Four months after starting to co-develop the preclinical autoimmune compound MGD010, Takeda Pharmaceutical and MacroGenics have launched an up-to-$1.6 billion-plus expansion of their collaboration by agreeing to develop four additional drugs based on the latter’s Dual-Affinity Re-Targeting (DART®) platform.

Each product candidate will be directed against jointly selected pairs of molecular targets using the DART platform, designed to enable the targeting of multiple antigens or cells by using a single molecule with an antibody-like structure.

MacroGenics has created more than 100 DART molecules which have been configured for the potential treatment of cancer, autoimmune disorders, and infectious disease. Among them is MGD010, a B-cell-targeted therapy that simultaneously targets the B-cell surface proteins CD32B and CD79B, and is indicated for lupus and rheumatoid arthritis.

“The breadth of our alliance with MacroGenics underscores our confidence in their research and development capabilities, as well as the robustness and versatility of their bi-specific DART platform,” Tetsuyuki Maruyama, Ph.D., general manager of Takeda’s pharmaceutical research division, said in a statement.

Under the expanded collaboration, Takeda won an option for an exclusive worldwide license for each of the four product candidates, and agreed to fund all R&D activities related to the programs, including reimbursing MacroGenics’ expenses.

In addition to the R&D reimbursement, MacroGenics could gain up to $400 million for successful development and commercialization by Takeda of each of the four drug candidates to be co-developed —reflecting program initiation, pre-clinical, clinical, regulatory, and commercialization milestone payments. For each drug commercialized, MacroGenics would also receive double-digit royalties on any global net sales, and has the option to co-promote each product candidate with Takeda in the U.S.

MacroGenics also won the option to fund a portion of Phase III clinical development of each product candidate, in exchange for a share of the drug’s North American profits.

For the initial collaboration on MGD010, Takeda paid MacroGenics $10 million upfront; and agreed to pay a possible $33 million if it exercises an option for an exclusive worldwide license following completion of a Phase Ia study. Takeda also agreed to pay up to an additional $468.5 million in clinical, regulatory, and commercialization milestone payments, with MacroGenics having the right to a North American profit share if it agrees to fund a portion of Phase III clinical development.

According to MacroGenics, DART molecules can be tailored for either short or prolonged pharmacokinetics and have demonstrated good stability and attractive manufacturability.

In June, MacroGenics launched the first Phase I clinical trial involving its first DART molecule, MGD006, which simultaneously targets the CD123 antigen [interleukin-3 receptor] and CD3. MGD006 is designed to redirect T cells via their CD3 component to kill CD123-expressing cells, and has shown that in preclinical studies. CD123 is believed to be overexpressed on malignant cells in a wide range of blood malignancies including AML and myelodysplastic syndrome (MDS). 

By year’s end, the company expects to advance its second DART molecule, MGD007, into clinical development. MGD007 is designed to redirect the body's T cells, via their CD3 component, to target colon cancer cells expressing the glycoprotein A33 antigen (gpA33), found on more than 95% of primary and metastatic human colorectal cancers, including cancer stem cells, and believed to be responsible for tumor recurrence and metastasis.

MGD007 is being developed for the treatment of colorectal cancer and other gastrointestinal-associated tumors. In July the FDA cleared the drug candidate to begin Phase I trials in humans. MacroGenics restated in its announcement of the expanded Takeda collaboration that it anticipates initiating a Phase I clinical study for MGD007 in the second half of this year.

Under a September 2012 agreement, MacroGenics granted Servier an option for an exclusive license to MGD007 in all territories outside North America, Japan, Korea and India. Servier may exercise its option for MGD007 upon MacroGenics' completion of the Phase I trial.

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