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Epizyme Announces Updated Tazemetostat Phase 1 Data Showing Clinical Activity in a Broader Range of Adults with INI1-Negative and SMARCA4-Negative Solid Tumors

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Epizyme Announces Updated Tazemetostat Phase 1 Data Showing Clinical Activity in a Broader Range of Adults with INI1-Negative and SMARCA4-Negative Solid Tumors September 26, 2015 Epizyme Announces Updated Tazemetostat Phase 1 Data Showing Clinical Activity in a Broader Range of Adults With INI1-Negative and SMARCA4-Negative Solid Tumors ● Partial response by RECIST criteria observed in heavily pretreated SMARCA4-negative malignant rhabdoid tumor of the ovary (MRTO) with duration over six months ● Previously reported complete response in INI1-negative malignant rhabdoid tumor (MRT) continues at 65 weeks ● Three patients achieved stable disease and remain on study for 24 or more weeks including two patients with epithelioid sarcoma and one with MRTO ● Pharmacologic target inhibition observed in tumor tissue ● Safety profile supports initiation of a registration-supporting phase 2 adult study and phase 1 pediatric study in patients with INI1-deficient tumors ● Company to hold conference call and webcast on Monday, September 28, 2015 at 8:00 a.m. ET VIENNA--(BUSINESS WIRE)-- Epizyme, Inc. (NASDAQ: EPZM) reported results today from the ongoing phase 1 trial of tazemetostat, its first-in-class EZH2 inhibitor. The data showed that tazemetostat demonstrated clinical activity in a broader group of patients with INI1-negative and SMARCA4-negative tumors than previously reported, achieved inhibition of EZH2 in tumor tissue, and had an acceptable safety profile when administered as oral monotherapy in adult patients with relapsed or refractory INI1-negative and SMARCA4-negative tumors. The data were presented at the European Cancer Congress 2015 (ECC) in Vienna, Austria by Antoine Italiano, M.D., Ph.D., of the Institut Bergonié in Bordeaux, France. Based on tazemetostat's clinical activity observed to date and other supportive research, Epizyme will initiate a global phase 2 study in adults and a global phase 1 study in children with INI1-negative tumors and synovial sarcoma in the fourth quarter of 2015. INI1-negative and SMARCA4-negative tumors, such as rhabdoid tumors and epithelioid sarcoma are serious and debilitating cancers. Approximately 1,400 patients each year in the major global markets develop these tumors1, which have no established standard of care. INI1 and SMARCA4 are critical proteins of the SWI/SNF complex, which oppose the activity of EZH2. Genetic alterations or loss of function of either can result in EZH2-dependent oncogenesis in certain cancer backgrounds, thus rendering these tumors sensitive to EZH2 inhibition. "INI1-negative tumors represent a group of devastating diseases with a very poor prognosis even for patients who can undergo a complete surgical resection. Tazemetostat has induced objective responses that are durable for some patients and has an excellent safety profile," said Dr. Italiano. "Our data provide evidence that potentially changes the landscape of clinical research in this group of tumors and could improve the treatment paradigm for these traditionally refractory diseases." "We are excited by these data, which show clinical activity in patients with INI1-negative and SMARCA4-negative tumors. These results are consistent with preclinical data that demonstrate the important role of EZH2 in INI1- and SMARCA4-negative tumors such as malignant rhabdoid tumors where median survival after relapse is approximately nine months," said Peter Ho, M.D., Ph.D., Chief Medical Officer, Epizyme. "We are now turning our attention to initiating global registration-supporting clinical trials in adults and children with these aggressive tumors, for which new treatments are needed." In total, 30 patients with solid tumors were enrolled into this ongoing phase 1 study, including eight patients in a food effect sub- study. Of these 30 patients, eight had INI1-negative tumors, comprised of five with malignant rhabdoid tumors and three with epithelioid sarcomas (ES). Additionally, three patients had SMARCA4-negative tumors including two patients with malignant rhabdoid tumor of the ovary, also referred to as small cell carcinoma of the ovary hypercalcemic type (SCCOHT), and one patient with thoracic sarcoma. Nineteen patients had other solid tumors that were not characterized by INI1 or SMARCA4 loss, including three patients with synovial sarcomas. Synovial sarcomas occur in approximately 1,800 patients each year in the major markets. Synovial sarcomas are INI1-deficient rather than INI1-negative. A fusion protein that is characteristic for synovial sarcoma displaces INI1 from the SWI/SNF complex. Displacement of INI1 confers dependence of these tumors on EZH2, and hence sensitivity to an EZH2 inhibitor in preclinical models. In addition to the 30 patients with solid tumors, 21 patients with advanced Non-Hodgkin Lymphoma (NHL) were also enrolled into this ongoing phase 1 study, and the safety data from the ECC update presentation includes these patients. The data cutoff for this presentation was August 31, 2015. Summary of Results ● A total of 11 patients with INI1-negative or SMARCA4-negative tumors have been treated. The tumor histology of these patients includes MRT, MRTO, ES and thoracic sarcoma. Nine of these 11 patients have been treated at or above the recommended phase 2 dose of 800 mg twice daily. ● Six of the 11 patients experienced a reduction in tumor size as best response, with four patients experiencing tumor reduction of over 30%. ● Of five patients with an INI1-negative malignant rhabdoid tumor, one patient achieved a complete response (CR) at week eight and remains on study and in CR through week 65. ● Of three patients with SMARCA4-negative tumors, two patients have malignant rhabdoid tumor of the ovary. One MRTO patient achieved a PR at week 8 and remains on study through week 25. A second MRTO patient remains on study with stable disease (SD) through week 26. ● Of three patients with an INI1-negative epithelioid sarcoma, one patient achieved a PR of short duration and remains on study with SD through week 25. The second patient remains on study with SD through week 24. ● Clinical activity was not observed in the 19 patients with other tumors, including the three patients with synovial sarcomas. ● Inhibition of EZH2, as measured by post-treatment H3K27 trimethylation compared to baseline, was observed in tumor tissue of INI1-negative patients as assessed by immunohistochemistry. ● The majority of adverse events observed in the study were grade 1 or grade 2 within the entire population of 51 patients with NHL and solid tumors. The most frequent adverse events regardless of attribution were asthenia, decreased appetite, thrombocytopenia, nausea, dyspnea, anemia and constipation. Five grade 3 or greater treatment-related adverse events have been observed including one each of: thrombocytopenia, neutropenia, hypertension, liver function test elevation and decreased appetite. ● Solid tumor patients enrolled in this study had been heavily pre-treated, with over half of patients having received three or more prior anti-cancer therapies. Study Design The data presented at ECC are from the ongoing first-in-human phase 1 trial of tazemetostat in adults with relapsed or refractory B-cell lymphomas or advanced solid tumors. The primary objective of the study was to determine the recommended phase 2 dose. Secondary endpoints included safety, pharmacokinetics, pharmacodynamics and tumor response evaluated every eight weeks. Tazemetostat is administered orally twice daily. Five cohorts were studied in the dose escalation phase: 100 mg, 200 mg, 400 mg, 800 mg and 1600 mg; and two cohorts, 800 mg and 1600 mg, were evaluated in the dose expansion phase. Patients enrolled into the food effects sub-study received tazemetostat at 400 mg. Expanded Tazemetostat Phase 1 and Phase 2 Plans A planned phase 2 trial studying tazemetostat in adult patients with INI1-negative solid tumors or synovial sarcoma is expected to begin in the fourth quarter of 2015. A phase 1 dose escalation study in pediatric patients with INI1-deficient solid tumors is also expected to start in the fourth quarter of 2015. The INI1-deficient tumor studies will enroll subjects in the U.S., EU and Australia. Epizyme is already enrolling patients into an international five-arm, multi-center, phase 2 study that will assess the safety and efficacy of tazemetostat in patients with relapsed or refractory NHL, stratified by cell of origin and EZH2 mutation status. The company plans to initiate additional trials of tazemetostat, including: ● A combination study of tazemetostat with R-CHOP in patients with diffuse large B-cell lymphoma (DLBCL), including higher risk front-line patients. R-CHOP, which represents the current first-line regimen for patients with DLBCL, is comprised of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. ● A combination study of tazemetostat with a B-cell signaling agent or other emerging targeted therapy for B-cell lymphomas. About EZH2 in Cancer EZH2 is a histone methyltransferase (HMT) that is increasingly understood to play a potentially oncogenic role in a number of cancers. These include non-Hodgkin lymphomas, rhabdoid tumors and other INI1-deficient cancers such as epithelioid sarcomas and synovial sarcoma as well as a range of other solid tumors. About Tazemetostat Epizyme is developing tazemetostat for the treatment of non-Hodgkin lymphoma patients and patients with INI1-deficient solid tumors. Tazemetostat is a first-in-class small molecule inhibitor of EZH2 created by Epizyme using its proprietary product platform. In many human cancers, aberrant EZH2 enzyme activity results in misregulation of genes that control cell proliferation resulting in the rapid
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