UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): May 4, 2018
Agios Pharmaceuticals, Inc.
(Exact Name of Registrant as Specified in Charter)
| Delaware | 001-36014 | 26-0662915 | ||
| (State or Other Jurisdiction of Incorporation) |
(Commission File Number) |
(IRS Employer Identification No.) | ||
| 88 Sidney Street, Cambridge, MA | 02139 | |||
| (Address of Principal Executive Offices) | (Zip Code) | |||
Registrant’s telephone number, including area code: (617) 649-8600
(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
| ☐ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| ☐ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| ☐ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| ☐ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
| ☐ | Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter). |
| ☐ | If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. |
| Item 2.02 | Results of Operations and Financial Condition. |
On May 4, 2018, Agios Pharmaceuticals, Inc. (the “Company”) issued a press release announcing its results for the quarter ended March 31, 2018. A copy of the press release is furnished as Exhibit 99.1 to this Current Report on Form 8-K.
The information responsive to Item 2.02 of this Form 8-K, including Exhibit 99.1, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such a filing.
| Item 7.01 | Regulation FD Disclosure. |
On May 4, 2018, the Company intends to make a slide presentation at its Investor Day. The slide presentation is being furnished as Exhibit 99.2 to this Current Report on Form 8-K.
The information responsive to Item 7.01 of this Form 8-K, including Exhibit 99.1, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”) or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such a filing.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits.
| Exhibit No. |
Description | |
| 99.1 | Press release issued May 4, 2018. | |
| 99.2 | Form of Presentation dated May 4, 2018 | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| AGIOS PHARMACEUTICALS, INC. | ||||||
| Date: May 4, 2018 | By: | /s/ David P. Schenkein | ||||
| David P. Schenkein, M.D. | ||||||
| President and Chief Executive Officer | ||||||
Exhibit 99.1
Agios Provides Business Update on Discovery Research Strategy and Pipeline, Progress on Clinical Programs, Commercial Launch Preparations and Reports First Quarter 2018 Financial Results at Investor Day
– Commercial Infrastructure In Place Ahead of August 21, 2018 PDUFA Action Date for TIBSOVO® (Ivosidenib) for IDH1m R/R AML –
– Clinical Portfolio Advancing with Four Compounds in Development and Five Pivotal Trials Ongoing or Planned Across Three Distinct Disease Areas –
– Drug Discovery Platform Poised to Deliver New Research Programs with Next IND Expected in Q4 2018; Three Rare Genetic Disease Programs Unveiled –
– Company in a Strong Financial Position to Launch TIBSOVO® (Ivosidenib) and Execute Research and Clinical Plans with Q1 2018 Ending Cash, Cash Equivalents and Marketable Securities of $995M –
CAMBRIDGE, Mass., May 4, 2018 — Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, is hosting an Investor Day in New York City today. During the event, the company will provide a comprehensive business update and report financial results for the first quarter ended March 31, 2018. The presentations will highlight how Agios’ drug discovery platform and broad clinical portfolio set Agios on the path to become a sustainable, multi-product biopharmaceutical company. The event will be webcast today starting at 8:00 a.m. ET at investor.agios.com.
“As we prepare to launch our second Agios-discovered and first wholly owned medicine later this year, we continue to invest in our productive drug discovery engine and advance a robust pipeline of first-in-class medicines,” said David Schenkein, M.D., chief executive officer at Agios. “Our first quarter progress against that objective was highlighted by the NDA acceptance of TIBSOVO® in IDH1m relapsed or refractory AML and multiple clinical trial initiations, including dosing the first patient with our MAT2A inhibitor AG-270 and the start of our AG-348 pivotal program in PK deficiency.”
HIGHLIGHTS FROM INVESTOR DAY PRESENTATIONS
| • | Communicated a robust research pipeline consisting of nine advanced drug discovery programs against novel targets across oncology, rare genetic diseases and metabolic immuno-oncology with the potential to deliver multiple INDs over the next 24 months. |
| • | Expanded rare genetic disease portfolio: |
| • | The company disclosed active research programs in three rare genetic diseases: phenylketonuria (PKU), erythroid porphyria and Friedreich’s ataxia |
| • | The most advanced research program is in PKU, where Agios has developed a novel approach to stabilize the mutant phenylalanine hydroxylase (PAH) protein and has demonstrated significantly decreased blood phenylalanine levels in a severe pre-clinical model of the disease. PKU is an autosomal recessive disease caused by mutations in the PAH gene affecting approximately 16,000 patients in the U.S.1 |
| • | Updated clinical milestones to advance the development of isocitrate dehydrogenase (IDH) 1 inhibitors in solid tumors: |
| • | Glioma pivotal development strategy expected to be finalized by year-end 2018 |
| • | Completion of enrollment of ClarIDHy, a global, registration-enabling randomized Phase 3 study for ivosidenib in IDH1m positive advanced cholangiocarcinoma, accelerated to the first half of 2019 |
| • | Announced acceptance of the following presentations at 2018 American Society of Clinical Oncology (ASCO) Annual Meeting: |
| • | Updated data from the expansion phase of the ongoing Phase 1 study of ivosidenib in IDH1m relapsed or refractory (R/R) acute myeloid leukemia (AML) |
| • | Updated data from the ongoing Phase 1/2 combination trial of enasidenib or ivosidenib with VIDAZA® in patients with newly diagnosed AML with an IDH2 or IDH1 mutation ineligible for intensive chemotherapy |
| • | First clinical data from the Phase 1 study of AG-881 in advanced IDHm positive solid tumors, including glioma |
| • | Completed commercial infrastructure build, including the deployment of an expanded sales force, to successfully launch TIBSOVO® (ivosidenib) within 48 hours of potential FDA approval. |
FIRST QUARTER 2018 HIGHLIGHTS & RECENT PROGRESS
| • | Initiated ACTIVATE-T, a single-arm pivotal trial for AG-348, in adult pyruvate kinase (PK) deficiency patients who receive regular blood transfusions. |
| • | Initiated PEAK, a global registry, for adult and pediatric patients with PK deficiency. |
| • | Initiated a perioperative ‘window’ trial with ivosidenib and AG-881 in IDHm low-grade glioma to further investigate their effects on brain tumor tissue. |
| • | Initiated a Phase 1 dose-escalation trial for AG-270, a first-in-class methionine adenosyltransferase 2a (MAT2A) inhibitor, in patients with methylthioadenosine phosphorylase (MTAP)-deleted tumors. |
| • | Announced FDA acceptance, priority review and a Prescription Drug User Fee Act (PDUFA) action date of August 21, 2018 for the new drug application (NDA) for TIBSOVO® (ivosidenib) for the treatment of patients with R/R AML with an IDH1 mutation. |
| • | Completed an underwritten public offering of 8,152,986 shares of common stock at the offering price of $67.00 per share, resulting in proceeds to the company, net of underwriting discounts and commissions, of approximately $516.2 million. |
UPCOMING 2018 MILESTONES & EXPECTED DATA PRESENTATIONS
The company expects to achieve the following additional milestones in 2018:
Cancer:
| • | Potential approval and commercialization of TIBSOVO® (ivosidenib) in the United States for R/R AML with an IDH1 mutation in the third quarter of 2018. |
| • | Submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for TIBSOVO® (ivosidenib) for the treatment of patients with R/R AML and an IDH1 mutation in the fourth quarter of 2018. |
| • | Support, in collaboration with Celgene, the initiation of HO150, an intergroup sponsored, global, registration-enabling Phase 3 trial combining ivosidenib or enasidenib with standard induction and consolidation chemotherapy in frontline AML patients with an IDH1 or IDH2 mutation in the fourth quarter of 2018. |
| • | Present updated data from the ongoing Phase 1 combination trial of enasidenib or ivosidenib with standard-of-care intensive chemotherapy in patients with newly diagnosed AML with an IDH2 or IDH1 mutation to the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition. |
Rare Genetic Diseases:
| • | Initiate ACTIVATE, a global, placebo-controlled, pivotal trial for AG-348 in approximately 80 adults with PK deficiency who do not receive regular blood transfusions in the second quarter of 2018. |
| • | Initiate a Phase 2 proof of concept trial of AG-348 in thalassemia in the fourth quarter of 2018. |
Research:
| • | Submit an investigational new drug (IND) application for our newest development candidate, AG-636, an inhibitor of the metabolic enzyme dihydroorotate dehydrogenase (DHODH) for the treatment of hematologic malignancies in the fourth quarter of 2018. |
FIRST QUARTER 2018 FINANCIAL RESULTS & CASH GUIDANCE
Revenue for the quarter ended March 31, 2018 was $8.8 million, which includes $7.4 million of collaboration revenue and $1.4 million of royalty revenue from net sales of IDHIFA®. Revenue for the quarter ended March 31, 2017 was $10.5 million and consisted solely of collaboration revenue. The decrease in collaboration revenue recognized for the quarter ended March 31, 2018 compared to the comparable period in 2017 was primarily driven by adoption of the new revenue recognition standard.
Research and development (R&D) expenses were $78.2 million, including $8.6 million of stock-based compensation expense, for the quarter ended March 31, 2018, compared to $62.7 million, including $7.0 million in stock-based compensation expense, for the comparable period in 2017. The increase in R&D expense was primarily attributable to start-up costs for the AG-348 pivotal program in PK deficiency, including the initiation of the ACTIVATE-T trial. R&D expense also increased as a result of the initiation of a Phase 1 dose-escalation study of AG-270, our first-in-class MAT2A inhibitor, and IND enabling activities for AG-636, our DHODH inhibitor.
General and administrative (G&A) expenses were $24.6 million, including $5.9 million of stock-based compensation expense, for the quarter ended March 31, 2018, compared to $14.8 million, including $3.7 million of stock-based compensation expense, for the quarter ended March 31, 2017. The increase in G&A expense was primarily attributable to the growth in our U.S. commercial organization in order to support the expected launch of TIBSOVO® (ivosidenib) in the third quarter of 2018.
Net loss for the quarter ended March 31, 2018 was $90.8 million, compared to a net loss of $66.2 million for the quarter ended March 31, 2017.
Cash, cash equivalents and marketable securities as of March 31, 2018 were $994.7 million, compared to $567.8 million as of December 31, 2017. The increase in cash was driven by the net proceeds of $516.2 million from the January follow on offering, $4.4 million of cost reimbursements under our collaboration agreements with Celgene and $12.3 million received from employee stock transactions. This was offset by expenditures to fund operations of $104.8 million during the quarter ended March 31, 2018.
The company expects that its cash, cash equivalents and marketable securities as of March 31, 2018, together with the anticipated product and royalty revenue, anticipated interest income, and anticipated expense reimbursements, but excluding any additional program-specific milestone payments, will enable the company to fund its anticipated operating expenses and capital expenditure requirements through at least the end of 2020.
WEBCAST INFORMATION
The live webcast from today’s event can be accessed under “Events & Presentations” in the Investors section of the company’s website at www.agios.com. The archived webcast will be available on the company’s website after the event.
About Agios
Agios is focused on discovering and developing novel investigational medicines to treat cancer and rare genetic diseases through scientific leadership in the field of cellular metabolism. In addition to an active research and discovery pipeline across both therapeutic areas, Agios has an approved oncology precision medicine and multiple first-in-class investigational therapies in
clinical and/or preclinical development. All Agios programs focus on genetically identified patient populations, leveraging our knowledge of metabolism, biology and genomics. For more information, please visit the company’s website at www.agios.com.
About Agios/Celgene Collaboration
IDHIFA® (enasidenib) and AG-881 are part of Agios’ global strategic collaboration with Celgene Corporation focused on cancer metabolism. Under the terms of the 2010 collaboration agreement, Celgene has worldwide development and commercialization rights for IDHIFA®. Agios continues to conduct certain clinical development activities within the IDHIFA® development program and is eligible to receive reimbursement for those development activities and up to $95 million in remaining payments assuming achievement of certain milestones, and royalties on any net sales. Celgene and Agios are currently co-commercializing IDHIFA® in the U.S. Celgene will reimburse Agios for costs incurred for its co-commercialization efforts. For AG-881, the companies have a joint worldwide development and 50/50 profit share collaboration, and Agios is eligible to receive regulatory milestone payments of up to $70 million. AG-270 is part of a 2016 global research collaboration agreement with Celgene. Through Phase 1 dose escalation, Celgene has the option, for a fee of at least $30 million, to participate in a worldwide cost and profit share with Agios. Upon exercise of the option the parties will share all development costs, subject to specified exceptions, and any profits on net sales and Agios will be eligible for up to $169 million in clinical and regulatory milestone payments for the program.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding Agios’ plans, strategies and expectations for its and its collaborator’s preclinical, clinical and commercial advancement of its drug development programs including IDHIFA®, TIBSOVO® (ivosidenib), AG-881, AG-348, AG-270 and AG-636; the potential benefits of Agios’ product candidates; its key milestones for 2018; its plans regarding future data presentations; its financial guidance regarding the period in which it will have capital available to fund its operations; and the potential benefit of its strategic plans and focus. The words “anticipate,” “believe,” “could,” “estimate,” “expect,” “hope,” “intend,” “may,” “milestone,” “path”, “plan,” “possible,” “potential,” “predict,” “prepare”, “project,” “strategy,” “will,” “would,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios’ current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios or its collaborator, Celgene, is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios’ product candidates will successfully continue. There can be no guarantee that any positive developments in Agios’ business will result in stock price appreciation. Management’s expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other important factors, including: Agios’ results of clinical trials and preclinical studies, including
subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. FDA and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Agios’ ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials; unplanned cash requirements and expenditures; competitive factors; Agios’ ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing; Agios’ ability to maintain key collaborations, such as its agreements with Celgene; and general economic and market conditions. These and other risks are described in greater detail under the caption “Risk Factors” included in Agios’ public filings with the Securities and Exchange Commission. Any forward-looking statements contained in this press release 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 otherwise, except as required by law.
Consolidated Balance Sheet Data
(in thousands)
(Unaudited)
| March 31, 2018 |
December 31, 2017 |
|||||||
| Cash, cash equivalents and marketable securities |
$ | 994,747 | $ | 567,750 | ||||
| Collaboration receivable – related party |
3,512 | 2,448 | ||||||
| Royalty receivable – related party |
1,417 | 1,222 | ||||||
| Total assets |
1,040,126 | 614,397 | ||||||
| Deferred revenue – related party |
121,043 | 163,640 | ||||||
| Stockholders’ equity |
865,594 | 375,503 | ||||||
Consolidated Statements of Operations Data
(in thousands, except share and per share data)
(Unaudited)
| Three Months Ended March 31, | ||||||||
| 2018 | 2017 | |||||||
| Collaboration revenue – related party |
$ | 7,345 | $ | 10,508 | ||||
| Royalty revenue – related party |
1,417 | — | ||||||
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|
|
|
|||||
| Total Revenue |
8,762 | 10,508 | ||||||
| Operating expenses: |
||||||||
| Research and development, net |
78,224 | 62,732 | ||||||
| General and administrative |
24,550 | 14,823 | ||||||
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|
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|
|
|||||
| Total operating expenses |
102,774 | 77,555 | ||||||
|
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|
|
|
|||||
| Loss from operations |
(94,012 | ) | (67,047 | ) | ||||
| Interest income |
3,187 | 881 | ||||||
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|
|
|||||
| Net loss |
$ | (90,825 | ) | $ | (66,166 | ) | ||
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| Net loss per share – basic and diluted |
$ | (1.63 | ) | $ | (1.56 | ) | ||
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|
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| Weighted-average number of common shares used in computing net loss per share – basic and diluted |
55,694,603 | 42,280,525 | ||||||
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# # #
| 1 | National PKU Alliance, www.npkua.org |
Investors:
Renee Leck, 617-649-8299
Senior Manager, Investor Relations
Renee.Leck@agios.com
Media:
Holly Manning, 617-844-6630
Associate Director, Corporate Communications
Holly.Manning@agios.com
Opening Remarks David Schenkein, M.D., Chief Executive Officer Exhibit 99.2
Forward Looking Statements This presentation and various remarks we make during this presentation contain forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding Agios’ plans, strategies and expectations for its and its collaborator’s preclinical, clinical and commercial advancement of its drug development programs including IDHIFA®, TIBSOVO® (ivosidenib), AG-881, AG-348, AG-270 and AG-636; the potential benefits of Agios' product candidates; its key milestones for 2018; its plans regarding future data presentations; its financial guidance regarding the period in which it will have capital available to fund its operations; and the potential benefit of its strategic plans and focus. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “prepare,” “project,” “would,” “could,” “potential,” “possible,” “hope,” “strategy,” “milestone,” “will,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios' current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios or its collaborator, Celgene, is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios' product candidates will successfully continue. There can be no guarantee that any positive developments in Agios' business will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this presentation and various remarks we make during this presentation could also be affected by risks and uncertainties relating to a number of other important factors, including: Agios' results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. FDA and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Agios' ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials; unplanned cash requirements and expenditures; competitive factors; Agios' ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing; Agios' ability to maintain key collaborations, such as its agreements with Celgene; and general economic and market conditions. These and other risks are described in greater detail under the caption "Risk Factors" included in Agios’ public filings with the Securities and Exchange Commission. Any forward-looking statements contained in this this presentation and various remarks we make 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 otherwise, except as required by law. 2
Time Speaker 8:00 - 8:15 a.m. Opening Remarks – David Schenkein, M.D., Chief Executive Officer Research 8:15 - 9:00 a.m. Discovery Strategy & Research Portfolio – Scott Biller, Ph.D., Chief Scientific Officer & Kevin Marks, Ph.D., Senior Director, Head of Cancer Biology 9:00 - 9:20 a.m. Q&A Part 1 Clinical Development, Commercial & Finance 9:20 - 10:00 a.m. Ivosidenib Clinical & Commercial Strategy in Acute Myeloid Leukemia – Darrin Miles, Vice President, IDH Program Management & Steve Hoerter, Chief Commercial Officer 10:00 - 10:30 a.m. Opportunity for IDH1 Inhibition in Solid Tumors – Susan Pandya, M.D., Senior Medical Director, Clinical Development & Maeve Lowery, M.B., B.Ch., B.A.O., Trinity College Dublin 10:30 - 11:00 a.m. AG-348 Clinical Development in Pyruvate Kinase Deficiency & Rare Hemolytic Anemias – Chris Bowden, M.D., Chief Medical Officer 11:00 - 11:15 a.m. Financial Overview & Q1 Results – Andrew Hirsch, Chief Financial Officer & Head of Corporate Development 11:15 - 12:00 p.m. Q&A Part 2 & Buffet Lunch Today’s Agenda
Agios is passionately committed to applying our scientific leadership in the field of cellular metabolism to transform the lives of patients with cancer and rare genetic diseases. Driven By a Clear Vision and Values CANCER METABOLISM METABOLIC IMMUNO-ONCOLOGY RARE GENETIC DISEASES ADJACENT BIOLOGY SPACE
Building One of the Next Great Pharmaceutical Companies Biotech startups Initiated clinical trials One drug approved Two drugs approved Sustainable multiproduct companies
Agios’ Scientific Platform Demonstrates Remarkable, Reproducible Productivity SCIENCE CULTURE DISCOVERY 400+ EMPLOYEES 1 VISION $50-60M INVESTED IN DRUG DISCOVERY ANNUALLY 40+ PEER-REVIEWED PUBLICATIONS IN 4 YEARS SINCE FIRST PATIENT DOSED 2 NDA ACCEPTED 3 ADDITIONAL COMPOUNDS IN CLINICAL DEVELOPMENT 1 MEDICINE APPROVED + + ST ND 6 INDs 10+ CLINICAL TRIALS IN 1,000+ PATIENTS TREATED IN CLINICAL TRIALS DISEASES 6
Current Clinical Portfolio Has Potential to Benefit Large Number of Patients ACUTE MYELOID LEUKEMIA CHOLANGIO- CARCINOMA LOW GRADE GLIOMA MTAP-DELETED TUMORS ~10,000 IDHm Patients AML Opportunity ~$2B ~3,000 IDH1m Patients ~9,000 IDH1m Patients >100,000 MTAP Deletion Patients PYRUVATE KINASE DEFICIENCY ~3,000 to ~8,000 Patients Oncology patient numbers represent annual U.S. and EU incidence; PK deficiency represent U.S. and EU prevalence
2018 Key Milestones Secure approval and commercialize ivosidenib for IDH1m R/R AML in the U.S. Initiate AG-348 PK deficiency pivotal trial ACTIVATE-T; Initiate ACTIVATE Initiate AG-270 Phase 1 dose-escalation trial in MTAP-deleted cancers Initiate AG-348 Phase 2 proof-of-concept trial in thalassemia Initiate Phase 3 frontline AML trial combining ivosidenib & enasidenib with 7+3 Submit ivosidenib European MAA in IDH1m R/R AML Initiate low grade glioma perioperative study with ivosidenib and AG-881 Submit 7th IND for DHODH ü ü ü
2018 Goals Set Stage for Building Long-Term Value Secure approval and commercialize ivosidenib for R/R AML in the U.S. Initiate Phase 3 frontline AML trial combining ivosidenib & enasidenib with 7+3 Initiate AG-348 PK deficiency pivotal trial (ACTIVATE-T) Initiate AG-270 Phase 1 dose-escalation trial Submit ivosidenib European MAA Initiate glioma perioperative study Initiate AG-348 Phase 2 trial in thalassemia Submit 7th IND for DHODH 2018 GOALS At least 3 approved medicines Research engine primed to potentially deliver multiple INDs over next 24 months Multibillion dollar commercial opportunity across clinical portfolio Vision for 2018 & Beyond ü ü ü
Our Pipeline CLINICAL PROGRAMS indication Drug discovery Early stage Clinical development Late stage clinical development APPROVED Primary commercial rights IDHIFA® Enasidenib (IDH2m Inhibitor) R/R AML Agios U.S. Co-promotion and Royalty Frontline AML Ivosidenib (IDH1m Inhibitor) R/R AML Frontline AML Cholangio Glioma AG-881 (pan-IDHm Inhibitor) Glioma AG-348 (PK (R) Activator) PK Deficiency AG-270 (MAT2A Inhibitor) MTAP-deleted Tumors RESEARCH PROGRAMS AG-636 (DHODH) CM Research Programs RGD Research Programs Metabolic IO Research Programs 10 NDA accepted
What You Will Hear and See Today Research engine poised to deliver next wave of development candidates Several new programs highlighted 9 programs currently in advanced drug discovery Robust clinical development plans in place across our early and late-stage programs Ready to launch our 2nd commercial product Well capitalized to execute on our business plan Culture focused on science and patient impact
Discovery Strategy & Research Portfolio Scott Biller, Ph.D., Chief Scientific Officer
Evolving the Agios Research Portfolio Into Adjacent Biologic Areas 2009 CANCER METABOLISM 2011 CANCER METABOLISM RARE GENETIC DISEASES 2016 CANCER METABOLISM METABOLIC IMMUNO-ONCOLOGY RARE GENETIC DISEASES Today ADJACENT BIOLOGY SPACE CANCER METABOLISM METABOLIC IMMUNO-ONCOLOGY RARE GENETIC DISEASES
Dysregulated Metabolism and Adjacent Areas of Biology Agios Research Focus Rare Genetic Diseases Restore defective metabolic pathways in disease cells that cause rare genetic diseases of metabolism Cancer Metabolism Inhibit key enzymes in cancer cell specific metabolic pathways to disrupt tumor cell proliferation & survival Metabolic Immuno-oncology Alter immune or cancer cell metabolism to enhance the body’s anti-tumor response Translational Systems Biology Platform
So Evolving our Technology Platform from our Historic Strength in Metabolism to a Cutting-Edge, Systems Biology Approach Metabolomics + Informatics + Modeling Multi-Omics + Imaging + Data Integration à New Knowledge Deep understanding of biology with a translational focus Single Cell RNA Sequencing Tissue Imaging Day 5 Drug Day 5 Vehicle Source: Agios data on file
Precision Medicine Program Criteria Animal model target validation Genetic and metabolic biomarkers High confidence in druggability High Probability of Success for Agios Drug Discovery Patient selection strategy Robust chemical starting points Proof of therapeutic strategy in vivo
What Differentiates Agios Research Strategy? First-in-Class Precision Medicines Internally Highly Integrated Deep Biological Interrogation Externally Hyper- Connected Early Translational Thinking Rapid Clinical Proof of Concept
Agios Preclinical Pipeline Program Target Discovery Target Validation Drug Discovery Drug Candidate Oncology Rare Genetic Diseases Metabolic Immuno-Oncology (Celgene Collaboration) Non-Metabolic Target Metabolic Target Metabolic and Non-Metabolic Targets Celgene Collaboration MAT2A Follow-Ons Heme Lineage: AG-636 DHODH Genetically Defined Heme Target Genetically Defined Solid Tumor Target Genetically Defined Heme Target Other Exploratory Programs Pyruvate Kinase Activator Follow-Ons Phenylketonuria (PKU) Erythroid Porphyria Friedreich’s Ataxia Other Exploratory Programs T-cell and Tumor Target Macrophage Target Macrophage Target Tumor Target Other Targets (T-cell, Macrophage, Tumor)
Agios Areas of Research Focus Rare Genetic Diseases Restore defective metabolic pathways in disease cells that cause rare genetic diseases of metabolism Cancer Metabolism Inhibit key enzymes in cancer cell specific metabolic pathways to disrupt tumor cell proliferation & survival Metabolic Immuno-oncology Alter immune or cancer cell metabolism to enhance the body’s anti-tumor response Translational Systems Biology Platform Dysregulated Metabolism and Adjacent Areas of Biology
Expanding the Playing Field in Rare Genetic Diseases (RGD) ~500 Rare Diseases of Metabolism ~5% of Rare Diseases have approved drugs High Medical Need Sources: http://rarediseaseday.us/; https://rarediseases.info.nih.gov/diseases/diseases-by-category/14/metabolic-disorders; http://150.214.214.5/metabolicpathways/
Rare Genetic Disease Pathogenesis Disrupted metabolic networks DNA Mutated metabolic enzyme Tissue, organ, system Gene therapies Diverse pathophysiology and disease phenotypes Genetic mutation(s) Biochemical defects Toxic or deficient metabolites
The Current Therapeutic Landscape Disrupted metabolic networks DNA Mutated metabolic enzyme Tissue, organ, system Gene therapies Emerging, but with delivery hurdles Diet, scavenging, chelation, etc. Palliative care Incompletely addressing disease mechanism, limited beneficial effects Enzyme replacement Mostly limited to lysosomal storage disorders Diverse pathophysiology and disease phenotypes Genetic mutation(s) Biochemical defects Toxic or deficient metabolites
Creating a New Wave of Transformational Therapies Understanding and correcting the root cause of the disease Success mostly limited in lysosomal storage disorders Disease-modifying small molecules targeting intracellular pathways leading to transformative outcomes for patients Agios Approach Diverse pathophysiology and disease phenotypes Disrupted metabolic networks DNA Mutated metabolic enzyme Tissue, organ, system Genetic mutation(s) Biochemical defects Toxic or deficient metabolites
Agios RGD Disease Selection Attributes Disease Selection Criteria and Differentiated Therapeutic Strategies High Unmet Need Feasible Clinical Path Effective Intervention Strategy
Defining Novel Therapeutic Strategies: Agios’ Competitive Advantage Develop deep insight into mechanism of disease pathophysiology Validate therapeutic strategies in disease models Patient derived cell models and genetically engineered animal models Design small molecule drugs using a combination of all-available technologies Discover pharmacodynamic and mechanistic biomarkers for rapid proof-of-concept in humans Effective Intervention Strategy
Small Molecule Strategies to Correct Disease Pathology Metabolite A Metabolite B Metabolite C Enzyme 1 Enzyme 2
Small Molecule Strategies to Correct Disease Pathology Metabolite A Metabolite B Metabolite C Substrate Reduction: Reduce toxic metabolite B by inhibiting upstream enzyme “Repair” Mutant Enzyme: Activate or stabilize defective protein Enzyme 1 Enzyme 2 ”Bypass” mutant enzyme Activate alternative pathway
Phenylketonuria (PKU): Mutations in Phenylalanine Hydroxylase (PAH) PAH fails to process the Phe to Tyr Normal Protein Diet A mixed diet provides your body with Defective PAH enzyme 1. This leads to high levels in the blood which results in neurocognitive defects Increase in Phenylalanine 2. 3. Phe Tyr PAH Phe Phe Sources: National PKU Alliance, www.npkua.org and Weisbren et al ‘Phenylalanine blood levels and clinical outcomes in phenylketonuria’ ~16,000 PKU patients in U.S. ~60% of patients have severe disease Severity of disease correlates with extent of phenylalanine elevation Phenylalanine elevation causes neurocognitive defects, demyelination and intellectual disability High unmet medical need remains: Highly restricted diet is key part of SOC No effective approved treatment for severe patients
Phenylketonuria (PKU): Mutations in Phenylalanine Hydroxylase (PAH) PAH fails to process the Phe to Tyr Normal Protein Diet A mixed diet provides your body with Defective PAH enzyme 1. This leads to high levels in the blood which results in neurocognitive defects Increase in Phenylalanine 2. 3. Phe Tyr PAH Phe Phe 120 Severity of disease correlates with extent of phenylalanine elevation Normal Blood Phenylalanine (uM) Elevated Phe (no treatment) Elevated Phe Mild PKU Classic, severe PKU (Agios Target Population) 360 600 1200 2000+ Phe
Therapeutic Strategy: Stabilize Mutant PAH to Rescue Enzyme Activity Stabilization leads to increase in active protein levels, leading to lower Phe levels different mutations found in PAH Majority result in misfolded protein leading to degradation Agios approach is to stabilize mutant PAH > 900 Source: PAHvdb (http://www.biopku.org/pah/); www.BIOPKU.org; https://www.ncbi.nlm.nih.gov/books/NBK1504/
Agios Lead Molecule Dramatically Decreases Blood Phenylalanine Levels in Severe PKU Mouse Model Blood Phe Concentration Blood Phe concentrations of treated mice normalized 360 Blood Phenylalanine (uM) 120 Severity of disease correlates with extent of phenylalanine elevation Normal Blood Phenylalanine (uM) Elevated Phe (no treatment) Elevated Phe Mild PKU Classic, severe PKU (Agios Target Population) 360 600 1200 2000+ Phe Source: Agios data on file
Agios Lead Molecule Increases PAH Protein Levels in the Liver of Severe PKU Mouse Stabilization of mutant PAH protein in knock-in mouse model of severe PKU Blood Phe concentration PAH GAPDH Western blot, 6 hours after final dose Control Compound A WT Blood Phe concentrations of treated mice normalized PAH protein levels in livers of treated mice increased Blood Phenylalanine (uM) Source: Agios data on file
Emerging Portfolio of First-in-Class RGD Programs Metabolic Target Program Target Discovery Target Validation Drug Discovery Development Candidate Pyruvate Kinase Activator Follow-Ons Phenylketonuria Erythroid Porphyria Friedreich’s Ataxia Exploratory (Multiple Diseases) Non-Metabolic Target Metabolic and Non-Metabolic Targets
Metabolic Immuno-oncology Alter immune or cancer cell metabolism to enhance the body’s anti-tumor response Agios Areas of Research Focus Rare Genetic Diseases Restore defective metabolic pathways in disease cells that cause rare genetic diseases of metabolism Cancer Metabolism Inhibit key enzymes in cancer cell specific metabolic pathways to disrupt tumor cell proliferation & survival Translational Systems Biology Platform Dysregulated Metabolism and Adjacent Areas of Biology
Agios Metabolic IO Strategy Immunosuppressive Tumor Microenvironment Metabolic Immuno-Oncology (IO) Discover targets with potential for single agent activity Increase response rates by utilizing patient selection strategies Identify mechanism based combination therapies Myeloid-derived suppressor cells Tumor associated macrophages Regulatory T cells Tumor Tumor Interstitial Fluid (TIF) Exhausted T cell
Integrated Metabolomics and Gene Expression Profiling Source: Agios collaboration with the Artyomov Lab, Washington University St. Louis / Immunity Journal March 2015, Volume 42 Issue 3
Inflammatory and Immunosuppressive Macrophages Have Dramatically Different Metabolic Programs Immunosuppressive Macrophage Inflammatory Macrophage Source: Immunity Journal March 2015, Volume 42 Issue 3 Glucose6P DHAP Pyruvate Citrate AKG Succinate Fumarate Malate Working TCA Cycle UDP-GlcNAc Glutamine Glutamate Glucose6P F1,6BP DHAP Pyruvate Lactate Glutamate AKG Aspartate Citruline Arginosuccinate NO Arginine Succinate Malate OAA Citrate Succinate AKG Disrupted TCA Cycle Glutamate Ribose-5P NADPH NADP+ Fatty Acids Itaconate Pentose Phosphate Pathway
Building a Comprehensive Translational Platform to Deeply Interrogate the Tumor Microenvironment Understanding the tumor microenvironment in mouse models and human tumors to: Uncover novel therapeutic mechanisms Discover new strategies for patient stratification Whole Tissue Imaging Single Cell Analysis Whole Tissue Analysis
Building a Comprehensive Translational Platform to Deeply Interrogate the Tumor Microenvironment Treated Tumor Interstitial Fluid Single Cell Analysis Whole Tissue Imaging Vehicle v Glutamine v Lactic acid Plasma TIF Tumor Plasma TIF Tumor Pink = T-Cell metabolite Yellow = B-Cell metabolite Blue = Macrophage metabolite MALDI Mass Spectroscopic Imaging Tissue Architecture Source: Agios data on file
Building a Network of Collaborators on Novel Targets and Technologies Ongoing collaborations with 16 leading investigators in immunology and metabolism In vivo immune cell metabolism & T cell exhaustion Identification of cancer-cell intrinsic immunotherapy targets Metabolomic analysis of MCA tumor microenvironment Collaboration Structure: 1.1 MM € total matching grant from NWO Collaboration between Agios, Leiden University and Maastricht University High resolution metabolic analysis of immune cells Development of an ultrasensitive robotic platform 3D cell culture screening techniques for high throughput screening of T-cells Single cell resolution of metabolites and tracers in cells with MS imaging Agios Pharmaceuticals NWO is The Netherlands Organization for Scientific Research
A Growing Portfolio of Metabolic Strategies to Activate Immune Cell Killing of Tumor Cells Immunosuppressive tumor microenvironment Immunosuppressive Tumor Microenvironment Activation of Tumor Cell Killing by the Immune System Helper T cell Inflammatory dendritic cell Tumor Inflammatory macrophage Effector Cytotoxic T cells Immunosuppressive Tumor Microenvironment Myeloid-derived suppressor cells Tumor associated macrophages Regulatory T cells Tumor Tumor Interstitial Fluid (TIF) Exhausted T cell Tumor Interstitial Fluid (TIF)
Inhibitor of Agios Macrophage Target Shows Predicted Immunomodulation and Antitumor Efficacy Single cell analyses Treated Day 5 T cells Dendritic cells Myeloid derived suppressor cells Tumor Vehicle Day 5 Tumor T cells Myeloid derived suppressor cells Dendritic cells Single cell RNA sequencing of tumor, immune cells and stroma Source: Agios data on file
Developing Metabolic Immuno-Oncology Pipeline Program Target Discovery Target Validation Drug Discovery Drug Candidate T-cell and Tumor Target Macrophage Target Macrophage Target Tumor Target Metabolic Immuno-Oncology Other Targets (T-cell, Macrophage, Tumor) Metabolic Target Celgene Collaboration
Oncology Research Portfolio Kevin Marks, Ph.D., Senior Director, Head of Cancer Biology
Multiple Paths to Precision Medicines in Oncology Clearly Defined Patient Populations Genetic Target Genetic Context Lineage Target genetically altered Gain-of-function mutations Fusions Amplification Synthetic lethal with an oncogene or tumor suppressor Synthetic lethal with a passenger gene deletion Lineage-specific dependency Example: mutant IDH Example: MAT2A Example: DHODH
Directly drugging gain-of-function (GOF) mutants has yielded transformative medicines But, despite deep sequencing of many tumor types, IDH1/2 remain the only metabolic GOF mutations IDH1/2m Precision Medicine in Cancer Metabolism EGFR WT NSCLC Patients EGFR Mutant NSCLC Patients Source: Zhang, et al, Lancet Oncology, 2012
MTAP Deletion Frequency While Gain-of-Function Driver Mutations Are Scarce, Loss-of-Function Mutations Are Common Sources: Marjon et al Cell Reports. 2016 Apr 19;15(3):574-587; Agios data on file; Illei et al Clinical Cancer Research. 2003 Jun; 9(6):2108-13; MTAP deletion frequencies are from Agios analysis of data from The Cancer Genome Atlas Source: Adapted from Beroukhim et al Nature 2010
A Key Insight: Deletion of MTAP Makes Cancers Vulnerable to Targeting of MAT2A MTAP deletion 1. MTAP enzyme MTA MTR-1P MTAP Chromosome 9p21 deleted in 15% of cancer MTA accumulates MTR-1P MTAP MTAP enzyme is lost 2. Substrate MTA accumulates MTA inhibits PRMT5 PRMT5 SAM Methylation MAT2A 3. Partial inhibition of PRMT5 Methionine 4. Sensitivity to a ‘second hit’: targeting MAT2A starves PRMT5 of its substrate Sources: Marjon et al Cell Reports. 2016 Apr 19;15(3):574-587 and MTAP deletion frequency from Agios analysis of data from The Cancer Genome Atlas
MTAP wt MTAP null Growth Inhibition in Cancer Cells +/- MTAP In vitro biochemical assay Cycloleucine AGI-24512 Cycloleucine Identification of MAT2A Inhibitors MTAP-selective Growth Inhibition % inhibition of MAT2A activity Source: Agios data on file Discovery of First in Class MAT2A Inhibitors and Validation of the MAT2A/MTAP Hypothesis
MTAP wt MTAP null Growth Inhibition in Cancer Cells +/- MTAP In vitro biochemical assay Cycloleucine AGI-24512 Cycloleucine Identification of MAT2A Inhibitors MTAP-selective Growth Inhibition MTAP-deleted Tumor Xenograft Model MTAP-WT Tumor Xenograft Model MAT2Ai MAT2Ai Tumor volume (mm3) Tumor volume (mm3) % inhibition of MAT2A activity Source: Agios data on file Discovery of First in Class MAT2A Inhibitors and Validation of the MAT2A/MTAP Hypothesis
Preclinical Studies Indicate Potential for Use in Variety of MTAP-Deleted Indications Patient-derived Xenograft (PDX) ‘clinical trial’ Efficacy (%Tumor Growth Inhibition) Patient-Derived Xenograft Models Esophageal (SCC) Model NSCLC (SCC) Model Regressions observed upon single agent AG-270 treatment in some models AG-270 is efficacious in MTAP-deleted PDX models from a variety of tissue origins including NSCLC, pancreatic, gastric & esophageal Tumor volume (mm3) Tumor volume (mm3) Study Days Study Days Source: Agios data on file
Emerging Mechanistic Understanding of the Pathway Downstream of MAT2A Source: Data presented at 2018 AACR Conference Gene Expression DNA Replication Genome Integrity RNA splicing concurrent with transcription 1. RNA Pol Splicing Complex Me Me Me Me Splicing complex requires PRMT5 2. PRMT5 SAM Gene Expression DNA Replication Genome Integrity MAT2A inhibition blocks splicing 3. MAT2A Methionine Defects in gene expression, DNA replication, genome integrity 4.
AG-270 Program Is Well Poised for Biomarker-driven Clinical Development Patient Selection Biomarkers Directly assess MTAP-status by IHC MTAP deficient PDAC MTAP positive PDAC 1. Next-gen sequencing for CDKN2A loss 2. Multiple Pharmacodynamic Biomarkers MAT2A inhibition Tumor-selective inhibition of PRMT5 Inhibition of PRMT5 targets including the spliceosome PATHWAY EFFECTS Antiproliferative & cytotoxic effects CLINICALLY APPLICABLE BIOMARKERS Monitor SAM in patient plasma Measure PRMT5 methyl marks in tumor Assess splicing using RNA seq & other assays Source: Agios data on file
AG-270 First-in-Human Phase 1 Clinical Trial Further evaluation of safety, tolerability and clinical activity Randomized Phase 1/2 trials Reduction in circulating concentrations of S-adenosylmethionine (SAM) and elevation of methionine Adequate safety & pharmacokinetics Maximum tolerated dose (MTD) Pharmacodynamics Dose Expansion ~50 advanced solid tumors or lymphoma patients with MTAP/CDKN2A deletion Dose Escalation Patient Selection Future Trials Trial initiated and enrolling patients ClinicalTrials.gov Identifier: NCT03435250
Source: Adapted from Beroukhim et al Nature 2010 Datamining of human tumor data CRISPR/shRNA screening platform Custom bioinformatics to identify best target/genotype pairs Prevalent deletions with significant unmet need Systematically Searching for Other MAT2A/MTAP-like Programs Agios’ oncology research team systematically searching for vulnerabilities associated with many other major deletions in cancer
Internally identified target with robust target validation in vitro and in vivo Next Wave Target Example: Novel Selective Vulnerability Target for PTEN-mutant Cancers PTEN-selective functional genomics (shRNA) screen Successful validation of Target X – dox + dox – dox + dox PTEN wt PTEN -/- days days * PTEN-selective growth phenotypes upon dox-inducible knockdown of Target X in vivo Tumor volume (mm3) Tumor volume (mm3) PTEN wt PTEN -/- Measure shRNA depletion via RNA-seq of barcodes Source: Agios data on file
Multiple Paths to Precision Medicines in Oncology Clearly Defined Patient Populations Genetic target Genetic context Lineage Target genetically altered gain-of-function mutations fusions Amplification Synthetic lethal with an oncogene or tumor suppressor Synthetic lethal with a passenger gene deletion Lineage-specific dependency Example: mutant IDH Example: MAT2A Example: DHODH
Cell line panel screen reveals selective AG-636 sensitivity in heme malignancies A Chemical Biology Screen Revealed an Unexpected Lineage Dependence on DHODH We tested a library of inhibitors of metabolic enzymes vs 100s of cancer cell lines, searching for selective agents DHODH inhibitor AG-636 blocks production of nucleotides for RNA & DNA Maximum Observed GI 0 50 100 150 GI50 (uM) 1 100 Selective efficacy: AG-636 active in 8% of cancer cell lines (n=356) Sensitivity Call resistant sensitive Source: Agios data on file
DHODH Inhibitor AG-636 is Efficacious in AML lysozyme locus KI 11/12 screen hits Inhibited DHODH Inhibition of DHODH overcomes differentiation blockade in AML… Source: Sykes et al, Cell 2016 …and drives substantial efficacy in vivo Efficacy in MOLM13 AML model AML PDX model Tumor volume (mm3) Tumor volume (mm3) Relative Expression 0 2 4 6 24HR 48HR 72HR 96HR 8 1µM AG-636 CD14 (mRNA) 96hr AG-636 DMSO 10nM 100nM 1000nM Count 0 20 40 60 101 102 103 104 80 CD14 100 105 Source: Agios data on file AG-636 AG-636
DHODH Inhibitor AG-636 is Efficacious in DLBCL Aggressive, triple-hit DLBCL PDX model Efficacy in OCILY19 DLBCL model Vehicle 100 mg/kg BID AG-636 Tumor volume (mm3) Tumor volume (mm3) AG-636 is active in wide range of DLBCL cell lines, including subtypes with poor prognosis [DHODHi] required for 50% reduction in growth rate 0.1 0.2 0.5 1.0 2.0 5.0 10.0 20.0 DLBCL cell lines Reported as double-hit Source: Drexler et al., Leukemia Lymphoma 2016 GCB subtype ABC subtype Sensitivity cutoff Source: Agios data on file Vehicle 100 mg/kg BID AG-636
Agios Preclinical Oncology Pipeline Program Target Discovery Target Validation Drug Discovery Drug Candidate Oncology Non-Metabolic Target Metabolic Target Metabolic and Non-Metabolic Targets Celgene Collaboration MAT2A Follow-Ons Heme Lineage: AG-636 DHODH Genetically Defined Heme Target Genetically Defined Solid Tumor Target Genetically Defined Heme Target Other Exploratory Programs
Agios Preclinical Pipeline Program Target Discovery Target Validation Drug Discovery Drug Candidate Oncology Rare Genetic Diseases Metabolic Immuno-Oncology (Celgene Collaboration) Non-Metabolic Target Metabolic Target Metabolic and Non-Metabolic Targets Celgene Collaboration MAT2A Follow-Ons Heme Lineage: AG-636 DHODH Genetically Defined Heme Target Genetically Defined Solid Tumor Target Genetically Defined Heme Target Other Exploratory Programs Pyruvate Kinase Activator Follow-Ons Phenylketonuria (PKU) Erythroid Porphyria Friedreich’s Ataxia Other Exploratory Programs T-cell and Tumor Target Macrophage Target Macrophage Target Tumor Target Other Targets (T-cell, Macrophage, Tumor)
Q&A
Ivosidenib Clinical Strategy in Acute Myeloid Leukemia Darrin Miles, Vice President, IDH Program Management
IDH Mutations Across Many Tumor Types ACUTE MYELOID LEUKEMIA (AML) ~20% of Patients Have IDH1 OR IDH2 Mutation ~10,000 IDHm Patients CHOLANGIO- CARCINOMA LOW GRADE GLIOMA ~14 % have IDH1 Mutation ~3,000 IDH1m Patients ~80% have IDH1 Mutation ~9,000 IDH1m Patients Patient numbers represent annual U.S. and EU incidence MYELODYSPLASTIC SYNDROMES (MDS) ~8% have IDH1 or IDH2 Mutation ~3,000 IDHm Patients CHONDROSARCOMAS ~50% have IDH1 Mutation ~900 IDH1m Patients Sources: SEER. Cancer Stat Facts: AML 2015 and Epiphany EPIC oncology numbers; American Cancer Society. AML 2017.; Visser et. Al. Incidence, survival and prevalence of myeloid malignancies in Europe. Eur J Cancer. 2012 Nov;48(17):3257-66 DiNardo et al. Leukemia 2016;30(4):980-4, Amary MF et al. J Pathol 2011;224:334-43, Epiphany Partners Epic Oncology, DC National Program of Cancer Registries (NPCR); Borger DR et al. Oncologist 2012;17:72-9.; Kipp BR et al. Hum Pathol 2012;43:1552-8.; Goyal L et al. Oncologist 2015;20:1019-27.SEER. Cancer Stat Facts, CBTRUS (Central Brain Tumor Registry in the US); Neurosurg Focus. 2015 Jan; 38(1): E6.
Multiple Opportunities Across IDHm Hematologic and Solid Cancers Originating from Agios Research Platform ACUTE MYELOID LEUKEMIA IDH1m Frontline Non-IC Ivosidenib + Aza Phase 3 (AGILE) Ongoing IDH2m R/R IDHIFA® Approved IDHm Frontline IC-Eligible Ivo/Ena + 7+3 Phase 3 Q4 2018 Start IDHm Frontline Non-IC Ivo/Ena + Aza Phase 1/2 Ongoing IDH1m R/R Ivosidenib NDA Accepted IDHm Frontline IC-Eligible Ivo/Ena + 7+3 Phase 1b Ongoing CHOLANGIOCARCINOMA LOW GRADE GLIOMA IDH1m R/R Ivosidenib Phase 3 (ClarIDHY) Ongoing IDH1m Ivosidenib & AG-881 Perioperative Study Ongoing IDH1m Ivosidenib Phase 1 Enrollment Complete IDH1m R/R Ivosidenib Phase 1 Enrollment Complete IDH1m AG-881 Phase 1 Enrollment Complete OTHER INDICATIONS IDHm R/R Ivosidenib Phase 1 Enrollment Complete MYELODYSPLASTIC SYNDROMES IDH1m R/R Ivosidenib Phase 1 Enrollment Complete CHONDROSARCOMAS
AML Landscape on the Brink of a Therapeutic Tidal Shift ~50K DIAGNOSED ANNUALLY in U.S. & EU 68 MEDIAN AGE OF DIAGNOSIS 20-25% FIVE-YEAR SURVIVAL RATE ~$2B POTENTIAL AS CORNERSTONE OF FUTURE AML THERAPY 4 NEW MEDICINES APPROVED FOR AML IN 2017 ~20% OF PATIENTS HAVE IDH1 OR IDH2 MUTATION (~10K PATIENTS ANNUALLY) OLDER PATIENTS GROWING INCIDENCE CHANGING LANDSCAPE IDH OPPORTUNITY POOR SURVIVAL WITH FEW CURES IDHm AN EARLY DRIVER Sources: SEER. Cancer Stat Facts: AML 2015 and Epiphany EPIC oncology numbers; American Cancer Society. AML 2017.; Visser et. Al. Incidence, survival and prevalence of myeloid malignancies in Europe. Eur J Cancer. 2012 Nov;48(17):3257-66; Thomas ED, N Engl J Med. 1979 Mayer, N Engl J Med. 1994, Fernandez H,N Engl J Med, 2009; Kumar C. Genetic Abnormalities and Challenges in the Treatment of Acute Myeloid Leukemia. Genes Cancer. 2011; 2:95–107; AML O/S: Klepin, et al, JCO, 32, 2014
Shifting the Treatment Paradigm for AML with Precision Medicine Sources:1) SEER. Cancer Stat Facts: AML 2015. 2) American Cancer Society. AML 2017. 3) Kumar C. Genetic Abnormalities and Challenges in the Treatment of Acute Myeloid Leukemia. Genes Cancer. 2011; 2:95–107 AML O/S: Klepin, et al, JCO, 32 Increase Cure Rate Prolong EFS/OS Provide Treatment Non-Intensive Therapy No Treatment Newly Diagnosed AML ~21K/year in U.S. 1,2,3 Intensive Therapy Induction + Consolidation + Maintenance Induction Combination and Treatment to Progression Active but Tolerable Option
Clinical Development of IDHm Inhibitors Spans All Treatment Lines to Become Cornerstone of Treatment ONGOING BROAD IST STRATEGY HOVON 7+3 PHASE 3 PLANNED BROAD IST STRATEGY NON-IC TREATMENT RELAPSED / REFRACTORY TREATMENT INTENSIVE CHEMO (IC) ~60-70% of AML Patients NON-IC TREATMENT ~30-40% of AML Patients IC INDUCTION CONSOLIDATION TRANSPLANT MAINTENANCE APPROVED IVOSIDENIB NDA ACCEPTED BROAD IST STRATEGY Source: SEER. Cancer Stat Facts: AML 2015
Ivosidenib Phase 1 R/R AML Data Median OS 8.8 months overall mOS for CR+CRh has not been reached 9.3 months for non-CR+CRh responders 3.9 months for non-responders Median follow-up, 14.8 months Data cutoff: 12May2017. CR, complete remission; CRh, CR with partial hematologic recovery; RBC, red blood cell Source: Data from ASH 2017 30.4% CR+CRh rate w/ median duration of 8.2 months (125 patient primary analysis set); Data to be updated at ASCO Overall Survival by Best Response in R/R AML (n=125) Transfusion Independence Across All Response Categories
Ivosidenib Phase 1 – Response in Untreated AML and MDS Source: Data from ASH 2017 aUntreated AML patients not eligible for standard of care therapies in expansion Arm 2 and from dose escalation whose starting dose was 500 mg QD bMDS patients in expansion Arm 3 and from dose escalation whose starting dose was 500 mg QD Untreated AML = patients not eligible for standard of care Median age (years) Untreated AML – 76.5 MDS – 72.5 Response Rates Untreated AML Arm 2a (n=34) MDS Arm 3b (n=12) Overall Response Rate, n (%) [95% CI] 19 (55.9) [37.9, 72.8] 11 (91.7) [61.5, 99.8] Duration of response, median [95% CI] months 9.2 [1.9, NE] NE [2.3, NE] Duration of CR, median [95% CI] months NE [5.6, NE] NE [2.8, NE] Best response, n (%) CR 7 (20.6) 5 (41.7) CRi/CRp 7 (20.6) n/a PR 1 (2.9) n/a MLFS/mCR 4 (11.8) 6 (50.0) SD 10 (29.4) 0 PD 3 (8.8) 1 (8.3) NA 2 (5.9) 0 Characteristics
Molecular MRD-Negative CR Associated with Prolonged Duration of CR+CRh and Improved Overall Survival (R/R AML, BMMCs) MC = Mutation Clearance, defined as the inability to detect the mIDH1 variant allele (lower limit of detection for mIDH1 alleles of 0.02–0.04% (2–4×10-4) from ≥1 on-study time point in a patient with detectable mIDH1 at screening. Duration of CR+CRh = date of first documented CR/CRh to date of first documented confirmed relapse or death Overall survival = time from first dose to the date of death due to any cause BMMC = bone marrow mononuclear cells Statistical testing not provided owing to small sample size and low event rate Overall Survival Duration Source: Data from ASH 2017
Potential for IDHm inhibitors in AML Frontline Setting: Encouraging Data from Ongoing Phase 1 Combination Trials Median age 60.5 years 69% (n=22) de novo AML Combination safe & well tolerated CR+ CRi/CRp rate for all patients = 77% (23 of 30) CR+CRi/CRp rate for de novo patients = 91% (19 of 21) Median age 76 years Combination safe & well tolerated ORR rate = 8 of 11 CR rate = 4 of 11 Ivosidenib plus 7+3 n=32 Ivosidenib plus Azacitidine n=11 Updated data expected at ASH Updated data at ASCO Source: Data from ASH 2017
“Improvement in EFS itself represents benefit to patients” FDA ASH 2017 Opportunity to Utilize Event-Free Survival (EFS) as Primary Endpoint Recent FDA/EMA approval of treatment for newly diagnosed de novo AML based on EFS primary Like OS, an EFS endpoint will reflect direct clinical benefit of ivosidenib but can be achieved faster than OS EFS endpoint enables patient cross-over and is not impacted by subsequent treatments Evaluating change of Phase 3 AGILE primary endpoint to EFS
HO150 Phase 3 Intergroup Frontline AML Trial in Collaboration with Celgene Planned for Q4 2018 Newly Diagnosed Patients with AML IDH1m (N=~500) Ivosidenib + 7+3 Regimen IDH2m (N=~500) Placebo + 7+3 Regimen Ivosidenib + Chemo HCT Ivosidenib Placebo Enasidenib + 7+3 Regimen Placebo + 7+3 Regimen Enasidenib Placebo INDUCTION (1-2 cycles) CONSOLIDATION (1 or 3 cycles or HCT) MAINTENANCE (up to 2 years) EFS primary endpoint; sponsored by HOVON and AML-SG Placebo + Chemo HCT Enasidenib + Chemo HCT Placebo + Chemo HCT EFS = Event Free Survival HCT = Hematopoietic Cell Transplantation
Randomization 1:1 Double Blinded Ivosidenib 500mg (n=196) + VIDAZA® Primary Endpoint OS Interim analyses for futility and superiority Phase 3 Frontline AGILE Ongoing Placebo (n=196) + VIDAZA® Final OS Analyses Secondary Endpoints: CR, CR+CRh, EFS, ORR Global Phase 3 Frontline IC-Ineligible IDH1m AML IC = intensive chemotherapy VIDAZA® is a registered trademark of Celgene Corporation Expect to complete enrollment in 2021 ClinicalTrials.gov Identifier:NCT03173248
Trial Design Line Ongoing Venetoclax combination R/R AML; potential frontline* Beat AML master trial (+ VIDAZA®)** Frontline AML Planned Maintenance** Frontline AML post stem cell transplant VYXEOSTM combination R/R AML VYXEOSTM combination Secondary AML Gilteritinib combination** R/R AML; potential frontline MDS monotherapy** Frontline and R/R AML MEKi combination R/R AML; potential frontline ATRA combination R/R AML; potential frontline Executing a Broad IST Strategy * potential to enroll patients who opt out of standard of care treatment or are otherwise considered ineligible ** Study includes ivosidenib and IDHIFA ® VIDAZA® is a registered trademark of Celgene Corporation VYXEOSTM is a trademark of Jazz Pharmaceuticals
Updated data from expansion phase of the Phase 1 study of ivosidenib in IDH1m R/R AML accepted to ASCO Accepted ASCO Abstracts Updated data from the Phase 1/2 combo trial of enasidenib or ivosidenib with VIDAZA® in newly diagnosed AML accepted to ASCO First clinical data from the Phase 1 study of AG-881 in advanced IDHm positive solid tumors, including glioma, accepted to ASCO VIDAZA® is a registered trademark of Celgene Corporation
Ivosidenib Commercial Strategy in Acute Myeloid Leukemia Steve Hoerter, Chief Commercial Officer
Building the Agios IDH Commercial Franchise IDHIFA® commercial performance update Scoping the IDH1 AML opportunity Ivosidenib launch preparations
IDHIFA® Launch Performance Q3 2017 Q4 2017 Q1 2018 Revenues reported by Celgene; 2017 Payer Mix, Agios Estimates
IDHIFA® Launch Performance Q3 2017 Q4 2017 Q1 2018 Revenues reported by Celgene; 2017 Payer Mix, Agios Estimates 2% Medicaid
2017 sales $20M (Q4 sales $13M) Early IDHIFA® Success Sales IDHIFA® Launch Metrics Update 2018 Q1 sales $14M IDH2m testing at ~50% as of October Diagnostic Testing IDH2m testing at ~70% as of January Early IDHIFA® Success IDHIFA® Launch Metrics Update Prescriber Base >250 unique prescribers >300 unique prescribers Early IDHIFA® Success IDHIFA® Launch Metrics Update IDHIFA® Launch Metrics Are on Track IDHIFA® awareness of ~50% as of October Awareness IDHIFA® awareness of ~60% as of January Early IDHIFA® Success IDHIFA® Launch Metrics Update Revenues reported by Celgene; Market research as of Oct. 2017 and January 2018; Agios estimates
NCCN Treatment Guidelines Address IDHm+ AML Enasidenib is recommended in patients with relapsed/refractory AML and an IDH2 mutation Enasidenib added as an option in the first-line setting in patients who are not candidates for intensive remission induction therapy, or who decline intensive therapy For patients who respond to first-line therapy with enasidenib, recommendation is to continue until disease progression Footnote added: Response to treatment with enasidenib may take 3-5 months Footnote added: Enasidenib increases the risk for differentiation syndrome and hyperleukocytosis that may require treatment with hydroxyurea and steroids IDH1 and IDH2 molecular analyses recommended for workup of all AML cases Molecular Testing IDH2 Mutated AML Source: NCCN version I.2018, updated February 7, 2018 Promotional efforts are limited to the IDH2m+ relapsed/refractory AML population
Building the Agios IDH Commercial Franchise IDHIFA® commercial performance update Scoping the IDH1 AML opportunity Ivosidenib launch preparations
AML Landscape on the Brink of a Therapeutic Tidal Shift ~50K DIAGNOSED ANNUALLY in U.S. & EU 68 MEDIAN AGE OF DIAGNOSIS 20-25% FIVE-YEAR SURVIVAL RATE ~$2B POTENTIAL AS CORNERSTONE OF FUTURE AML THERAPY 4 NEW MEDICINES APPROVED FOR AML IN 2017 ~20% OF PATIENTS HAVE IDH1 OR IDH2 MUTATION (~10K PATIENTS ANNUALLY) OLDER PATIENTS GROWING INCIDENCE CHANGING LANDSCAPE IDH OPPORTUNITY POOR SURVIVAL WITH FEW CURES IDHm AN EARLY DRIVER Sources: SEER. Cancer Stat Facts: AML 2015 and Epiphany EPIC oncology numbers; American Cancer Society. AML 2017.; Visser et. Al. Incidence, survival and prevalence of myeloid malignancies in Europe. Eur J Cancer. 2012 Nov;48(17):3257-66; Thomas ED, N Engl J Med. 1979 Mayer, N Engl J Med. 1994, Fernandez H,N Engl J Med, 2009; Kumar C. Genetic Abnormalities and Challenges in the Treatment of Acute Myeloid Leukemia. Genes Cancer. 2011; 2:95–107; AML O/S: Klepin, et al, JCO, 32, 2014
Fit for Intensive Chemotherapy Not Fit for Intensive Chemotherapy Pre-2017 Today & The Future Treatments based on patients eligibility (or not) for intensive chemotherapy Targeted treatments offering personalized approach Unselected treatments that offer improvements over current SoC New Medicines to Treat AML: Great News for Patients
How We Taught Ourselves to Pronounce Ivosidenib
How We Taught Ourselves to Pronounce Ivosidenib
U.S. AML Epidemiology and Treatment Approach – IDH1 Opportunity Relapsed/Refractory ~50% Initial targeted indication: ~700 to ~1,100 eligible IDH1m patients per year Currently Untreated U.S. Annual Newly Diagnosed AML Patients ~21K (IDH1m is 6-10%: ~1,300-2,100 patients) Intensive Therapy ~60-70% Non-Intensive Therapy ~30-40% Sources: 1. National Cancer Institute. https://seer.cancer.gov/statfacts/html/amyl.html. Accessed December 7, 2017. 2. DiNardo CD, et al. Poster presented at: American Society of Hematology Annual Meeting & Exposition; December 9-12, 2017; Atlanta, GA. 3. Walter RB, et al. Leukemia. 2015;29(2):312-320. Treated Population
Building the Agios IDH Commercial Franchise IDHIFA® commercial performance update Scoping the IDH1 AML opportunity Ivosidenib launch preparations
Strategic Imperatives for the TIBSOVO® Launch Physicians test for IDH1m TIBSOVO® is recognized as the best option for IDH1m+ R/R AML Patients have access to TIBSOVO®
Sales Team Deployed to Cover Prescriber Base Top Tier AML Centers
Patient Access Our Approach to Patient Access is Multifaceted Patient Services Copay card for commercial patients Patient Assistance Program Commercial insurance coverage interruption Referrals to independent third-parties for additional support Distribution Channel Limited specialty pharmacy network Hospital accounts serviced via specialty distributors Payer Education Expert field payer team Focus on education & payer resources Educate on disease burden Address payer concerns
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IDH1m Inhibition in Solid Tumors Susan Pandya, M.D., Senior Medical Director
IDH1 Mutation Present in Multiple Solid Tumors Patient numbers represent annual U.S. and EU incidence CHOLANGIOCARCINOMA ~14% have IDH1 mutation ~3,000 IDH1m patients LOW GRADE GLIOMA ~80% have IDH1 mutation ~9,000 IDH1m patients IDH1m R/R Ivosidenib Phase 3 (ClarIDHY) Ongoing IDH1m Ivosidenib & AG-881 Perioperative Study Ongoing IDH1m Ivosidenib Phase 1 Enrollment Complete IDH1m R/R Ivosidenib Phase 1 Enrollment Complete IDH1m AG-881 Phase 1 Enrollment Complete CHONDROSARCOMAS ~50% have IDH1 mutation ~900 IDH1m patients IDH1m R/R Ivosidenib Phase 1 Enrollment Complete IDH1m Natural History of Tumor Volume Sources: Amary MF et al. J Pathol 2011;224:334-43, Epiphany Partners Epic Oncology, DC National Program of Cancer Registries (NPCR); Borger DR et al. Oncologist 2012;17:72-9.; Kipp BR et al. Hum Pathol 2012;43:1552-8.; Goyal L et al. Oncologist 2015;20:1019-27.SEER. Cancer Stat Facts, CBTRUS (Central Brain Tumor Registry in the US); Neurosurg Focus. 2015 Jan; 38(1): E6.
The Story of IDHm Inhibition in Solid Tumors is Evolving 2012 Nature. ; 483(7390): 474–478. doi:10.1038/nature10860 Reprinted by permission from Macmillan Publishers Ltd: NATURE 513:110-114, copyright 14 2014, Saha et al.
The Story of IDHm Inhibition in Solid Tumors is Evolving 2012 2013 - 2014 Nature. ; 483(7390): 474–478. doi:10.1038/nature10860 Reprinted by permission from Macmillan Publishers Ltd: NATURE 513:110-114, copyright 14 2014, Saha et al.
The Story of IDHm Inhibition in Solid Tumors is Evolving 2012 2013 - 2014 2014 - Present Nature. ; 483(7390): 474–478. doi:10.1038/nature10860 Reprinted by permission from Macmillan Publishers Ltd: NATURE 513:110-114, copyright 14 2014, Saha et al.
Opportunity for an IDH1m Inhibitor in Solid Tumors Frequency of IDH1 mutation in a variety of solid tumors + unmet need in these indications = opportunity to make a difference in the treatment paradigm for these patients Active clinical development plans in cholangiocarcinoma & glioma Understanding the IDH mutation’s role in the treatment of solid tumors is evolving Opportunity for IO combinations
Cholangiocarcinoma Maeve Lowery, M.B., B.Ch., B.A.O., Trinity College Dublin
Increase in laboratory tests: Cholangiocarcinoma a Devastating Disease with No Approved Targeted Therapies Alkalane phosphastase GGT Total (direct) bilirubin AST/ALT CA 19-9 (elevated in ~65% cholangiocarcinoma) Sources: http://www.alltohealth.com; www.uptodate.com; https://gi.jhsps.org Symptoms: Abdominal pain (30-50%) Weight loss (30-50%) Fever (20%) Itching Jaundice
Sources: CDC National Program of Cancer Registries (NPCR); Epiphany Partners Epic Oncology; Decision Resources; Market Research; Borger DR et al. Oncologist 2012;17:72-9.; Kipp BR et al. Hum Pathol 2012;43:1552-8.; Goyal L et al. Oncologist 2015;20:1019-27. Cholangiocarcinoma a Devastating Disease with No Approved Targeted Therapies ~21K DIAGNOSED ANNUALLY U.S. & EU ~9% FIVE-YEAR OVERALL SURVIVAL RATE 0 APPROVED THERAPIES ~14% OF PATIENTS HAVE IDH1 MUTATION (~3K PATIENTS ANNUALLY) LOW SURVIVAL RATES INCIDENCE INCREASES W/ AGE ENCOURAGING DATA SHOWN W/ IVOSIDENIB FEW OPTIONS IDH1m AN EARLY DRIVER
Genetic Alterations in Biliary Tract Cancer GB specific ICC specific Biliary duct common ICC and ECC shared ECC specific EGFR, ERBB3, PTEN, ARID2, MLL2, MLL3, TERT promoter mutation APOBEC signature TP53, BRCA1, BRCA2, PIK3CA mutation Poor-prognosis subtype with high immune checkpoint activity PRKACA or PRKACB fusion, ELF3, ARID1B mutation, better prognosis subtype KRAS, SMAD4, ARID1A, GNAS mutation FGFR2 fusion IDH1/2, EPHA2, BAP1 mutation C>T at CpG signature Source: © Nakamura et al, Nature Genetics 2015
Current Treatments are Limited to Chemotherapy-Based Regimens Phase 3 ABC-02 Gemcitabine and Cisplatin – standard of care for newly diagnosed metastatic disease OS – 11.7 months Gem/Cis vs. 8 months for Gem alone PFS – 8 months for Gem/Cis vs. 5 months for Gem alone OS PFS Source: Valle J. N Engl J Med. 2010
Outcomes with Second Line Chemotherapy Remain Poor and Highlight Need for Novel Treatments • Median PFS range is 2-3 months and PFS6 is 10-25% • No available historic placebo PFS benchmark OS mOS – approx. 7 mo PFS mPFS – 2-3 mo Sources: T. Walter et al. / European Journal of Cancer 49 (2013) 329-335
Durable Disease Control with Ivosidenib in a Heavily Pre-treated Population Source: Data from ASCO 2017 61% disease control rate (PR + SD) 0 10 20 30 40 50 60 70 80 90 100 Treatment duration (wk) PR SD PD NA First response Ongoing Radiographic progression On-treatment death
Durable Disease Control with Ivosidenib in a Phase 1 Heavily Pre-treated Population 38.5% OF PATIENTS PROGRESSION FREE AND ALIVE AT SIX MONTHS ENCOURAGING DATA SHOWN W/ IVOSIDENIB Ivosidenib well-tolerated in heavily pre-treated population (most common drug-related AEs: fatigue, nausea & vomiting) Median of 2 prior systemic therapies (range 1-5) Durable disease control with six month PFS rate of 38.5% and 12 month PFS rate of 20.7%; median PFS of 3.8 months Source: Data from ASCO 2017
Radiographic Changes in a Patient with a PR on Ivosidenib Data from ASCO 2017 Computed tomography scans of a 66-year-old woman with intrahepatic CC previously treated with neoadjuvant cisplatin + gemcitabine who then received AG-120 Source: Data from ASCO 2017
Ivosidenib Promotes Morphologic Changes to Cholangiolar Patterns Data from CCF 2018 Sources: 1. Liau JY et al. Mod Pathol 2014;27:1163-73, 2. Komuta M et al. Hepatology 2012;55:1876-88. 3. Komuta M et al. Hepatology 2008;47:1544-56, 4. V. Deshpande, unpublished data, 2017. ‘Normal’ cholangiolar pattern composed of glands in the shape of antler horns1-3 Associated w/ better clinical outcomes in patients w/ ICC 1,4 Untreated IDH1m+ ICCs often show heterogeneous histoarchitecture Treatment with ivosidenib shows increased cholangiolar histology and decreased cytoplasm Baseline 40x Cycle 7, Day 1 (PR) 40x 20x Cholangiolar pattern4
2:1 Double Blind Randomization (n=186) Ivosidenib Arm 500mg Registration-Enabling Phase 3 Cholangiocarcinoma Study Ongoing Placebo Arm Primary Endpoint: PFS Crossover at time of progression Secondary Endpoints: OS, ORR, safety, QoL Global Phase 3 Previously Treated Advanced IDH1m Cholangiocarcinoma (no more than 2 prior therapies) ClinicalTrials.gov Identifier: NCT02989857 Expect to complete enrollment in 1H 2019 The study has 96% power to detect a hazard ratio of 0.5 with a one-sided alpha of 0.025
Clinical Development in Glioma Susan Pandya, M.D., Senior Medical Director
Low Grade Glioma (LGG): High Unmet Need Not Adequately Addressed by Chemotherapy or Radiation Sources: Semin Radiat Oncol 25:219-224; NATURE REVIEWS | NEUROLOGY, APRIL 2016 | VOLUME 12, 204-2016 Mean age of diagnosis of 41 ~80% of LGG patients present with seizure as initial symptom and up to 90% of patients will have seizures during disease course Acute and chronic toxicity associated with chemotherapy and radiation can lead to progressive decline in quality of life (e.g. neurocognitive impairment)
IDHm Glioma Is a Distinct Disease Source: N Engl J Med 2015;372:2481-98
Sources: CDC National Program of Cancer Registries (NPCR); SEER. Cancer Stat Facts; Market research; CBTRUS (Central Brain Tumor Registry in the US); Neurosurg Focus. 2015 Jan; 38(1): E6. Low Grade Glioma: High Unmet Need Not Adequately Addressed by Chemotherapy or Radiation ~11K DIAGNOSED ANNUALLY IN U.S. & EU 41 MEAN AGE OF DIAGNOSIS 0 CURATIVE OR APPROVED TARGETED THERAPIES 33% FIVE-YEAR SURVIVAL RATE IN GLIOMA ~80% OF PATIENTS HAVE IDH1 MUTATION (~9K PATIENTS ANNUALLY) YOUNG PATIENTS GRADE 2/3 GLIOMA INCIDENCE POOR LONG-TERM PROGNOSIS ENCOURAGING PHASE 1 DATA TREATMENT OPTIONS LIMITED IDH1: EARLY MUTATION, DEFINES DISEASE 16 MONTHS MEDIAN TREATMENT DURATION IN IVOSIDENIB PHASE 1
Current Treatment Paradigm for IDHm Gliomas IDH-mutant 1p/19q non-codeleted (ATRX mutant, TP53 mutant) WHO grade II WHO grade III WHO grade II WHO grade III WHO grade IV Watch and wait Radiotherapy PCV (or temozolomide plus radiotherapy temozolomide) Watch and wait Radiotherapy temozolomide (or radiotherapy PCV) Temozolomide and radiotherapy temozolomide 1p/19q-codeleted (TERTp mutant) Source: Lancet Oncol 2017; 18: e315–29
4 8 12 16 20 24 28 32 Treatment duration (mos) 0 Durable Stable Disease Signal with Ivosidenib Phase 1 Data Median treatment duration: 16 mos (range 1.4, 27.1) 63% of patients treated for > 1 yr Source: Data presented at SNO 2017 MR SD PD First response Ongoing Progression Ivosidenib well tolerated Durable stable disease signal encouraging; 51% of patients still on treatment Reduction of tumor growth rates also observed Tumor grade at screening Gr 2 Gr 3 Gr 4 Unknown
Oligodendroglioma 1p19q co-del Biopsy 2007 Temozolomide 2007-2008 No Radiation AG-120 Start 10/2015 H1 MRI: 10/2014 Remains on treatment (18 mos @ cutoff) Best RANO response: SD Ivosidenib Phase 1 Data – Reduction in Tumor Growth Rate Historical 1 Screening On-treatment H1 = historical pre-treatment scans; Screen = screening Source: Data presented at SNO 2017
Ivosidenib Phase 1 Data – Reduction in Tumor Growth Rate Historical 1 - Historical 2 - Screening - Pre-treatment changes On-treatment changes Screening - - AG-120_ late cycle - AG-120_ early cycle Source: Data presented at SNO 2017
Evaluate evidence of target engagement showing 2-HG suppression in brain tumor tissue IDH1m Low Grade Glioma Patients Eligible for Resection Active Arm: Ivosidenib or AG-881 Control Arm: N=5 N=~45 Ongoing Phase 1 Perioperative Study with Ivosidenib and AG-881 Evaluating Evidence of Target Engagement 4 weeks Study Objectives: Determine amount of drug penetration in the brain Confirm magnitude of IDHm target engagement as measured by 2HG levels in brain tumor tissue (pre-clincally 85% seen with ivosidenib & 98% with AG-881) Assess impact of IDHm inhibition on differentiation and epigenetic profiles in tumor tissue Assess the safety of both molecules Dose Surgery ClinicalTrials.gov Identifier: NCT03343197 Trial initiated in Q1; Patients Enrolling
Next Steps in Glioma Finalize Decision on Pivotal Path by Year End AG-881 Phase 1 Safety + preliminary efficacy accepted at ASCO 2018 Ivosidenib Phase 1 Robust dataset from SNO 2017 + longer follow-up Ivosidenib + AG-881 Data from Perioperative study Regulatory Feedback in 2018 + + +
PKR Activation & PK Deficiency Chris Bowden, M.D., Chief Medical Officer
Inadequate production: ATP deficiency Pyruvate Kinase Deficiency PEP Pyruvate mPKR Proof of concept achieved Cellular demand: ATP production meets demand Normal Red Cell Cellular demand: PEP Pyruvate wtPKR PK Activation Represents Opportunities Across Hemolytic Anemias Increased demand: ATP deficiency Other Hemolytic Anemias PEP Pyruvate wtPKR Cellular demand: Thalassemia: Expect to initiate Phase 2 proof-of-concept study in Q4 2018 Sickle cell: Planning underway
Opportunity for AG-348 to be the First Disease-Modifying Treatment for PK Deficiency ~3-8K IN U.S. & EU MOST PATIENTS ARE NOT REGULARLY TRANSFUSED 0 APPROVED TARGETED THERAPIES 3.4 g/dL MEAN MAXIMUM HEMOGLOBIN INCREASE WITH AG-3481 PATIENTS ARE BORN WITH DISEASE AND LIVE TO ADULTHOOD TRANSFUSIONS PREVELANCE COMPELLING CLINICAL ACTIVITY SUPPORTIVE CARE ONLY LIFELONG HEMOLYTIC ANEMIA ACTIVATE-T initiated and ACTIVATE to begin in Q2 2018 Sources: Estimated prevalence range from ~1:20K to ~1:485K Grace R et al. Am J Hematol 2015;90(9):825-30; 1Mohrenweiser HW PNAS 1981;78(8):5046-50; 2Carey PJ et al. Blood 2000;96(12):4005-6; 3Beutler E & Gelbart T Blood 2000;95(11):3585-8; 4deMedicis et al. Hum Hered 1992;42(3):179-83; data presented at ASH 2017 1Mean maximum hemoglobin increase of 3.4 g/dL in patients to had a >1.0 g/dL increase in haemoglobin on study
Infants Jaundice, severe anemia, exchange transfusions Toddlers, Children Splenectomy leading to increased infection risk, antibiotic prophylaxis Adults Iron overload leading to liver cirrhosis, cardiac and endocrine issues PK Deficiency Carries Lifelong Burden
Global Patient Finding Efforts 2015 2016 2017
Boston Children’s Natural History Study Initiated in 2014, 278 patients enrolled in 30 sites (North America & EU) Understanding symptoms and complications of the disease: Transfusion burden Incidence & timing of splenectomy Prevalence & treatment of iron overload Identifying patients & treatment centers Identifying molecular characteristics
PK Deficiency: Burden of Disease is Extensive IRON OVERLOAD (47%) CHOLELITHIASIS (45%) CHOLECYSTECTOMY (40%) SPLENECTOMY (59%) THROMBOSIS (Overall, 7%) (Post-splenectomy, 11%) OSTEOPENIA/ BONE FRACTURES (17%) APLASTIC CRISIS (14%) Grace et al. Blood, prepublished online March 16, 2018 Baseline and Retrospective Data from 254 NHS Patients EXTRAMEDULLARY HEMATOPOIESIS (9%) LEG ULCERS (2%) PULMONARY HYPERTENSION (3%) LIVER CIRRHOSIS (3%) ENDOCRINE DISEASE (10%) THYROID DISORDERS (5%)
Over 300 Mutations Cause a Range of Defective PKR Proteins Sources: R van Wijk, Blood 2005; Bianchi P et al. poster, 2017 ASH Annual Meeting Mutations in PKR have been described in PK deficiency, belonging to one of two categories: Missense mutations cause a single amino acid change in the protein – generally some functional protein Non-missense mutation any mutation other than a missense mutation (e.g., stop, frameshift, deletion) – generally little functional protein At least 1 missense mutation ~85% ~15% Non-missense / Non-missense mutation
PEAK Registry Enrolling Patients * This list is not exhaustive, and may change Natural History Study countries Potential additional countries for registry* Primary objective is to develop greater understanding of the longitudinal clinical implications of pyruvate kinase deficiency, including: Natural history Treatments and outcomes Variability of clinical care Disease burden Adult and pediatric patients eligible Will be followed for at least 2 years Will include up to 20 countries, 60 sites and up to 500 patients ClinicalTrials.gov Identifier: NCT03481738
Hematologists specializing in benign heme diseases are most familiar Physician Opinion of Disease Severity is Highly Variable and a Function of Patient Experience PK deficiency patients are characterized by the overall disease burden Anemia Iron overload, splenectomy, cholelithiasis Reduced stress response to viral infections, pregnancy Worsening symptoms with age Significant gaps need to be addressed in the adult PK deficiency patient population Age characteristics of common complications, disease course, prognosis Risk factors for complications or for overall disease severity Source: Agios PKD KOL advisory board, November 2017
Living with PK deficiency Patients Describe a Constellation of Signs and Symptoms That Challenge Their Efforts to “Be Normal” “I know more about my disease than my hematologist.” Anxiety about keeping disease private from employers Strong desire to participate in advocacy efforts & trials Physical burden Financial burden Emotional burden Adequate health insurance Disease impact increases as patients age Major life decisions (career, marriage, parenting) and everyday choices (travel, social life) affected Social QoL impact, not being able to “keep up” Bone pain, cognition impact, infections, iron overload, downstream co-morbidities / secondary conditions Relationships with HCPs vary widely No published standards of care Patients actively keep up with research to compensate for gaps in care & disease education Source: Agios 2017 patient advisory board Caring for PK deficiency
Agios PRO Tool Integrates Patient Perspective into Disease Burden Assesses signs & symptoms and the impact on patients reported outcomes Signs & Symptoms Physical limitations Appearance Daily life Social impacts Emotional impacts Fatigue / tiredness Lack of / low energy Exhaustion Weakness Dizziness / lightheadedness Shortness of breath Decreased stamina Jaundice Pale skin Cognitive impairment Bone pain Joint pain Need for additional rest Difficulty with exercise / sports Difficulty with stairs / walking uphill Susceptibility to illness Negative impact on appearance Difficulty with household activities Lack of motivation Less productive Negative impact on social activities Negative impact on relationships with family/friends Receiving unwanted attention Concern about the future Endpoint in pivotal trials to evaluate treatment benefit
AG-348 Clinical Development Plan
The baseline value is the average of all central assessments within the screening period (42 days prior to Day 1) Maximum Hb increases observed by genotype Source: Data presented at 2017 ASH Annual Meeting AG-348 continues to be well tolerated Measurements of hormone levels in men at doses ≤50 mg BID suggest mild aromatase inhibition Robust Hemoglobin Increases with AG-348 in DRIVE PK
AG-348 ACTIVATE Trial for Non-Regularly Transfused Patients Screening Randomized, Double-Blind, Placebo Controlled N=~80 Extension Placebo patients cross-over to AG-348 Placebo 5 mg 50 mg 20 mg 1:1 Randomization Optimized AG-348 Dose “Optimized” Placebo Primary Efficacy Endpoint: Proportion of patients who achieve at least a 1.5 g/dL increase in hemoglobin sustained over multiple visits 6 weeks 3 months 3 months
AG-348 ACTIVATE-T Trial for Regularly Transfused Patients Retrospective Collection of Transfusion History Primary Endpoint: Reduction in transfusion burden over a 6 month period compared to the patient’s transfusion history Trial Initiation & Screening Individualized Dose Optimization (Part 1) Optimized Dose Period (Part 2) Optimized Dose Approximately 20 regularly transfused patients who have required a minimum of 6 transfusions over the year preceding enrollment 5 mg 50 mg 20 mg 1 year ≤8 weeks Up to 6 months 6 months
Inadequate production: ATP deficiency Pyruvate Kinase Deficiency PEP Pyruvate mPKR Proof of concept achieved Cellular demand: ATP production meets demand Normal Red Cell Cellular demand: PEP Pyruvate wtPKR PK Activation Represents Opportunities Across Hemolytic Anemias Increased demand: ATP deficiency Other Hemolytic Anemias PEP Pyruvate wtPKR Cellular demand: Thalassemia: Expect to initiate Phase 2 proof-of-concept study in Q4 2018 Sickle cell: Planning underway
Treatment with AG-348 for up to 2 months shows sustained improvement in hematological parameters Sharp reduction in circulating immature red cells suggests amelioration of ineffective erythropoiesis ~50% increase in lifespan of peripheral RBCs Hemoglobin Reticulocytes ATP AG-348 Improves Red Cell Parameters in a Beta-thalassemia Mouse Model Source: Lucia de Franceschi, University of Verona 9.1 10.9 29.5 34.0 260 150 51,233 84700 Reticulocytes ATP RBC Life Span 260 150 150 84,700 9.6 14.5 AG-348 (8 weeks) vehicle 0 5 10 15 20 RBC Half Life (days) Vehicle AG-348 (Hb, reticulocytes & ATP, 21 days RBC half life, 8 weeks)
Thalassemia Phase 2 Proof-of-Concept in Non-Transfusion Dependent Adults 50 mg BID 100 mg BID Screening AG-348 Core Treatment Period (N= ~20) 4 weeks 8 weeks ≤ 6 weeks 12 weeks Interim Analysis Extension Treatment or Follow-Up Visit Open-label trial in ~20 patients with hemoglobin < 9.0. Primary endpoint is hemoglobin response, using a definition of 1.0 g/dl over baseline at 12 weeks
2,3-DPG Regulates Hemoglobin Oxygenation in Sickle Cell Disease Sickle cells (SS) have higher 2,3-DPG compared to normal (AA) Sources: Journal of clinical sleep medicine JCSM, 3. 313-5; L J Clin Invest. 1970 Apr; 49(4): 806–812 Decreased O2 affinity can contribute to sickling in SCD Same affinity for O2 in Sickle (Hb S) & normal (Hb A)
Therapeutic Hypothesis for AG-348: Modulation of 2,3-DPG and ATP Levels Will Reduce HbS Polymerization Activation of WT PKR in healthy volunteer clinical studies shows ~50% reduction in 2,3-DPG C DPG depletion shifts T to R -DPG +DPG Mean blood concentration-time profiles of 2,3-DPG following multiple oral doses of AG-348 (cohorts 1 and 2 only) Sources: Agios 2016 EHA presentation, Eaton & Bunn, Blood, 2017
Defining the Potential for PKR Activation in Hemolytic Anemias Pyruvate Kinase Deficiency Pivotal program underway for global registration PEAK registry and Natural History Study will further define disease burden Life Cycle Expansion Phase 2 proof-of-concept in Thalassemia to start 4Q’18 Planning for clinical development in sickle cell underway Assessing biomarker endpoints and study designs for proof-of-mechanism and clinical concept Committed to investigating AG-348 in hemolytic anemias where PKR activation can help patients
Financial Overview & Q1 2018 Financial Results Andrew Hirsch, Chief Financial Officer & Head of Corporate Development
Agios Approach to Drug Discovery and Development Drives Shareholder Value Discovery Research 6 INDs in 8 years 7th planned for Q4 2018 Discover new cancer or rare genetic disease targets or develop new biological insight to known pathway Rapidly validate the biology pre-clinically Develop small molecule chemistry to hit targets Since 2009 Clinical Development 10+ clinical trials in 6 diseases Efficiently advance targets into clinic to attain proof-of-concept Aggressively expand therapeutic opportunity if mechanism warrants Since 2013 Commercialization 1st medicine approved 2nd NDA under review Profitably commercialize each approved product Since 2017
Capital Formation and Investment Approach Clinical Portfolio Investment Profit from Commercialized Products External Funding $50-60M Annual Research Discovery Investment 6 INDs in 8 years 7th IND planned for Q4 2018 9 programs in late preclinical development IDHIFA NDA Approval <4 years from 1st patient dosed TIBSOVO® NDA under priority review 10+ clinical trials across 6 disease areas IDHIFA royalty TIBSOVO® PDUFA date 8/21/18 Commercial team in place and “launch ready” ~$1.5 billion in equity raised from public markets ~$500 million received from Celgene collaborations
87.94 39.85 $83.77 $18.00 57.6M 31.0M $4.8B $0.6B Shareholder Value Creation Since IPO At IPO (July 2013) Today (May 1, 2018) Market Capitalization +700% Share Count +85% ($1.5 billion raised) Share Price +365% XBI Performance +120% $ $
Not likely to pursue clinical investment Aggressive investment and development No clinical investment Measured investment and development Clinical Development Decisions Driven By Our Vision and Values Transform the lives of Patients = Unmet Need/Market Opportunity Scientific Leadership = Assessment of Probability of Technical Success
First Quarter Financial Results Balance Sheet March 31, 2018 December 31, 2017 Variance Cash, Cash Equivalents and Marketable Securities $995M $568M $427M Total Assets $1,040M $614M $426M Statement of Operations Three Months Ended March 31, 2018 Three Months Ended March 31, 2017 Variance Collaboration Revenue $7.3M $10.5M ($3.2M) Royalty Revenue $1.4M -- $1.4M Research & Development Expense (1) $78.2M $62.7M $15.5M General & Administrative Expense $24.6M $14.8M $9.7M 1) The R&D expenses reported for the three months ended March 31, 2017 are reported net of cost reimbursements of $2.8 million, for the three months ended March 31, 2018 cost reimbursements are reflected in Collaboration Revenue. March 31, 2018 cash balance provides runway through at least the end of 2020
Q&A