EPZ-5676 DOT1L Inhibitor Program Phase 1 Dose Escalation Top-Line - PowerPoint PPT Presentation

Personalized Therapeutics Ÿ Ÿ The Power of Epigenetics EPZ-5676 – DOT1L Inhibitor Program Phase 1 Dose Escalation – Top-Line Data 14 November 2013

Forward Looking Statements The outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials, and interim results of a clinical trial such as the results of our Phase 1 clinical trial of EPZ-5676 described in this presentation do not necessarily predict final results. The treatment effects observed in our Phase 1 clinical trial of EPZ-5676 were achieved by only a small number of patients in an open-label setting, were not statistically significant, might not represent any clinical benefit and might not be achieved by any other patient treated with EPZ-5676. This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operations, prospects, plans and objectives of management, are forward- looking statements. The words ‘‘anticipate,’’ ‘‘believe,’’ ‘‘estimate,’’ ‘‘expect,’’ ‘‘intend,’’ ‘‘may,’’ ‘‘plan,’’ ‘‘predict,’’ ‘‘project,’’ ‘‘target,’’ ‘‘potential,’’ ‘‘will,’’ ‘‘would,’’ ‘‘could,’’ ‘‘should,’’ ‘‘continue,’’ and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including the uncertainties inherent in the initiation of future clinical trials, expectations of expanding ongoing clinical trials, availability and timing of data from ongoing clinical trials, expectations for regulatory approvals, development progress of the Company’s companion diagnostics, availability of funding sufficient for the Company’s foreseeable and unforeseeable operating expenses and capital expenditure requirements, other matters that could affect the availability or commercial potential of the Company’s therapeutic candidates or companion diagnostics and other factors discussed in the “Risk Factors” section of the Company’s 10-Q filed with the Securities and Exchange Commission on October 23, 2013. 2 14 N OVEMBER 2013

Agenda • EPZ-5676 Program Overview and Phase 1 Dose Escalation Summary • Phase 1 Dose Escalation Top-Line Data and Program Plans • Pre-clinical Highlights 3 14 N OVEMBER 2013

EPZ-5676 – Program Overview • First-in-class small molecule inhibitor of DOT1L , a histone methyltransferase that is a driving oncogene in acute leukemias with genetic alterations of MLL • Therapeutic mechanism of action – In cancers with MLL genetic alterations, sustained DOT1L inhibition expected to lead to terminal effects including blast differentiation and leukemia cell apoptosis – Pre-clinical data shows durable anti-leukemic effects and tumor regressions with well-tolerated DOT1L inhibition in MLL-r models with no anti-leukemic effects expected or observed in cancer cells without MLL genetic alterations • Target indications – MLL-r primary indication – genetically defined subset of AML and ALL, adult and pediatric – MLL-PTD expansion indication – genetically defined subset of adult AML • Two-stage Phase 1 study ongoing – Dose escalation stage nearing completion – includes but does not require MLL-r patients – MLL-r only expansion cohort stage initiating December 2013 • Epizyme has 100% US development and commercialization rights – Partnered with Celgene ex-US – Ongoing joint global clinical development 4 14 N OVEMBER 2013

EPZ-5676 – Phase 1 Dose Escalation Summary Favorable safety profile, treatment effects observed in MLL-r patients • Four dose cohorts have been completed (12, 24, 36 and 54 mg/m2) – Dosing schedule: 21-day continuous IV infusion, 7-day drug holiday per cycle – 16 total patients, 8 acute leukemia with MLL-r, 1 CMML with MLL-r – Fifth cohort (80 mg/m2, 21/7 schedule) enrolling • Tolerability and safety profile has been favorable – No DLTs, drug-related treatment discontinuations, or dose-toxicity relationship • Pharmacokinetics: dose-proportional exposure • Pharmacodynamics: methyl mark reduction is dose- and time-dependent • Treatment effects observed in 4 of 8 acute leukemia MLL-r patients – No effects seen in non-MLL-r patients Heavily pre-treated population – • Initiating MLL-r expansion stage with uninterrupted administration – Starting dose in expansion cohort 80 mg/m2 – Continuous enrollment design allows for further dose escalation 5 14 N OVEMBER 2013

Agenda • EPZ-5676 Program Overview and Phase 1 Dose Escalation Summary • Phase 1 Dose Escalation Top-Line Data and Program Plans • Pre-clinical Highlights 6 14 N OVEMBER 2013

Epizyme’s Clinical Development Strategy Dose Expansion Registration Registration Escalation Cohort Study • Safety • Initial assessment of • Study plan based on • MTD therapeutic effect expansion cohort results • PK • Only patients with • Companion diagnostic • PD including genetically defined cancers methyl mark • Companion diagnostic 2012-2013 2013-2014 7 14 N OVEMBER 2013

EPZ-5676 – Dose Escalation Demographics • Four dose cohorts have been completed (12, 24, 36 and 54 mg/m2) - 16 patients, 8 acute leukemia with MLL-r - Heavily pre-treated population • Dosing schedule: 21-day continuous IV infusion, 7-day drug holiday per cycle • Enrolling fifth cohort (80 mg/m2, 21-day continuous IV infusion, 7- day drug holiday per cycle) Age Median (range) 55 (22-81) • Gender Male: 11 • Female: 5 • Diagnosis AML: 13 (7 MLL-r) • ALL: 1 (MLL-r) • ALL (Ph +): 1 • CMML: 1 (MLL-r) 1 • # Prior Therapies Median (range) 4 (1-8) • Prior Allogeneic SCT Yes: 6 • No: 10 • 1 CMML patient in transformation with MLL-r translocation 8 14 N OVEMBER 2013

EPZ-5676 Dose Escalation – Safety Summary As of 3 November 2013 • No dose limiting toxicities (DLTs) or MTD • No AEs requiring treatment interruption or dose reduction • No evidence of dose-toxicity relationship to date • 1 AE-related discontinuation, not drug-related 1 • Only 1 patient with possible drug-related event (Gr 3 neutropenia, not treatment-limiting) 2 1 Intracranial bleeding in setting of disease progression, not drug-related 2 Excludes treatment-related leukocytosis (n=2) 9 14 N OVEMBER 2013

EPZ-5676 Dose Escalation – PK Summary Dose-proportional exposure (cohorts 1-4) with planned continued escalation in MLL-r expansion stage 2000 Steady State Exposure (Adjusted Mean Value)* Systemic Exposure (ng/mL) 1500 Individual Patient Values Data Point Excluded from Mean Adjusted Mean Value * 1000 500 0 0 10 20 30 40 50 60 70 80 Dose (mg/m 2 /day) *Adjusted mean value excludes a single outlier in cohort 3 10 14 N OVEMBER 2013

EPZ-5676 – Pharmacodynamic Summary 1. Methyl mark continues to decline throughout 21-day treatment period 2. Methyl mark rebounds during 7-day treatment holiday 3. Modeling predicts continued methyl mark decline with uninterrupted treatment 4. Safety of drug allows for dose escalation and uninterrupted administration in MLL-r expansion stage EPZ-5676 Dosing Period Drug 120 120 Holiday 100 100 100 % control (H3K79me2) % Control (H3K79me2) % Control (H3K79me2) 80 80 Methyl Mark Rebound 60 60 During Drug Holiday 40 40 Projected time course with uninterrupted treatment 20 20 0 0 0 0 60 0 0 10 10 20 20 30 30 40 40 50 50 60 60 Days Days Days - Mean value of data from cohort 3 and 4 patients (7 patients total) 11 14 N OVEMBER 2013

EPZ-5676 Dose Escalation – MLL-r Patient Summary Cohort Dx Treatment Effects Cycles Completed Dose 90% circulating blast reduction (no bone marrow ALL aspirate available) Cycle 1 + 2 Resolution of fevers (24 mg/m2) AML None observed Cycle 1 + Maturation in blood and marrow (no change % marrow blasts) AML Cycle 3 + Leukocytosis Resolution of cachexia 3 Maturation in blood (36 mg/m2) (no change % marrow blasts) AML Cycle 2 + Leukocytosis Resolution of leukemia cutis AML None observed Cycle 1 + AML None observed Cycle 2 + Maturation in marrow AML On study (2 nd cycle) 4 % marrow blast decrease (20% à à 2%) (54 mg/m2) AML None observed Cycle 1 + CMML Too early to evaluate On study (2 nd cycle) *Maximum inhibition during treatment period + Discontinuation due to disease progression 12 14 N OVEMBER 2013

EPZ-5676 Dose Escalation – Treatment Effect Resolution of leukemia cutis in patient with AML MLL-r Day 0 Day 28* *Occurred in context of pleomorphic leukocytosis, onset ~ day 15 13 14 N OVEMBER 2013

EPZ-5676 Dose Escalation – Differentiation Effects Consistent with pre-clinical data, EPZ-5676 differentiation effects observed among patients with MLL-r Evidence of maturation of Evidence of maturation of Pleomorphic Leukocytosis leukemic blasts (peripheral blood) leukemic blasts (bone marrow) (MLL Break apart FISH) Leukemic blasts (Day 0) (Day 0) Neutrophils (Day 28) (Day 15) Representative images from dose escalation 14 14 N OVEMBER 2013