On June 21, 2019 Epizyme, Inc. (Nasdaq: EPZM), a late-stage biopharmaceutical company developing novel epigenetic therapies,reported positive interim data from an ongoing Phase 2 trial of its lead candidate, tazemetostat, as a monotherapy for patients with relapsed or refractory follicular lymphoma (FL) who have received at least two prior lines of systemic therapy (Press release, Epizyme, JUN 21, 2019, View Source [SID1234537217]). The data show that tazemetostat demonstrated meaningful clinical activity and was generally well tolerated in both patients with EZH2 activating mutations and those with wild-type EZH2.

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The data will be presented today in an oral presentation entitled "Interim update from a Phase 2 multicenter study of tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory follicular lymphoma" at the International Conference on Malignant Lymphoma (ICML) by Franck Morschhauser, M.D., Ph.D., Centre Hospitalier Régional Universitaire de Lille, France, an investigator in the Phase 2 trial.

"FL is an indolent, incurable disease, for which patients are in need of new effective and tolerable treatment options," said Dr. Shefali Agarwal, chief medical officer of Epizyme. "We continue to be encouraged by the demonstration of clinical activity and tolerability seen with tazemetostat treatment in these relapsed or refractory patients. We are pleased with the activity and durability we are seeing in both cohorts, and expect to see the data in patients with EZH2 mutations to continue to mature, given some patients are newer on study. Preparations for our NDA submission for tazemetostat for FL are underway, and we remain on track for submission in the fourth quarter of this year. We look forward to advancing those efforts, and further engaging with the FDA on our confirmatory study plans, as we work toward our goal of bringing tazemetostat to these patients."

Follicular Lymphoma Phase 2 Cohort Design
Follicular lymphoma patients who had been previously treated with two or more systemic therapies were enrolled into two cohorts in the Phase 2 study. One cohort enrolled patients with EZH2 activating mutations and completed target enrollment of 45 patients in December 2018. A second cohort enrolled patients with wild-type EZH2, which completed enrollment of 54 patients in 2017. The study enrolled a difficult to treat population. In the cohort of patients with EZH2 activating mutations, 40% of patients were refractory to their last treatment; 40% were refractory to a rituximab regimen; and 22% were double refractory. In the wild-type EZH2 cohort, 37% were refractory to their last treatment; 61% were refractory to a rituximab regimen; and 39% were double refractory. All patients were treated with 800 mg of tazemetostat, administered orally twice a day. The primary endpoint of the study is objective response rate (ORR) as assessed by the investigator defined as a complete response (CR) or partial response (PR). Secondary endpoints include duration of response, overall survival and progression free survival and safety.

Interim Efficacy Data
All data are reported as of a June 7, 2019 data cutoff date. In the cohort of patients with EZH2 activating mutations, 43 patients were evaluable for efficacy. The ORR in this cohort was 77%, and 100% of patients experienced a reduction in tumor burden, with no patients having experienced progressive disease as best response. Seven percent of patients achieved a CR, 70% achieved a PR and 23% achieved stable disease (SD) as best response. Of those patients with SD, 9% remain on study with the potential to respond. At the time of this analysis, the median duration of response (DOR) was 8.3 months, with several new responders included since the prior data cutoff. The median progression-free survival (PFS) was 11.1 months and median follow-up time was 15.9 months.

In the cohort of FL patients with wild-type EZH2, 53 patients were evaluable for efficacy, as one patient withdrew consent for personal reasons within the first two weeks of treatment and is censored from the database. The ORR in this cohort was 34%, and 71% of patients experienced a reduction in tumor volume. Six percent of patients achieved a CR, 28% achieved a PR and 30% of patients achieved SD as best response. The median DOR is now mature at 13 months. The median PFS was 5.7 months and median follow-up time was 24.9 months.

Updated efficacy findings are summarized below:

Best Response

FL with EZH2 MT

FL with EZH2 WT

Evaluable for efficacy on June 7, 2019

n =43

n =53

Objective Response Rate (CR + PR)

77% (n=33)

34% (n=18)

Complete Response (CR)

7% (n=3)

6% (n=3)

Partial Response (PR)

70% (n=30)

28% (n=15)

Stable Disease (SD)

23% (n=10)

30% (n=16)

SD study drug ongoing

9% (n=4)

n=0

Progressive Disease

n=0

36% (n=19)

Overall Survival (OS)

Not reached1

38.4 months

Median Duration of Response (DOR)

8.3 months1
(36 weeks)

13 months
(56.1 weeks)

Median Progression-Free Survival (PFS)

11.1 months1
(48.1 weeks)

5.7 months
(24.6 weeks)

Data continue to mature
Interim Safety Data
Favorable safety and tolerability have been observed with tazemetostat in these Phase 2 study cohorts. Interim safety results at the time of this analysis show only 5% of FL patients discontinued treatment due to treatment-related adverse events (AEs) and 9% had dose reductions due to treatment-related AEs. Treatment-related AEs of Grade 3 or higher were reported in 17% of patients, the most frequent of which included thrombocytopenia (3%), anemia (2%), asthenia (2%), vomiting (1%) and fatigue (1%).

"The data reported today are meaningful for our FL program and importantly, continue to provide confidence in our planned NDA submission for tazemetostat in FL in the fourth quarter," said Robert Bazemore, president and chief executive officer of Epizyme. "We believe strongly in tazemetostat’s potential to make a difference for these patients, and our ultimate goal is to reach FL patients across all lines of therapy. With several combination studies planned for this year with tazemetostat, we are making progress toward that goal. I am incredibly thankful to our team for their hard work in advancing tazemetostat, and to the patients, caregivers and physicians who have participated in our clinical program, making this all possible."

Investor Conference Call
Epizyme will host an investor conference call and webcast today at 8:30 a.m. To participate in the call, please dial (877) 844-6886 (domestic) or (970) 315-0315 (international) and refer to conference ID 7765222. A live webcast will be available in the investor section of the company’s website at www.epizyme.com. The webcast will be archived on the website for 60 days.

About the Tazemetostat Clinical Trial Program
Tazemetostat, an oral, potent, first-in-class EZH2 inhibitor, is currently being studied as a monotherapy in ongoing clinical programs in patients with certain molecularly defined solid tumors, including epithelioid sarcoma and other INI1-negative tumors, and in patients with follicular lymphoma, both with and without EZH2 activating mutations. Multiple clinical studies are underway through collaborations assessing tazemetostat as a combination treatment for patients with diffuse large B-cell lymphoma. Epizyme also plans to conduct multiple additional clinical trials designed to evaluate the potential benefit of tazemetostat in earlier lines of therapy for follicular lymphoma, as well as new combinations and cancer indications.