) 3 (16.7) Peripheral edema 3 (16.7) 0 3 (16.7) Sepsis 0 3 3 (16.7) Cough 2 (11.1) 0 2 (11.1) Diarrhea 1 (5.6) 1 (5.6) 2 (11.1) Fatigue 1 (5.6) 1 (5.6) 2 (11.1) Leukocytosis 0 2 (11.1) 2 (11.1) Neutropenia 1 (5.6) 1 (5.6) 2 (11.1) Petechia 2 (11.1) 0 2 (11.1) Rash 1 (5.6) 1 (5.6) 2 (11.1) *Based on number of subjects with AE data reported in database as of 25 April 2014 AG-221 Phase 1 Early Data: Most Common Side Effects Data Presented at European Hematology Association (EHA) on June 14, 2014 31 Total Subjects* (N=18) n (%) |
32 Phase 1 ASH 2014 Initiated October 2014 AG-221 Phase I Trial in AML & Other Heme Malignancies Expansion Cohorts Advanced Heme Malignancies Ongoing Dose Escalation |
Phase 1 Ongoing Dose Escalation Initiated October 2014 Safety-dose limiting toxicity, dose modifications, chronic toxicity Pharmacokinetics-exposure, half-life, variability Pharmacodynamics-2-HG reduction Clinical activity: remissions and durability Dose Selection Criteria Dose Selected for Start of Expansion Cohorts: Multiple Factors Considered 100 mg Single Daily Dose IDH2m+ AML and Heme malignancies Dose Selected ASH 2014 Expansion Cohorts Advanced Heme Malignancies |
AG-221: Phase I Expansion Cohorts: Homogenous patient populations Phase 1 Ongoing Dose Escalation Initiated October 2014 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 60 yrs (transplant ineligible) n=25 Dose Selected ASH 2014 Advanced Heme Malignancies Expansion Cohorts |
BREADTH Phase 1 Initiated October 2014 AG-221 Clinical Development Considerations Relapsed/Refractory AML Front-Line | Unfit Patients Maintenance (Post BM Transplant) Front-Line | Fit Patients SPEED ASH 2014 Additional heme malignancies (e.g. MDS) Potential Future Directions in Collaboration with Celgene Options informed by: Advanced Heme Malignancies Ongoing Dose Escalation Expansion Cohorts • Clinical data • Regulatory input |
36 Accelerated Pathway: - Response rates - Duration of response - Reduction in transfusions & Infections Standard Pathway: Potential Endpoints for Regulatory Approval in Heme and Solid Tumor Cancers with an IDH Mutation U.S. Regulatory Approval Global Regulatory Approval Potential Regulatory Pathways Primary endpoint Secondary endpoints Overall survival Relapse free survival Improvement in disease related symptoms |
37 Untreated AML - (no APML) ~ 17K pts 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 Consolidation Relapsed Patients Yes No Front-Line Refractory Patients Clinical Setting Landscape 1 Line Treatment ~60% Source: Market research Willingness to receive tx Supportive care “Gentle” regimen Clinical Trial ~60-70% ~30-40% st |
38 AG-120: Potent & Selective Inhibitor of IDH1 Mutations • Current Status: Two Phase 1 studies initiated in March 2014 • What’s new: Early data from Phase 1 Heme at EORTC/AACR in November Multiple expansion cohorts IHCC, chondrosarcoma, glioma, others Phase 1 Trials Advanced hematologic malignancies Study Designs “3 + 3” design All patients IDH1m+ Assess safety, PK Assess 2HG levels, Advanced Solid Tumors Current Status • AML MDS MPD Potential Future Directions in Collaboration with Celgene Expansion Studies Full Development Potential for rapid entry into definitive efficacy trials in IDH1m+ patients Hematology: “Speed” and “Breadth” options in AML/MDS, similar to AG- 221 program Rare IDH disorders Solid tumors: fast path opportunities • • Multiple expansion cohorts differentiation, efficacy |
39 IDH Inhibitors as Potential Foundation of Therapy for IDH Mutant Cancers Early Development - IDH mutation positive patients only - Partner with research for strong correlative science Speed - Data driven expansion cohorts - High unmet medical need populations Breadth - In-depth understanding of entire IDHm+ population indication - Randomized trials targeting global registration and reimbursement Keys to Success in Clinical Development |
IDH-Mutant Inhibitors Clinical Development Strategy – Early Clinical Evidence October 15, 2014 Chris Bowden, M.D., Chief Medical Officer |
Rare Genetic Disorders of Metabolism: Pyruvate Kinase Deficiency and PKR Activator, AG-348 Scott Biller, Ph.D., Chief Scientific Officer October 15, 2014 |
2 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 PK deficiency patient blood ex vivo A suite of biomarkers have been implemented in our healthy volunteer trials and will be included in patient trials This is very cool science! |
3 Rare Genetic Disorders of Metabolism Archibald Garrod >1900’s >1980’s-00’s 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 phenotypes >2010’s Enzyme Replacement Therapies (mostly Lysosomal Storage Disorders) 600 RGDs described featuring inherited mutation in single metabolic enzyme Unaddressed rare disorders of metabolism Significant unmet need |
4 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 Diseases (RGD-M) Multiple genes causing disease = Gene = Disease condition Gene causing multiple diseases Agios analysis of databases of genetic disorders: >600 Rare Genetic Disorders of Metabolism Systematic Disease Selection Frequency |
5 Agios Approach to Correct Metabolic Pathway Defects Metabolite A pool Enzyme 1 Metabolite B pool Metabolite C pool Enzyme 2* (mutant) |
6 Alternative Pathway Pathway modulation: Reduce toxic metabolites or bypass metabolic defect by targeting upstream/adjacent pathway Allosteric modulation: Restore metabolic flow by directly modulating biochemical activity or stabilizing the protein Metabolite B pool Metabolite C pool Metabolite A pool Agios Approach to Correct Metabolic Pathway Defects Enzyme 1 Enzyme 2* (restored) |
7 Pyruvate Kinase (PK) Deficiency: Rare Hematological Genetic Disorder Caused by >160 hypomorphic mutations in PKR Autosomal recessive disorder characterized by chronic hemolytic anemia Poor prognosis - Presents in infancy or childhood with severe hemolytic anemia and jaundice - No disease-altering therapies - Transfusions and splenectomy common to manage symptoms - Lifelong risks from chronic hemolysis and iron overload Blood smear in PK Deficiency Disease Characteristics Agios’ Therapeutic Approach PKR enzyme catalyzes the final step in glycolysis in red blood cells In PK Deficiency, low PKR activity leads to low ATP levels and high rate of hemolysis in red blood cells Agios has developed AG-348, a small molecule activator that restores activity of mutant PKR |
8 Glycolysis Glycolysis Glycolysis Glycolysis ATP ATP ATP ATP PKR PKR mPKR mPKR PKR mutations lead to low pyruvate kinase activity and ATP levels Low ATP levels result in decreased red cell life span, hemolysis and anemia Red Blood Cells are Highly Dependent on Glycolysis for ATP Generation Normal Red Cell PK Deficient Red Cell |
9 Glycolysis Glycolysis Glycolysis Glycolysis ATP ATP mPKR + AG 348 mPKR + AG 348 AG-348 Restores PKR Activity and Corrects the Metabolic Deficiency PK Deficient Red Cell PK Deficient Red Cell + AG-348 mPKR mPKR ATP ATP |
10 AG-348 Active Site PKR Enzyme: Active Tetramer Indicating Mutations and AG-348 Binding Site AG-348 binds at the PKR dimer-dimer interface, distal to common mutations associated with PK deficiency AG-348 is Designed to Activate a Wide Variety of Mutant PKR Enzymes |
11 Enzyme thermal stability of the most common unstable mutant R510Q AG-348 activates PKR WT and nearly all PKR mutant enzymes tested AG-348 increases the thermal stability of unstable mutant enzymes AG-348 activates 10 of 11 common mutants, as well as WT PKR AG-348 Increases Catalytic Efficiency and Improves Stability of Mutant Enzymes Source: Kung, ASH poster 2013 |
12 Two Mechanisms for AG-348 Action Increased catalytic efficiency ATP Glycolysis Glycolysis ATP |
13 Degradation Glycolysis Two Mechanisms for AG-348 Action Increased protein stability ATP |
14 PK Deficient Red Cells Have Metabolic Defects That Result in Chronic Hemolysis Glucose 1,3-DPG 3-PG PEP Pyruvate PKR 2,3-DPG ` ATP Glucose 1,3-DPG 3-PG PEP Pyruvate mPKR ` ATP WT PKR Mutant PKR WT PKD 2,3-DPG ATP 2,3-DPG Source: Kung, ASH poster 2013 2,3-DPG levels are elevated and ATP levels reduced in PK deficient red cells |
15 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 |
16 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 - Multiple doses lower 2,3-DPG and raise ATP levels Source: Agios internal research |
17 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 13C 3 labeled Unlabeled +AG-348 13C 3 labeled Unlabeled Vehicle Source: Agios internal research |
18 Robust Suite of Metabolic Biomarkers in Place for Healthy Volunteer and Patient Trials 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 Pharmacodynamic Biomarkers Glycolytic Flux Source: Kung, ASH poster 2013 |
19 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 incorporated into the healthy volunteer studies to evaluate WT PKR activation and metabolic response |
Rare Genetic Disorders of Metabolism: Pyruvate Kinase Deficiency and PKR Activator, AG-348 Scott Biller, Ph.D., Chief Scientific Officer October 15, 2014 |
Sam Agresta, MD, MPH & TM VP, Head of Clinical Development Pyruvate Kinase-R (PKR) Program Disease Background & Clinical Development Strategy October 15, 2014 |
22 Today’s Key Takeaways 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 underway University of Milan Stanford |
23 Source: Zanella. Blood Rev. 2007; 21(4):217;, Blood and Bone Marrow Pathology; Wintrobe’s Clinical Hematology; Physician Interviews; Market Research. Pyruvate Kinase (PK) Deficiency A Destructive Red Blood Cell Disease Disease Pathophysiology Description • Rare genetic disease often presenting at birth Etiology • Caused by mutations in PK-LR gene coding for Erythrocyte Pyruvate Kinase Clinical Presentation • Lifelong hemolytic anemia and associated morbidities Diagnosis • PKR enzyme activity and genetic testing Disease Overview PK deficiency Normal Red Blood Cell Blood Smear |
24 Disease Progression from Infants to Adults Splenectomy Jaundice Iron Overload Pyruvate kinase deficiency is the most common enzyme abnormality of the glycolytic pathway |
25 Source: Physician Interviews; Zanella. Blood Rev. 2007; 21(4):217; Market Research Hb: Hemoglobin. Majority of Patients Have Moderate to Severe Disease Adult and Pediatric Diagnosed PK Deficiency Population Mild (20 – 30%) Moderate (20 – 30%) Severe (40 – 50%) Description • Transfusion typically required during stressors: pregnancy or infection • Patients are often diagnosed in 30s and 40s after suffering from aplastic crisis • Severity and symptoms range • Diagnosed at all ages • Seek treatment and diagnosis when intolerant of low Hb Annual Transfusions > 12 0 2 <1Transfusions Per Year 4 6 8 10 > 12 0 2 1 – 4 Transfusions Per Year 4 6 8 10 > 12 0 2 >4 Transfusions Per Year 4 6 8 10 • Present at an early age and diagnosed in childhood • Require aggressive blood transfusion management • Disease severity may attenuate |
26 Sources: Wintrobe’s Clinical Hematology; Physician Interviews; Market Research PK Deficiency Diagnosis Currently Requires Many Steps to Confirm Step Key Details • Initial symptoms of anemia may include pallor, fatigue, weakness, or reduced exercise tolerance • Complete blood count confirms anemia • Blood smear is often performed concurrently to evaluate cell morphology • Reticulocyte count demonstrates reticulocytosis which is indicative of hemolytic anemia • An enzyme assay for the activity of PKR or a genetic test can confirm disorder • Tests may also be performed to differentiate against other forms of hemolytic anemia Presentation and Symptom Evaluation Evaluation for Anemia Evaluation for Hemolytic Anemia Evaluation for PK Deficiency |
27 Description Distribution of Patient Age at Time of Diagnosis • Seek diagnosis due to inability to function with current level of anemia • Diagnosis occurs when growth and activity are closely monitored • Most common in severe patients or those with siblings who are also afflicted Age Group Source: Market Research Majority of Patients are Diagnosed due to Symptoms Pediatric ~50% Adult ~40% ~10% Neonatal Pediatric 1 Month – 18 years Adult > 18 years Neonatal < 1 Month |
28 Availability of a therapy may increase awareness and willingness to diagnose patients Estimated PK Deficiency Patient Population (U.S. and EU5) Estimate Source: Physician Interviews; Zanella. Blood Rev. 2007; 21(4):217; Market Research Estimates based on genetic modeling Severe (40 – 50%) Similar to Other Rare Genetic Diseases, PK Deficiency is Largely Undiagnosed Diagnosed Patients (~2.4 K) Total U.S. and EU5 Population (~32 K) Mild (20 – 30%) Moderate (20 – 30%) 5 – 10% diagnosed with PK deficiency |
29 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-leukemia Chemotherapy may cause a more common and milder form of PK deficiency Source: Etiemble et al, 1980 |
30 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) gallstones Transient aplastic anemia caused by infection Folic acid deficiency secondary to increased requirements Clinically significant iron overload Growth delay, frontal bossing, skin ulcers Chronic Hemolysis • • • • • • • • • |
31 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 newborns require multiple transfusions and/or a splenectomy 30% patients are transfusion-dependent in childhood or until splenectomy Gallstones Cholecystectomy 30% 25% Transfusions 64% Clinical Data in 61 Patients with PK Deficiency Median Age at Diagnosis 16 yrs (1 day- 65 yrs) |
32 Transfusion Requirements in an Infant with PK Deficiency Source: Smiers et al, 2007 |
33 Splenectomy Offers Minimal Disease Impact Spleen intact Spleen removed Source: Zanella et al. 2005 Normal level • |
34 Extra-Medullary Hematopoiesis Abnormal bone marrow production Source: Pratt et al. 2005 60 year old woman with PK Deficiency with spinal cord compression |
35 Iron Overload Impacts Mortality Iron Deposition in the Liver Liver Pathology Clinical Symptoms Source: Morton et al. 2011 Normal Portal and Central Veins No Signs of Fibrosis |
36 AG-348: Clinical Development Current: Supportive only Future: Targeting enzyme defect Bone Marrow Transplant Transfusion Iron chelation and Phototherapy Lifelong Antibiotics Chole- cystectomy Folic acid Splenectom y AG-348 |
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 37 |
38 PK Deficiency Natural History Study Designed to Inform Registration Path Study will capture retrospective and prospective clinical data, annual quality of life measures, and genetic diagnostic information Understanding the Disease & Identifying Patients and Treatment Centers Study Design Longitudinal cohort with retrospective, baseline, and annual collection of data from routine care visits for PK deficiency and its complications Participants will be followed for at least 2 years Population: Participants of any age with PK deficiency Approximately 100 participants Objectives: Increase understanding of range of symptoms and complications of PK deficiency Transfusion burden in splenectomized and non-splenectomized PK deficiency Association of patient reported outcome measures with clinical parameters Incidence and timing of splenectomy Prevalence and treatment of iron overload Prevalence of co-morbidities Determine pregnancy outcomes Description of Genotypic/Phenotypic variation |
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 39 |
40 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 healthy volunteer studies at ASH 2014 Natural History Study: 23 sites and >50 patients enrolled AG-348: Profile Activator of the PK enzyme Orally dosed Corrects underlying metabolic defect in preclinical models |
41 Phase 1 Phase 2 to Late Development AG-348 Clinical Development Status Single ascending dose (SAD) escalation (Healthy Volunteer Clinical Studies) Current Status Potential Future Directions Study Designs Multiple ascending dose (MAD) escalation Randomized double blind placebo controlled trials Single experienced U.S. site Assess safety, PK and PD Potential for activation of wild type PK enzyme and effect on metabolites Select dose range for Phase 2 study in PK deficiency patients Plan to initiate Phase 2 trial in adults with PK deficiency by early 2015 Development in pediatric patients based on POC in adults |
42 Phase 2 Study Considerations Potential Open-label Global (US, EU) Single-Arm Phase 2 End of Treatment Treatment: - Dose/Schedule decided by healthy volunteer studies Clinical endpoints: - Safety - Efficacy • Hemoglobin: stabilization and/or increase • Transfusion frequency and amount - Quality of life (endpoints evaluated in NHS) PK/PD Markers Screening/Observati on Period Hemoglobin Set Point Transfusion Requirements* Hemolysis Markers Reticulocytes QOL’s AG-348 Treatment |
43 Potential Regulatory Endpoints for Approval Key clinical endpoints: - Reduction in transfusion(s) - Avoid splenectomy - Change in hemoglobin - QOL assessments PILOT (Phase II) TRIUMPH (Phase III) SHEPHERD (Phase III) Patient Enrollment 11 transfusion- dependent PNH patients 4 transfusions in past year 87 transfusion-dependent PNH patients 4 transfusions in past year 97 transfusion-dependent PNH patients 1 transfusion in past 2 years, but 3 in past year Length ~12 week ~26 week 52 week Primary and Secondary Endpoints Pharmacokinetics Evaluated reduction in incidence of intravascular hemolysis, hemoglobinuria and transfusion requirements Determine efficacy via stabilization of hemoglobin and number of packed RBCs transfused Compared transfusion requirements and LDH against placebo Evaluated primary efficacy endpoints of hemolysis as determined by LDH Secondary endpoints: Fatigue and quality of life as determined by survey Soliris® (Eculizumab) in PNH may provide regulatory precedent |
44 Source: Market Research AG-348: Potential Benefit Across All of PK Deficiency Patients • Patients receiving transfusions suffer from anemia, poor QOL, and potentially severe adverse events • Although rarely transfused, underlying hemolytic anemia causes morbidity ILLUSTRATIVE Potential Addressable Population Expansion All Other Patients with Poor Quality of Life Patients with >4 Annual Transfusions Patients with >1 Annual Transfusion |
45 Summary Potential for AG-348 to be first medicine to target underlying defect 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 underway |
Sam Agresta, MD, MPH & TM VP, Head of Clinical Development Pyruvate Kinase-R (PKR) Program Disease Background & Clinical Development Strategy October 15, 2014 |
October 15, 2014 David Schenkein, M.D., Chief Executive Officer Closing Remarks & Q&A |
48 Clinical Pipeline Progress: Building Momentum Healthy volunteer data at ASH 2014 Initiate Ph 2 in PK deficiency patients by early 2015 AG - 221 AG - 120 AG - 348 Remaining 2014 Potential Product Milestones AG - 221 AG - 120 AG - 348 Ph 1 heme data at EORTC/AACR (Nov. 19) Clear POC Initiated expansion cohorts Fast Track & Orphan Drug Designations in US Two Phase 1 trials ( IDH1m+ heme and solid tumors) initiated and enrolling well Additional Phase 1 data at ASH 2014 On track to initiate trial in IDH2m+ solid tumors 2014 Product Milestones Achieved Completed SAD study; Met primary endpoint in SAD & MAD studies |