Phase 1 phenomenon

First-in-class EZH2 inhibitor demonstrates safety and efficacy

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CAMBRIDGE, Mass.—Epizyme Inc., a clinical-stage company that develops epigenetic therapies, recently had its first-in-human data on the effects of EZH2 inhibition in patients with advanced solid tumors and B cell non-Hodgkin lymphoma (NHL) published in The Lancet Oncology. The Phase 1 dose-escalation portion of the study was designed to evaluate the safety and tolerability of orally dosed tazemetostat, a first-in-class selective inhibitor of EZH2. The data confirm the science of tazemetostat as a potent, selective, orally available EZH2 inhibitor.
EZH2 inhibits genes responsible for suppressing tumor development. Blocking its activity may slow tumor growth. The study, which established the recommended dose of 800 mg twice daily for the Phase 2 expansion study, demonstrated favorable safety findings and antitumor activity.
Preliminary antitumor activity was seen across several tumor types. In B cell NHL, durable objective responses were observed in eight patients. Three patients had a complete response, one with diffuse large B cell lymphoma (DLBCL) and two with follicular lymphoma (FL). Five additional patients experienced a partial response, three with DLBCL, one with FL and one with marginal zone lymphoma.
As explained by Prof. Antoine Italiano of Institut Bergonie, lead author of the paper, the open-label Phase 1 study was designed to evaluate the maximally tolerated dose and supported defining the recommended Phase 2 dose (RP2D) of tazemetostat. Tazemetostat was dosed twice daily as a single agent in patients with relapsed or refractory B-cell NHL or with advanced solid tumors, including molecularly defined INI1- or SMARCA4-negative tumors. Additional study objectives were to evaluate the adverse events, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of the agent.
The results of the safety, PK and PD analyses helped determine the RP2D of 800 mg twice daily. The most common treatment-related adverse events, regardless of attribution, were grade 1 or 2 asthenia, anorexia, anemia, muscle spasms, nausea and vomiting. One single dose-limiting toxicity of grade 4 thrombocytopenia was identified at the highest dose of 1600 mg, but no other grade 3 or 4 toxicities were observed at a frequency greater than 5 percent.
Of the patients with solid tumors enrolled in this study, 13 had INI1- or SMARCA4-negative tumors. Activity was observed in five of these patients, including a complete response in one patient with a malignant rhabdoid tumor and a partial response in one patient with SMARCA4-negative malignant rhabdoid tumor of the ovary (MRTO). Prolonged stable disease was observed in a patient with MRTO, and two patients with epithelioid sarcoma experienced prolonged stable disease greater than 20 months.
The results from this early-phase study established the groundwork for further exploration of tazemetostat in larger trials as a targeted approach to treat molecularly defined tumors predicted to be dependent on EZH2 activity, such as ES and NHL. Phase 2 studies in adults and a Phase 1 study for children, adolescents and young adults are currently enrolling patients living with these types of cancer.
Epizyme began as a biopharmaceutical research company in 2007 with a mission of “translating key discoveries in the field of epigenetics into novel pharmaceutical agents. Since then, the organization has evolved into a clinical-stage biopharmaceutical company committed to rewriting treatment for cancer and other serious diseases through novel epigenetic medicines. Since 2011, the company has discovered five novel epigenetic therapies, three of which are in clinical development. Two have begun, or will soon begin, IND-enabling studies.
Epizyme is pioneering the discovery and development of small-molecule inhibitors of histone methyltransferases, histone acetyltransferases and helicases. This work in epigenetic drug development led to the identification and advancement of the company’s lead product candidate, tazemetostat.
In early clinical development, tazemetostat has demonstrated clinical activity and a generally well-tolerated safety profile in both patients with hematological malignancies and genetically defined solid tumors. Currently, tazemetostat is being studied as a monotherapy in ongoing Phase 1 and 2 programs in certain molecularly defined solid tumors, including epithelioid sarcoma and other INI1-negative tumors; both FL and DLBCL forms of NHL; mesothelioma; and combination studies in DLBCL.
In addition to tazemetostat, Epizyme has two programs in its pipeline that are currently in clinical development; pinometostat and a PRMT5 inhibitor, which is being developed in collaboration with GlaxoSmithKline. As tazemetostat is still being evaluated in Phase 1 and 2 trials, it is premature to speculate on the commercial potential for the molecule.

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