Merck’s MK-3475 Deals: Assets, Risk and Innovation in Immunotherapy Pipelines

The recent news that Merck will aggressively partner the anti-PD-1 program MK-3475 with competitors Pfizer and Amgen, and biotech Incyte, was a welcome recognition that the immunotherapy landscape is too vast and complex for most companies to handle alone. Companies that will succeed in this space over the long haul will position themselves to “sample” many assets and technologies, particularly in combination settings. Why? First, because many combination therapies will fail or be too toxic to use, second, therapeutic modalities will evolve rapidly or be replaced, and third, personalized oncology practice will fragment patient populations.

Merck’s anti-PD-1 antibody MK-3475 is an example of the first generation of immune checkpoint inhibitors, for which we have clinical data. Other first generation therapeutics are ipilimumab (Vervoytm) approved for the treatment of metastatic melanoma, and nivolumab, an anti-PD-1 antibody moving toward regulatory submission this year, both from Bristol Myers Squibb. There are other anti-CTLA4 and anti-PD-1 pathway antibodies in clinical development, just a bit behind, including antibodies to PD-L1 from Roche (RG7446) and Astra Zeneca (MEDI-4736) and to CTLA4 from Pfizer (tremelimumab). It is fair to say that Merck has generated intense buzz around the MK-3475 program, driven by excellent clinical data and an aggressive approval strategy.

If we look over the details of the Merck collaborations we see a convergence of technologies around combination therapy. The Merck/Amgen collaboration centers on developing the oncolytic vaccine T-Vec in combination with MK-3475. The therapeutic hypothesis is relatively straightforward. The immune response to vaccines built using tumor antigens is blunted, in part, because of the immunosuppressive signals induced by PD-L1 expression on tumor cells. So blocking PD-L1/PD-1 mediated immunosuppression may allow a more robust immune response to anti-tumor vaccination strategies. I’ll note here that Amgen recently reported Phase 3 results from their T-Vec trial in metastatic melanoma, hitting the primary clinical endpoint of durable response but just missing the secondary endpoint of improving patient overall survival, which is an endpoint that the immune checkpoint inhibitors do hit. So Amgen has clear motivation here to combine T-Vec with immune checkpoint inhibitors. In addition to the collaboration with Merck, Amgen also has a collaboration with Bristol-Myers Squibb to clinical evaluate the combination of ipilimumab and T-Vec in metastatic melanoma.

The collaboration between Merck and Incyte is also focused on disabling immunosuppressive signaling, in this case as mediated by inhibition of indoleamine 2,3-dioxygenase (IDO), a pathway that regulates T cell responses by depleting tryptophan from the local tumor environment. IDO also appears to regulate T cell activity in lymph nodes draining the tumor site. IDO inhibitors promote T cell effector function while reducing the immunosuppressive activity of T regulatory cells. Incyte’s IDO inhibitor INCB24360 is in Phase 2 clinical trials in metastatic melanoma and in ovarian cancer. In this case then we are considering the potential of dual immune checkpoint inhibition, blocking PD-1 and IDO simultaneously. Incyte already has a Phase 1/2 trial in metastatic melanoma of INCB24360 in combination with ipilimumab and a Phase 1 trial in late stage melanoma in combination with a tumor vaccine.

Merck’s MK-3474 collaboration with Pfizer is very interesting. A phase 1/2 combination trila with axitinib a VEGFR-selective multi-kinase inhibitor (Inlytatm), will be run in renal cell carcinoma. Axitinib is approved as second line therapy in kidney cancer, but the drug has limited potential as a long term therapy and has struggled to distinguish itself from the older multi-kinase inhibitor sorafenib (Nexavartm, from Bayer/Onyx). It is very hard to guess what such a trial will yield, but such combinations of targeted therapies (kinase inhibition in this case) and immune-checkpoint modulators will have to be tried. A recent example, combining ipilimumab and the BRAF inhibitor vemurafenib (Zelboraftm, from Roche) in metastatic melanoma induced unacceptable liver toxicity and was stopped after only four patients had received the combination. Ipilimumab and nivolumab have very different toxicity profiles, and attempts at different combinations are certainly warranted.

The collaboration between Merck and Pfizer also includes development of the combination of MK-3475 with Pfizer’s PF-05082566, an agonist anti-4-1BB antibody. 4-1BB is a potent immune stimulatory pathway that acts by boosting T cell activity. Of interest, PF-05082566 is already in a Phase 1 solid tumor (as monotherapy) and B cell lymphoma (as dual therapy, with Roche’s anti-CD20 mAb rituximab). Finally, Merck and Pfizer have an second agreement to investigate the combination of MK-3475 with palbociclib, a CDK4/6 inhibitor that recently showed encouraging data in advanced breast cancer, although without yet demonstrating an impact on overall survival. These types of combinations are designed to give that precise boost in efficacy, allowing at least some patients the benefit of long term responses that impact disease progression and survival.

Merck’s internal immunotherapy pipeline is thin but as we noted the other day they are beginning to target other pathways, in part via the Agenus/4-Antibody platform deal.

I titled this post “Risks, Assets and Innovation in Immunotherapy Pipelines” because Merck’s efforts around MK-3475 illustrate some clear themes in this space. One, already mentioned, is that going into this space solo is something no company, except perhaps Bristol Myers Squibb (BMY), can contemplate. Even BMY reached outside the company recently to license an anti-KIR antibody from Innate Pharma and to partner with Five Prime Therapeutics on antibody discovery. Why is BMY in such a dominant position? They were innovative (CTLA4 biology) and they have multiple assets including antibodies to CTLA4, PD-1, LAG-3, KIR, 4-1BB and PD-L1, with more on the way. Note that I’m not saying that BMY’s anti-PD-1 antibody nivolumab is better or worse than Merck’s MK-3475, nor do I much care which gets approval first, a race that lots of folks are watching. No one horse will win this field, which brings us back to assets and pipelines.

Beyond BMY, companies like Merck are aggressively partnering because as the immunotherapy field was developing they were less innovative, took fewer risks, and therefore have fewer assets in this space. Companies like Pfizer and Novartis that spent the last decade chasing one oncogenic mutation after another down the rabbit hole found themselves very quickly on the outside looking in. They are now buying and partnering to build portfolios.

And that’s just fine; further, this should be a “pull” environment that motivates the biotech community to generate an abundance of assets. Small biotechs are classically trying to be innovative (to differentiate), take risks (to return dollars on investment) and therefore develop new assets. These are the fundamentals that should drive further expansion of the immunotherapy portfolio across the industry. So how is biotech doing in this new landscape? It is a mixed picture. There is a dearth of new first and second-generation immunotherapeutics, a space that I believe should be asset-rich. This is why Five Prime, 4-Antibody and Costim were all able to do healthy deals relatively early in their development – there is just not a lot of competition.

What happened? Why aren’t there half a dozen anti-PD-1 and anti-PD-L1 antibodies looking for partners, or a dozen agonist antibodies to 4-1BB, OX40, and GITR, and multiple inhibitors of TIM-3 and Lag3? I think this is a case of history repeating itself. After remicade and etanercept were approved, biotechs ran from the TNF inhibitor space, all believing, incorrectly, that they would never be able to compete. Seven TNF inhibitors later, this class still dominates the rheumatoid arthritis market. I wonder if small biotechs are reluctant to follow-on with additional antibodies to the first and second-generation immune checkpoint space because they think they are “too late” – in other words, the value proposition is too risky. If so, I believe they are wrong. The appetite is clearly there, with large biopharma and antibody engineering companies hungry for assets to pull into their pipelines.

Instead, many small biotechs are trying to stay well ahead on the innovation curve, chasing new targets. The problem, as always, is that no one wants to fund that work, because the risk is very high. So the answer is to try to balance innovation and risk in order to create assets that investors will fund. Its a tricky proposition, but essential to biotech’s ability to continue contributing to immunotherapy, and driving value creation. That said, there are some terrific innovative programs out there, in the hands of focused and smart small companies. In the meantime, there are more companies seeking validated assets than there are good programs developing these assets. SugarCone Biotech spends a lot of time building strategic programs for biotechs and a lot of time matching quality assets with partners and investors, so we see this first- hand.

Why else would we need more assets? Straight off, the existing immune checkpoint antibodies ipilimumab and nivolumab induce some terrific responses, but the response rates could be improved. Second, development of the existing combination therapy of ipilimumab and nivolumab has been tricky, with excellent efficacy but troubling toxicity. Note here that BMY can tinker with the dosage and dose schedule of each agent in such combination trials, because they own them both. Less asset-rich companies seeking to develop combination therapy strategies either have to partner their programs (Merck, as discussed here, but AbbVie might be another good example), or acquire everything they can afford (Novartis).

We’ll be watching closely.

stay tuned.