The Day Big Pharma's Earth Stood Still

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Updated below: 9/1/16 and 9/10/16.

Prior to Bristol-Myers' failure of its anti-PD-1 drug and cancer immunotherapy nivolumab/Opdivo as a monotherapy for patients with advanced non-small-cell lung cancer (NSCLC), when in the "era" of anti-PD-1/PD-L1 therapy had one of these drugs or drug compounds failed a pivotal clinical trial.

Since the Big Pharma's announcement on August 5th of this "shocking" or "stunning" outcome, as of this writing, BMS' share price has fallen about 25% (while MRK's has risen about 7%, with a roughly flat S&P 500), which would be equivalent to a loss in market capitalization of about $30 billion.

The "era" of course can be measured in a mere handful of years. It was not that long ago, in 2011, when anti-CTLA-4 drug ipilimumab (Yervoy, Bristol-Myers) was approved for metastatic or advanced melanoma, while "relative" tremelimumab (Pfizer, subsequently licensed to AstraZeneca and MedImmune) failed its own pivotal melanoma trials.

Bristol's failure was attributed by some (or many) to a failure in trial design, and its share price was treated like that of a small biotechnology company that failed its pivotal study. When has that happened? Was failure really attributable simply and strictly to trial design, or was there a calculated risk-reward calculation that merely did not pan out? Consider that Bristol-Myers was running two pivotal trials essentially for the same indication and patient population; one of nivo as a monotherapy, and one of nivo and ipi as a combination regimen.

Nivolumab's August failure may have the exposed anti-PD-1/PD-L1 therapy in at least two ways. First, anti-PD-1/PD-L1 drugs need help. And second, combinations (two therapies and/or treatments) and cocktails (three or more) "now" are the order of the day for end-stage cancer patients.

What started out a few years ago as throwing poop on a wall and observing what stuck in regards to exploring combinations and cocktails for end-stage patients appears to have evolved into or towards thinking more about the poop before it is thrown and wondering what each poop in the pairing or triplet brings to the table individually and collectively in regards to baseline immunologic signalling, biomarkers, pharmacokinetics, etc. -- that is, clear, definable, understandable, synergistic value. See, for example, Immunological “ignition switch” (August 26, 2016) on the blog's Current News page.

What happens to a Big Pharma owner of an anti-PD-1/PD-L1 drug or agent if it doesn't find the right (i.e., synergistic) partner for its checkpoint inhibitor, and when a/one competitor does?

Updated (9/1/16): A Bristol-Myers (BMS) location visited this blog post yesterday (August). In July this same Internet Protocol (IP) address visited September 9, 2014 blog post Bristol-Myers vs. The Field (ex-Provectus):

"Last week Bristol-Myers filed a lawsuit against Merck over [anti-]PD-1 agent pembrolizumab (trade name Keytruda), which was approved last week by the FDA for late-stage or metastatic melanoma. 

Specifically, Bristol-Myers claims that Merck is violating the patent on its Opdivo mediation for tackling melanoma, which was recently approved in Japan and became the first so-called PD-1 inhibitor to win regulatory backing anywhere. A PD-1 inhibitor blocks a protein that acts as a brake on certain immune system cells and prevents them from attacking healthy tissue. (Bristol-Myers Sues Merck Over a Patent on its new Cancer Drug, The Wall Street Journal, September 8, 2014)"

In February this visitor exited via a link to November 5, 2015 press release, Reports Immune Mechanism of Action Data for PV-10 Presented at Society for Immunotherapy of Cancer Annual Meeting Authored by Researchers at Moffitt Cancer Center.

A second BMS IP address from the same location (e.g., the same visitor from a different spot, a different visitor from a different spot) visited the blog's Current News page. This same IP address exited the three links below in May 2015 (I cannot recall yet from which blog post or news page these links came):

• GEN News Highlights, December 16, 2011, "Autophagy Key to Triggering Immune Responses to Cancer Post-Chemotherapy,"

• "Autophagy-Dependent Anticancer Immune Responses Induced by Chemotherapeutic Agents in Mice," Michaud et al., Science, 16 Dec 2011: Vol. 334, Issue 6062, pp. 1573-1577, and

• "Autophagy in Tumor Immunity," Amaravadi, Science, 16 Dec 2011: Vol. 334, Issue 6062, pp. 1501-1502.

Updated (9/10/16): One of the above BMS IP addresses visited the blog's landing page on September 7th.

A different location (and thus IP address) from the one location/2 IP addresses above brushed by (did not visit, but rather clicked on and then quickly closed the tab or went away) June 1, 2016 blog post Intralesional PV-10 for In-Transit Melanoma—A Single-Center Experience via Google Japan.