Merck KGaA and GlaxoSmithKline (GSK) are working together to develop and commercialize the immunotherapy candidate M7824 (bintrafusp alfa) as a potential treatment for multiple, difficult-to-treat types of cancer.

M7824 is being developed by Merck KGaA, which operates as by EMD Serono in the U.S. and Canada, and will be assisted in these efforts by GSK. The therapy candidate has a dual mechanism of action, combining a so-called TGF-beta trap with an anti-PD-L1 mechanism.

While the TGF-beta signaling pathway suppresses tumor growth in healthy cells, such inhibition is overcome in cancer, so that TGF-beta promotes tumor development. In turn, binding of PD-1 on T-cells to PD-L1 on tumor cells is a strategy used by cancers to evade immune attacks against them.

By having both the TGF-beta trap and the anti-PD-L1 mechanism, M7824 — a so-called bifunctional antibody — is designed to have greater efficacy than stand-alone therapies, including immune checkpoint inhibitors such as Keytruda (pembrolizumab, by Merck) or their combinations.

“Our bifunctional fusion protein M7824 has the potential to bring new answers to patients living with cancer,” Belén Garijo, an executive board member and CEO Healthcare of Merck KGaA, said in a press release. “Together with GSK we aim to drive a paradigm shift in the treatment of cancer.”

The two companies look forward to “harnessing the full potential of M7824 across a broad range of cancer indications,” Garijo added.

M7824 is being assessed both as a single agent and in combination with other treatments in Phase 1 trials in solid tumors, and in an international Phase 2 study (NCT03631706) in advanced non-small cell lung cancer (NSCLC), where it is being compared to Keytruda as a first-line treatment for tumors expressing the PD-L1 protein. This Phase 2 study is recruiting patients at sites across the U.S. and Europe, more information is available here.

Results of a Phase 1 trial (NCT02517398) in advanced NSCLC showed that treatment with M7824 reduced tumor size in a subset of patients, with greater success in patients with high PD-L1 levels.

Hal Barron, GSK’s chief scientific officer, noted that “M7824 brings together two different biological functions in a single molecule and we have observed encouraging clinical results in treating certain cancer patients, particularly those people with non-small cell lung cancer.”

“I’m excited by the potential impact this first-in-class immunotherapy could have on the lives of cancer patients,” he added.

With this global partnership, Merck KGaA and GSK – which recently acquired the oncology-focused Tesaro – become leaders in the development of this new class of fusion protein immunotherapies.

According to Merck KGaA, nearly 700 patients have been treated with M7824 to date in Phase 1 trials across over 10 tumor types. In pre-clinical studies, the therapy’s anti-tumor activity outperformed that of anti-PD-L1 alone or combined with TGF-beta trap.

As part of the agreement, Merck KGaA will receive an upfront payment of €300 million (about $338 million) and may receive up to €500 million more if milestones related to the development of M7824 in lung cancer are reached.

The deal’s total potential value is up to €3.7 billion (about $4.2 billion), as Merck KGaA may also receive payments for approval and commercial milestones of up to €2.9 billion. All profits and costs will be shared equally by two companies. A multimedia news release covering the partnership is available here.

A total of eight high priority immuno-oncology clinical trials are ongoing or planned to start in 2019, including NSCLC and biliary tract cancer.