Merck cautiously steps into the PD-(L)1/CTLA-4 checkpoint fray. But should it ‘go big or go home’ instead?

Merck’s strategy on developing its PD-1 checkpoint drug Keytruda could be summarized as: If we have any kind of a shot at a legitimate target, we’re going to take it. Then we’ll start a combo trial ASAP.

Now it’s moved into an early-stage study in what is looming as the next big challenge that will either distinguish the leaders or set up the next great pitfall: A PD-(L)1/CTLA-4 combo.

Tim Anderson

The thinking behind this, outlined in a note from Bernstein’s Tim Anderson, helps illustrate just how intensely competitive this game of blockbusters has become, pitting Merck $MRK against Bristol-Myers Squibb $BMY (again) and a very ambitious group at AstraZeneca $AZN that has been making some closely-watched inroads in the field this year.

Merck’s latest early-stage combo matches its in-house CTLA-4 drug MK-1308 with Keytruda, its checkpoint star that has moved into a dominant position in the fast-changing field.

Roger Perlmutter, Merck

“(T)here is a differentiation that we’re hoping for. And it is a molecule that was obtained in part externally and refined internally,” Merck R&D chief Roger Perlmutter told Anderson. “We’ve been working on it for some time.”

As Anderson observes, there is only one CTLA-4 drug on the market. That is Bristol-Myers Yervoy, which is in a combination study already. AstraZeneca, though, is coming up fast with a combination of Imfinzi and its CTLA-4 tremelimumab in their MYSTIC study, which will either help them vault ahead or illustrate why there has been growing skepticism about the combo. Yervoy and CTLA-4 drugs in general have been linked with considerable toxicity, and more recent reports underscore some strong doubts about its future in checkpoint combos.

Perlmutter admitted as much to Anderson, who thinks that Merck would be better off shooting for a combination study with Yervoy now rather than waiting for the experimental in-house drug to come along. Anderson writes:

We have felt that if MRK is going to pursue CTLA4 combo – either as a hedge, or because it genuinely believes in the opportunity – it either needs to “go big or go home.”  As a compound just entering first-in-human studies, MK-1308 is far behind BMY and AZN.  Unless MRK believes it has a differentiated product, it is difficult to justify development of this new molecule given the substantial lead-time advantage that its two competitors have in this area.

However, MRK’s pursuit of MK-1308 becomes easier to justify if MRK were to simultaneously get its feet wet more quickly by a combination study of Keytruda+Yervoy (even if only a shorter, quicker, “practice-enabling” study, similar to what BMY’s CM-568 was supposed to be).  This way, Keytruda would remain relevant in the nearer-term in a CTLA4 combination setting should trials like MYSTIC (AZN) or Checkmate-227 (BMY) show favorable results.  As long as MRK generates clinical data like this, physicians would likely feel comfortable mixing-and-matching MRK’s and BMY’s separate products.  Then, MRK has more time to eventually come in with a CTLA4 of its own.

We’ll find out later this year and next how these checkpoint combos line up against the checkpoint/chemo combinations that have been moving into practice. But Anderson also notes that there is a swelling wave of follow-up trials to watch with IDO and more combinations moving into Phase III.

Individual combination strategies have to evolve. Just don’t look for any of the big players, or the second-gen competitors lining up, to slow down now.

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