Merck tries to climb back into PD-1 combo race

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Merck & Co could strike the first blow in the race to get an antibody targeting the PD-1 pathway on the market, but so far it has lagged behind Bristol-Myers Squibb in the combination approach that is thought will make the most of this immunotherapeutic weapon. Now it is taking a partner-with-everyone strategy that could help it remain in that game.

Three separate oncology collaborations will test MK-3475 with projects from Pfizer, Incyte and Amgen, trials that should give researchers a clearer understanding of its benefit when combined with different mechanisms of action. With Bristol-Myers threatening to dominate the PD-1 space with its nivolumab-Yervoy pairing, analysts said the new ventures showed Merck was at last showing some urgency as the science rapidly matures.

Playing the field

The collaborations, financial details of which were not disclosed, bring in two Pfizer projects, and one each from Incyte and Amgen. Perhaps the most significant is a phase I/II study in renal cell carcinoma with Pfizer’s marketed Inlyta; success here might entail fewer regulatory hurdles.

Significantly, Bristol-Myers’ rival, nivolumab, has yet to be tested in the clinic with a kinase inhibitor modulating vascular endothelial growth factor (VEGF) like Inlyta, though the New York group has planned a phase II trial with the VEGF antibody Avastin in recurrent glioblastoma.

The remaining Merck combination trials are with developmental agents: Pfizer’s anti-CD137/4-1BB MAb PF-05082566, in “multiple cancer types”; Incyte’s INCB24360, which modulates the indoleamine 2,3-dioxygenase (IDO) pathway that can alter T-cell response, in lung and other cancers; and Amgen’s oncolytic virus talimogene laherparepvec, also known as T-vec, in melanoma.

None of the collaborations are exclusive, Merck research chief Roger Perlmutter said in the company’s fourth-quarter earnings call yesterday. In that, this resembles the non-exclusive strategy followed by Bristol-Myers Squibb and Johnson & Johnson in hepatitis C once Gilead Sciences established a decisive lead  (EP Vantage interview - BMS collaborating to win in hepatitis C, April 20, 2012).

Who responds?

News of these three collaborations came just a couple of weeks after Merck announced that it was also trialling ‘3475 with Bristol-Myers’ Yervoy (Latest combo study goes to the heart of the PD-L1 biomarker question, January 22, 2014).

Combining the mechanisms of Yervoy and nivolumab is part of the reason that hopes are so high for Bristol-Myers in this space.

Mr Perlmutter acknowledges that there is much yet to be learned about agents in this class – which combinations will work best is an obvious point as well as the effectiveness of a PD-1 agent in monotherapy, but also the relevance of biomarkers for PD-L1. He noted that there were many responders in ‘3475 trials that have tested negative for the presence of PD-L1.

Similarly, AstraZeneca, which is also a contender in this race but is well behind at this stage, has also declined to commit to a biomarker strategy. At the company’s annual results today its chief medical officer, Briggs Morrison, described it as an “evolving area of science”.

“We don’t have enough data on our own molecules to have an opinion [on biomarkers] yet, and we are continuing to treat a broad range of patients,” he told journalists at a press conference.

Astra, which has both an anti-PD-1 and an anti-PD-L1 in the pipeline, has combination studies ongoing with the anti-CTLA4 antibody tremelimumab it licensed from Pfizer and GlaxoSmithKline’s MEK and BRAF inhibitors; it plans to announce data from these studies, as well as plans for further combination work, at Asco.

The endgame in PD-1s is far from clear, even if Merck might have stuck a nose in front with its US monotherapy filing last month. Tactically it has managed to get back into the pack with new collaborations, but it might eventually need to license or acquire another agent to reap the full economic benefits of its asset.

To contact the writer of this story email Jonathan Gardner in London at jonathang@epvantage.com or follow @JonEPVantage on Twitter

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