Agios Pharmaceuticals, Inc. · NASDAQ:AGIO
Agios Pharmaceuticals — Investor Day (October 2015)
145 slides from Agios Pharmaceuticals's investor day presentation, Oct 16, 2015
Slide 1: What’s Possible at Agios
What’s Possible at Agios October 16, David Schenkein, M.D. Chief Executive Officer
Slide 2: Cautionary Note Regarding Forward-Looking Statements
Cautionary Note Regarding Forward-Looking Statements This “2015 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 3: We Are Driven By a Clear Vision and Values
We Are Driven By a Clear 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 4: Making a Difference for Patients & Building Long-Term Value
Making a Difference for Patients & Building Long-Term Value Vision Science Team/Culture Execution
Slide 5: Building a Great Sustainable Biopharmaceutical Company
Building a Great Sustainable Biopharmaceutical Company Commercial Capabilities Begin to Build Research Platform Continues to Expand AG-221/AG- AG-348 5th Agios Agios Labs IDH Celgene 120 Proof of Proof of medicine Open Discovery Partnership Concept Mechanism entering clinic; 200th employee 2009 2009
Slide 6: Agios 2015
Agios 2015 Five clinical stage investigational medicines with possibility to help a large number of genetically identified patients Two investigational medicines accelerating towards approval and commercialization A robust and novel pre-clinical pipeline in both cancer and RGDs A organization prepar
Slide 7: Key Updates
Key Updates Advancing the IDHm inhibitors to market as quickly and broadly as possible Design and initiation of AG-221 AML Phase 3 trial (IDHENTIFY) Design of combination trial with “7 + 3” Design of combination trial with azacitidine Driving the PK activator program 5th Agios molecule entering clin
Slide 8: What’s Possible: Our Science
What’s Possible: Our Science
Slide 9: Find the Source of the Problem and Correct It
Find the Source of the Problem and Correct It Discovering novel unprecedented targets Tackling tough chemistry with allosteric inhibitors and activators Requiring a predictive marker prior to development candidate selection Exploiting intersection of several key fields: metabolism, genomics, epigene
Slide 10: Find the Source of the Problem and Correct It
Find the Source of the Problem and Correct It A Intensity units) intensity 149.50 Peak (arbitrary B m/z A 146.50 signal C 11.50 time 14.00 2- R132H HG WT signal intensity Day 28 Day 15 Day 0
Slide 11: Find the Source of the Problem and Correct It
Find the Source of the Problem and Correct It 2,3-DPG ruvate Glucose AG-348 Patient A (R510Q/G511R) Arm 1 300 mg q12hr R - PK by Optional Screening Randomization Stratified genotype 3rd Arm Arm 2 mg q12hr L) Dosing period Placebo m g/ ATP m 200 15 mg q12hr n ( i tion 60 mg q12hr a 120 mg q24hr 100 1
Slide 12: What’s Possible: For Patients
What’s Possible: For Patients
Slide 13: What’s Possible for IDHm Patients
What’s Possible for IDHm Patients Next Now Relapsed/ Refractory AML
Slide 14: What’s Possible for IDHm Patients
What’s Possible for IDHm Patients Next Frontline AML Combination trials Maintenance MDS Other hematologic malignancies
Slide 15: What’s Possible for IDHm Patients
What’s Possible for IDHm Patients Goal All IDHm patients screened and treated with an IDHm inhibitor for the entire course of their disease
Slide 16: Exploration of PK Activation in Other Hemolytic Anemias
Exploration of PK Activation in Other Hemolytic Anemias Disease Molecular Lesion Red Cell Characteristics Normal physiology None Biconcave Pyruvate kinase deficiency PKR mutations Echinocyte Sickle cell disease HbS mutation Sickled Beta-globin loss of Beta-thalassemia Microcytic function Mutations i
Slide 17: Novel First-in-Class Clinical Portfolio
Novel First-in-Class Clinical Portfolio Early Stage Late Stage Candidate Indication Primary Commercial Rights Clinical Development Clinical Development R/R AML Phase 3 R/R AML Phase 1 Dose Escalation Expansion 5th Cohort AG-221 Frontline AML Phase 1b Combinations (Q4’15) (IDH2m inhibitor) Frontline
Slide 18: Novel First-in-Class Research Portfolio
Novel First-in-Class Research Portfolio Target Validation Compound Optimization Target C Two Cancer Metabolism Multiple Other Oncology Targets Wave Rare Genetic Metabolic Disorders Multiple RGD Targets Multiple Cancer Metabolism Oncology Three Targets Wave Rare Genetic Multiple RGD Metabolic Disorde
Slide 19: Today’s Agenda
Today’s Agenda Time Speaker 8:30—9:00 am Registration and breakfast 9:00—9:20 am Opening Remarks – What’s Possible at Agios (David Schenkein) IDH Program 9:20—9:40am AG-221/AG-120 and Hematologic Malignancies (Courtney DiNardo—MD Anderson) 9:40—10:00am Clinical and Regulatory Overview (Chris Bowden)
Slide 20: What You’ll Come Away with Today
What You’ll Come Away with Today Confident that we are leading the way in the disruptive field of dysregulated metabolism Clear that we are building world class clinical development and commercial capabilities on the foundation of our innovative research expertise Enthusiastic in your commitment to
Slide 21: IDHm Inhibitors and Hematologic Malignancies
IDHm Inhibitors and Hematologic Malignancies October 16, 2015 Courtney DiNardo, M.D. University of Texas MD Anderson Cancer Center, Houston, TX, USA
Slide 22: AML Is a Devastating Blood Cancer
AML Is a Devastating Blood Cancer Most common leukemia in adults Rapid growth of abnormal white blood cells interfere with normal blood cell production Few treatment options, with no improvements in decades 5-year survival rate is 20-25% Median age at diagnosis 68-72 years Many cannot tolerate stand
Slide 23: Few Advances in AML in Decades
Few Advances in AML in Decades Allogeneic ATRA for Daunorubicin transplant t15;17+ APL 90 mg/m2 1970 1980 1990 2000 2010 “7+3” Ara-C Induction Consolidation Acute Promyelocytic Leukemia(APL) All-trans retinoic acid (ATRA) induces terminal differentiation of APL cells, leading to cures when combined
Slide 24: Treatment Options for Newly Diagnosed AML
Treatment Options for Newly Diagnosed AML CR Consolidation CTX Fit for Intensive Transplant if Treatment (IC) 7+3 Eligible ~10-12K patients Non- AML CR 2nd Induction ~18,860 patients Vidaza Unfit for IC HMA/LDAC* Factors Influencing ~5-7K Patients Supportive Care Therapy Selection Clinical Trial Per
Slide 25: Limited Treatment Options for Relapsed/Refractory (R/R) AML
Limited Treatment Options for Relapsed/Refractory (R/R) AML Intensive Salvage Fit for Intensive CTX Treatment (IC) Transplant Clinical Trial Factors Influencing Therapy Selection R/R AML Performance Status Cytogenetics HMA/LDAC* Molecular Analysis Unfit for IC Supportive Care Clinical Trial CTX = Ch
Slide 26: Limited Treatment Options for Relapsed/Refractory (R/R) AML
Limited Treatment Options for Relapsed/Refractory (R/R) AML Factors Influencing Therapy Selection R/R AML Performance Status Cytogenetics Molecular Analysis CTX = Chemotherapy HMA = Hypomethylating Agent LDAC = Low Dose Cytarabine Thol F, Blood. 2015
Slide 27: Mutations in IDH Occur Frequently in AML and MDS
Mutations in IDH Occur Frequently in AML and MDS IDH1m and IDH2m occur frequently in AML and MDS and are associated with a poor prognosis 2-HG acts as a competitive inhibitor of á-KG, which includes DNA and histone modifying enzymes and prolyl hydroxylases involved in collagen metabolism and hypoxia
Slide 28: IDH Mutations Lead to Unchecked Proliferation
IDH Mutations Lead to Unchecked Proliferation Mutations in IDH1 and IDH2 confer neomorphic activity Increased levels of 2-HG affect epigenetic control of the cell Inhibiting mutant IDH1 and IDH2 promotes maturation IDH Epigenetic “Re-Wiring” Unchecked Cell Proliferation Isocitrate mIDH 2HG CANCER aK
Slide 29: First-in-Class, Oral, Potent, Selective, Reversible Inhibitors
First-in-Class, Oral, Potent, Selective, Reversible Inhibitors AG-221 is an inhibitor of mutant IDH2 Study AG-221 Design Single-arm, open-label dose escalation and expansion Participants Patients with IDH2 mutation-positive hematologic malignancies, including R/R AML, MDS and untreated AML Treatment
Slide 30: Patients Are Heavily Pre-Treated in Both Studies
Patients Are Heavily Pre-Treated in Both Studies AG-221 Demographics All patients R/R AML N=177 n=124 Age in years, median 69 67 (range)(22–90)(22–90) ECOG performance status, n (%) 0 43 (24) 30 (24) 93 (53) 65 (52) 35 (20) 27 (22) No. of prior regimens, median 2 2 (range)(0-11)(1-11) Prior Transpla
Slide 31: AG-221 and AG-120 Demonstrate Favorable Safety Profiles
AG-221 and AG-120 Demonstrate Favorable Safety Profiles AG-221 Safety Summary Therapy has been well tolerated up to 450 mg QD – MTD not reached – Recommended dose for expansion is 100 mg PO QD 30-day all-cause mortality of 4.5%; 60-day, 11.3% Isolated increases in indirect bilirubin observed AG-120
Slide 32: Traditional Response Criteria May Overlook Certain Aspects of Clinical Benefit
Traditional Response Criteria May Overlook Certain Aspects of Clinical Benefit Modified IWG Absolute Neutrophil Blasts Platelets Criteria Count (ANC) Marrow CR < 5% No recovery No recovery CR < 5% > 100K >1,000 CRi/CRp <5% > 100K OR > 1,000 50% decrease Partial Remission > 100K > 1,000 to 5-25% Does
Slide 33: AG-221 Single-Agent Response Rates of 30-50% in Phase 1
AG-221 Single-Agent Response Rates of 30-50% in Phase 1 R/R AML Untreated MDS Other Total n=111 AML n=14 n=10 N=157 n=22 CR, n (%) 20 (18.0) 3 (13.6) 2(14.3) 1 (10.0) 26 (16.6) CRp, n 1 — 1 1 3 PR, n 16 2 — — 18 mCR, n 8 1 4 1 14 CRi, n 1 1 — — 2 SD, n 49 7 4 7 67 PD, n 7 5 2 — 14 NE, n 9 3 1 — 13 O
Slide 34: Similar Magnitude of Response for AG-120
Similar Magnitude of Response for AG-120 Cohorts 1 + 2 Cohort 3 Cohort 4 Cohort 5 Total ?300 mg/day 500 mg QD 800 mg QD 1200 mg QD N=52 n=8 n=22 n=15 n=7 CR, n 2 3 1 2 8 CRp, n — — — 1 1 PR, n — 1 3 — 4 Marrow CR, n — 3 — — 3 SD, n 5 13 7 2 27 PD, n 1 2 4 1 8 NE, n — — — 1 1 ORR, n(%) 2/8 (25) 7/22
Slide 35: IDHm Inhibitor Response Fundamentally Different from Chemotherapy
IDHm Inhibitor Response Fundamentally Different from Chemotherapy D15 Marrow Conventional Chemotherapy Maturation of Biopsy post mutated cells in conventional response to chemotherapy IDHm treatment shows an empty through the first marrow cycle Image: Min Xu M.D. Data Presented at AACR, 4/2014
Slide 36: Durable Responses Associated with Both AG-221 and AG-120
Durable Responses Associated with Both AG-221 and AG-120 AG-221 Treatment duration: 3-month = 88.0% 6-month = 76.1% Median = Not estimable AG-120 Treatment duration: 3-month = 79.1% 6-month = 50.2% Data Presented at EHA, 6/13/15
Slide 37: Rethinking Clinical Benefit for IDHm Inhibitors in AML
Rethinking Clinical Benefit for IDHm Inhibitors in AML Patient with Partial Response Shows Recovery of Platelet and Neutrophil Counts Response to AG-221 appears to be fundamentally different compared to cytotoxic chemotherapy Partial responses convert to complete remission and/or remain as best resp
Slide 38: Rethinking Clinical Benefit for IDHm Inhibitors in AML
Rethinking Clinical Benefit for IDHm Inhibitors in AML Patients with Stable Disease Staying on Treatment Up to 10+ Months AG-221 AG-120 Data Presented at EHA, 6/13/15 Treatment duration estimated using Kaplan-Meier method
Slide 39: Rethinking Clinical Benefit for IDHm Inhibitors in AML
Rethinking Clinical Benefit for IDHm Inhibitors in AML Potential Benefit Associated with Stable Disease for a Patient Treated with AG-221 Day 1 AG-221 Platelets Normal Range Day 1 AG-221 Absolute Neutrophil Count Normal Range Blast count remains elevated with recovery of platelets and neutrophils fo
Slide 40: Hematologic Recovery in Patient with High Risk MDS
Hematologic Recovery in Patient with High Risk Myelodysplastic Syndromes (MDS) Improvement in hematologic parameters and platelet count on AG-221 Hematologic Parameters Counts 4 Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day -4 1 4 11 18 25 32 46 62 75 92 120 148 175 204 232 WBC 1.1
Slide 41: Key Takeaways
Key Takeaways IDHm inhibitors work by a unique mechanism entirely different from conventional chemotherapy Treatment with oral drugs AG-221 and AG-120 is well-tolerated AG-221 and AG-120 show clear activity as single agents – Durable complete remissions – Durable non-CR responses – Prolonged stable
Slide 42: Bringing AG-221 and AG-120 To Patients
Bringing AG-221 and AG-120 To Patients Clinical and Regulatory Overview October 16, 2015 Chris Bowden, M.D. Chief Medical Officer
Slide 43: Phase 1 Program Rapidly Defined Single-Agent Profile for IDHm Inhibitors in R/R AML
Phase 1 Program Rapidly Defined Single-Agent Profile for IDHm Inhibitors in R/R AML Phase 1 expansion cohorts designed to demonstrate compelling clinical benefit with registration quality data Efficacy Complete Remissions AG-120 AML IDH1m Partial Remissions Expansion Cohort R/R AML N~125 Safety Adve
Slide 44: Development Program Targets Multiple Lines of Treatment
Development Program Targets Multiple Lines of Treatment from R/R to Frontline AML Relapsed Newly Diagnosed (Untreated) 2nd+ Relapse Intensive Non-Intensive Phase 1? 2 Phase 1 Phase 1 IDHm+ VIDAZA® AG-221 Expansion IDHm+ Induction (7+3) + + AG-221 or AG-120 AG-221 or AG-120 Ongoing Phase 1 Planned AG
Slide 45: “IDHENTIFY” Trial
“IDHENTIFY” Trial A Phase 3, multicenter, open-label, randomized study comparing the efficacy and safety of AG-221 (CC-90007) vs. conventional care regimens in older patients with late stage Acute Myeloid Leukemia harboring an IDH2 mutation
Slide 46: IDHENTIFY: Global Phase 3 Study of AG-221 in R/R AML
IDHENTIFY: Global Phase 3 Study to Evaluate the Efficacy of AG-221 in R/R AML KEY INCLUSION AG-221/CC-90007 1° ENDPOINT > 60 years Starting 100 mg QD OS IDH2+ 28 day cycles KEY 2° 280 patients nd rd Randomization R/R AML after 2 /3 No crossover ENDPOINTS line COMPARATOR EFS STRATIFIED BY Best Suppor
Slide 47: IDHENTIFY Is a Global Phase 3 Study
IDHENTIFY Is a Global Phase 3 Study U.K. German y Russia Canada Belgium Denmark France Austria South Korea ~130 sites will U.S. Spain Italy participate Brazil Australia
Slide 48: What’s Possible for IDHm Patients
What’s Possible for IDHm Patients A Roadmap for Speed and Breadth All IDHm patients screened and Goal treated with an IDHm inhibitor for the entire course of their disease Next Frontline AML Combination trials Now Maintenance MDS Other hematologic malignancies Relapsed/ Refractory AML
Slide 49: Frontline Therapy: Novel Clinical Development Strategies
Frontline Therapy: Novel Clinical Development Strategies Phase 1 Eligible for Intensive 7+3 * Newly + Chemotherapy Diagnosed AG-221 or AG-120 Potential AML Registration IDH1m+ Trials or Phase 1/2 Not Eligible for IDH2m+ Intensive VIDAZA® + Chemotherapy AG-221 or AG-120 *7+3-Ara-C (Days 1-7), Daunoru
Slide 50: Intensive Eligible Patients: Adding IDHm Inhibitors to Standard of Care
Intensive Eligible Patients: Adding IDHm Inhibitors to Standard of Care IDH1m (N~45) AG-120 AG-120 + + AG-120 (7+3) Ara-C* Newly Phase 1 Trial Objectives: Diagnosed AML MAINTENANCE Safety IDHm INDUCTION CONSOLIDATION (1 year) PK Eligible for 7+3 PD IDH2m (N~45) Preliminary efficacy Not Eligible for
Slide 51: Non-Intensive Patients: Adding IDHm Inhibitors to Standard of Care
Non-Intensive Patients: Adding IDHm Inhibitors to Standard of Care PHASE 1 RANDOMIZED PHASE 2 Establish Safety for Compare Efficacy of Combination combinations versus VIDAZA® Newly VIDAZA® Diagnosed IDH1m AML AG120 + VIDAZA® IDH1m+ IDHm VIDAZA® +AG-120 Not Eligible VIDAZA® for 7+3 IDH2m AG-221+VIDAZ
Slide 52: MDS Is a New Development Horizon
MDS Is a New Development Horizon Clinical development strategies for MDS are being evaluated VIDAZA® one of few approved agents High-risk MDS after failure of hypomethylating agent remains an area of high unmet medical need Also potential in low-risk population (role for oral drug) 11 Image: David S
Slide 53: What’s Next at ASH
What’s Next at ASH Seven abstracts accepted (four for AG-221 and AG-120) New data from dose escalation and expansion cohorts New molecular data
Slide 54: Key Takeaways
Key Takeaways R/R AML expansion cohorts in full operational mode Broadening AML clinical development program into frontline Novel trial design goals – Bringing IDH1m and IDH2m patients into the same protocol – Efficiently transition from Phase 1 to Phase 2 IDHm inhibitors have the potential for a pa
Slide 55: IDH Development in Solid Tumors
IDH Development in Solid Tumors October 16, 2015 Sam Agresta, M.D., Agios Tim Cloughesy, M.D., UCLA
Slide 56: Key Takeaways for Solid Tumors
Key Takeaways for Solid Tumors Significant opportunity to develop targeted therapies across IDHm solid tumors Uncharted development area with new biology and potential for differentiation treatment approach High prevalence IDHm solid tumors are difficult-to-treat diseases with surgery as the only ef
Slide 57: Changing the Natural History of IDHm Solid Tumors
Changing the Natural History of IDHm Solid Tumors Our vision is to develop a foundational therapy used through multiple stages of any IDHm tumor where POC is established Post-resection to prevent Adjuvant recurrence ? potential cure Relapsed/Refractory Setting Suppress driver mutation as Frontline m
Slide 58: Understanding the Role of Differentiation Therapy in Solid Tumors
Understanding the Role of Differentiation Therapy in Solid Tumors Differentiation Restored Epigenetic Inhibitor “Re-Wiring” IDH Isocitrate mIDH 2HG Normal Cell Death / Homeostasis Differentiation aKG HSC Progenitor Mature Cell
Slide 59: Goal is to Explore AG-120 and AG-221 in IDHm Solid Tumors
Goal is to Explore IDH Mutations AG-120 and AG-221 in IDHm occur across multiple solid tumor indications Solid Tumors Intrahepatic Glioma Chondrosarcoma Cholangiocarcinoma (IHCC) Low grade and 2ary GBM Bile ducts Cartilage Incidence 5K 2K – 4K 700-1000 (cases/year U.S.) Prevalence (U.S.) 24K 5K — ID
Slide 60: Glioma
Glioma Tim Cloughesy M.D., UCLA
Slide 61: Glioma Is a Devastating CNS Neoplasm
Glioma Is a Devastating CNS Neoplasm Patient with an IDH1m right temporal lobe low-grade glioma (LGG) 34 year old 37 years old 39 years old 41 years old Treated with surgery followed by radiation Stable disease, observation Progressive disease. Attempts to control disease with multiple chemotherapie
Slide 62: Glioma: Primary CNS Neoplasms
Glioma: Primary CNS Neoplasms Multiple neuroglial cells (eg., astrocytes, oligodendrocytes) Varying degrees of tumor aggressiveness - Slower growing: LGG are WHO Grades 1 and 2 - Rapidly progressive: High-grade glioma (HGG) are WHO Grades 3 and 4 About 23,000 cases of expected in U.S. (2015) Common
Slide 63: IDHm Glioma Is a Distinct Disease
IDHm Glioma Is a Distinct Disease Discovered in GBM samples in 2008 Different genetic/ epigenetic profile as compared to IDH wild type The Cancer Genome Atlas Research Network. N Engl J Med 2015;372:2481-2498
Slide 64: IDHm Is Common in Low-Grade Glioma
IDHm Is Common in Low-Grade (II and III) Glioma IDH1m highly prevalent: – 5% primary GBM – 83% secondary GBM – 60-80% of low-grade diffuse glioma – IDH2m are uncommon Yan et al. N Engl J Med. (2009) 360(8): 765–773.
Slide 65: IDH1m GBMs Have Distinct MRI Appearance and Pathology
IDH1m GBMs Have Distinct MRI Appearance and Pathology Conventional imaging and interpretation of pathology is different for IDHm CNS disease 11 Lai et al. J Clin Oncol (2011) 29:4482-4490
Slide 66: Non-Invasive in vivo Detection of 2-HG by MR Spectroscopy
Non-Invasive in vivo Detection of 2-HG by MR Spectroscopy MR Spectroscopy may serve as an adjunct to conventional imaging modalities to understand response in IDHm glioma 12 Andronesi et al., Sci Transl Med (2012);4:116 Pope et al. J Neurooncol (2012) 107:197–205
Slide 67: IDHm Positive Glioma Manifests in Younger Patients with Longer Survival
IDHm Positive Glioma Manifests in Younger Patients with Longer Survival Lai et al. J Clin Oncol (2011) 29:4482-4490
Slide 68: Radiation and Chemotherapy Prolong Survival but with High Morbidity
Radiation and Chemotherapy Prolong Survival but with High Morbidity and Functional Decline Patient with a IDH1m right frontal lobe Anaplastic Astrocytoma 45 year old (2003) 46 years old 50 year old 57 years old (2015)
Slide 69: Surgical Resection Is Mainstay of Treatment Followed by Radiation and/or Chemotherapy
Surgical Resection Is Mainstay of Treatment Followed by Radiation and/or Chemotherapy Treatment Algorithm for Glioma Newly diagnosed – Surgical intervention – Treatment post-surgery depends on grade Observation alone Chemotherapy Radiation (RT) Chemotherapy plus RT Limited effective treatment option
Slide 70: Key Takeaways: Glioma
Key Takeaways: Glioma IDHm glioma is a distinct disease where IDHm is an early event ? potential driver Conventional imaging modalities are inadequate to assess treatment activity Surgery is the mainstay of treatment for LGG – Chemotherapy plus radiation for HGG Limited treatment options for recurre
Slide 71: Chondrosarcoma
Chondrosarcoma October 16, 2015 Sam Agresta, M.D.
Slide 72: Chondrosarcoma Is a Rare and Potentially Deadly Disease
Chondrosarcoma (CS) Is a Rare and Potentially Deadly Disease Central CS Peripheral CS Heterogeneous group of cancers that arise from cartilage in the bone and joint 3rd most common type of bone cancer – 700-1000 diagnosed per year in the U.S. IDH1/2 mutations occur in 40-50% of central chondrosarcom
Slide 73: IDHm Occur Early in the Transformation Process
IDHm Occur Early in the Transformation Process Proposed multistep genetic model for central chondrosarcoma development and candidates for targeted treatment IDH 1/2 mutations Chondrosarcoma 19 Amary MF. Nature Genetics, 2011 Modified Bovée J,. Lancet Oncology 2006.
Slide 74: Surgery Is Only Curative Option for Chondrosarcoma
Surgery Is Only Curative Option for Chondrosarcoma Surgery is the mainstay of treatment – Complete surgical resection curative, but not possible in advanced disease Radiation is not effective Chemotherapy is of limited benefit – Primarily used in neoadjuvant setting to convert nonresectable to resec
Slide 75: Chondrosarcoma Typically Metastasizes to the Lungs
Chondrosarcoma Typically Metastasizes to the Lungs Surgery and radiation are palliative Clinical trials preferred option Chemotherapy resistant – Single agent ifosphamide or methotrexate, or doxorubicin plus cisplatin are used No therapies have demonstrated efficacy 21 Source: Emori et al. World Jou
Slide 76: Conventional Response Assessments Are Inadequate for Chondrosarcoma
Conventional Response Assessments Are Inadequate for Chondrosarcoma Residual calcification after chemotherapy poses challenges to conventional response assessment 22 Source: radiopaedia.org
Slide 77: Intrahepatic Cholangiocarcinoma
Intrahepatic Cholangiocarcinoma October 16, Sam Agresta, M.D.
Slide 78: Cholangiocarcinoma Is a Rare Cancer of the Bile Duct and Liver
Cholangiocarcinoma Is a Rare Cancer of the Bile Duct and Liver 2,000-4,000 new cases per year (U.S.) 50% of cases occur within the liver (intrahepatic cholangiocarcinoma, IHCC) – Prognosis: Worse for IHCC than other biliary tract tumors – Incidence of IHCC is increasing due to cirrhosis, alcoholic l
Slide 79: IDH Mutations Are Common in IHCC
IDH Mutations Are Common in IHCC IDH1/2 mutations present in approximately 25% of IHCCs – Not present in extrahepatic CC or gallbladder cancers – Majority of mutations are IDH1 IDH mutations do not affect prognosis Zhu A, Oncologist, 2015
Slide 80: Options for Metastatic Cholangiocarcinoma Are Limited
Options for Metastatic Cholangiocarcinoma Are Limited Gemcitabine-Based Regimens Surgery possibility curative, if not metastatic – IHCC has the lowest resectability rates (due to late presentation) – Five-year OS post-resection: 14-40% – Majority of patients recur despite complete resection Cisplati
Slide 81: Key Takeaways: Chondrosarcoma & IHCC
Key Takeaways: Chondrosarcoma & IHCC Current treatments are inadequate Surgery is the only chance for cure for localized disease Surgery, radiation and chemotherapy are palliative for metastatic disease IDHm commonly occurs in these diseases IDHm inhibitors should be fully explored as potential new
Slide 82: AG-120: Current Development Status in Advanced Solid Tumors
AG-120: Current Development Status in Advanced Solid Tumors Phase 1 All IDH1m Advanced hematologic malignancies Advanced solid tumors IHCC Chondrosarcoma Glioma Other advanced solid tumors Phase 1 dose escalation study in advanced solid tumors Study initiated in March 2014 First data expected at AAC
Slide 83: AG-881: Brain Penetrant, Pan-IDHm Inhibitor
AG-881: Brain Penetrant, Pan-IDHm Inhibitor Now in Clinical Development, Two Phase 1 Studies Initiated Phase 1 IDH1m or IDH2m Advanced solid tumors Advanced hematologic malignancies Study initiated in June 2015 Assess safety, tolerability and clinical activity of AG-881 as a single agent Administere
Slide 84: Potential for IDHm Inhibitors in Solid Tumors
Potential for IDHm Inhibitors in Solid Tumors Committed to IDH exploring mutations both IDHm found in blood inhibition and solid cancer, in solid tumors No precedent clinical for development solid tumor programs differentiation and timelines are therapy exists Different today Realizing the full pote
Slide 85: What We Know About PK Deficiency
What We Know About PK Deficiency October 16, 2015 Ann Barbier, M.D., Ph.D. VP, Clinical Development, Rare Genetic Diseases
Slide 86: Little Support for Patients and Caregivers
Little Support for Patients and Caregivers No formal, organized PK deficiency patient advocacy group to date – Informal network of patients and caregivers are engaged online and via social media Agios is organizing U.S. and EU patient ad boards for direct engagement and opportunity to listen/underst
Slide 87: Pyruvate Kinase (PK) Deficiency: What We Know Today
Pyruvate Kinase (PK) Deficiency: What We Know Today Disease Overview Description Etiology Clinical Presentation Diagnosis Rare genetic disease often presenting at birth as neonatal jaundice ~2400 diagnosed in US and EU5* Caused by mutations in PK-LR gene coding for Erythrocyte Pyruvate Kinase Lifelo
Slide 88: Red Blood Cells Are Dependent on Glycolysis for ATP Generation
Red Blood Cells Are Dependent on Glycolysis for ATP Generation Normal Red Cell PK Deficient Red Cell PKR is a crucial step in the maintenance of red blood cell energy levels PKR mutations lead to low pyruvate kinase activity and ATP levels Low ATP levels result in decreased red cell life span, hemol
Slide 89: PK Deficiency Is a Severe, Inherited Disease
PK Deficiency Is a Severe, Inherited Disease Autosomal recessive inheritance – Most affected individuals are compound heterozygous for two different mutant alleles – More than 200 different causative mutations have been identified – AG-348 activates a wide variety of mutant PKR enzymes Still underst
Slide 90: Disease Progression from Infants to Adults Showcases Lifetime of Burden
Disease Progression from Infants to Adults Showcases Lifetime of Burden Infants Toddlers, Children Adults Jaundice, severe anemia, exchange transfusions Splenectomy, increased infection risk, antibiotic prophylaxis Iron overload leading to liver cirrhosis, cardiac and endocrine issues
Slide 91: Hemoglobin Is a Key Parameter Measuring Severity of Anemia
Hemoglobin Is a Key Parameter Measuring Severity of Anemia in a Variety of Diseases g/dL Healthy range (male) 13-17 Healthy range (female) 12-15 Anemia of chronic disease 9.5-10.5 Paroxysmal nocturnal 5.8-10.1 hemoglobinuria Thalassemia intermedia 7-10 Thalassemia major < 7 PK deficiency Mild >10 Mo
Slide 92: Current Therapies are Supportive Only
Current Therapies are Supportive Only Lifelong Splenectomy Antibiotics Cholecystectomy Folic Acid Phototherapy Transfusion Bone Iron Marrow Chelation Transplant
Slide 93: Natural History Study Designed to Inform Development
Natural History Study Designed to Inform Development Key objectives: Understanding the disease, including range of symptoms and complications: – Transfusion burden – Patient reported outcome measures – Incidence and timing of splenectomy – Prevalence and treatment of iron overload – Prevalence of co
Slide 94: Natural History Study Enrolling Patients at Treatment Centers Globally
Natural History Study Enrolling Patients at Treatment Centers Globally Up to 250 participants of any age will be followed for at least two years As of September 2015: 189 patients in 27 sites
Slide 95: PK Deficiency is a Serious Disease with Varied, Frequent Complications
PK Deficiency is a Serious Disease with Varied, Frequent Complications Baseline and retrospective data from 75 NHS patients Source : R. Grace, poster EHA 2015 Complications in PK Deficiency n=75 Gallstones and cholecystectomy frequent Aplastic crises and thrombosis are rare, but potentially serious
Slide 96: Iron Overload Common in PK Deficiency Patients Across Severity Groups
Iron Overload Common in PK Deficiency Patients Across Severity Groups Source : R. Grace, poster EHA 2015 Splenectomized Upper Limit of Normal (~300 mcg/L)
Slide 97: Iron Overload Impacts Mortality
Iron Overload Impacts Mortality Symptoms of iron overload Cardiac arrhythmias and cardiomyopathy Liver cirrhosis Testicular atrophy Diabetes Hepatomegaly Arthritis Bronze skin Memory loss Vertigo Liver Pathology Normal vs. Iron Deposits Normal Liver Iron Deposition in the Liver
Slide 98: Takeaways for PK Deficiency
Takeaways for PK Deficiency Key Learnings to Date PK deficiency is a severe, rare hemolytic anemia Clinical spectrum ranges from mild to life-limiting Emerging picture of disease severity Current treatments are Of limited efficacy Often burdensome Supportive only Next data from the natural history s
Slide 99: Driving Forward Our PKR Activators: Clinical and Regulatory Overview
Driving Forward Our PKR Activators: Clinical and Regulatory Overview October 16, 2015 Chris Bowden, M.D. Chief Medical Officer
Slide 100: AG-348 Phase 1 Clinical Development in Healthy Volunteers
AG-348 Phase 1 Clinical Development in Healthy Volunteers Completed Studies Single Ascending Dose Multiple Ascending Dose Objectives Short-term safety Pharmacokinetics Pharmacodynamics Proof of mechanism Healthy volunteer studies provide important guidance for longer trials in people with PK deficie
Slide 101: Multiple Ascending Dose Study Design
Multiple Ascending Dose Study Design MAD: Establish the safety and tolerability and PD effects of AG-348 Randomized, double-blind, placebo controlled Healthy men and postmenopausal study with 14 days of continuous dosing women (age 18–60 years) In-patient period Dosing Day: –1 1 8 14 19 22 29 Final
Slide 102: AG-348 Well Tolerated Across a Range of Dose Levels
AG-348 Well Tolerated Across a Range of Dose Levels 14 day safety data provide a range of doses for consideration in patient studies Drug-related events were Grade 1 and 2; one Grade 3 event at 700mg q12h (increased LFTs – DLT) Placebo 15–360 mg q12hr 700 mg q12hr AE, n (%) n=12 n=30 n=6 Any AE 4 (3
Slide 103: Hormone Changes Seen with MAD Study: Reversible Aromatase Inhibition
Hormone Changes Seen with MAD Study: Reversible Aromatase Inhibition Mean levels of serum estradiol and free testosterone in male subjects Changes in serum androgens and estrogens were observed Most changes remained within normal reference ranges for age and sex Levels recovered to baseline Endocrin
Slide 104: AG-348 Increases ATP Levels Across a Range of Doses
AG-348 Increases ATP Levels Across a Range of Doses A ~50% increase of ATP from baseline was observed with >60 mg AG-348 q12hr Levels remained elevated through 120hr after the final dose 6 Day 0 = Baseline value. Day 14 is the final day of dosing Data Presented at EHA, 6/13/15 Placebo 15 mg q12hr 60
Slide 105: AG-348 Clinical Development: Phase 2 DRIVE PK Study
AG-348 Clinical Development: Phase 2 DRIVE PK Study Single Ascending Dose DRIVE PK Multiple Ascending Dose Completed AG-348 Ongoing Study of AG-348 in Healthy Volunteers Studies Transfusion Independent Adults with PK Deficiency Go Objectives: Objectives: ? Short-term safety • Safety – chronic dosing
Slide 106: Global Phase 2 DRIVE PK Study Open and Enrolling
Global Phase 2 DRIVE PK Study Open and Enrolling Transfusion-independent PK-deficient adults n=25 in each arm Arm 1 300 mg q12hr genotype R PK—Optional 3rd by Arm Screening Randomization Stratified Arm 2 50 mg q12hr
Slide 107: Global Phase 2 DRIVE PK Study Open and Enrolling
Global Phase 2 DRIVE PK Study Open and Enrolling Transfusion-independent PK-deficient adults n=25 in each arm Arm 1 300 mg q12hr genotype R 6-month - Optional 3rd PK dosing by Arm period Screening Randomization Stratified Arm 2 50 mg q12hr Primary endpoints: Safety and tolerability Secondary endpoin
Slide 108: Follow-on PKR Activator AG-519
Follow-on PKR Activator AG-519 AG-519 is a potent, highly selective and orally bioavailable PKR activator Differentiated chemical structure versus AG-348 No activity against the aromatase enzyme AG-519 has similar activity in vitro, in vivo and ex vivo (patient samples) relative to AG-348 Clinical s
Slide 109: AG-519 Healthy Volunteer Study to Open in 1Q 2016
AG-519 Healthy Volunteer Study to Open in 1Q 2016 One protocol, two steps, healthy volunteers Step 1: SD (single dose) – MD (multiple dose) Step 2: Bioavailability with food effect Step 1: Integrated SD-MD 4 dose-ascending cohorts: Step 2 : Bioavailability 8 subjects per cohort (n=32) and Food Effec
Slide 110: AG-519 Provides Optionality for Clinical Development
AG-519 Provides Optionality for Clinical Development AG-348 Healthy AG-348 DRIVE PK Efficacy Volunteer Studies PK Deficiency Pivotal Trials: (Completed) (Ongoing) Safety Adults AG-519 Healthy PK • Adolescents Volunteer Studies • Children (Q1 2016) PD Clinical data from AG-519 and AG-348 trials will
Slide 111: Takeaways: PK Deficiency Clinical Development
Takeaways: PK Deficiency Clinical Development Key Learnings to Date AG-348 activates PKR in humans AG-348 set the path for DRIVE PK, which is on track and enrolling AG-519 increases flexibility in the clinic with multiple assets with the potential to target multiple indications Key Questions for the
Slide 112: Agios Discovery Strategies
Agios Discovery Strategies October 16, 2015 Scott A. Biller, Ph.D. Chief Scientific Officer
Slide 113: Leveraging Our Scientific Competencies: “The Engine”
Leveraging Our Scientific Competencies: “The Engine” 2 Agios Core Capabilities “Disruptive Science” Cancer Metabolism Untapped target space Precision medicine strategy Genetic- or metabolic-biomarkers for patient selection Rare Genetic Metabolic Disorders Clear causation by defined genetic lesions N
Slide 114: What You’ll Hear Today
What You’ll Hear Today 3 New therapeutic opportunities for PK activators in other hemolytic anemias A precision medicine strategy catalyzes progress in our oncology portfolio Potential for extending of our platform to other therapeutic opportunities
Slide 115: What’s Possible for PK Activators
What’s Possible for PK Activators 4 PK Deficient Red Cell Glucose mPKR PK-Deficient Red Blood Cell + AG-348 Glucose mPKR + AG-348 ATP Red cells require high energy demand to maintain membrane integrity throughout their 120 day life cycle Low ATP ? fragile cell membranes ? hemolysis Agios PKR activat
Slide 116: What’s Possible for PK Activators
What’s Possible for PK Activators 5 Erythrocytes must undergo severe changes in membrane structure, a process that requires adequate ATP supply Erythrocyte Passage through the spleen Shear stress ATP is required to maintain membrane integrity and the biconcave shape No stimulus ATP depletion ATP dep
Slide 117: Molecular Lesions in Red Cell Proteins Cause Hemolytic Anemia
Molecular Lesions in Red Cell Proteins Cause Hemolytic Anemia in Broad Range of Disorders 6 Disease Molecular Lesion Red Cell Characteristics Normal physiology None Biconcave Pyruvate kinase deficiency PKR mutations Echinocytic Sickle cell disease HbS mutation Sickled Beta-globin loss of Beta-thalas
Slide 118: Disruptions to Red Cell Membrane Can Result in Greater ATP Demand
Disruptions to Red Cell Membrane Can Result in Greater ATP Demand to Maintain Cell Fitness 7 Normal Red Cell PEP wtPKR Pyruvate Cellular demand: ATP production meets demand Pyruvate Kinase Deficiency PEP mPKR Pyruvate Cellular demand: Inadequate production: ATP Deficiency PKR activators in PK defici
Slide 119: Disruptions to Red Cell Membrane Can Result in Greater ATP Demand
Disruptions to Red Cell Membrane Can Result in Greater ATP Demand to Maintain Cell Fitness 8 Normal Red Cell PEP wtPKR Pyruvate Cellular demand: ATP production meets demand Other Hemolytic Anemias PEP wtPKR Pyruvate Cellular demand: Increased demand: ATP Deficiency PKR activators in other hemolytic
Slide 120: AG-348 Improves Red Cell Parameters in a Beta-thalassemia Mouse Model
AG-348 Improves Red Cell Parameters in a Beta-thalassemia Mouse Model 9 Hemoglobin 9.1 10.9 Hematocrit 34.0 29.5 Reticulocytes ATP AG-348 increases Hb by 1.8 g/dL and reduces reticulocyte count by 40% after 21 days of oral treatment in th3/+ beta-thalassemia mouse model These effects are comparable
Slide 121: Evolving Portfolio in Cancer Metabolism
Evolving Portfolio in Cancer Metabolism
Slide 122: High Bar for Novel Targets Leads to Higher Probability of Success
High Bar for Novel Targets Leads to Higher Probability of Success 11 Requirements for oncology drug discovery programs: Cancer dependency in vivo The tumor cares Patient selection strategy Genetic and metabolic biomarkers Robust chemical starting points High confidence in druggability Precision Medi
Slide 123: Driving Precision Medicine Approaches in Cancer Metabolism
Driving Precision Medicine Approaches in Cancer Metabolism 12 A precision medicine strategy increases the probability of success while maximizing patient benefit EGFR WT NSCLC Patients 100 Ge?tinib (n=25) (%) Placebo (n=24) ival 80 v sur HR 0·86 (95% CI 0·48–1·51) e 60 fr e n—40 Gefitinib i o ess Pr
Slide 124: The Metabolome: Untapped Opportunity for Novel Precision Medicines
The Metabolome: Untapped Opportunity for Novel Precision Medicines 13 Combining the metabolome and the genome provides insight into metabolic vulnerabilities ? Mutations in metabolic genes or metabolic regulators ? Tumor specific isoforms ? Deletions in metabolic genes ? Lineage dependence ? Fusions
Slide 125: The Metabolome: Untapped Opportunity for Novel Precision Medicines
The Metabolome: Untapped Opportunity for Novel Precision Medicines 14 Combining the metabolome and the genome provides insight into metabolic vulnerabilities ? Mutations in metabolic genes or metabolic regulators ? Tumor specific isoforms ? Deletions in metabolic genes ? Lineage dependence ? Fusions
Slide 126: Identifying Opportunities to Drug Cancers with Deletions in Metabolic Genes
Identifying Opportunities to Drug Cancers with Deletions in Metabolic Genes 15 Metabolic genes are frequently deleted across the cancer genome, and occur across different tumor types Deletions induce metabolic vulnerabilities that are specific to the tumor, and are not present in normal tissues ncer
Slide 127: Leveraging the Cancer Genome for Patient Selection
Leveraging the Cancer Genome for Patient Selection: Metabolic Vulnerability Due to Gene Deletion 16 Normal Cell Genome Tumor Metabolic Suppressor Gene A Gene B
Slide 128: Leveraging the Cancer Genome for Patient Selection
Leveraging the Cancer Genome for Patient Selection: Metabolic Vulnerability Due to Gene Deletion Normal Cell Genome Tumor Metabolic Suppressor Gene A Gene B Deletions in metabolic genes are common Cancer Cell Genome Tumor Metabolic Suppressor Gene A Gene B Genetic Selection Markers
Slide 129: Leveraging the Cancer Genome for Patient Selection
Leveraging the Cancer Genome for Patient Selection: Metabolic Vulnerability Due to Gene Deletion Normal Cell Genome Tumor Metabolic Suppressor Gene A Gene B Deletions leads to metabolic vulnerabilities Cancer Cell Genome Affected Tumor Metabolic Metabolic Suppressor Gene A Gene C Gene B Drug Target
Slide 130: From the Genome to the Metabolome: Deleted Gene Induces Metabolic Vulnerability
From the Genome to the Metabolome: Deleted Gene in Tumor Induces Metabolic Vulnerability C A
Slide 131: From the Genome to the Metabolome: Deleted Gene Induces Metabolic Vulnerability
From the Genome to the Metabolome: Deleted Gene in Tumor Induces Metabolic Vulnerability C A C A
Slide 132: From the Genome to the Metabolome: Deleted Gene Provides Patient Selection Marker
From the Genome to the Metabolome: Deleted Gene in Tumor Provides Patient Selection Marker C A C A C A Drug Target Deleted gene in tumor: 1. Induces metabolic vulnerability 2. Provides patient selection marker Absence of deletion in normal tissue provides therapeutic window
Slide 133: Metabolic Vulnerability Creates Sensitivity to Inhibitors of Novel Target
Metabolic Vulnerability Due to Deletion Creates Sensitivity to Inhibitors of Novel Target Time Course for Metabolic Flux Through Target C Inhibitor dose response (uM) 0.625 1.25 2.5 5 20 10 10 0 20406080 100 Time (min) Potent inhibitors of Target C dramatically inhibit the flux of metabolites throug
Slide 134: Novel Inhibitors Selectively Block Growth of Tumors with Deletion In Vivo
Novel Inhibitors Selectively Block Growth of Tumors with Deletion In Vivo ‘Deletion A’ Tumor HCT-116 Xenograft MTAP -/- Model ) 3 Vehicle (mm 1200 Target C Inhibitor Volume 800 or 600 u m T 400 erage 200 +/- S.E.M A v 0 15 20 25 30 35 40 Days post implant WT Tumor HCT-116 Xenograft MTAP +/+ Model )
Slide 135: High Bar for Novel Targets Leads to Higher Probability of Success
High Bar for Novel Targets Leads to Higher Probability of Success Requirements for oncology drug discovery programs: Cancer dependency in vivo HCT-116 MTAP -/- ) 3 Target C (mm 1200 Inhibitor me 1000 V olu 800 or Tum 400 ge a er 200 +/- S.E.M Av 0 15 20 25 30 35 40 Days post implant Oral efficacy wi
Slide 136: Novel First-in-Class Research Portfolio
Novel First-in-Class Research Portfolio Target Validation Compound Optimization Cancer Metabolism Portfolio Two Metabolic Deletion Target C Lineage Dependence Wave Metabolic Deletion Multiple Oncology Targets Metabolic Deletion Three Multiple Lineage Dependence Oncology Wave Others Targets
Slide 137: Novel First-in-Class Research Portfolio
Novel First-in-Class Research Portfolio Target Validation Compound Optimization Target C Two Cancer Metabolism Multiple Other Oncology Targets Wave Rare Genetic Multiple RGD Targets Metabolic Disorders Cancer Metabolism Multiple Oncology Three Targets Wave Rare Genetic Multiple RGD Metabolic Disorde
Slide 138: Integrated Approach to Metabolic Target Discovery
Integrated Approach to Metabolic Target Discovery Genetic Screens Metabolomic Screens Genomics shRNA screen Deletion Wild type with Cells for value ctivity p -Sele gene Fold Change (ordered by SUM log2 difference) (genotype A vs B) Mutant Identify targets with “locked-in” metabolic vulnerabilities
Slide 139: Agios Expertise Applied to the Immunology Setting
Agios Expertise Applied to the Immunology Setting Published in the journal Immunity (2015) Agios – Washington University St. Louis Collaboration Integration of metabolomics and gene expression profiles revealed key metabolic pathways required for macrophage polarization A. Jha et al, Immunity 2015
Slide 140: Key Takeaways: Drug Discovery Strategy
Key Takeaways: Drug Discovery Strategy Precision medicine strategy increases the probability of technical success while maximizing patient benefit Marrying the genome and metabolome enables a portfolio of novel precision medicine targets PK activators may have utility in other hemolytic anemias, wit
Slide 141: Closing Remarks
Closing Remarks October 16, 2015 David Schenkein, M.D. Chief Executive Officer
Slide 142: Making a Difference for Patients & Building Long-Term Value
Making a Difference for Patients & Building Long-Term Value Vision Science Team/Culture Execution
Slide 143: Key Updates
Key Updates Advancing the IDHm inhibitors to market as quickly and broadly as possible Design and initiation of AG-221 AML Phase 3 trial (IDHENTIFY) Design of combination trial with “7 + 3” Design of combination trial with azacitidine Driving the PK activator program 5th Agios molecule entering clin
Slide 144: What We Hope You Came Away with Today
What We Hope You Came Away with Today Confident that we are leading the way in the disruptive field of dysregulated metabolism Clear that we are building world class clinical development and commercial capabilities on the foundation of our innovative research expertise Enthusiastic in your commitmen
Slide 145: agios
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