Date: 2016-01-11
Type of information: Termination of an agreement
Compound: evofosfamide (TH-302)
Company: Merck KGaA, Merck Serono (Germany) Threshold Pharmaceuticals (USA)
Therapeutic area: Cancer - Oncology
Type agreement: development
commercialisation
Action mechanism: TH-302 is a hypoxia-activated prodrug consisting of a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard. The product has been discovered by Threshold scientists. It is designed as a prodrug that is selectively activated under the extreme hypoxic conditions commonly found in tumors, but not typically in healthy tissues. Within regions of tumor hypoxia, TH-302 is converted to its active form, bromo isophoramide mustard (Br-IPM). Variants of IPM are clinically validated potent DNA alkylating agents, which kill tumor cells by causing DNA to crosslink thereby rendering cells unable to replicate their DNA and divide. Once activated in hypoxic tissues, Br-IPM can also diffuse into surrounding oxygenated regions of the tumor and kill cells there via a “bystander effect”.
Disease: soft tissue sarcoma, pancreatic cancer
Details: * On February 3, 2012, Merck KGaA has signed a global agreement with Threshold Pharmaceuticals, Inc., South San Francisco, to co-develop and commercialize TH-302, Threshold’s small molecule hypoxia-targeted drug. Under the terms of the agreement, Merck will receive co-development rights, exclusive global commercialization rights and will provide Threshold an option to co-commercialize the therapeutic in the United States. In the United States, Threshold will have primary responsibility for development of TH-302 in the soft tissue sarcoma indication. Threshold and Merck will jointly develop TH-302 in all other cancer indications being pursued. Merck will pay 70% of worldwide development costs for TH-302. Subject to FDA approval in the United States, Merck will initially be responsible for commercialization of TH-302 with Threshold receiving a tiered, double-digit royalty on sales. Under the royalty-bearing portion of the agreement, Threshold retains the option to co-promote TH-302 in the United States. Additionally, Threshold retains the option to co-commercialize TH-302 allowing the company to participate in up to 50% of the profits in the United States, based on certain revenue tiers. Outside of the United States, Merck will be solely responsible for the commercialization of TH-302 with Threshold receiving a tiered, double-digit royalty on sales in these territories. TH-302 has been investigated in over 550 patients in Phase I/II clinical trials to date in a broad spectrum of tumor types, both as a monotherapy and in combination with chemotherapy treatments and other targeted cancer drugs. Threshold has several ongoing clinical trials including, but not limited to: a controlled Phase II trial of TH-302 in combination with gemcitabine versus gemcitabine alone in patients with advanced pancreatic cancer and a Phase III study evaluating TH-302 in combination with doxorubicin versus doxorubicin alone in patients with soft tissue sarcoma. A Phase III trial of TH-302 in patients with first-line advanced soft tissue sarcoma (STS) was initiated in September, 2011, based on results from a Phase I/II trial investigating its use in combination with the chemotherapeutic doxorubicin. This randomized, multi-center Phase III trial will investigate the use of TH-302 plus doxorubicin compared with doxorubicin alone. The primary efficacy endpoint is overall survival. The study is conducted under a Special Protocol Assessment with the U.S. Food and Drug Administration. It is being run in partnership with the Sarcoma Alliance for Research through Collaboration (SARC) and aims to enroll 450 patients with metastatic or locally advanced unresectable STS. Results from a randomized, controlled, multi-center Phase II trial of TH-302 in patients with first-line pancreatic cancer are expected to be announced in February, 2012. This trial of 214 previously untreated patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma started in June, 2010, and completed enrollment in June, 2011. Two different doses of TH-302 in combination with the chemotherapeutic gemcitabine were compared to gemcitabine alone, with progression free survival (PFS) as the primary endpoint.
Financial terms: In exchange, Threshold will receive an upfront payment of € 19 million ($ 25 million) and could receive up to € 26.5 million ($ 35 million) in additional development milestones during 2012. Threshold is also eligible to receive a € 15 million ($ 20 million) milestone payment based on positive results from its randomized Phase II trial in pancreatic cancer.
Latest news: * On January 11, 2016, Threshold Pharmaceuticals announced an update on its evofosfamide program including that Threshold and Merck KGaA have agreed upon key terms for the licensing back of all rights to evofosfamide to Threshold. The decision to return rights to evofosfamide to Threshold follows the unblinding of two Phase 3 clinical trials of evofosfamide (TH-CR-406 and MAESTRO) and a previously unplanned, subsequent interim futility analysis of a Phase 2 clinical trial of evofosfamide in patients with non-squamous non-small cell lung cancer. As previously announced, both Phase 3 trials failed to meet the primary endpoint of demonstrating a statistically significant improvement in overall survival. Following the topline results from the two Phase 3 clinical trials, Threshold and Merck KGaA, Darmstadt, Germany decided to unblind the Phase 2 clinical trial in n-s NSCLC and conduct an interim futility analysis. The Phase 2 trial was designed to enroll 440 patients with advanced n-s NSCLC. A total of 265 patients were enrolled and 112 events (deaths) were reported at the time of the interim analysis. An independent Data Safety Monitoring Board conducted the analysis and concluded that the trial is unlikely to reach its primary endpoint of improving overall survival with statistical significance. As a result, further enrollment in this trial will be closed. Additional findings from the interim analysis indicated that evofosfamide plus pemetrexed demonstrated longer progression-free survival (PFS) associated with a reduction in the risk of progression or death by approximately 30%. No new safety findings were reported. Data for this trial will be finalized and results presented at a future medical meeting. * On November 18, 2015, Threshold Pharmaceuticals announced that it finalized a definitive co-promotion agreement for evofosfamide with Merck KGaA pursuant to the companies' license and co-development agreement entered into on February 2, 2012 . Under the terms of the agreement, Threshold may co-promote evofosfamide (previously known as TH-302) in the U.S. subject to FDA approval of evofosfamide. Under the commercial leadership of Merck KGaA, the terms of the agreement give Threshold the right, at its own cost, to field and be responsible for its own sales force in collaboration with Merck KGaA's sales force in the U.S. pursuant to the terms of the new co-promotion agreement. Merck KGaA remains responsible for all other commercial and medical affairs functions associated with the launch and promotion of evofosfamide. The development milestone payment and royalty payment portions of the license and co-commercialization agreement remain the same. To date Threshold has received upfront and milestone payments of $110 million and can earn additional potential milestone payments of up to $440 million .
