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.

Checkpoint Inhibition Differentiation or Death: Proprietary Combinations with Protectable Agents

Updated below.

From this project's Twitter feed: Dr. Sally Church, PhD, ‏@MaverickNY

Click to enlarge. Tweet image source

How would Big Pharma distinguish each of its immune checkpoint inhibitors (CIs) from another? Efficacy? Tolerability? Cancer indication? Cost? Within groups (e.g., PD-1s, PD-L1s, etc.), efficacy and safety should equivalent. Different antibodies — for example, with the PD-1s, like nivolumab/Opdivo and pembrolizumab/Keytruda — function in almost identical fashion and differ only by means of manufacture and corporate decisions made with regards to clinical development (e.g., dose schedule, target indication). Magically, there is parity in pricing.

Based on drug sales to date and sales projections thus far, captured in part by @grhyasen's tweet graphic above, Bristol-Myers (nivolumab/Opdivo) and Merck & Co. (pembrolizumab/Keytruda) may be in no serious rush to differentiate their CIs beyond their current, respective corporate strategies. But Roche (atezolizumab/Tecentriq), AstraZeneca (durvalumab) and Merck KGaA/Pfizer (avelumab), all with "late to market" CIs, surely must be thinking about ways to differentiate their respective compounds.

Does meaningful, sustainable and profitable differentiation come in the form of combination, and thus in the form of a partner compound for a CI? In other words, could combination create branded differentiation — ultimately based on efficacy, tolerability, indication and cost of the combination. Proprietary combinations with protectable agents.

Novartis, one Big Pharma without a "lead CI" but having PD-1, TIM-3, LAG-3 and PD-L1 CIs within its pipeline, seems to have begun its brand differentiation by expanding its strategic thinking to include or focus on first-in-class combinations. See Pharmaceuticals and Oncology Business Units, Meet Novartis Management, May 24-25, 2016:

Click to enlarge. Fuzzy orange rectangle is mine

Click to enlarge. Fuzzy orange rectangle is mine

PV-10's, and thus Provectus', value proposition to the likes of Roche, AstraZeneca, Merck KGaA, Novartis, etc. might be to (a) combine their CI with PV-10 and (b) use Provectus' combo patent* to defend the unique combination thus formed — a proprietary combination with a protected agent.

* United States Patent No. 9,107,887, Eagle et al., August 18, 2015, Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer

Updated (6/11/16): Deena Beasley, Reuters, June 11th, Regulator says too many drugmakers chasing same cancer strategy:

"A new type of cancer drug that takes the brakes off the body's immune system has given drugmakers some remarkable wins against the deadly disease, but a top U.S. regulator says too many companies are focused on the same approach. 

Dr. Richard Pazdur, head of the Food and Drug Administration's office of oncology products, was referring to therapies designed to disable the PD-1 protein that tumors use to evade the immune system...  

"People should ask themselves ... would we be better off spending those resources into looking at more novel drugs?" Pazdur told Reuters during the annual American Society of Clinical Oncology (ASCO) meeting in Chicago this week.... 

"As with everything in drug development, it is about reduction of risk," he said. But the number of similar drugs in development at the same time is a first in the oncology field, and latecomers to the PD-1 market will likely be relegated to "niche" indications, he added. 

Drug company executives disputed Pazdur's critique. In interviews with Reuters, they argued that the science around cancer is advancing rapidly, with a focus on how to best combine therapies to attack multiple mechanisms of the disease, determine which patients are most likely to respond to them and how long patients will need to be treated."

Blumenthal and Pazdur, Response Rate as an Approval End Point in Oncology, JAMA Oncol. 2016;2(6):780-781.

"Overall response rate (ORR) as a surrogate end point in oncology drug approval has a long history. In the 1970s, the US Food and Drug Administration (FDA) usually approved drugs on the basis of ORR. In the 1980s, after discussions with the Oncologic Drug Advisory Committee, the FDA determined that cancer drug approval should be based on more direct evidence of clinical benefit, such as improvements in overall survival (OS), tumor-related symptoms, or physical function.1 In the past decade, due to an improved understanding of the genomic underpinnings of cancer, better molecular characterization of tumors, and more precisely targeted agents, unprecedented rates of response have radically altered the therapeutic landscape in a number of malignant neoplasms. Therefore, ORR and duration of response as assessed in single-arm trials has served as the basis of accelerated approval and at times regular approval in a number of refractory malignant neoplasms, including non–small-cell lung cancer (NSCLC), lymphoma, melanoma, and myeloma."

This presumably works [very well] only for systemic drugs using standard RECIST. Provectus' pivotal melanoma Phase 3 is employing [standard] RECIST 1.1.

Road tripping:

My proxy vote should be posted by June 14th.

PV-10 at AACR 2016: T cell mediated immunity after combination therapy with intralesional PV-10

Presentation Title: T cell mediated immunity after combination therapy with intralesional PV-10 and co-inhibitory blockade in a melanoma model

Author Block: Amy M. Weber, Hao Liu, Krithika N. Kodumudi, Amod A. Sarnaik, Shari Pilon-Thomas. H. Lee Moffitt Cancer Center, Tampa, FL

Abstract:

PV-10 is a 10% solution of Rose Bengal, a xanthene dye that was originally developed for ophthalmic use and later used in liver function studies. PV-10 was formulated for intralesional (IL) injection and is currently being investigated as a novel cancer therapeutic. In murine studies, we have previously shown that intralesional (IL) injection of PV-10 leads to a regression of both injected tumors and untreated bystander tumors. We have also shown that combination therapy of IL PV-10 with blockade of PD-1 and PDL-1 leads to increased anti-tumor immunity. In this study, we have examined the role played by specific immune cell populations in eliciting this response in a murine melanoma model. We first investigated the antigen specificity of CD8+ T cells in the spleens of mice treated with the combination therapy of IL PV-10 and systemic co-inhibitory blockade. We found that splenocytes from mice treated with the combination of IL PV-10 and anti PD-1 antibody have an increased mean percentage of OVA antigen-specific CD8+ T cells (5.77%) compared to single treatment with anti PD-1 antibody (3.8%) or IL PV-10 (3.60%) alone in OVA-expressing B16 tumor bearing mice. To investigate the role of T cell subsets in mediating an immune response, OVA-expressing B16 tumor bearing mice were treated with IL PV-10 followed by intraperitoneal injection of anti-PD-1 antibody. In addition, mice were given either 2.43 antibody to deplete CD8+ T cells, GK1.5 antibody to deplete CD4+ T cells, or PC61 to deplete regulatory T cells (Tregs). We found that depletion of CD4+ T cells in combination with IL PV-10 and anti-PD-1 antibody treatment resulted in an enhanced anti-tumor effect, with an average tumor size of 52.8 mm2 on day 25 compared to the control group (173.7 mm2), and depletion of Tregs resulted in an even greater anti-tumor effect, with an average tumor size of 1.2 mm2 on day 25 (p<0.05). In contrast, mice treated with the CD8+ depleting antibody exhibited diminished anti-tumor immunity compared to the control group, with an average tumor size of 200 mm2 on day 25. Together, these studies indicate that the effect of combination therapy with IL PV-10 and co-inhibitory blockade is mediated by CD8+ T cells, and that depletion of both CD4+ T cells and CD25+ Tregs significantly enhances anti-tumor immunity in a melanoma model.

{my bolded and underlined emphasis above}

The Early Obsolescence of Checkpoint Inhibitors

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Take as a starting point Inman et al.’s 2007 article entitled Costimulation, coinhibition and cancer, and their statement therein: (underlined emphasis is mine):

“If sufficient co-stimulation is provided in the presence of adequate tumor-associated antigenic stimulation, the immune system will act against tumor antigen and, thus, destroy early tumors before they become fully established. Contrarily, if co-inhibitory signaling dominates, the immune system will be tolerized to tumor antigens, and the tumor will be permitted to grow unfettered and unmolested by the immune system. If neither co-stimulatory nor co-inhibitory signals dominate, the adaptive immune system may remain in a tenuous state of equilibrium, militating against tumor outgrowth with varying degrees of success.”

The essence of the authors’ view might be that the immune system is capable of decisively acting against cancer only in the situation where or circumstance that co-stimulation dominates co-inhibition. Take also as context to this starting point, however, that what we don’t know about the immune system probably dwarfs what we know about it.

The notion of “releasing the brakes” in the medical literature and mainstream press describes the approach of inhibiting cancer’s ability to suppress or block the body’s immune system from acting, and thus to evade attack. Although possibly coined in the early-2000s (see, for example, Tirapu et al.’s 2002 article entitled Effective tumor immunotherapy: start the engine, release the brakes, step on the gas pedal,...and get ready to face autoimmunity), use of the releasing-the-brakes phrase may have grown more widespread starting in the late-2000s and around the time of Dr. James Allison, Ph.D’s seminal work of blocking (inhibiting) the CTLA-4 protein receptor (using Bristol-Myers’ ipilimumab) and, later, the follow-up scientific exploration of blocking (inhibiting) PD-1 and PD-L1 ligands too (and associated PD-1 therapeutics pembrolizumab and nivolumab, for example, from Merck and Bristol-Myers, respectively).

Medical literature has more sparsely touched on, and mainstream press much less so, the other two components of the get-the-car-moving analogy (where the car is the immune system), “starting the engine” and “stepping on the gas pedal,” where these phrases relate to different aspects of stimulating the body’s immune system.

Possibly over-using the car analogy further, with the potential risk of over-simplifying it inappropriately, consider T cell immunity as a car at rest. More immunogenic tumors and their associated cancers like melanoma are like a car sitting on a slight incline. Release its brakes by treating the tumors (and thus the cancer) with checkpoint inhibitors, and the car may roll forward move some distance, notable or otherwise. With other less or non-immunogenic cancers, think of the car as sitting on a flat surface. Releasing the brakes does not enable the car to move any meaningful distance, if at all.

If you want to get the car to really move, you have to start its engine, and then step on its gas pedal. Releasing the brakes might help the car move farther and faster, but it also is quite possible the car may be able to move sufficiently without the need for further action other than to start its engine and/or stepping on its gas pedal.

The continued use of get-the-car-moving analogy of course requires the assumption the car can drive by itself; that is, the immune system can handle its own business once it has been started, and is appropriately up and running from stepping on the gas pedal.

Now consider Winograd et al.’s 2015 article entitled Induction of T cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. In particular, note the underlined sentences (my emphasis) from the article’s abstract:

“Disabling the function of immune checkpoint molecules can unlock T cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4 resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFN-γin this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with PD-1 mAb, with or without CTLA-4 mAb, failed in well-established tumors, recapitulating clinical results. Agonist CD40 mAb with chemotherapy induced T cell immunity and reversed the complete resistance of pancreatic tumors to PD-1 and CTLA-4. The combination of αCD40/chemotherapy plus PD-1 and/or CTLA-4 induced regression of subcutaneous tumors, improved overall survival, and confered curative protection from multiple rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers although no cures were observed. Our findings suggest that in pancreatic carcinoma, a non-immunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T cell response with αCD40/chemotherapy.”

CD40 is a co-stimulatory protein, while chemotherapy has been understood to act in a stimulatory fashion through the subsequent release of cancer antigens.

Achieving T cell immunity almost if not actually by definition should mean overcoming resistance to cancer, thus overcoming checkpoint blockade and mitigating the need to artificially release the brakes.

Should stimulation via stimulatory therapeutics and therapies start the engine and enables the gas pedal to be stepped on sufficiently and appropriately (i.e., with minimal or manageable side effects or adverse events) so as to achieve T cell immunity, brakes may not be necessary once the car is moving (in context, and given the car [the immune system] can drive itself and not careen off the road because it then should know what it is doing).

Over time, however, road friction may start slowing the car down to the point where waning immunosurveillance (the immune system recognizing and eliminating continuously arising cancerous cells) no longer can protect the patient from relapse (analogous to how waning varicella zoster antibody titers may result in a bout of shingles). Keeping the brakes disengaged, especially with non-immunogenic tumors, should have some role going forward, making Merck, Bristol-Myers, Roche, AstraZeneca, Pfizer and other companies’ checkpoint inhibitors not necessarily obsolete as much as persnickety.