Epizyme has entered into strategic collaborations for several therapeutic programs. These collaborations are important elements of our strategy to build a leading, independent biopharmaceutical company. We believe that our collaborations contribute to our ability to rapidly advance our therapeutic product candidates, build our product platform and concurrently progress a wide range of discovery and development programs. Our therapeutic collaborations have provided us with more than $200 million in non-equity funding. We have retained global rights to tazemetostat, our first-in-class EZH2 inhibitor, outside of Japan in our Eisai collaboration, and have retained commercialization rights in the United States for two of the programs in our Celgene collaboration. We are eligible for milestones and royalties on net product sales in our GSK collaboration.
In November 2018, we entered a collaboration with Boehringer Ingelheim focused on the research, development, and commercialization of novel small molecule inhibitors directed toward two previously unaddressed epigenetic targets as potential therapies for people with cancer. Specifically, these targets are enzymes within the helicase and histone acetyltransferase (HAT) families that when dysregulated have been linked to the development of cancers that currently lack therapeutic options.
In June 2016, we entered into a collaboration agreement with Genentech, a member of the Roche Group, to conduct a clinical trial to investigate the combination of tazemetostat and Genentech’s approved anti-PD-L1 cancer immunotherapy, Tecentriq™ (atezolizumab), for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma (NHL). Under the agreement, Genentech is managing study operations for the Phase 1b clinical trial.
In May 2016, we entered into a collaboration agreement with the Lymphoma Study Association (LYSA) to investigate the combination of tazemetostat with R-CHOP, a standard chemotherapy for NHL, as a front-line treatment in elderly, high-risk patients with newly diagnosed DLBCL. LYSA is a premier cooperative group in France dedicated to clinical and translational research for lymphoma, and is certified by the French National Cancer Institute. This Phase 1b/2 study is being conducted with the Lymphoma Academic Research Organisation (LYSARC), the operational arm of LYSA, at multiple sites in France.
In March 2015, we entered into an amended and restated collaboration and license agreement with Eisai, under which we reacquired worldwide rights excluding Japan to tazemetostat. Under the original collaboration and license agreement, we granted Eisai an exclusive worldwide license to our EZH2 program, including tazemetostat, while retaining an opt-in right to co-develop, co-commercialize and share profits with Eisai as to licensed products in the United States.
Under the amended and restated collaboration and license agreement, we are responsible for global development, manufacturing, and commercialization outside of Japan of tazemetostat and any other EZH2 product candidates, with Eisai retaining development and commercialization rights in Japan, as well as a right to elect to manufacture tazemetostat and any other EZH2 product candidates in Japan. In connection with the amended and restated agreement, we paid Eisai an upfront payment of $40 million, and agreed to pay specified milestone payments based on our development and commercialization of EZH2 products outside of Japan and royalties on net sales of EZH2 products outside of Japan.
In December 2012, together with Eisai, we entered into an agreement with Roche Molecular Systems, Inc., to develop and to commercialize a companion diagnostic to identify patients who have certain EZH2 mutations that are targeted by tazemetostat. We are using the diagnostic designed in collaboration with Roche to identify EZH2 mutations in patients in our five-arm Phase 2 study in NHL.
In April 2012, we entered into a collaboration and license agreement with Celgene under which we granted Celgene an exclusive license to our DOT1L program, among other programs, outside the United States, including pinometostat (EPZ-5676), the therapeutic candidate now in clinical development. We retained 100 percent of United States rights and are eligible to receive royalties on net product sales outside of the United States. Celgene made a $65 million upfront payment and made an equity investment of an additional $25 million.
In July 2015, we amended and restated our agreement with Celgene to extend the research collaboration between the two companies for at least three additional years. Under the collaboration, Celgene will have the option to license histone methyltransferase (HMT) inhibitors being developed by Epizyme against three predefined targets. Epizyme regained global rights to the remainder of its pipeline, as Celgene’s option to license ex-US rights for any other preclinical programs was terminated.
Under the terms of the amended and restated agreement, we received a $10 million extension fee from Celgene in return for an option to individually license global rights for two of the targets and ex-U.S. rights for the third target. Celgene has the right to exercise its option with respect to each of the targets at the time of the IND filing for an additional pre-specified license payment. In addition, Epizyme will be responsible for leading and funding development for each target candidate through Phase 1 clinical trials. Following the completion of Phase 1, if Celgene chooses to continue its license for a specific target, it may do so by making an additional pre-specified payment.
We may earn total potential milestones of up to $610 million on the three targets, including up to $75 million in development milestones and license fees, $365 million in regulatory milestones, and $170 million in sales milestones. We also may earn a royalty of up to a low double-digit percentage on worldwide net sales for two of the product candidates, and on ex-U.S. net sales for the third product candidate.
For pinometostat, we may earn total potential milestones of up to $35 million in remaining potential clinical milestones and up to $100 million in potential regulatory milestones, plus royalties to a mid-teen percentage on ex-U.S. net sales.
In January 2011, we entered into a collaboration and license agreement with GSK to discover, develop and commercialize novel small molecule HMT inhibitors directed to three targets from our product platform. Under the agreement, we received an upfront payment of $20 million. In addition, we have received a $3 million payment upon the execution of an agreement amendment, $6 million of fixed research funding, $9 million in research funding payments and $15 million in milestone payments and are eligible to receive up to $620 million in additional milestone payments, comprising aggregate research, development and regulatory milestone payments of up to $402 million and sales-based milestone payments of up to $218 million. In addition, GSK is required to pay us royalties on worldwide net product sales.