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September 14, 2016

Life & Death, and the Biggest Checkbook

Without being in the situation (because, um, close to doesn't cut it), a Provectus shareholder cannot fully evaluate the possible quality/quantity of potential introductory, follow-up and/or advanced meetings Provectus could/may have had, and/or could/may be having, with prospective Big Pharma partners about combination or cocktail therapy for end-stage cancer patients. The question a shareholder asks of course is to what extent is Big Pharma interested in and/or kicking the tires of chemical small molecule, ablative immunotherapy PV-10 for potential combination with their respective systemic immunomodulatory or targeted cancer agents, with the goal of such discussions being to hopefully and eventually arrive at a clinical combination and business collaboration.

Some shareholders may have read about or heard rumors of recent discussions with Big Pharma that on the surface seem to denote interest. I cannot speak to that; all I can observe are the single or multiple, domestic or international, visitors and visits to or brush bys this blog via corporate-named routers from Amgen, Astellas Pharma, Bristol-Myers, F. Hoffmann-La Roche, Genentech (Roche), Gilead Sciences, Johnson & Johnson, MedImmune (AstraZeneca), Merck and Co., Novartis, Onxeo, and Pfizer. Visits could suggest blog reading. Brush bys may be the result of Internet search engine keyword searches. There could be other or more visits from Big Pharma and/or biotech folks via visitors' Internet service providers but I have no way of telling other than the occasional, reasoned guess about a location, such as Kenilworth, New Jersey (possibly for Merck and Co.) or Abingdon, Oxfordshire, UK (possibly for PsiOxus Therapeutics).

What is it that we really know about Provectus' progress, if any, towards a so-called co-development transaction that company management has insinuated, implied, suggested or said is imminent, around the corner, near-term, close, etc. for several years now (the volume of which seems to have grown louder this quarter)?

As early as the summer of 2014, I recall hearing of entreaties regarding combination studies to Merck and Co. by a strategic advisory board member and an oncology key opinion leader on behalf of Provectus. There also were rumors of several possible related interactions over time, such as a visit by a Merck executive to a medical conference to hear a Moffitt Cancer Center speaker talk about PV-10, and preclinical oncology work by the Big Pharma using off-the-shelf Rose Bengal.

As 2015 turned to fall, with apparently no partner(s) in sight, let alone in hand, to pay for a checkpoint inhibitor-based clinical combination study involving PV-10, Provectus issued press release "Announces Initiation of Phase 1b/2 Clinical Trial to Study PV-10 in Combination with Immune Check Point Inhibitor Pembrolizumab" in September to commence its own clinical combination work on advanced (metastatic; Stage IV) melanoma. The trial protocol for this study obviously was developed well before the announcement. There was no need for a supply agreement with Merck (i.e., no official collaboration) because pembro already was approved for the solid tumor cancer indication under investigation, and its trial cost thus would have been reimbursed. Provectus was going to be the sole sponsor of the clinical work.

The press release laid out management's then preclinical, clinical and intellectual property management plan to present and protect PV-10 as the ideal (perfect?) primer or front-end for Big Pharma's so-called checkpoint inhibitor backbone for treating end-stage cancer patients:
At the time Provectus management seemed to have a heightened sense of expectation Pfizer would make a big deal of the patent award, which did not materialize save for a tortured inclusion of Pfizer's name in a press release. This perspective of "let's not undermine Pfizer" emanated at the time from both COO and Interim CEO Peter Culpepper and CTO Dr. Eric Wachter, PhD, who preferred I not blog about the patent award date (that I had learned about several weeks earlier via the US PTO's Patent Application Information Retrieval website) until after the patent award was awarded (patent awards are made on Tuesdays by the PTO). See Pfizer's Just Not That Into You (August 21, 2015) and Intellectual Property (August 18, 2015) on the blog's Archived V News page,
  • The initiation of the company's own melanoma combination therapy study program in September was Step #2.
By sponsoring/conducting the trial by itself, Provectus owns all study data (per standard contract language applicable to clinical investigators, trial sites, CROs, etc. involved in the study). It will be customary to report top-line data in public venues like biomedical conferences and journals (e.g., potentially a 1Q17 conference); however, the full data set remains under the company's control, which is typical of any sponsored clinical trial. The detailed clinical data regulators ultimately would review, however, remains solely the property of Provectus, unless the company enters into a deal that affords access or rights to a third party, and
  • Step #3 was the completion/publication in May 2016 of Moffitt Cancer Center's mechanism of action work in melanoma on PV-10.
Entitled "Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1," Eric noted its importance and context on Provectus' August 10th 2Q16 business update call, saying that after "...years of work conducted by Moffitt Cancer Center both in animals and man...it is now clearly accepted that tumor ablation with PV-10 can lead to stimulation of a useful anti-tumor immune response." In other words, PV-10 is an immunotherapy. See January 19, 2016 blog post PV-10 is an immunotherapy and May 12, 2016 blog post Moffitt: IL RB in melanoma elicits tumor immunity via activation of DCs by the release of HMGB1.
But by this time, the spring of 2016, there still was no co-development transaction (let alone multiple ones the company thought, and still thinks, could materialize). Possible explanations, aside from simply lack of interest on the part of Big Pharma, might have included to a greater or lesser degree:
  • The September 30, 2015 approval of the combination of nivolumab and ipilimumab for patients with advanced melanoma (BRAF V600 wild-type), which may have temporarily stymied interest in combination therapies for this indication,
  • The need to at least wait for the October 2015 approval of fellow intralesional (IL) or oncolytic therapy talimogene laherparepvec (T-Vec, Imlygic®),
  • Pfizer saying, at the January 2016 JP Morgan Healthcare conference, that is would bypass melanoma for its checkpoint inhibitor, anti-PD-L1 agent avelumab, to pursue "less competitive" cancer indications. If Pfizer were uninterested in melanoma for avelumab as a monotherapy, it would seem to suggest the Big Pharma also would be uninterested in combination therapy just for melanoma too, and
  • The growing realization checkpoint inhibitors no longer were/are the panacea the pharmaceutical industry and its constituent sycophants first thought they were. Clear, unequivocal limitations include:
    • Applicability to 20-30% of cancer patient population,
    • Ineffectiveness in less immunogenic cancer indications (i.e., cold or colder tumors),
    • Reaching toxicity and adverse event limits of checkpoint inhibitors (and targeted therapies) as both monotherapies and combination therapies (but since they are better than chemotherapies, management of such has grown acceptable), and
    • Realizing another set of tools, so-called primers or front-ends (i.e., co-stimulatory, agonists, "turn on the engine," "press the gas pedal," etc.), were necessary to combine with "back-end" co-inhibitory blockade.
If I had to summarize the above "explanations" in hopes of elucidating why a co-development transaction has not yet materialized for Provectus, I now might solely focus on the need for Provectus to:
  • Move beyond melanoma to show combinatorial, primer or front-end relevance in other solid tumor cancer indications, and
  • Establish predictive tools or measures of treatment success in a nascent, overhyped era of precision medicine, like immune biomarkers derived from both peripheral blood and tumor tissue, also in multiple solid tumor cancer indications.
Nevertheless, one could reasonably argue Provectus and other biomedical researchers have made preclinical, clinical and intellectual property management progress toward presenting and protecting PV-10 as the perfect primer or most complementary front-end to most if not every major cancer treatment category: chemotherapy, radiation therapy, targeted therapy, and immunotherapy.
  • Preclinical data related to combination therapy
  • Clinical data related to combination therapy
    • PV-10 + radiotherapy
  • Intellectual property related to combination therapy
It is possible at least three Big Pharma could have some level of interest in pairing PV-10 with their immunotherapy agents: Pfizer (anti-PD-L1 with Merck KGaA), Merck & Co. (anti-PD-1), and Bristol-Myers Squibb (anti-PD-1).

Pfizer Inc. Over at least the last five years Pfizer has been consistently wrong or late to the oncology/immuno-oncology (I-O) game:
  • November 2014: Pfizer buys (out-licenses) an anti-PD-L1 agent, later named avelumab, from Merck KGaA for an $850 million upfront payment and other considerations. Merck gets anti-PD-1 drug pembrolizumab approved for metastatic melanoma as Keytruda® in September 2014, while Bristol-Myers gets its anti-PD-1 relative nivolumab approved for the same indication as Opdivo® in December of the same year,
  • September 2015: Bristol-Myers gets its combination of anti-CTLA-4 Yervoy® and anti-PD-1 Opdivo® approved for metastatic melanoma. Following Bristol-Myers' non-small cell lung cancer trial failure of Opdivo as a monotherapy, Wall Street analysts peg AstraZeneca's combination of anti-CTLA-4 tremelimumab (previously in-licensed from Pfizer) and anti-PD-L1 durvalumab as capable of potentially taking market share away eventually from Bristol-Myers' approved combination therapy. See Pfizer sale/outlicense above,
Click to enlarge
  • January 2016: Having admitted the company was late to immuno-oncology, Pfizer says during the JPMorgan Healthcare Conference that it will be "a leading player in the second wave of combinations." As of this writing, Pfizer has 8 open oncology combination studies, compared to 180 for Merck and 132 for Bristol-Myers, and
  • August 2016: Pfizer buys Medivation for $14 billion, more than 50% higher than Sanofi's initial April bid in April.
But, Pfizer is the one of these three Big Pharmas with the biggest checkbook, and into August 2016 still was working with Provectus to advance their joint oncology combination therapy patent portfolio (one patent and two patent applications). See More Intellectual Property Management (September 11, 2016) and Is Pfizer paying more [IP] attention to Provectus? (September 2, 2016) on the blog's Current News page.

Pfizer seemed to have entered Provectus' picture around late-2010 to early-2011 when Provectus and it appeared to have begun writing and then initially filing (in March 2011) the combination therapy patent application that eventually would be jointly awarded to them by the U.S. Patent and Trademark Office (US PTO) in August 2015 as "Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer" noted above.

Initial interest in and the rationale for combining an immunomodulatory agent (anti-CTLA-4 compound tremelimumab) with PV-10 began with Provectus strategic advisory board member and Pfizer executive Dr. Craig Eagle, MD, who apparently conceived of the idea apart from Provectus' co-founders. Eagle reasoned an antigen cascade or "storm" ("antigenization") would be kicked off or initiated by the substantial size and scope of tumor destruction initially caused by PV-10 ablation (injection). The subsequent PV-10-based antigenization would induce an immune response -- otherwise known as priming -- that then could be boosted by the immunomodulatory (or targeted) agent. CTO Dr. Eric Wachter, PhD noted as much in a recent US PTO filing when he wrote "President" and co-founder Dr. Tim Scott, PhD did not anticipate tumor ablation would have "a downstream immune system priming systemic effect" and that this systemic priming effect could "synergize with known systemic agents."

Ironically, from today's perspective and pharmaceutical industry focus on oncology combinations and cocktails, it would seem Eagle thought enough of PV-10 to suggest its combination with anti-CTLA-4 agent and ipilimumab relative tremelimumab, but not enough to expansively protect Pfizer's interest in the ensuing combination therapy patent. According to Provectus, Pfizer does not benefit from its co-ownership of the combination therapy patent portfolio unless it acquires the company.

But, as I wrote before, Pfizer has the biggest checkbook -- if it wishes to open it -- in the event it again is late to the I-O game by not initially entering into a co-development relationship with Provectus before another Big Pharma does.

Merck & Co. Anti-PD-1 drug pembrolizumab (trade name: Keytruda®), first approved in for patients with advanced melanoma in September 2014, breathed new life into Merck's oncology franchise almost 18 months after current head of R&D Dr. Roger Perlmutter, MD, PhD re-joined this company from Amgen in March 2013.

In a Barron's August 31st article entitled "Merck: Lung Cancer Lead Depends On “How Smart It Plays Its Hand,”" Bernstein analyst Tim Anderson said:
"One of the frequent criticisms with MRK’s I/O program has been that, relative to competitors like BMY/AZN and Roche, its “combination” strategy is less clear, with many believing MRK could be left in the cold over the long run because of this. This is too simplistic of a view, in our opinion. 
MRK has already placed its bets on “chemo combo” through the earlier initiation of trials like Keynote-189 and Keynote-407. In the area of CTLA4 combinations, we believe the chances are high that MRK will soon initiate a phase 3 development program (exact scope unclear) if only to hedge its bets in the event that trials like Checkmate-227 and MYSTIC/NEPTUNE are positive. 
While the onus is on BMY and AZN to fully validate CTLA4 combinations, all MRK has to do is imitate given its sudden lead in the monotherapy 1L lung cancer market that came about through the very different fates of Keynote-024 and Checkmate-026. 
In other potential combination areas with anti-PDx therapies and “3rd generation” agents (e.g. OX40, GITR, IDO, and more) the playing field is more level across the different drug companies. Like its competitors, MRK already has various assets in development – either owned in entirety or accessed through partnership. Progress with almost all of these later generation drugs, across all companies, has seemed to be on the slower side; activity in a single-agent setting, for example, has often seemed underwhelming, in contrast to the single agent activity seen with the anti-PDx’s and anti-CTLa4′s. 
Lastly, even if “combination therapy” comes to fruition and the data is compelling (whatever the regimen), there will likely be the attendant trade-offs of incremental toxicity and higher cost. Therefore, it seems likely that some segment of the 1L lung cancer market will continue to exist for anti-PDx monotherapy, where MRK has a first-mover advantage. 
On balance, we continue to think investors under-appreciate the potential durability (and value) of MRK’s coming lead in 1L lung cancer. Part of this depends on how smart MRK plays its hand from here."
I recounted above what I believe is Merck's historical curiosity or interest (is there a better descriptor?) in PV-10. Below is a quickly constructed, cursory overview of combination collaborations (e.g., announced, supply agreements only, etc.) between Merck and other companies for pembrolizumab in advanced melanoma.
Click to enlarge.
A search of CT.gov for "pembrolizumab combination melanoma intratumoral" yields six open studies; there are three other trials for different indications (a total of 9). "Pembrolizumab combination intralesional" yields two trials (PV-10, T-Vec).

What kind of agent is Merck searching for to pair with pembrolizumab? What defines an ideal drug partner for pembro? One way to answer these questions is to consider former Moffitt and current NYU Langone Medical Center key opinion leader's comments to me that (paraphrasing) the utility of a primer is simply its ability to synergize with the immune agent in question in terms of clinical effect when given prior to the second agent. Moffitt data showing the strength of the systemic responses PV-10 can stimulate (i.e., efficacy of PV-10 plus a checkpoint inhibitor >> efficacy of the checkpoint inhibitor alone) should make this/his point). See August 17, 2014 Immune Surveillance.

Another way is to recount Moffitt's Dr. Vernon Sondak, MD's (and Provectus consultant's) characterization of PV-10; see June 29, 2014 blog post Properties of PV-10:
  • Simple to store, handle and use and reuse,
  • Modest local toxicity and minimal to no systemic toxicity,
  • Rapid and complete induction of necrosis/antigen release in injected lesions,
  • Excellent healing of the injected site after tumor necrosis, and
  • Reliable and reproducible induction of regional and systemic immune effects capable of destroying occult tumor cells, "bystander lesions" and distant metastatic lesions regardless of prior treatments.
If Merck settles on what it believes to be a more ideal partner for pembrolizumab, it further breathes life into its cancer immunotherapy franchise. As such, I am intrigued by Merck's most recent collaboration with Biothera, which pairs pembro with a pathogen-associated molecular pattern-based (PAMP-based) compound. PAMPs are "molecules associated with groups of pathogens, that are recognized by cells of the innate immune system." It would seem Merck is creeping closer and closer to understanding how to turn (induce) cold or cold tumors hotter (via Biothera's PAMP) so as to boost the immune response subsequently generated by pembro.

Well, PV-10 could be called a DAMP-based compound. "Damage-associated molecular pattern molecules (DAMPs) also known as danger-associated molecular pattern molecules, are host molecules that can initiate and perpetuate a noninfectious inflammatory response." And, DAMPS are recognized by both the innate and adaptive immune systems. See Immunological “ignition switch” (August 26, 2016) on the blog's Current News page.

Click to enlarge. Image source
Bristol-Myers Squibb. And then there's Bristol-Myers, which has the most to lose of these three Big Pharmas with its interchangeable, anti-PD-1 drug nivolumab (Opdivo®), also approved initially for melanoma shortly after Merck's version. Bristol executives faced a "near-death experience" on August 5th that continues by virtue of a declining share price that currently shows no sign of abating. See August 30, 2016
The Day Big Pharma's Earth Stood Still, which was visited by several times by Bristol-Myers Internet Protocol addresses (among other visits to this blog).

If nivolumab and pembrolizumab are interchangeable, and Bristol-Myers has no meaningfully different marketing department than Merck's, Bristol-Myers' "death" potential remains viable so long as it does not find an ideal combination partner for Opdivo® and Merck does. Should cancer combinations (or cocktails) rule the day for late-stage cancer patients for the time being, the ideal primer or most complementary front-end for a combination therapy would seem to be the greater or greatest differentiation. See February 18, 2015 The Early Obsolescence of Checkpoint Inhibitors. Own it, live. Lose it, die.
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