"Intralesional rose bengal as an ablative immunotherapy for hepatic tumors"

Abstracts from the 26th Annual Conference of APASL (February 15th to 19th) are available here, including that of Provectus (shown below).

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Rose Bengal (PV-10): HCC, Colorectal liver mets

Provectus issued a press release today regarding its clinical liver cancer work, "Announces Two Poster Presentations on PV-10 for Liver Tumors." As of this writing no associated 8-K was filed.

The press release highlighted two abstracts and upcoming [poster, presumably] presentations of results from the company's ongoing liver Phase 1 trial, which has evolved into (a) a "basket study" treating patients with and collecting data on a range of tumor types affecting the liver, and (b) a study of hepatocellular carcinoma (HCC) (primary liver cancer).

Results from patients with colorectal cancer that has metastasized to the liver, and treated with PV-10 (Rose Bengal) will be presented at the 2017 Symposium on Clinical Interventional Oncology (CIO) (CIO) on February 4-5 in Hollywood, Florida. These data should comprise results from at least 5 patients (see the slide from Provectus' November 14th 3Q16 business update call below). The title of the abstract is "Percutaneous Rose Bengal as an Ablative Immunotherapy for Hepatic Metastases," with my underlined emphasis.

Results from patients with HCC, and treated with PV-10 (Rose Bengal), the original goal or initial phase of the liver Phase 1 study, will be presented at the 26th Conference of the Asian Pacific Association for the Study of the Liver (APASL) on February 15-19 in Shanghai, China. These data should comprise results from the original/initial patients (see the slide below). The title of the abstract is "Intralesional Rose Bengal as an Ablative Immunotherapy for Hepatic Tumors," with my underlined emphasis.

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Initial liver data was presented in Barcelona, Spain and Osaka, Japan in July 2015, "Phase 1 Study of PV-10 for Chemoablation of Hepatocellular Cancer and Cancer Metastatic to the Liver." Note the absence of the word "immunotherapy" in the abstract/poster's title.

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.

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.

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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.

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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.

A new article, a new clinical trial

Last week Reuters' Bill Berkrot wrote an article on Provectus, its drug PV-10 and the drug's active pharmaceutical ingredient Rose Bengal entitled Old red dye shows promise as new cancer foe. Provectus also initiated a new clinical trial last week entitled A Phase 1 Study of PV-10 Chemoablation of Neuroendocrine Tumours (NET) Metastatic to the Liver. Some thoughts of mine regarding my takeaways from and questions about them are below.

Article. (1) By far the biggest takeaway for me from Berkrot's article was the association, finally, between PV-10/Rose Bengal and an immune system response.

Click to enlarge. Purple emphasis is mine.
Screenshot of Old red dye shows promise as new cancer foe

The article effectively labeled or categorized PV-10 as an immunotherapy (at least a potential one), like Bristol-Myers' ipilimumab (Yervoy) and nivolumab (Opdivo), Merck & Co.'s pembrolizumab (Keytruda) and Amgen's talimogene laherparepvec (Imylgic), among others.

PV-10's consideration as an immunotherapy, or potential one, is nothing new given Moffitt Cancer Center's long-time work (presented and published since 2012; first pre-clinical, then clinical) and the University of Illinois at Chicago's more recent work (presented and published since 2015; pre-clinical to date). But, PV-10 hasn't been readily recognized as an immunotherapy or a potential one, despite both pre-clinical and clinical, company and third party work that should have at least encouraged such thinking. I believe this is changing, such as PV-10 and Rose Bengal's treatment in Garbe et al.'s 2016 review paper Intralesional immunotherapy as a strategy to treat melanoma. See T cells (February 24, 2016) on the blog's Current News page for more information.

(2) Another major takeaway for me was the presentation of the article's content, which was came across as a down-the-middle-of-the-fairway, opening journalistic piece, delivering facts and perspective with little or no opinion, and providing information about Rose Bengal's long, unique history.

Rose Bengal is an industrial chemical that has been around for well over a century. It's been used as a dye. It's been used as food coloring. It's been used as a diagnostic. It's inexpensive to manufacture. Berkrot and/or his editors could have colored some of that perspective, but I think wisely elected not to. In doing so, the article can be a foundational piece of information for those new to or unaware of Rose Bengal, PV-10 and Provectus' stories.

For example, the author wrote:

"While some doctors are encouraged by the research, government approval is years off and not guaranteed. The company must replicate its early results on a bigger scale, and a U.S. Food and Drug Administration decision is not expected before 2019."

Factually true. Provectus' pivotal melanoma Phase 3 trial, per its ClinicalTrials.gov webpage, has an estimated study completion date of October 2017. Add to this some time for preparation of a new drug application (NDA), a 60-day NDA filing review period and normally a 10-month period for the FDA to review new drugs, and one can easily understand Berkrot's 2019 timeframe. Nowhere in a down-the-middle-of-the-fairway article could there be room for, say, management's guidance of a mid-year interim assessment of efficacy and safety or pursuing accelerated approval on the basis of such data.

In another example, Berkrot wrote:

"In a study of 80 people with advanced melanoma, half of the patients who had all of their lesions injected appeared cancer free after an average of two months. A year later, 11 percent continued to show no signs of cancer, according to a report published the Annals of Surgical Oncology. The lesions were destroyed from the inside with no apparent harm to healthy tissue, researchers said. Reported side effects included injection site pain and blistering."

Again, factually true. PV-10 treatment is safe and potentially effective.

The author does not broach the detail that patients who had all of their lesions injected in the above Phase 2 trial received a second injection of PV-10 into all of their melanoma tumors two months after the first injection. In Provectus' ongoing Phase 3 trial, patients will have all of their lesions injected once a month until their lesions go away.

In a third example Berkrot factually and crisply summarizes the goal of this Phase 3 trial, which is to demonstrate PV-10 can prevent or forestall the progression of Stage III melanoma to Stage IV (underlined emphasis below is mine):

"Final results from an ongoing 225-patient melanoma trial of the experimental drug compared to chemotherapy are expected in early 2018. The hope is that the drug, known as PV-10, will prevent melanoma from progressing beyond Stage III, in which the disease has spread but not yet to other organs, and allow patients with more advanced cancer to live longer."

(3) Another minor takeaway would be Berkrot's take on the discovery of Rose Bengal's therapeutic benefit: an accident, but what was the real accident?

That Japanese researchers investigating Rose Bengal's food dye version in the 1980s first observed its therapeutic benefit (i.e., dose-dependent survival) but did nothing, or that Big Pharma researchers in their global, decades-long attempts to boil the oceans in search of new drug compounds did not find this work?

(4) A final and minor takeaway is the author not mentioning anything or making a "big deal" about the local agent's administration (i.e., no specific mention of intralesional (IL) delivery by name; rather, simply the observation PV-10 is injected).

Trial. Takeaways for and questions from me about the initiation of this new clinical trial include:

(1) It's a liver trial.

Specifically, it's a cancer metastatic to the liver or secondary liver cancer trial, rather than a hepatocellular carcinoma (HCC) or primary liver cancer trial.

The company currently is running a Phase 1 liver trial, A Study to Assess PV-10 Chemoablation of Cancer of the Liver, which has explored and is exploring HCC and cancer metastatic to the liver. Preliminary results from this work noted the treatment of several different types or kids of liver mets including colorectal, non-small cell lung, melanoma, and ovarian. I also previously noted a NET metastatic to the liver had been treated with PV-10.  See New clinical study (February 26, 2016) on the blog's Current News page for more information.

(2) Where is the previously management-guided progression of the original Phase 1 liver trial?

In July 2015 presentations of Provectus' preliminary liver cancer data, both HCC and metastatic, the company's CTO Dr. Eric Wachter, PhD indicated the next step in this clinical program would be an Asia-Pacific Phase 1b/2 combination study of HCC (i.e., a single arm trial of regional standard of care + PV-10, followed by a randomized control trial of regional standard of care + PV-10).

Why was a NET metastatic liver Phase 1 trial initiated before the Asia-Pacific Phase 1b trial? What is the significance of NET mets?

(3) Dosing and the number of lesions that can be treated have increased.

The original Phase 1 liver trial permitted treatment of a single lesion up to a maximum PV-10 dose of 7.5 mL. As the trial expanded, an expansion cohort (Expansion Cohort 1, or EC1) was established where a single lesion was treated with up to a maximum PV-10 dose of 15 mL.

In addition, the same two-step dosing approach (two cohorts, low and high PV-10 doses: Expansion Cohort 2.1 or EC2.1 and Expansion Cohort 2.1 or EC2.1, respectively) was provided to patients already receiving sorafenib.

The new Phase 1 liver trial will permit treatment of, first, a single lesion up to a maximum PV-10 dose of 15 mL, and second, if safety is established, all amenable lesions to a maximum dose of 15 mL.

(4) The new liver trial will collect biomarker, symptom and quality of life data.

The original trial collected changes in markers of hepatic function, pharmacokinetics of PV-10 in the bloodstream following IL injection, and pharmacokinetics of sorafenib in the bloodstream following IL injection.

The full title of the new trial is A Phase 1 Study to Assess the Safety, Tolerability and Effectiveness of PV-10 Chemoablation of Neuroendocrine Tumours (NET) Metastatic to the Liver in the Reduction of Biochemical Markers and Symptoms Caused by Secretory Products. Information to be collected includes:

• Change in NET biomarkers (chromogranin A or CgA, and/or 5-Hydroxyindole Acetic Acid or 5-HIAA),
• Reduction in major symptoms (diarrhea and flushing) using EORTC QLQ-C30 and GI.NET21 symptom scores vs. baseline values,
• Reduction in other symptoms (including bronchoconstriction and abdominal cramping) using the same approach immediately above, and 
• Change in peripheral blood mononuclear cells (PBMC), which was measured by Moffitt Cancer Center's Phase 1 feasibility study.

See NET symptoms below:

Click to enlarge. Image source

(5) Initial efficacy data to be collected in the new liver trial will be objective response rates.

On February 26th the FDA approved Novartis' everolimus (Afinitor) for the treatment of adult patients with progressive, well-differentiated non-functional, NET of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.

From Novartis' pivotal trial "...overall response rates were 2% in the everolimus arm and 1% in the placebo arm. At the planned interim analysis, there was no statistically significant difference in overall survival between arms...Everolimus was discontinued for adverse reactions in 29% of patients and dose reduction or delay was required in 70% of everolimus-treated patients. Serious adverse reactions occurred in 42% of everolimus-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock)." {Underlined emphasis is mine}

Click to enlarge. Image source

One obviously cannot compare the following for many reasons, but I believe it is worthwhile to note that in Provectus' preliminary liver cancer data, a tumor-specific objective response rate of 50% was achieved -- in 4 patients, however.

Click to enlarge. Image source

(6) I imagine Provectus will press release more information about the new liver trial this coming week.

Generating Clinical Data

Image source

"We firmly believe that Phase 3 testing should not be started unless you can adequately predict the outcome. It's critical to understand what the drug is doing, which patients are most likely to benefit, what other options those patients have, and which endpoints would be most convincing for government agencies to approved the labelled indication for the drug."

— Dr. Eric Wachter, PhD, Chief Technology Officer, Provectus Biopharmaceuticals, June 19, 2014 investor conference call 

"With an agent that is so promising in laboratory, it’s incumbent on us, the management of Provectus, to ensure that clinical trials are designed and executed to understand what this means in patients with melanoma and other cancers. 

As Chief Technology Officer, it’s my responsibility to carefully design the right studies to safely collect not just data, but the most appropriate data needed to understand any drug effect and detect any signal, hopefully, improvement in cancer patients. Each of our clinical studies: present, past and future, is designed with that purpose in mind." 

— Eric Wachter, November 5, 2015 3Q15 business update conference call

Evolving thoughts about Provectus' trials and "tribulations" in pursuit of generating more clinical data, randomized and otherwise.

Official title: PV-10 Intralesional Injection vs Systemic Chemotherapy for Treatment of Locally Advanced Cutaneous Melanoma Without Distant Metastases

• Crux: The initial pathway of approval for PV-10

• Hypotheses:

• Complete response of injected tumors is tantamount to elimination of disease symptoms

• PV-10 can forestall or prevent the spread of the disease from Stage III to Stage IV if all of it is treated

• Ideology: Focus on earlier treatment of cancer patients (i.e., < Stage III) (this will be a longer fight in order to change long-held beliefs and attitudes long-term)

• Comparison: PV-10 vs. dacarbazine (or temozolomide) (for approval as a single agent therapy for use in patients with Stage III disease)

• Process speculation:

• Demonstrate statistically significant progression-free survival (PFS) (primary endpoint) curve separation

• Collect qualitative and quantitative patient-reported outcome (PRO) data

• Undertake an interim data readout

• Submit for accelerated approval consideration

• Complete the Phase 3 trial as a post-marketing commitment in order to collect overall survival (OS) (secondary endpoint) data

• Question: The larger the difference between the treatment drug's treatment effect and the control drug's treatment effect, the smaller the number of patients required to achieve statistically significant curve clinical endpoint separation. If all control arm patients progress and no treatment arm patients progress -- how many patients are required?

Official title: A Phase 1b/2 Study of PV-10 Intralesional Injection in Combination With Systemic Immune Checkpoint Inhibition for Treatment of Metastatic Melanoma

• Crux: That PV-10 can work in combination with another drug or drug compound, proving orthogonality from both safety and efficacy perspectives

• Hypothesis: PV-10, together with a checkpoint inhibitor, can benefit patients (Stage IV) with disease inaccessible to PV-10 injection

• Ideology: Demonstrate a PV-10 solution for end-stage patients

• Comparison: Standard of care (SOC) (pembrolizumab) vs. SOC + PV-10 (for approval as a single agent for use in patients with Stage IV disease)

• Process speculation (partial process):

• Demonstrate safety and tolerability (i.e., frequency, duration, severity and attribution of adverse events and toxicities)

• Demonstrate efficacy via PFS (primary endpoint) and objective response rate (secondary endpoint)

• Populate electronic data room with preliminary initial data, and present some of this data

• Question: How good could this data be? It has to be in order to rise notably above the noise of the many combination therapies trials already being run.

The liver cancer study into which the current expanded Phase 1 study, which evolved from its Phase 1 study, will evolve

• Official title: ?

• Hypothesis: PV-10 can benefit patients with loco-regional hepatocellular carcinoma (HCC)

• Ideology: Demonstrate multi-indication viability

• Comparison:

• Asia (China, Singapore, Taiwan, South Korea): SOC (local ablation technology) vs. SOC + PV-10 (for approval as a single agent for use in patients with loco-regional HCC)

• U.S. & Western Europe: SOC (sorafenib) vs. SOC + PV-10 (for approval as a single agent for use in patients with loco-regional HCC)

• Process speculation (partial process):

• File and have accepted by the FDA a Phase 2 randomized control trial of sorafenib vs. sorafenib + PV-10

• File and have accepted by the CFDA (and other regional regulatory authorities) a Phase 1b of local ablation technology + PV-10

Potential Catalysts & "Catalysts"

Caveat: I have been hilariously off-base in the past. See, for example, my August 31, 2014 blog post Potential Catalysts.

Updated (8/9/15): To reflect a longer period of pivotal melanoma Phase 3 site activation, and to include as a catalyst the potential approval of Amgen's intralesional agent for metastatic melanoma talimogene laherparepvec (T-Vec).

Updated (8/9/15): To reflect a year-end start to a Phase 1b trial combining PV-10 and an immune checkpoint inhibitor in patients with advanced melanoma.

Click to enlarge.

Click to enlarge.

Potential Catalysts

Potential catalysts through 1Q15 could include:

Click to enlarge.

Commencing enrollment of its pivotal late-stage trial for melanoma (locally advanced unresectable/unresected cutaneous melanoma) is a key milestone and important catalyst for Provectus because the eventual outcome should provide clarity about the prospects for PV-10's regulatory validation (i.e., the drug's initial pathway to approval).

Securing a good-to-great regional transaction or two, in these cases for the world's two most populous countries, among other things (i) validates the drug's commercial prospects, (ii) more than bolsters Provectus' balance sheet with non-dilutive monies, (iii) brings partners to the fore that can facilitate late-stage trials in their respective geographies for primary liver cancer (and potentially breast cancer), further strengthening PV-10's multi-indication viability, and (iv) establishes a viable non-U.S. centric go-to-market strategy.

Moffitt Cancer Center's presentation of pre-clinical work underscoring their contention (initially conveyed at the 2014 annual meeting of the American Society of Clinical Oncology, and later at the 4th European Post-Chicago Melanoma & Skin Cancer Meeting) -- intralesional PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma, and PV-10 would be a good candidate to evaluate in conjunction with available systemic therapies and new agents in development (respectively) -- could be the catalyst for a drug combination study of PV-10 and an anti-PD-1 agent like nivolumab or pembrolizumab. I think a study only materializes if (because) the data is sufficiently compelling to encourage one of the Big Pharmas to accede to more favorable non-clinical-related terms and conditions than to what other combo study partners have agreed. This data should be presented by Moffitt at the 2014 annual meeting of the Society for Immunotherapy of Cancer in early-November.

PV-10's Pharmaceutical Alpha

In investment management, there are several measures of risk-return (aka risk-reward), including alpha, beta and Sharpe Ratio (see, for example, Forbes' Measuring Risk With Alpha, Beta and Sharpe Ratio by Richard Loth). Most investment professionals and retail investors do not outperform the market. Most investment funds, mutual, hedge or otherwise, after fees and expenses (and, more often than not, before too) do not generate alpha.

Alpha measures the value an investment manager adds to his or her fund portfolio. Warren Buffett, Jim Simmons, Ray Dalio, etc. established their reputations by generating lots of alpha for notable periods of times. Beta measure volatility. A beta greater than 1 means a portfolio (or security) will be more volatile than the market (less than 1 means less volatile, and equal to 1 means the same volatility). Many hedge funds generate high beta; that is, when the market goes up they go up higher, and when the market goes down they go down more. Some funds are low beta ones; they go up less when the market goes up and go down less when the market goes down. "Investors would most likely prefer a high alpha and a low beta." Sharpe Ratio measures risk-adjusted performance, and "...tells investors whether an investment's returns are due to smart investment decisions or are the result of excess risk."

While far from a perfect analogy, many or most of the pharmaceutical industry's oncology drugs generate beta. Few, if any, generate real alpha. Most have forgettable Sharpes. Layer on the cost of treatment (i.e., mutual fund costs or hedge fund fees and expenses), only the most effective drugs (i.e., the very best investment managers) deliver a compelling patient (i.e., investor) value proposition.

As I have written before on the blog before, and continue with the above analogy:

• Pharmaceutical Risk = Safety,
• Pharmaceutical Return = Efficacy, and
• Pharmaceutical Fees & Expenses = Treatment Cost.

PV-10 for melanoma (or any of the solid tumor cancers for which it likely should have great potential) is like a very high alpha, very low beta, very inexpensive-to-own fund.

Safe. Efficacious. Broad spectrum of use. Low cost.

✩     ✭     ✩     ✭     ✩

January 28th press release: Provectus Announces PV-10's Assessment for Drug-Drug Interaction Potential is Subject of Article Published by Xenobiotica

Byline: Demonstrates Risk of Clinically Relevant Drug-Drug Interactions with Rose Bengal is Low

Key Statement:

• "The published research indicated that the risk of PV-10 causing clinically relevant drug-drug interactions is likely minimal."
• "Sorafenib is a competitive inhibitor of cytochrome P450 (CYP) drug metabolism enzymes and is reliant on the UDP-glucuronosyltransferase (UGT) pathway for efficient clearance. CYP and UGT enzymes help to biotransform small lipophilic drugs like sorafenib into water-soluble excretable metabolites."
• "As we discuss our clinical results with regulatory authorities, we continue to be intensely committed to building all sections of the prescribing information for a future package insert for PV-10."

The paper's Discussion section helps to place the conclusion of low risk of clinically relevant or significant drug-drug interaction in context, and discusses what is known, what can by hypothesized, what is not known, and what requires or deserves more work. The paper and the PR begin to reveal more of PV-10's orthogonality (drug-drug interaction) potential. My posts on orthogonality are here, here, here and here.

Orthogonal, as you know, refers to the the idea of perpendicular, non-overlapping, independently varying or uncorrelated items. Two lines at right angles to each other are perpendicular, or orthogonal. X, Y and Z axes conventions reflect axes perpendicular (or orthogonal) to each other.

I think there are at least two key takeaways from this work and PR. First, clinical trial outcome. Sorafenib, co-developed and co-marketed as Nexavar by Bayer and Onyx Pharmaceuticals (acquired by Amgen in August 2013) is the standard of care for the treatment of advanced hepatocellular carcinoma. The company currently is running an expanded liver cancer Phase 1 trial comparing sorafenib (cohort 1) to PV-10 plus sorafenib (cohort 2). Sorafenib/Nexavar is not a very good drug, but it remains the go-to-solution for physicians for this disease.

By demonstrating low clinically relevant drug-drug interaction, all or most of the difference in efficacy between cohort 1 and 2 should be attributed, positively (more efficacy in 2 than 1) or negatively (less efficacy in 2 than 1), to PV-10. The trial is permitting a single intralesional injection of PV-10 in patients with either recurrent hepatocellular carcinoma (HCC) or cancer metastatic to the liver. Success data (higher efficacy in cohort 2 v. cohort 1), likely measurements should include overall response (complete, partial, stable) of injected tumors, would inform the FDA and impress Big Pharma, particularly if they are even remotely close to what was demonstrated for locally advanced cutaneous melanoma. Provectus has not updated the market on its liver cancer Phase 1 trial save this old information from its current website presentation.

Click the figure to enlarge it.

This biochemistry work published today is very useful for when the company shows its expanded liver trial efficacy results and analysis to the FDA and Pfizer, er, Big Pharma.

Second, market opportunity. "Three fourths of worldwide liver cancer cases in males and two thirds in females occur in the fifteen Asian countries." Sorafenib is not well liked in Asia for its utility (more so than in the U.S.). Sorafenib/Nexavar's price certainly is not liked there either. Nevertheless, the drug is the standard of care, until it is not.

"The drug, which is particularly effective on late-stage kidney and liver cancer, costs approximately $69,000 per year in India, so in March 2012 an Indian court granted a license to an Indian company to produce to the drug at a 97 percent discount" (quote source, and for the two quotes below, is here) "Nexavar costs approximately $96,000 per year in the United States, but Bayer assures “western patients” that they can have access to the drug for a $100 copay." [Bold and underlined emphasis is mine.] "In an interview with Bloomberg Businessweek, Bayer CEO Marijn Dekkers said that his company’s new cancer drug, Nexavar, isn’t “for Indians,” but “for western patients who can afford it.”"

A generic version of Nexavar may hurt Bayer/Amgen. PV-10 reducing Nexavar to near obsolescence certainly won't kill Bayer/Amgen, but the companies certainly will miss the sales (and that will impact earnings to an extent balance sheet financial engineering cannot fix). For example, in the U.S., $96,000 per year for Sorafenib/Nexavar, or a $20,000-30,000 "one shot, one kill," single use (multiple injections, if necessary) 100 mL vial of PV-10. The issue of treatment cost, in the U.S. and around the world, is far from resolved. The market opportunity for liver cancer for PV-10 still remains a very, very large addressable market times PV-10's likely very large market share times some price per treatment.

The lack of drug-drug interaction makes possible the combination of PV-10 and other drug therapies (chemotherapy, immunotherapies). That's, um, Pfizer and Provectus' joint patent application (Combination of Local and Systemic Immunomodulative Therapies for Enhanced Treatment of Cancer), which should be fully approved later this year.

This biochemistry work published today, assuming expanded liver cancer Phase 1 study data is consistent with other PV-10 liver and other cancer indication tumor results and more work conducted on combination therapies including PV-10 is successful, should open very significant market opportunities for Provectus and PV-10

$PVCT Going For The Deep Ball

My post entitled Counting Down elicited several inquiries from blog readers exclusively focused on whether or not Provectus had submitted a breakthrough therapy designation application ("BTD") to the FDA. The collection of opinions I sought over the last few days varied from "no" to "yes." Dot 1: I lean towards "yes."

On Friday, I was trying to verify a rumor that Peter was in China. He previously had been in Europe (Amsterdam) attending ECCO 2013, followed up by various investor and shareholder meetings (from what I gathered listening to several people). Dot 2: Follow-up suggested it was not likely he in China, but was he somewhere with the Chinese (i.e., Eddingpharm and/or Hisun-Pfizer)?

Speaking of ECCO 2013, on Friday, two more articles emerged from the conference about Provectus' poster presentation: FirstWord Pharma's Intralesional PV-10 Shows High Response Rate in Advanced Melanoma, Evidence of Systemic Effects and ecancer News' PV-10 in Metastatic Melanoma: blistering predicts good outcomes. The latter was written by the same author who penned Wednesday's PharmiWeb.com's Metastatic Melanoma: blistering in PV-10 treatment predicts good outcome. Like with the first article, there were some interesting content and quotes, by Dr Agarwala and, this time, Eric.

"“The principle is that this agent has a local chemoablative effect, one where we believe it enters into lysosomes causing local necrosis, and sometimes blistering of the lesion -- and then, in some patients, a systemic effect that we believe is immunologically mediated,” Dr. Agarwala explained. Further evidence of systemic effects, he noted, comes from a 54% complete plus partial response rate in uninjected “bystander” lesions." FirstWord article. Bold emphasis mine.

"Dr. Agarwala proposed 3 possible scenarios for PV-10 use -- for if and when it receives approval. First, it might be used in patients who are refractory to all other therapies and who have injectable disease. Second, it might be used in patients who have injectable lesions but who are not eligible for systemic therapy (e.g., the elderly or those with comorbidities). Third, it might be used in combination with other therapies (e.g., ipilimumab or nivolumab or both). “Of course, all of these need to be tested in clinical trials,” he said. A further option for PV-10 use, Dr. Agarwala added, would be in an attempt to turn unresectable lesions into resectable ones. “Beyond this, many of my surgical colleagues are interested in the idea of using PV-10 to stimulate the immune system before surgery to potentially lower the odds of recurrence,” he commented." FirstWord article. Bold emphasis mine.

"“Now we have the mechanistic explanation for our bystander effect, that we’re inducing a highly-specific T cell mediated response,” said Wachter. Data on the immunological mechanism of action, he added, suggested that PV-10 might be particularly relevant for patients with inhomogeneous clonal populations." ecancer article. Bold emphasis mine. As clarification, according to Eric, "inhomogeneous" and "heterogeneous" have equivalent meanings in this context.

You may recall my posts on tumor heterogeneity, such as $PVCT: #Tumor Heterogeneity. I’ve previously written that to understand PV-10 is to understand the relationship between chemoablation and immune-mediated signaling. It's what Craig means when he says the immune system responds in direct proportion to the degree of insult. Think of PV-10 chemoablation as the proxy for the degree of insult, which is rapid, complete and durable in the case of PV-10. But when Craig describes his approach in this way, what is he really getting at? How did he approach tackling or solving tumor heterogeneity?

Tumor heterogeneity is a critical problem. In any given cell there are, say, 15,000 unique mRNAs at any given second. A few seconds later, illustratively, 15,000 new ones. There are, for example, at least 15,000 to 20,000 unique proteins on a membrane surface at any one time. These change continuously. Does picking one of them to form the basis of a cancer treatment make sense? Does targeting a specific antigen as a holistic solution make sense? Heterogeneity is so wide, trying to target a specific antigen might be tough if not hopeless task. A needle in a haystack? Maybe a needle in an entire whole galaxy. Treating as many tumors as you can with PV-10 intratumorally achieves two significant positive outcomes. First, you lower the patient's overall tumor burden so as to allow the immune system to work better. Second, you allow more of the heterogeneous antigens (from the injected heterogeneous tumor) to be seen by the immune system. The more tumors treated by PV-10 the better.

Consider a 2012 article by Zhang and Austin, Physics of Cancer: The Impact of Heterogeneity (Annual Review of Condensed Matter Physics): "It is a common mistake to view cancer as a single disease with a single possible cure which we have just not found yet. In reality cancer takes on many forms that share a common symptom: uncontrolled cell growth and successful invasion of cancer colonies to remote regions of the body. The key reason why we may never be able to defeat cancer may lie in the extreme heterogeneity of the population of the cells in a tumor: there is no one magic bullet." This link, if you click on it, automatically will download a copy of the article.

Friday's statements dovetail with Wednesday's article's final sentence: "Provectus Pharmaceuticals believe they now have sufficient data to seek regulatory approval for PV-10." I've written about this before, and it seems even more clear. Management is seeking approval for the use of PV-10 in patients (metastatic melanoma Stage IIIb and IIIc) who are refractory to all other therapies and who have injectable disease because the data showed results: "...[f]or all subjects, BORR was 51% (26% complete response, 25% partial response) with the amount of tumour burden accessible to PV-10 injection prognostic for outcome." Furthermore, Provectus demonstrated clinical response predicted outcome in another way: "“If blistering occurs you can reassure patients that they’re likely to achieve a good response. It provides further evidence for an immunological basis for the mechanism of action.”" Dot 3: Management is seeking approval of PV-10 for this "narrow" label or claim, something that has become more obvious, at least to me, only over the last few months.

But how does Dot 3 relate to BTD? It's here where and about this I am fuzzy. Is Provectus seeking outright approval of PV-10, for the narrow claim above, under the BTD umbrella or separate from and in addition it? Did management simply move beyond the SPA, obfuscating its non-pursuit pursuit, to focus on what they've been trying to do since 2010, which is/was to convince the FDA to approve PV-10 for the narrow label of patients who are refractory to all other therapies and who have injectable disease.

I don't think just asking or focusing on whether the company submitted the/a BTD application alone or in a vacuum is productive or fulfilling. What else would be necessary to gain approval? Completing certain key elements of a new drug application ("NDA") filing? It's a topic I've queried management about for several months.

If Peter continues to speak with the Chinese (and the Indians), what then would be the ramifications on regional deal valuations and payment components of outright approval of PV-10? Again, it gets a little fuzzy here for me. Provectus is seeking outright approval of PV-10 for patients who are refractory to all other therapies and who have injectable metastatic melanoma, the company's lead indication. Yet, the lead indication for discussions with the Chinese and Indians is liver cancer ("HCC," or hepatocellular carcinoma). What then are the ramifications of an approval for melanoma, and/or BTD for it, on discussions related to HCC?

You'll recall Peter's slip of the pen, so to speak. In my post entitled And Now For Something Completely Different: $PVCT I wrote: Peter's TWST transcript revision is interesting. It was changed from "So our goals are to be in a Phase III trial in melanoma or submitting for FDA approval, and to be in Phase II in liver cancer, potentially with breakthrough therapy designation, because we have also filed the application for breakthrough therapy designation in both the melanoma and liver indications" to "So our goals are to be in a Phase III trial in melanoma or submitting for  FDA approval, and to be in Phase II in liver cancer, potentially with breakthrough therapy designation, which means an application for breakthrough therapy designation in both the melanoma and liver indications." Dot 4: How can regional license discussions advance on the basis of the sparse liver information made available by Provectus thus far?

I'm not saying the company has submitted BTD applications for melanoma and liver cancer. Still, what happened to progress towards the expanded Phase 1 HCC trial comparing sorafenib and sorafenib plus PV-10? Haven't one or a couple of patients (?) or more (?) been enrolled and treated? Haven't more sites (?) been added to the existing ones in San Diego (Sharp Memorial Hospital) and Florida (The Southeastern Center for Digestive Disorders & Pancreatic Cancer)?

In my investment letter posted on Seeking Alhpa, I wrote in regards to if I am wrong what would that scenario look like, management could be unable to monetize Provectus at a valuation commensurate with their innovation. In his TWST interview, Peter said management believes they "…could potentially do something along the lines of a Celgene-Abraxis type transaction, where Celgene acquired Abraxis for $2.9 billion upfront…" Bridging the valuation gap between Friday's $113 million market capitalization and a multi-billion payout will require definitive regulatory clarity, sizable commercial validation, and a copious amount of stock market exuberance. Dot 5: What exactly are the terms of a China deal (and/or of an Indian one, which I think mirrors the Chinese deal, or vice versa) in light of a focus on liver as the lead indication rather than melanoma?

I presume management is striving to protect the economics, particularly for HCC, which is the third leading cause of deaths related to cancer in the world. I had heard, albeit not verified by any stretch, that regional value components were in the range of $10 million upfront and $40-50 million upon some indeterminate regulatory clarity. That seems light to me, which makes me wonder just exactly what is management negotiating (and seeking) and how much money gets unlocked when regulatory clarity arrives.

A Hail Mary pass, "a very long forward pass in American football, made in desperation with only a small chance of success," by definition, is a deep ball (in U.S. football parlance). A deep ball is not a Hail Mary pass. A deep ball is a pass attempt over 20 yards in distance, and can be a key aspect part of a successful offensive strategy. With good to great X and Z wide receivers, defenses can't necessarily stack the box to stop the run, or overly focus on the slot receivers or tight ends running routes in the middle of the field. Of course, you have to have a good running game to which you commit, and capable slot receivers/tight ends. But well schemed offenses thoughtfully employing deep balls catch defenses napping and often lead to touchdowns when well executed.