Takeda Pharmaceutical and Amag Pharmaceuticals said today they “mutually” terminated their 2010 license, development, and commercialization agreement granting Takeda exclusive rights to market ferumoxytol in Canada, the European Union (EU) and Switzerland, and other unspecified geographic territories.

Ferumoxytol is marketed as Rienso® outside Canada, where the drug is sold as Feraheme® .

As a result of the termimination, Amag will regain all worldwide development and commercialization rights for Feraheme/Rienso. Takeda will make a payment of undisclosed amount to Amag in connection with the termination, and provide “certain transition services” to Amag for up to 180 days after the marketing authorization transfer in each territory, the companies said.

In addition, both companies agreed to undertake a transfer of the regulatory files for the product in each respective territory, while Takeda agreed not to participate in any future development or commercialization activities. The companies also said Amag will assess various alternative commercialization strategies for Feraheme in Canada and Rienso in the EU based, in part, on pending regulatory decisions which are expected in 2015.

Amag received $60 million upfront from Takeda under the collaboration, which had been projected to generate up to $280 million; the remaining $220 million had been based on milestones. At the time, Takeda agreed to commercialize ferumoxytol in the EU and Canada as well as former Soviet states, Turkey, and several Asia Pacific countries excluding China, Japan, and Taiwan.

In the U.S., where ferumoxytol is also marketed as Feraheme, the companies tried but failed to win FDA approval about a year ago for a supplemental new drug application for Feraheme® injection for intravenous (IV) use. The companies sought to expand the drug’s approval beyond the chronic kidney disease indication to include all adult iron deficiency anemia (IDA) patients who have failed or cannot tolerate oral iron treatment.

Instead, the FDA issued a complete response letter stating that Amag had not provided sufficient information to permit labeling of Feraheme for safe and effective use for the expanded indication. The FDA cited cumulative ferumoxytol data, including the global phase III IDA program and global post-marketing safety reports.

The FDA also suggested that Amag generate additional clinical trial data in the proposed broad IDA patient population with a primary composite safety endpoint of serious hypersensitivity/anaphylaxis, cardiovascular events, and death—as well as evaluate alternative dosing and/or administration of Feraheme.

In response, Amag in June submitted to FDA proposed label changes in the U.S., which the company said would enhance patient safety by strengthening the label’s warnings and precautions section, as well as mitigating the risk of serious hypersensitivity reactions, including anaphylaxis. Label changes have also been requested by the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) and confirmed by the Committee for Medicinal Products for Human Use.

In agreement with PRAC, Takeda earlier this year issued a Direct Healthcare Professional Communication letter reminding physicians in Europe of certain risks included in the special warnings and precautions sections of the Rienso label. Hypersensitivity reactions, including anaphylaxis/anaphylactoid reactions, which can be life-threatening or fatal, have also been reported with other approved intravenous IV iron products.

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