Epizyme and HUTCHMED Announce Strategic Collaboration to Develop and Commercialize TAZVERIK® (tazemetostat) in Greater China
Collaboration designed to accelerate global development and investigate TAZVERIK® combinations with HUTCHMED’s novel oncology medicines portfolio
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TAZVERIK® is a methyltransferase inhibitor of EZH2 developed by
“We are thrilled to be able to launch this collaboration designed to bring TAZVERIK® to patients in
“We view the activity of TAZVERIK® and its epigenetic mechanism in controlling the expression of certain genes as highly complementary and potentially synergistic with our broad portfolio of novel oncology assets,” said Mr.
Under the terms of the agreement,
Webcast and Conference Call
Analysts and investors are invited to join a webcast and conference call scheduled today –
About Epigenetics, EZH2, Its Role in Cancer and TAZVERIK®’s Complementary Role with HUTCHMED’s Portfolio of Drug Candidates
Epigenetics refers to a broad regulatory system that controls gene expression without altering the sequence of the genes themselves. EZH2 is one member of a class of histone methyltransferases (“HMTs”). It catalyzes the methylation of histone H3 at lysine 27 (H3K27) which controls expression of various genes and in turn plays a role in the normal physiology of many cell types.
Dysregulation of EZH2 has been seen in a wide range of cancers and is associated with poor clinical prognosis and outcomes.1,2 It is associated with follicular lymphoma and diffuse large B-cell lymphoma, B-cell malignancies that are estimated to respectively account for approximately 17% and 32% of the estimated 544,000 new cases of non-Hodgkin Lymphoma (NHL) worldwide in 2020.3,4 EZH2 dysregulation has been described in the five most common solid tumors (breast, lung, colorectum, prostate and stomach) with an estimated combined incidence of over 1 million in 2020 globally.
TAZVERIK® inhibits EZH2 which allows transcription of genes involved in functions such as cell cycle control and terminal differentiation and thus TAZVERIK® action inhibits cancer cell proliferation. This mechanism of action is highly complementary and potentially synergistic with HUTCHMED’s portfolio of cancer drug candidates. For solid tumors, these include fruquintinib, a highly selective inhibitor of vascular endothelial growth factor receptor, and surufatinib, a unique compound that inhibits angiogenesis and promotes the body’s immune response against tumor cells.5 For hematological malignancies, these include many assets including inhibitors of the B-cell signaling pathway such as the highly selective and potent PI3Kδ inhibitor HMPL-689, the Syk inhibitor HMPL-523 and third generation BTK inhibitor HMPL-7606, as well the IDH1/2 inhibitor HMPL-306, the ERK inhibitor HMPL-295, the FGFR inhibitor HMPL-453 and the CD47 antibody HMPL-A83. The potential for broad applicability and favorable safety profile of TAZVERIK® may provide more effective inhibition of tumor growth and metastasis when used in combination therapy.
About TAZVERIK® (tazemetostat)
TAZVERIK® is a methyltransferase inhibitor indicated in
- Adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
- Adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least two prior systemic therapies.
- Adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options.
These indications are approved under accelerated approval by the
About TAZVERIK® Accelerated Approval in FL
TAZVERIK® was approved in the
The efficacy of TAZVERIK® was evaluated in an open-label, single-arm, multi-center Phase II clinical trial in patients with histologically confirmed FL whose disease had progressed following at least two prior systemic treatment regimens. Patients were enrolled into two cohorts: one cohort enrolled 45 patients with EZH2 activating mutations and a second cohort enrolled 54 patients with wild-type EZH2. All patients were treated with 800 mg of tazemetostat, administered orally twice a day. The major efficacy outcome measures were ORR and DOR according to the International Working Group Non-Hodgkin Lymphoma (IWG-NHL) criteria (Cheson 2007) as assessed by Independent Review Committee. Median duration of follow-up was 22 months for patients with EZH2 activating mutations and 36 months for patients with wild-type EZH2.
Results of this study were published in The Lancet Oncology.7 Data from the label is below. Among the 45 FL patients with an EZH2 activating mutation who received TAZVERIK®, the median age was 62 years (range 38 to 80); 42% were male; 42% had early progression following front-line therapy (“POD24”); and all had an
Among the 54 FL patients with wild-type EZH2 who received TAZVERIK®, the median age was 61 years (range 36 to 87); 63% were male; 59% had POD24; and 91% had an ECOG PS of 0 or 1. The median number of lines of prior systemic therapy was 3.0 (range 1 to 8); 59% were refractory to rituximab and 41% were refractory to their last therapy. In the 53 patients treated with at least 2 prior systemic therapies, the ORR (95% confidence interval) was 34% (22%, 48%), with 4% of patients achieving a complete response and 30% achieving a partial response. The median DOR was 13.0 months.
Serious adverse reactions, irrespective of attribution, occurred in 30% of patients receiving TAZVERIK®. Serious adverse reactions in ≥2% of patients who received TAZVERIK® were general physical health deterioration, abdominal pain, pneumonia, sepsis, and anemia. The most common (≥20%) adverse reactions are fatigue, upper respiratory tract infection, musculoskeletal pain, nausea and abdominal pain.
Eight patients (8%) discontinued due to adverse reaction during the trial. There were no reported deaths on study, and no black box warnings or contraindications.
The most common (≥20%) adverse reactions in patients with follicular lymphoma are fatigue, upper respiratory tract infection, musculoskeletal pain, nausea and abdominal pain.
EZH-302 is a global, randomized, double-blind, active-controlled, biomarker enrichment, adaptive design Phase Ib/III confirmatory trial (clinicaltrials.gov identifier: NCT04224493) assessing the combination of TAZVERIK® with R² (REVLIMID® plus rituximab), an approved chemotherapy-free treatment regimen, compared with R² plus placebo for relapsed or refractory FL patients followed by maintenance TAZVERIK or placebo in the second-line or later treatment setting. The trial is expected to enroll approximately 500 FL patients.
About TAZVERIK® Accelerated Approval in ES
TAZVERIK® was approved in the
The efficacy of TAZVERIK® was evaluated in an open-label, single-arm cohort (Cohort 5) of a multi-center study in patients with histologically confirmed, metastatic or locally advanced epithelioid sarcoma. Patients were required to have INI1 loss, detected using local tests, and an ECOG PS of 0-2. Patients received TAZVERIK® 800 mg orally twice daily until disease progression or unacceptable toxicity. Tumor response assessments were performed every 8 weeks. The major efficacy outcome measures were confirmed ORR according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by blinded independent central review (BICR) and DOR. Median duration of follow-up was 14 months (range 0.4 to 31).
Results of this study were published in The Lancet Oncology.8 Data from the label is below. Among the 62 patients who received TAZVERIK®, median age was 34 years (range 16 to 79); 63% were male, 76% were White, 11% were Asian, 44% had proximal disease, 92% had an ECOG PS of 0 or 1, and 8% had an ECOG PS of 2. Prior surgery occurred in 77% of patients; 61% received prior systemic chemotherapy.
In the total 62 patients treated, the ORR (95% confidence interval) was 15% (7%, 26%), with 1.6% of patients achieving a complete response and 13% achieving a partial response. Among responders in the trial, 67% had a duration of response of six months or longer.
Serious adverse reactions occurred in 37% of patients receiving TAZVERIK®. Serious adverse reactions in ≥3% of patients who received TAZVERIK® were hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress.
One patient (2%) permanently discontinued TAZVERIK® due to an adverse reaction of altered mood.
The most common (≥20%) adverse reactions in patients with epithelioid sarcoma are pain, fatigue, nausea, decreased appetite, vomiting and constipation.
EZH-301 is a global, randomized, double-blind, placebo-controlled controlled Phase Ib/III confirmatory trial (clinicaltrials.gov identifier: NCT04204941) assessing TAZVERIK® in combination with doxorubicin compared with doxorubicin plus placebo as a front-line treatment for ES. The trial is expected to enroll approximately 150 patients.
About Other TAZVERIK® Clinical Development
In addition to the studies in FL and ES, TAZVERIK® is also being developed in DLBCL and in prostate cancer and ovarian cancer.
TAZVERIK® is a registered trademark of
Cautionary Note on Forward-Looking Statements
This announcement contains forward-looking statements within the meaning of the “safe harbor” provisions of the
This announcement contains inside information for the purposes of Article 7 of Regulation (EU) No 596/2014 (as it forms part of retained EU law as defined in the
1 Beguelin W, Popovic R, Teater M, et al. EZH2 Is Required for Germinal Center Formation and Somatic EZH2 Mutations Promote Lymphoid Transformation. Cancer Cell. 2013;23(5):677-92.
2 Boheng L, Chang WJ. EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications. J Hematol Oncol. 2019;12(1):118.
3 NCCN Guideline on B-Cell Lymphomas. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed
4 Globocan. https://gco.iarc.fr/today/data/factsheets/cancers/34-Non-hodgkin-lymphoma-fact-sheet.pdf. Accessed
5Lu C, Han HD, Mangala LS, et al. Regulation of tumor angiogenesis by EZH2. Cancer Cell. 2010;18(2):185-197. doi:10.1016/j.ccr.2010.06.016
6 Keats J, Lee A, Cunniff J,et al. Abstract 1161: EZH2 inhibitor tazemetostat demonstrates activity in preclinical models of Bruton's tyrosine kinase inhibitor-resistant relapsed/refractory mantle cell lymphoma. Cancer Res
7 Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442. doi:10.1016/S1470-2045(20)30441-1
8 Gounder M, Schöffski P, Jones RL, et al. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol. 2020;21(11):1423-1432. doi:10.1016/S1470-2045(20)30451-4
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