Turning [more anti-PD-1] non-responders into responders

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Updated below: 10/19/16.

What is PV-10's clinical value proposition to Merck & Co. (pembrolizumab, Keytruda®) and Bristol-Myers (nivolumab, Opdivo®), among other Big Pharma in the oncology space? In no particular order, is it, among other things:

• As a primer, front-end, turner-on-of-the-engine, stepper-on-the-gas pedal, [insert your favorite over-, weakly- or wrongly-used analogy or metaphor],

• Synergism, where from an efficacy perspective 1 + 1 >> 2,

• Agnosticism to tumor type/cancer indication,

• Safety profile, and/or

• Turning cold tumors hot, and hot tumors hotter?

Industry discussion appears to recognize immune checkpoint inhibitors work — when/where they do work — in a portion of cancer patients. Is the summary clinical value proposition of PV-10 in combination with Keytruda/Opdivo to make the latter (i.e., these anti-PD-1 drugs) work better when and where they work? Or is PV-10's proposition, the more powerful one, to show it can make Keytruda/Opdivo work better where they do not work?

PV-10's clinical value proposition to Merck & Co. (pembrolizumab, Keytruda®) and Bristol-Myers (nivolumab, Opdivo®) is that it (PV-10) can turn more anti-PD-1 non-responders into responders than any other partner drug or investigational compound.

For this blog post, consider, among other things, two combinations with pembrolizumab (for advanced melanoma):

• Intralesional* agent electroporation with plasmid interleukin-12 (epIL-12) (ImmunoPulse, OncoSec), the combination of a medical device and an investigational agent, and

• Intratumoral* agent toll-like receptor 9 (TLR9) agonist SD-101 (Dynavax), an investigational agent too.

* Intralesional = intratumoral

OncoSec. OncoSec announced in November 2014 it would combine ImmunoPulse and pembrolizumab, UC San Francisco and OncoSec Medical Collaborate to Evaluate Investigational Combination of ImmunoPulse and Anti-PD-1 Treatment. Data from this investigator-initiated study were presented at AACR 2016 (April), "Positive Melanoma Clinical Data at American Association for Cancer Research (AACR) Annual Meeting 2016," where patients initially were treated with ImmunoPulse and, then, some went to receive systemic anti-PD-1/PD-L1 therapy. Notably, however, OncoSec announced this month data from the same study would be presented at SITC 2016 (November), "Acceptance of Late Breaking Abstract at Upcoming Society for Immunotherapy of Cancer (SITC) Annual Meeting 2016," where the focus would be on [clinical data from] patients with a low likelihood of response to an anti-PD-1 alone (i.e., anti-PD-1 failures).

Dynavax. Dynavax and Merck & Co. announced a collaboration in June 2015, Investigating the Combination of Immuno-Oncology Therapies. Initial clinical data of the combination of SD-101 and pembrolizumab in patients with metastatic melanoma was presented at ESMO 2016, "Phase 1b/2, Open-Label, Multicenter, Dose-Escalation and Expansion Trial of Intratumoral SD-101 in Combination With Pembrolizumab in Patients with Metastatic Melanoma." Preclinical work on SD-101 was presented at AACR 2016 by Dynavax observed, "These data provide a strong rationale for the clinical assessment of SD-101 in combination with agents blocking the PD-1/PD-L1 pathway in patients unresponsive to PD-1 blockade alone." Dynavax and Merck jointly observed on their ESMO 2016 poster, "Preclinical studies suggest that the immunostimulatory effects of SD-101 might also boost the activity of PD-1 checkpoint inhibitor therapy. In mouse models, SD-101 converted anti-PD-1 non-responders into responders by increasing the quantity and quality of tumor-specific T cells." {my underlined emphasis}

In order for Provectus CTO Dr. Eric Wachter, PhD to put Provectus in a position to garner a collaboration with a Big Pharma and its immune checkpoint inhibitor, he has to provide a compelling demonstration of the features of PV-10 in combination with an anti-PD-1 drug like pembrolizumab (e.g., clinical trial PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma). The features of this demonstration would include (a) preliminary safety and efficacy results, (b) immune biomarkers to facilitate appropriate patient selection if and when the combination is approved, and, presumably, (c) the ability of PV-10 to better turn anti-PD-1 non-responders into responders.

Contesting anti-PD-1 non-responders into responders should be a big deal for Merck and Bristol-Myers because such contestation is all about eating more of the rest of the pie, much more so than fighting over the same sliver of it.

Updated (10/19/16): OncoSec. ref. "OncoSec (ONCS) Q4 2016 Earnings Call Transcript," Seeking Alpha

I referenced epIL-12 (and OncoSec) above because of the useful information regarding anti-PD-1 failures or non-responders. The oncology playing field continues to evolve, and combination therapy approaches clearly are evolving as well across multiple dimensions, like (i) determining which patients when and how [immune biomarkers], and (ii) expanding the addressable market from responders to non-responders.

Among other aspects of an analysis of epIL-12 (and OncoSec), which historically has been mentioned together with Amgen's T-Vec and Provectus' PV-10, like at ASCO 2014 (see "Expert Point of View: Axel Hauschild, MD," The ASCO Post, Caroline Helwick, July 25, 2014), (a) there does not appear to be an initial pathway to approval yet (if at all) for epIL-12 as a monotherapy and (b) the investigator-initiated study was neither designed nor powered to transition to a pivotal trial as a combination therapy. OncoSec hopes to secure agreement with (acquiescence by) the FDA on a pivotal/registration trial design by the end of the year. Initial pathways to approval, like what Provectus has with PV-10 as a monotherapy for locally advanced cutaneous melanoma, as with valuable beachfront property, is valuable drug treatment "real estate." Nevertheless, it is a good strategy for OncoSec to focus on PD-1 failures; using emerging biomarker data to select "likely" PD-1 failures, however, is likely to prove somewhat more challenging. It will be interesting to see how this plays out.

Dynavax. This is a true treatment combination and company collaboration (compared to the OncoSec treatment combination, for which the clinical trial protocol is here). The results are interesting, if not very preliminary (e.g., efficacy from 5 patients, measurement [for purposes of the ESMO 2016 abstract] was made after only 12 weeks). One would have hoped they could have provided a few more details (e.g, the number of injections of SD-101 [presumably 11 in total], more details on patient stage [particularly Stage IV, like M1a, M1b and/or M1c], what the grade 4 SAE was, etc.).

A 25% serious adverse event (SAE) rate seems a bit high, and this is kind of an odd way to report safety data; usually this is reported as CTCAE Grade 3 or higher events since this includes both severe AEs and the subset of those that qualify as SAEs. Robert et al. reported 10.1-13.3% rate of Grade 3 or higher AEs for pembrolizumab alone (NEJM 2015;372:26).

Notably, investigators/clinical sites on the poster included Agarwala/St. Luke's. The trial itself also is recruiting at Huntsman Cancer Institute (Andtbacka).

Since this is a collaboration with Merck, it would appear the Big Pharma is not requiring rigorous safety testing before the project moves to Phase 2 (a Merck staffer is a co-author on the ESMO 2016 poster). The poster's Methods section notes the trial is a dose-escalation and dose expansion study. It shows data from dose-escalation (i.e., 2 mg, 4 mg, 8 mg), but does appear to refer to the dose expansion portion, which normally would be additional patients at the highest tolerated dose. The N = 6 at 8 mg is dose expansion but, again, if Merck wants to green light this work to a Phase 2 trial, [as a Big Pharma] they probably are not going to get significant push-back from the FDA or institutional review boards (IRBs). If a small biotechnology company has a major player backing it, it is possible to do things that are not plausible for outsiders (i.e., the golden rule). Finally, this study might give Amgen pause, since SD-101 appears to function similarly to T-Vec, may produce a more robust effect than T-Vec and, most importantly, is not a live virus.

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:

• According to the company, Step #1 was achieved in August with the joint award of the combination therapy patent, "Pfizer, Provectus Biopharmaceuticals Awarded US Patent Protecting Use of PV-10 as Part of Combination Therapy for Cancer."

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

• PV-10 + chemotherapy: Generation of an Antitumor Response and Immunity Using a Small Molecule Drug (PV-10) (Provectus) -- Presented October 2012 (SITC)

• PV-10 + targeted therapy (sorafenib): In vitro inhibition of human liver cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes by rose bengal: system-dependent effects on inhibitory potential -- Published January 2014

• PV-10 + immunotherapy (anti-CTLA-4, -PD-1 and PD-L1): Efficacy of Intralesional Injection with PV-10 in Combination with Co-Inhibitory Blockade in a Murine Model of Melanoma (Moffitt Cancer Center) -- Presented November 2014 (SITC)

• Clinical data related to combination therapy

• PV-10 + radiotherapy

• A novel treatment for metastatic melanoma with intralesional rose bengal and radiotherapy: a case series (Princess Alexandra Hospital, Australia investigator-initiated) -- Published January 2010

• A phase 2 study of intralesional PV-10 followed by radiotherapy for localized in transit or recurrent metastatic melanoma (Princess Alexandra Hospital, Australia investigator-initiated) -- Published May 2016

• PV-10 + immunotherapy (anti-PD-1): A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination With Systemic Immune Checkpoint Inhibition for Treatment of Metastatic Melanoma -- Clinical study program initiated September 2015

• Intellectual property related to combination therapy

• US PTO patent #9,107,887 -- awarded August 2015: Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer (Provectus + Pfizer)

• US PTO application #14/748608 -- advanced September 2016: Combination of Local and Systemic Immunomodulative Therapies for Enhanced Treatment of Cancer (Provectus + Pfizer)

• US PTO application #14/748579 -- advanced August 2016: Combination of Local and Systemic Immunomodulative Therapies for Enhanced Treatment of Cancer (Provectus)

• US PTO application #14/748634 -- advanced August 2016: Combination of Local and Systemic Immunomodulative Therapies for Enhanced Treatment of Cancer (Provectus + Pfizer)

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:

• October 2011: Pfizer sells (out-licenses) anti-CTLA-4 agent tremelimumab to MedImmune/ AstraZeneca (financial terms were not disclosed). Bristol-Myers gets anti-CTLA-4 relative and drug ipilimumab approved for metastatic melanoma as Yervoy® in March of the same year,

• 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,

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• 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.

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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.

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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.

There's additivity, synergy, and then there's PV-10 (1 + 1 = 3)

PART A

I previously wrote about the concepts of additivity and synergy when adding two agents together (a "combination") or three or more together (a "cocktail"). See The bar (June 24, 2016) and Additive: 1 + 1 < 2. Synergistic: 1 + 1 > 2 (best case, >> 2) (June 25, 2016) on the blog's Current News page.

Additive in the context of immuno-oncology combinations and cocktails represents one plus one is less than or equal to two (or, in the case of three agents, one plus one plus one is less than or equal to three). Efficacy (e.g., response rate, and perhaps other survival and survival surrogate endpoints) of the combination is better than the individual efficacies of the pair's components. That is, the sum of the parts is greater than the whole.

• 1 + 1 < 2, 1 + 1 + 1 < 3

A synergistic combination, however, should generate efficacy greater than the sum of the individual efficacies, and, in a best case, much greater than the sum, That is, the whole is greater than the sum of the parts

• 1 + 1 > 2, and in the best case 1 + 1 >> 2

I updated MD Anderson's Dr. Merrick Ross, MD's slide no. 160 of ASCO 2016 Melanoma Symposium's "The Role of Immunotherapy in the Medical Management of Melanoma: An Overview for the Oncologist" for preliminary combination data of oncolytic virus CVA 21 (Coxsackievirus A21) and ipilimumab/Yervoy in Stage III and IV melanoma patients. The upshot for this latest addition, which Dr. Ross probably didn't include because the data is partial (some of the patients treated, but not all) and preliminary, is that CVA 21 and ipilimumab are synergistic, as are oncolytic virus T-Vec and ipi; however, T-Vec and pembro are potentially additive but not synergistic.

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PART B

As I noted under Is Pfizer paying more [IP] attention to Provectus? (September 2, 2016) on the blog's Current News page, Provectus recently advanced daughter combination therapy patent application '318 (co-assigned with Pfizer) after an initial non-final rejection decision by the U.S. Patent and Trademark Office. Provectus' CTO Dr. Eric Wachter, PhD had a document, as part of this advancement, filed on August 31st. See the several pages below, with my orange emphasis.

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PART C

H/t InvestorVillage poster STARLIGHT66 for a Barron's August 31st article entitled "Merck: Lung Cancer Lead Depends On “How Smart It Plays Its Hand,”" notably the quote by Bernstein analyst Tim Anderson:

"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 think it's pretty clear Eric is signalling or outright saying the combination of Provectus' intralesional agent PV-10 (Rose Bengal) and Merck & Co.'s anti-PD-1 drug pembrolizumab for patients with advanced melanoma is synergistic. Is he foretelling the results are stellar? Could efficacy exceed, at a minimum, the response rate of Bristol-Myers' combination of anti-CTLA-4 drug ipilimumab and anti-PD-1 drug nivolumab?

The Barron's article suggests Merck is searching for the ideal front-end (perfect primer) to marry to/combine with pembrolizumab. How will the Big Pharma "play its hand?"

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.

Seeking Co-Development

Updated below: 8/17/16.

The company's CTO, board of directors member and a co-founder Dr. Eric Wachter, PhD said several things in regard to PV-10 as an immunotherapy on Provectus' August 10th 2Q16 business update conference call.

Among them, in no particular order:

• "After a long haul, it is now clearly accepted that tumor ablation with PV-10 can lead to stimulation of a useful anti-tumor immune response."

• "...over the last several years we have worked with colleagues at Moffitt Cancer Center, we have done some work internally, and we have done some work at the University of Illinois-Chicago to show that PV-10 unambiguously triggers that first step, the destruction of tumor. And that event performs all of the expected downstream signaling of the immune system, leading eventually to a functional immune response against an untreated tumor."

• "So, when we started this work in Australia in the clinic in 2005, we described that as a an bystander response, which was the common terminology at the time. Immuno-oncology was not particularly well regarded at that period. It got to be even less of an important area of investigation as we approached the end of the first decade of the 21st century. And then, it became a very hot area with the approval of anti-CTLA drug Urvay [sp] and subsequent approvals of a number of anti-PD-1s and presumably eventually anti-PD-L1s, all drugs that harness T cells to have a functional--or improve their functional response against tumor tissue."

• "So, I think that the story [that ] is now very well documented in the literature. We have shown that this occurs in [unintelligible] models of melanoma. We have shown this occurs in [unintelligible] models of colorectal carcinoma. We have evidence to show that this happens in [unintelligible] breast carcinoma. And, most importantly, we have shown that key elements of this signaling are occurring in melanoma patients."

• "Our next tumor on the radar will be hepatocellular carcinoma because there are challenges in HCC that are comparable to those in melanoma. We already know that we can destroy HCC with this ablative process and the hypothesis that that should lead to similar signaling, which can have implications for--well, single-agent therapy [unintelligible] HCC, but more importantly for combination with things like anti-PD-1 [unintelligible] . We have already shown that the basic immunology occurs in HCC models, so I would say that--one of the things I’m highly confident in, I’m highly confident that we will show that this same functional immune signaling functions in HCC."

As I noted under Church (August 15, 2016) on the blog's Current News page, Dr. Sally Church, PhD wrote a Biotech Strategy Blog post entitled "Beyond T-Vec - a look at oncolytic viral immunotherapy." Dr. Church does not appear to be either an innovator or an early adopter (as labeled on the technology adoption life cycle). Rather, her professional experience, among other things, biases her (which is neither "right" nor "wrong") towards early or late majorities (I'd lean towards early). I think it is worth paying attention when she begins to opine on a newer or novel category of drug. In the case of oncolytic viruses (OVs) (she does not categorize them explicitly as intralesional or intratumoral presumably because OVs have been explored via both intralesional and intravenous administration), she is commenting as the majorities begin to pick up on what the innovators and early adopters (e.g., Agarwala, Andtbacka, Weber, etc.) have been saying for a while. She is, however, rightfully wanting to know more about durability of responses and survivability, which these innovators and early adopters also have been wanting to see as well.

Two thoughts crystallized quickly [in my head] but only after reading Dr. Church's blog post. The second one is the field of melanoma, and for Provectus, what immunology in other indications they must show to secure a co-development transaction more on their terms than not. This is represented by the screenshot from her post below, and which is the subject or focus of this blog post.

Click to enlarge. Image source

First, the threshold for differentiating one's combination therapy for melanoma appears to be, in Dr. Church's mind, is the approved combination of anti-CTLA-4 ipilimumab (Yervoy) and anti-PD-1 nivolumab (Opdivo).

Second, is combination data of PV-10 and pembrolizumab in advanced melanoma sufficient to get any co-development deal for Provectus, let alone the deal management presumably desires? Probably not, and I believe they already have recognized such. Big Pharma also may want certain immunology (and not just ablation) data for other indications, such as hepatocellular carcinoma.

Updated (8/17/16): For some time Provectus' COO and interim CEO Peter Culpepper has publicly and routinely described the kinds of co-development combination therapy deals there could be and he seeks. As recently as the 2Q16 quarterly financial statements filing, the company noted:

"An interim transaction could be a co-development deal like Roche-NewLink, Bristol-Celldex or AstraZeneca-Incyte. The Company is not in discussions regarding the sale of its business, and there can be no assurance that the Company will be able to monetize PV-10 or PH-10 in the manner described herein."

Setting aside both Peter and Eric's immense historical difficulties with expectation setting (e.g., in the case of co-dev combo deals as early as June 2014 that one could be/was coming), the above quote is endemic of their historical challenge with guidance (see Forward Guidance (August 14, 2016) on the blog's Current News page).

What is it that you mean? What do you want to say, and why do you want to say it?

I don't believe they are saying things that are not true, or that they don't believe; however, in trying to communicate strategy and tactics, Provectus management often conflates the desire to provide genuine insight into what is going on (Peter, Eric) with poorly set or communicating expectations (Eric, Peter) and ineffective (Peter) or ideological-driven approach to providing (Eric) guidance. Eric's comments on the August 10th 2Q16 business update conference call regarding PH-10 are another example:

"Turning to PH-10, we're sorting through the immunologic and histopathologic data from our mechanism of action study of topical PH-10. I, unfortunately, can't go into detail yet about what we're learning, but in general, my assessment is that these results will be as important to PH-10 as the Moffett work has been to PV-10. 

When new kinds of therapy come along, everyone likes to understand the biologic story underlying clinical observations, and it appears that this may be a very interesting story that explains observations we've made throughout clinical development of the drug. I look forward to sharing details on this with our stakeholders in the next few months."

While Eric's first paragraph is more appropriate to describe his perspective of the PH-10 mechanism of action (MOA) results that Rockefeller University's Dr. James G. Krueger, MD, PhD and his Laboratory for Investigative Dermatology have arrived at thus far, Eric's second paragraph conveys his excitement about the results (imprecise as those comments are by phraseology like "very interesting"). Eric is saying Rockefeller's MOA work and results should be as important to PH-10 as Moffitt's work/results were to PV-10, which established the oncology use of Rose Bengal as immunotherapeutic (i.e., "After a long haul, it is now clearly accepted that tumor ablation with PV-10 can lead to stimulation of a useful anti-tumor immune response") and that is of assistance in discussions with Big Pharma (among other preclinical and clinical work/data).

So, when Peter "talks" Bristol-Celldex, AstraZeneca-Incyte and Roche-NewLink (in chronological order), what does he mean? What does he want to say, and why does he want to say it?

Whether you agree with this or not (I agree with him in context), to the get the valuation he wants for Provectus Peter believes the company requires an interim value-creating (-recognizing) transaction. This transaction, in his view, is more likely a co-dev combo deal/relationship rather than a geographic license deal/relationship because of factors such as size, scope, validation, etc.

Click to enlarge.

His illustrative co-dev combo deals provide a range of potential outcomes for Provectus and the prospective Big Pharma partner, and thus for Provectus shareholders:

• Deal type A (Bristol-Myers/Celldex), where there would be clear recognition of the partner's interest in Rose Bengal as a promising component of the pairing/combination regimen. A combo collaboration begins,

• Deal type B (Genentech-Roche/NewLink), where there would be much, much stronger recognition of the partner's interest by its licensing of PV-10 for cancer combo therapy, or

• Deal type C (MedImmune-AstraZeneca/Incyte), where there would be overt or tacit recognition of the partner's interest or acquiescence but with no strings attached.

Provectus of course understands there is no reason now to enter into a type C because the company's combination therapy study work already is underway (i.e., PV-10 in Combination With Pembrolizumab for Treatment of Metastatic Melanoma), together with prior work such as that of Moffitt's (e.g., "Efficacy of Intralesional Injection with PV-10 in Combination with Co-Inhibitory Blockade in a Murine Model of Melanoma"). A recent type C deal (August 15th) is Bavarian Nordic's drug supply agreement with Bristol-Myers of anti-PD-1 nivolumab (Opdivo) for use in a combination therapy clinical study of the former's vaccine CV301 and the latter's checkpoint inhibitor for patients with previously treated non-small cell lung cancer (NSCLC).

The difference between type A and B deals is the prospective partner's interest to dip a toe into the pool, or to dive into it. The decision of how wet to get probably depends on how much data each Big Pharma requires for whatever degree of waterlogged-ness they seek or with which they are comfortable. Both types, however, can co-exist with an eventual transaction to buy the company because Provectus management wants to advance the therapeutic use of PV-10 as a monotherapy and in combination with other cancer treatments.

The co-dev combo relationship Peter has been seeking for some time (i.e., the company ineffectively stated strategy) comprises something to the effect of:

• A multi-indication collaboration (e.g., melanoma, HCC, NSCLC, etc.),

• An upfront payment and/or paid-for study/development costs. No upfront payment but paid-for costs could be a nice second. Peter understands the stock market and industry recognize validation is seen with Big Pharma dollars in the deal, whether soft, hard or both,

• Trial sponsorship is an interesting topic because I would imagine Eric would want to have Provectus conduct (control) it; however, Big Pharma might want to do it in a more expeditious manner than for which Eric has been known,

• Non-exclusive clinical combination would be preferable to Provectus since PV-10 is orthogonal to the class of PD-1s (and PD-L1s); that is, PV-10 would be synergistic to any checkpoint inhibitor, as management has publicly stated of Keytruda and Opdivo. Why not do combination therapy trials with both PD-1s? Because non-exclusivity might/would not be preferable to the prospective partner, and

• Time-limited right of exclusive negotiation for licensing rights likely would be a given. If Provectus can get what it wants (vis a vis core business terms), the prospective partner would like a right of first something.

The 2016 "version" of the 2014 Bristol-Myers-Celldex type A deal (aside from some stuff related to the historical relationship prior to the combo co-dev transaction that may have manifested themselves in the co-dev deal) would appear to be the Bristol-Myers-PsiOxus transaction. The latter essentially is the sentiment and structure of what Peter is seeking on behalf of Provectus. There will be continue to be an open question from many-to-most company shareholders (and I would imagine the Street, the stock market, and the industry ecosystem at large) about whether he can get the deal Peter wants for Provectus, however, until he answers the question and does.

Combining PV-10 with a Checkpoint Inhibitor Enhances the Systematic Immune Response of PV-10

{Bolded and underlined emphasis below is mine}

2013: In Chen and Mellman's Oncology Meets Immunology: The Cancer-Immunity Cycle [1], cell death is Step #1 (Release of cancer cell antigens [cancer cell death]) below.

Click to enlarge.
Figure 1, The Cancer-Immunity Cycle

Therapies and therapeutics that cause cell death are highlighted in Chen & Mellman's Figure 2 below, again Step #1:

Click to enlarge.
Figure 2, Therapies that Might Affect the Cancer-Immunity Cycle

I think it is well documented in biomedical literature that treatments like chemotherapy, radiation therapy (or radiotherapy), and targeted therapy drugs lead to immunogenic cell death ("ICD").

June 2014: At ASCO, then Senior Member of the H. Lee Moffitt Cancer Center and Director of its Donald A. Adam Comprehensive Melanoma Research Center, and now senior faculty of NYU Langone Medical Center and its Laura and Isaac Perlmutter Cancer Center, Deputy Director of the Perlmutter Cancer Center and Co-director of its Melanoma Program, Dr. Jeffrey Weber, MD, PhD said of clinical PV-10 work undertaken by Moffitt, where patients had metastatic disease refractory to previous ipilimumab, anti PD-1 and/or vemurabenib therapy:

"This data provides more and more evidence that you are altering both local and systemic immunity in a positive way. It also provides a rationale for combination trials of PV-10 with check point protein inhibitors, such as ipilimumab, pembrolizumab and nivolumab. PV-10 might offer the perfect way to prime the immune system." [2]

November 2014: At SITC Moffitt presented their melanoma combination poster entitled Efficacy of Intralesional Injection with PV-10 in Combination with Co-Inhibitory Blockade in a Murine Model of Melanoma; i.e., PV-10 + one of {anti-CTLA4, anti-PD1, anti-PDL1}. I wrote about this in November 18, 2014's blog post Provectus notebook, where the preclinical Moffitt study comprised a single injection of PV-10. Of course, contrast that study approach, which had focused goals, with Provectus' Phase 1b/2 combination therapy clinical development program that sees Stage IV melanoma patients receive injections of PV-10 into all accessible disease (I believe) every 3 weeks for the duration of the study, together with immune checkpoint inhibitor pembrolizumab.

At the time frequent medical writer of PV-10 Janet Fricker wrote article in Medical News Today about Moffitt's SITC 2014 poster presentation entitled Melanoma shows improved regression with combination of PV-10 and checkpoint inhibitor. The article has an interesting quote from the cancer center's Dr. Shari Pilon-Thomas, Ph.D. about their work:

"The spirit of our study was to determine whether combining PV-10 with a checkpoint inhibitor would enhance the systematic immune responses of the initial injection of PV-10."

Phrased via slightly different editing: The spirit of the study was to determine whether combining ABC (PV-10) with XYZ ver 2.0 (e.g., pembro) would enhance the systematic immune responses of ABC (PV-10). Not, whether combining XYZ (pembro) with ABC (PV-10) would help XYZ ver 2.0 (pembro).

January 2016: At the 2016 Genitourinary Cancers Symposium Galsky et al. surmised in Phase II trial of gemcitabine + cisplatin + ipilimumab in patients with metastatic urothelial cancer:

"We hypothesized that chemotherapy may lead to immunogenic cell death, and other immunomodulatory effects, which could subsequently be exploited with the addition of ipilimumab."

Phrased via slightly different editing: Combining DEF (chemotherapy) with XYZ ver 1.0 (e.g., ipi) might enhance/exploit the immune response of DEF.

January/February 2016: At the 2016 Academic Surgical Congress the University of Illinois at Chicago ("UIC") will note:

"Therefore, based on these results, further evaluation of PV-10 as a potential agent to stimulate immunologic cell death in solid tumors is warranted."

Takeaways:

• Immunogenic cell death is critical to the commencement of the cancer immunity cycle.

• The potency of the initial generation of ICD likely dictates the prolonged or sustained potency of the subsequent cycle steps or cascade.

• Adding a key combination partner to the mix likely augments the potency and sustainability of the immunity cycle.

• The greater the synergy between the components of the combination -- the two elements of the pairing -- the greater the potency and sustainability, or durability.

• Oncolytic viruses, like Amgen's talimogene laherparepvec (Imylgic), also can cause ICD. See, for example, "Oncolytic Virotherapy and Immunogenic Cancer Cell Death: Sharpening the Sword for Improved Cancer Treatment Strategies," Workenhe et al., Molecular Therapy (2014); 22 2, 251–256.

• Moffitt and UIC, independent of each other, now have shown PV-10 causes potent ICD.

• Provectus' clinical data from its A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination With Systemic Immune Checkpoint Inhibition for Treatment of Metastatic Melanoma has to be good enough to rise notably above the noise of the many combination therapies trials already being run.

[1] Oncology Meets Immunology: The Cancer-Immunity Cycle, Chen et al., Immunity, Volume 39, Issue 1, 1-10
[2] Provectus outlines path forward for PV-10, Janet Fricker, ecancernews, June 10, 2014

They ARE out to get me...

My reading of Frank David's March 2nd Forbes article entitled Only The Paranoid Biotechs Will Survive converged interestingly with Peter's presentation at the 8th Annual European Life Science CEO Forum & Exhibition. David wrote:

"The drug industry is surely at a similar “strategic inflection point”. Sales forces are less effective, prices are under constant and increasing assault, and physicians and patients alike are raising the bar for how they define clinical value. (My prior takes here, here, here and here.) High prices and huge sales forces used to prop up even minimally differentiated drugs, especially in big markets like hypercholesterolemia and depression. But today, something is changing: commercial muscle no longer guarantees success unless you also have a compelling clinical benefit. 

But I’d argue we’re in the midst of a “strategic inflection point” that threatens many biotechs’ ability to secure Pharma deals. Whereas the biggest hazard to biotechs in the past was moving too slowly or running out of funds, it’s hard to deny that today, the risk of not demonstrating clinical differentiation is far greater." {Underlined emphasis is mine}

Pembrolizumab. In his presentation Peter noted Merck & Co.'s approved anti-PD-1 therapeutic pembrolizumab (Keytruda) as the control in a planned Phase 1b/2 combination study of PV-10 + immune checkpoint blockade — see Updated presentation slides (March 3, 2015) on the blog's News page.

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Peter has a somewhat "annoying" (because I have to regularly and carefully read, search and sometimes parse them) but mostly helpful (because there often are relevant or germane regulatory, clinical development and commercial bits and bobs in them) habit of placing Easter Eggs of a sort in Provectus' corporate website/investor presentations.

This particular egg referenced Merck's PD-1 drug as the other drug and control in a pairing with PV-10. The "trial" title then would be Pembrolizumab With or Without PV-10 in Unresected Melanoma.

For comparison, Amgen and Merck announced their collaboration and combining of T-Vec and pembrolizumab (MK-3475 at the time) in February 2014 — Amgen's press release is here. The trial protocol of this pairing was filed on ClinicalTrials. gov in September. Recruitment began in December.

If one assumes this egg is not spurious, then Peter's placement was purposefully communicative. While I'm not in a position to opine on whether or not Bristol-Myers will prevail in its lawsuit against Merck U.S. over each other's anti-PD-1 agent, I imagine Craig et al. would not consider doing a trial — with Merck, or by themselves (since the trial size of oncology Phase 1bs can range from 20-25 patients — in a potential future scenario where Bristol-Myers prevails over Merck.

First-in-class. I chuckled when I saw the cover slide of Peter's presentation read "first-in-class halogenated xanthene dye." Before I explain my snorting, it would appear first-in-class means to the FDA (or is defined by the Agency) "...drugs which...use a new and unique mechanism of action for treating a medical condition." Is this another Easter Egg? I believe it is, presumably emanating from further discussions with the FDA.

Click to enlarge.

Can Drug A be called first-in-class [with its associated mechanism of action ("MOA")] if it is approved for Indication X? If Drug B is approved second for X, is it second-in-class? Or, if A is approved before B, is A then just first-in-class [with MOA]. By this fragile, inexperienced logic, pembrolizumab is a first-in-class PD-1 inhibitor or anti-PD-1 antibody. Is nivolumab second-in-class?

I laughed at the non-FDA contextual use of the entire phrase — first-in-class halogenated xanthene dye — because while pembrolizumab is owned by Merck US, and nivolumab is owned by Bristol-Myers, and Pfizer has a PD-1 inhibitor, and AstraZeneca's for now is labelled MEDI0680, etc., Provectus owns Rose Bengal and related xanthenes (e.g., first-in-class, second-in-class, etc.).

Competition? Amgen will have its FDA PDUFA completion date for T-Vec in October 2015, but the Agency will meet to hold an AdComm meeting in April. In this instance T-Vec is being considered as a monotherapy for advanced melanoma (i.e., the the treatment of patients with injectable regionally or distantly metastatic melanoma).

Interestingly, Amgen filed a trial protocol on ClinicalTrials.gov in November 2014 entitled Phase 2, Open-Label, Single-arm Trial to Evaluate the Correlation Between ORR and Baseline Intratumoral CD8+ Cell Density in Subjects With Unresected Stage IIIB to IVM1c Melanoma With Talimogene Laherparepvec. The trial appears to be taking place in Spain, and may soon begin recruiting. The purpose of the study is to evaluate the correlation between CD8+ cell density and response rate. Cell density (the number of cells per unit volume, such as cells per microliter) presumably plays an important role in immunotherapy effectiveness (i.e., the higher the density, the better the effectiveness). I do wonder whether this density figure, which measures quantity or concentration, also includes a measure of quality too.

In a February 2013 Cancer Watch article entitled Back to Phase 1: Understanding Systemic Effects of PV-10, it was written:

While adoptive cell transfer offers the advantage that enough T cells can be obtained for infusion in all patients, the T-cell receptors transfected into the T cells have a limited antigen-specificity. The strategy works, Dr. Sarnaik said, only about half the time. “We generate large numbers of T-lymphocytes, but we don’t have control over their quality. We think one of the limitations is that the T cells you get out of the tumor just aren’t good enough.” PV-10, however, does cause an immune response, suggesting that a combination treatment may improve the quality of the T-lymphocytes and have a greater impact on the disease. 

When Shari Pilon-Thomas, PhD, also a Moffitt researcher, demonstrated that T-lymphocytes recovered from mice treated with PV-10 do appear to be of a higher quality, as evidenced by stronger tumor reactivity, the stage was set for Dr. Sarnaik’s current 15-patient pilot study. In it, one of two resectable melanoma tumors is injected with PV-10. Both are removed several weeks later. Serum is assessed before and after treatment to look for changes in the infiltration of immune cells. In patients with an immune response, PV-10 therapy can be continued. 

“This is a straightforward study that will give a yes or no answer,” Dr. Sarnaik said. 

Bristol-Myers/Amgen's combination trial that paired ipilimumab and T-Vec. Ipi with or without T-Vec) provided germane information on immunologic signaling (see below, on the right), where PBMC stands for peripheral blood mononuclear cell. PBMCs "...are the populations of immune cells that remain at the less dense, upper interface of the Ficoll layer...PBMCs include lymphocytes (T cells, B cells, and NK cells), monocytes, and dendritic cells."

Click to enlarge.

My takeaway for this blog post, by returning to David's article, is, again, risk-reward. The potentially vast reward opportunity for Provectus is to effectively demonstrate and communicate that compelling clinical benefit and differentiation.