Date: 2015-04-01
Type of information: Exercise of an option agreement
Compound: therapeutics targeting EZH2 including EPZ-6438
Company: Eisai (Japan) Epizyme (USA - MA)
Therapeutic area: Cancer - Oncology - Rare diseases
Type agreement: development licensing commercialisation
Action mechanism: enzyme inhibitor/histone methyltransferase inhibitor. EZH2 is one of the proteins that make up the histone methyltransferases (HMTs) that alter gene expression. EZH2 is known to methylate lysine 27 of the protein H3 (H3K27), H3 being one of the five major histone groups (H1, H2A, H2B, H3 and H4) that together help to store DNA in eukaryotic cell nuclei. H3K27 methylation is also known to suppress gene transcription. It is believed that EZH2 regulates cell proliferation, and may have an important role in carcinogenesis. Also, deletion of the INI1 subunit SWI/SNF chromatin-remodeling complex occurs in nearly all malignant rhabdoid tumors (MRT), a rare cancer, but with a particularly poor prognosis. An antagonistic relationship has been demonstrated between the biochemical action of the SWI/SNF complex and EZH2 on chromatin, which is relieved in MRT due to the INI1 deletion. EZH2 may be a potential driving oncogene in these cancers and therefore an important therapeutic target requiring further investigation. Created through Epizyme\'s proprietary product platform, E7438 (EPZ-6438) is a first-in-class selective small molecule inhibitor of the epigenetic enzyme EZH2.
Disease:
Details: On March 10, 2011, Epizyme announced a worldwide partnership with Eisai Co., Ltd., Tokyo, Japan to discover, develop and commercialize therapeutics targeting EZH2, an epigenetic enzyme, for the treatment of lymphoma and other cancers in genetically-defined patients.
Financial terms: Under the terms of the agreement, Epizyme will receive $6M in upfront and initial milestone payments, and may earn more than $200M in additional research, development and sales milestones, and up to double-digit royalties. Additionally, Eisai will fund 100 percent of R&D through human proof-of-concept, at which point Epizyme has the right to opt into a profit share and co-commercialization arrangement for the United States.
Latest news: * On March 12, 2015, Eisai and Epizyme announced that have agreed to change the scope of collaboration for their worldwide partnership initiated in March 2011 to discover, develop and commercialize cancer therapeutics targeting the epigenetic enzyme EZH2. Epizyme has reacquired global rights to its EZH2 program, including EPZ-6438, from its partner. Epizyme will assume responsibility for development and commercialization in regions outside of Japan and Eisai retaining responsibility for development and commercialization within Japan as well as having the right of first negotiation for licensing rights in Asia. The decision to change the scope of the partnership was agreed upon by the two companies in consideration of the priorities of each company\'s pipeline strategy and the maximization of the potential value of the compounds including E7438. EPZ-6438 is currently being evaluated in a Phase 1/2 clinical study for the treatment of B-cell non-? Hodgkin lymphoma (NHL) and INI1-deficient solid tumors, such as synovial sarcoma and malignant rhabdoid tumor. “As we began to see the quality and duration of the responses, including two complete responses, in relapsed and refractory NHL and INI1-deficient patients treated with EPZ-6438 as a monotherapy, it became clear to us that having worldwide development and commercialization responsibility for a targeted therapeutic like 6438 would be transformative for Epizyme” said Robert Gould, Ph.D., President and Chief Executive Officer, Epizyme. Following completion of the transition of EPZ-6438 from Eisai to Epizyme, Epizyme plans to conduct a five-?arm Phase 2 study in approximately 150 patients with NHL. This study will evaluate EPZ-?6438 in the following patient cohorts: • Diffuse large B-cell lymphoma, germinal center B-cell-like (GCB) type with wild-type EZH2
• Diffuse large B-cell lymphoma, GCB type with mutant EZH2
• Follicular lymphoma with wild-type EZH2
• Follicular lymphoma with mutant EZH2
• Diffuse large B-cell lymphoma, non-GCB type
The cohort of patients with diffuse large B-cell non-GCB type is expected to include predominantly patients with wild-type EZH2, since the frequency of EZH2 mutations is approximately 5 percent in this sub-population of diffuse large B-?cell lymphoma.
In addition, Epizyme plans to initiate a Phase 2 study in adults with INI1-deficient tumors, including synovial sarcoma, and a Phase 1 study in children with INI1-deficient tumors, including malignant rhabdoid tumors. Epizyme will also continue the clinical pharmacology studies that are part of the Eisai / Epizyme clinical plan.
Under the terms of the agreement, Epizyme will be responsible for global development, manufacturing and commercialization. Epizyme will fund 100 percent of global development costs, and Eisai will fund 100 percent of Japan-specific development costs. Epizyme will make a $40 million upfront payment to Eisai, with a total of up to $20 million in potential clinical milestone payments and up to $50 million in potential regulatory milestone payments. Epizyme will pay Eisai a royalty at a percentage in the mid-?teens on sales of EPZ-6438 outside of Japan, and Eisai will pay Epizyme a royalty at a percentage in the mid-teens on sales in Japan. Eisai will have a limited right of first negotiation for Asia rights if Epizyme decides to license Asia rights to a third party.
