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.

Intralesional PV-10 for In-Transit Melanoma—A Single-Center Experience

Article: Lippey et al., "Intralesional PV-10 for in-transit melanoma-A single-center experience," J Surg Oncol, 2016 May 30.

H/t a shareholder and regular hatter for access to the above paper. Bolding-in-paragraph and underlined emphasis below is mine.

[From the end of the paper] "Synopsis: This paper reviews a single metropolitan cancer hospitals experience with PV-10 for the treatment of in-transit melanoma. Over a 4-year period, we have treated 19 patients with PV-10 for melanoma and achieved disease control in 68% of patients. We find it a helpful tool in our armory for local control of this often-difficult clinical scenario."

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"Toxicity: The majority of treatments (73%, 24/33) were well tolerated without any reported side effects. Edema, pain and erythema were the most common side effects, although these were minor in severity, limited in duration, and easily managed by simple analgesia. Five patients required opiate analgesia for pain associated with PV-10 injection.

One patient was readmitted to hospital 1 week following treatment with lower limb cellulitis requiring intravenous antibiotics for 2 days. This patient was obese and elderly and the cellulitis arose in the area of recent injection."

"Treatment Response: After a median follow up of 11.7 months, disease control was achieved in 63% of patients. Five patients (26%) achieved a complete response, another five (26%) patients achieved a partial response, and two patients had stable disease (11%) at the time of last follow-up. Seventy-four percent (14/19) of patients had a clinical response at time of first follow-up (median time 21 days); range 8–91 days. Younger patients and those with smaller lesions were more likely to respond to treatment (Table III). The number of injected lesions and the time from primary diagnosis to treatment were not predictive of response.

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Ten patients did not have all lesions injected, primarily due to the number of lesions present. A bystander response was noted in un-injected lesions in 50% of patients who did not have all their lesions directly injected (Table II). After a median follow up of 11.7 months, eight patients had died

from metastatic melanoma."

"DISCUSSION: This single-center retrospective review demonstrates that intralesional PV-10 is an effective, safe, and well-tolerated treatment option for patients with ITMs and loco-regional recurrence of melanoma. Treatment was delivered to a group of patients who were elderly (median age 82 years) and in many cases considered inappropriate for more aggressive and potentially toxic therapies such as ipilimumab or isolated limb infusion.

There have been several previous reports of success with intratumoral injection of PV-10, providing local control in this group of patients with an acceptable toxicity profile. There is still a lack of data about durability of PV-10 as well as a lack of long-term survival data. The largest published study assessing the use of PV-10 in the setting of refractory melanoma published in 2014 analyzed 80 patients from seven international sites. In this study, a 52% overall response rate and 26% complete response rate were described which is comparable to the overall response rate of 63% and complete response rate of 26% in the current series as well as in another previously published single-center series (Table IV).

The effective treatment options for metastatic and locoregional inoperable disease melanoma have rapidly improved over the last 5 years. With the introduction of novel systemic agents targeting immune checkpoints (ipilimumab, pembrolizumab, nivolumab), and mutations in the MAP kinase

pathway (dabrafenib and trametinib), the treatment options for patients with unresectable metastases have increased and the prognosis for these patients has significantly improved. However, these agents may be associated with significant toxicity and in the case of PD-1 targeted therapy require frequent hospital visits for infusions. Intralesional PV-10 compares favorably with other

intralesional therapies including talimogene laherparepvec (T-VEC) which in the recently published OPTiM study demonstrated on overall response rate of 26.1%. It is important to note that the

patient population in the OPTiM study had more advanced disease than the population in the current study, and the response rate for patients with all lesions injected lesions with T-VEC was 33%. For an

elderly patient with ITM, a simple and effective local therapy with minimal side effects is an attractive option. In our center, the use of ILI has steeply decreased with the availability of PV-10.

In the modern era of effective systemic therapies, patient selection for intralesional therapy is critical. Previously described factors predictive of response include the presence of ulceration, blistering, eschar, or pain following injection. In the current study, lesion size was also found to be predictive. Of the five patients who achieved a complete response, the average lesion diameter was 3 mm compared to the cohort average size of 6.3 mm. We did not specifically collect data on eschar formation but anecdotally have seen significant ulceration and eschar in most responders which may represent a brisk immune response to treatment or a direct toxic

effect.

Aside from the local toxicity of pain and edema and an isolated report of photosensitivity, PV-10 remains a very safe treatment option. As compared to radiotherapy, PV-10 has the advantages of allowing a wider field of treatment which may be repeated if necessary. A successful combination of radiotherapy and intralesional PV-10 has been reported and may warrant further

investigation.

The limitations to this study are the retrospective nature and the variable treatment regimens which were tailored to patients according to social, geographic, and oncological factors. As our cohort consisted of elderly and comorbid patients, we often limited their required visits to hospital which is reflected in the short follow-up intervals.

There are a growing number of options for the treatment of unresectable in-transit disease and choice depends on many factors including availability of treatment, patient suitability, and disease factors. Intralesional PV-10 compares favorably in that it is well tolerated especially in an elderly patient or one with significant comorbidities.

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:

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(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}

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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.

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

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.

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Revolutionize, Perfect, Quintessential

In regards to PV-10, Moffitt Cancer has said over the last couple of years:

• Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows (Moffitt press release, August 2013),

• PV-10 might offer the perfect way to prime the immune system (interview of Moffitt's Dr. Jeffrey Weber, MD, PhD, ASCO 2014, May-June 2014), and

• [PV-10 injection]...stimulated release of interferon-gamma, the “quintessential antitumor cytokine.” (interview of Moffitt's Dr. Amod Sarnaik, Dermatology Times, May 2015).

Speaking of cytokines...

Image and article source

Cytokines are the messengers of the immune system. Cytokines are substances, either proteins or glycoproteins, secreted by immune cells. They have autocrine and paracrine functions, so that they function locally or at a distance to enhance or suppress immunity. In cancer therapy, we generally use cytokines to enhance immunity. 

Cytokines regulate the innate immune system: natural killer (NK) cells, macrophages, and neutrophils. They also regulate the adaptive immune system, the T and B cell immune responses. In the immune system, cytokines function in cascades. Thus clinical trials of individual cytokines are rarely useful, since cytokines tend not to work individually. Some of the individual cytokines that have been tested and found ineffective for cancer treatment include interleukin 1 beta (IL-1 beta), although it may be useful because it helps to mediate the severe toxicity of interleukin 2 (IL-2). Tumor necrosis factor (TNF) certainly sounded promising, but in fact caused severe hypotension when used systemically. Interleukin 4 (IL-4) showed minimal anti-cancer activity and was toxic. Interleukin 6 (IL-6) had some activity against cancer cells, but turned out to be a growth factor for myeloma cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF), used primarily in stem cell transplant to reconstitute the myeloid series, has been studied for melanoma with controversial results. 

Which cytokines are important for cancer? IL-2 and interferon-alfa 2b are two cytokines approved by the FDA for treatment of cancer. IL-2 has demonstrated activity against renal cell, melanoma, lymphoma, and leukemia. Interferon has activity in the same histologies but also in Kaposi's sarcoma, chronic myelogenous leukemia, and hairy cell leukemia. Overall, cytokines are substances that appear to have application in the treatment of hematologic malignancies or immunogenic tumors. {Underlined emphasis is mine}

Why I Remain Long Provectus Biopharmaceuticals

§  My investment thesis is intact. Up until this point FDA regulatory clarity had been lacking and therefore commercial validation was absent despite compelling clinical and business value propositions of Provectus’ Rose Bengal-based investigational oncology and dermatology compounds PV-10 and PH-10, respectively. Company management achieved regulatory clarity. Commercial validation should follow. Thus, I remain long the stock. 

§  The first pathway to oncology approval for ablative immunotherapy PV-10 is the pivotal Phase 3 trial of PV-10 as a monotherapy versus systemic chemotherapy for Stage IIIB and Stage IIIC patients with unresectable locally advanced cutaneous melanoma. If successful, PV-10 would become the standard of care for this patient population. 

§  The oncology clinical development program should expand this year with first, a Phase 1b/2 trial of PV-10 in combination with immune checkpoint inhibition for patients with advanced melanoma, and second,a domestic pivotal trial of PV-10 as a monotherapy versus sorafenib for patients with hepatocellular carcinoma and cancer metastatic to the liver. The program’s expansion asserts PV-10’s multi-indication viability, utility across disease stage spectrum, and functionality as a monotherapy as well as in combination with other treatments. 

§  Regulatory clarity from U.S. and local international regulators should facilitate commercial validation, such as geographic PV-10 licenses in China, India and/or other countries. A key element of these relationships should be joint undertakings with commercial partners of Phase 1b/2 trials of PV-10 as a monotherapy versus each region’s standard of care for patients with hepatocellular carcinoma and cancer metastatic to the liver, thus further expanding the clinical development program in 2016. 

§  Inflammatory dermatoses therapeutic PH-10 finally should garner more public attention. A Phase 2 mechanism of action study began in January. The issuance of a key patent followed in March, and interestingly may suggest non-dermatology applications of PH-10. Together with several completed preclinical toxicity studies, clinical mechanism data due by year-end should facilitate FDA discussions about consensus pivotal Phase 3 trial designs for psoriasis and/or atopic dermatitis. The protocol(s) and regulatory clarity may help the Company secure a global or regional license deal for PH-10 in 2016. 

§  More data should be presented, published and available for due diligence in 2015, such as liver cancer (clinical), PV-10’s mechanism (clinical), PV-10 in combination with immune checkpoint inhibition (preclinical), and PV-10 in combination with external beam radiation therapy (clinical). Mechanism, overall survival-focused liver data and interim melanoma Phase 3 data would affirm that complete response of cancerous tumors after PV-10 injection results in the disease staying away. 

§  Favorable pharmaceutical industry trends should further improve Provectus’ M&A valuation prospects. Big Pharma oncology franchises are separating into those with immune checkpoint inhibition that understand the need for an immune system primer to assist their inhibitors, those with inhibitors that don’t fully embrace this need, and those who have a stimulatory compound, an inhibitor or neither and know they need a matching set to remain relevant.

My investment thesis remains intact

The value proposition of Provectus’ two Rose Bengal-based drugs — intratumorally injected PV-10 for oncology (a 10% solution of Rose Bengal) and topically applied PH-10 for dermatology (a 0.001% to 0.01% gel of the active pharmaceutical ingredient) — is compelling: pristine safety profiles, well tolerated treatments easily administered to and compliable for patients, ready-made products with probable high gross margins inexpensively manufactured at scale, and the potential to fully serve vast addressable markets of unmet needs very profitably over time. Increasing amounts of medical and scientific data as well as independent validation of results and claims confirm the Company’s intrinsic value.

From inception through this year Knoxville, Tennessee-based Provectus Biopharmaceuticals, Inc.[1] (“Provectus” or the “Company”) (NYSE MKT: PVCT) was best described as an early-stage drug development company. Provectus was founded in 2002 by three scientists from nearby Oak Ridge National Laboratory, a U.S Department of Energy (“DOE”) multi-program science and technology facility with a rich history of discovery and innovation (and a member of the DOE network of laboratories that includes Lawrence Berkeley, Lawrence Livermore, Los Alamos, and Sandia). Up until now the Company had been developing PV-10 and PH-10 with no regulatory clarity (i.e., discernible, initial pathways to approval).

Rose Bengal is a unique compound with an extensive and very long clinical history. A water-soluble dye originally created by Gnehm in 1882[2], it has a molecular weight of approximately 1,000 Daltons, which effectively makes it a small molecule. Rose Bengal’s century of prior clinical use includes being added to Safranin Victoria Yellow for treating ocular pneumococcal infection (Römer, 1914)[3], a stain for visualizing corneal ulcers (Kleefeld, 1919)[4], and a marker for observing impaired liver function (Delprat, 1925)[5]. It also has an established FDA safety profile as an intravenous hepatic diagnostic (Robengatope®) as well as a topical ophthalmic diagnostic (Rosettes® and Minims®). To date there are 3,696 medical literature citations of Rose Bengal[6], 233 related to cancer[7]. Rose Bengal’s therapeutic benefits remained hidden until the 1980s when the FDA and the Japanese Ministry of Health and Welfare began scrutinizing artificial food colorings. Japanese researchers evaluated the tumorigenicity of red food dye No. 105 (also made from Rose Bengal), and observed dose-dependent survival increased in the mice receiving it.[8]

In 1998 Provectus’ multi-disciplinary team of founders — a molecular virologist (Dr. Craig Dees, Ph.D.), a chemical engineer (Dr. Timothy Scott, Ph.D.) and an organic chemist (Dr. Eric Wachter, Ph.D.) — looking for drug candidates having antineoplastic activity also happened to come across Rose Bengal.[9] A commercial data search by the former Oak Ridge scientists identified numerous candidates. Subsequent proprietary screening promptly zeroed in on Rose Bengal and other members of the halogenated xanthene family. Preclinical tests with bacterial and cancer cell lines quickly demonstrated Rose Bengal’s impressive cytotoxic activity. Subsequent animal and human studies confirmed Rose Bengal delivered directly into tumors by injection was a selective and potent agent for ablating cancers and harnessing the immune system.

PV-10’s therapeutic value, established preclinically and clinically by Provectus, has been independently repeated and reproduced by affiliated and unaffiliated investigators and researchers around the world:

• Dual ablative and immunotherapeutic mechanisms of action: Primary ablation in 1 to 2 hours that kills cancer tumors into which PV-10 is injected by selectively passing through cell membranes and accumulating in lysosomes to force cell death with no biochemical action or effect, and secondary immunomodulation in 1 to 2 weeks where cell death resulting from local tumor injection attracts tumor-specific T-cells and causes an up-regulating immune effect, which leads to a systemic, tumor-specific immune response in untreated tumors and distant disease[10],

• Simple to store, handle, and use and reuse[11],

• Modest local toxicity predominantly confined to the injection site, and minimal to no systemic toxicity^{11, [12], [13]},

• Rapid, durable and complete tumor destruction, as well as induction of antigen release in injected lesions^{11, 13},

• Prompt, complete healing of injected lesion sites after tumor destruction¹¹,

• Reliable, reproducible induction of loco-regional and systemic immune effects capable of destroying occult tumor cells, untreated lesions and distant metastatic lesions regardless of prior therapies and treatments ^{11, [14]},

• Multi-indication viability: Up to 260 cancer patients treated with PV-10 — 12 in a recurrent breast cancer Phase 1 trial, 6 in a liver cancer Phase 1 trial, 100 in melanoma Phase 1 and 2 trials, 15 in a melanoma Phase 1 mechanism study, 100 patients having cutaneous and subcutaneous tumors irrespective of indication treated through 2013 in Provectus’ compassionate use program (“CUP”), and up to 25 in an investigator-initiated melanoma study of PV-10 in combination with external beam radiation therapy (“XRT”)^{14, [15]}. The Company has not yet reported patient numbers for the expanded liver cancer Phase 1 trial and in the CUP in 2014,

• Orthogonality (i.e., low clinically relevant drug-drug interaction)[16] and synergy with other therapies and therapeutics: targeted therapy¹⁶, systemic chemotherapy[17], XRT[18], and immune checkpoint inhibition[19]^{, [20]}, and

• Third-party validation[21]: Apoptosis, tissue and cell selectivity, clinically relevant loco-regional and systemic effects, tumor-specific immunity, T-cell engagement, immune-mediated response, multi-indication viability.

The initial pathway to approval is set

Provectus’ pivotal melanoma Phase 3 trial should begin treating patients in April. The trial tests the hypothesis that complete response (“CR”) of melanoma lesions after PV-10 injection results in melanoma staying away.^[22] The trial’s patient population should be the same as the patient subgroup in the Company’s Phase 2 trial that received PV-10 injection of all existing melanoma. The subgroup achieved progression-free survival (“PFS”) under modified RECIST of more than 9.8 months, a complete response rate (“CRR”) of 50% and loco-regional disease control (complete response [“CR”] + partial response [“PR”] + stable disease) of 82% despite receiving a limited number of injections over a limited period of time. An initial injection and up to three more [if needed] were delivered to a patient’s lesion during the first 16 weeks of the trial. The majority of lesions in the subgroup achieved CR with only 1 or 2 injections.[23]^{, [24]}

By accepting the registration study’s design and protocol[25] — 225 patients, a primary endpoint of PFS, a comparator of systemic chemotherapy (dacarbazine), and secondary endpoints of CRR, overall survival (“OS”) and the number of adverse events — the FDA acknowledged this intratumorally delivered agent may have a meaningful role to play in the treatment of the systemic disease that is melanoma. The Phase 3 trial will have no restriction on the number of injections a patient’s lesions may receive (which benefits PFS and CRR), the number of lesions a patient may have treated (which benefits OS) or the time over which injections are provided (which benefits PFS, CRR and OS). There is an imperfect trial inclusion criterion: Patients must have failed or not be a candidate for at least one systemic immunotherapy (Bristol-Myers’ ipilimumab, Merck’s pembrolizumab and Bristol-Myers’ nivolumab).

The Agency’s recognizes the severity of loco-regional melanoma and need for better patient treatment options. In October 2014 the FDA requested public comment on “[m]elanoma, specifically unresectable loco-regional disease.”[26] The Agency also accepted Amgen’s biologics license application for intralesional agent and oncolytic virus talimogene laherparepvec (referred to as T-Vec), setting a Prescription Drug User Fee Act date of October 27, 2015. An April 29, 2015 meeting of FDA advisory committees should elucidate the Agency’s views about T-Vec, especially given questions surrounding its pivotal melanoma Phase 3 trial’s comparator (GM-CSF) and endpoints (durable response rate), and the potential deleterious effects of viral shedding[27].

Management has endeavored to build value in Provectus’ fully owned cancer and dermatology assets (unsuccessfully thus far when measured by the Company’s current market capitalization) by differentiating PV-10 and PH-10’s product profiles, innovating unique mechanisms of action (outsourced to Moffitt Cancer Center [“Moffitt”] and rumored Rockefeller University for independent explanation of oncology and dermatology, respectively), demonstrating best-in-class efficacy, persevering in their discussions with the Agency to establish new standards of care (management acknowledged they did not fully listen to the FDA in the past), demonstrating negligible side-effect profiles as well as easy physician and compliable patient administration modes, and targeting therapeutic areas with unmet clinical and commercial needs.[28]

Provectus faced two obstacles during its existence as an early-stage drug development company. First, there was regulator and pharmaceutical industry reservation about using locally delivered agents to treat melanoma. This bias resulted from a lack of material, long-lasting clinical success, illustrated by the initial promise but ultimate failure of Bacille Calmette-Guérin (“BCG”) for melanoma in the 1970s (serious adverse events and no significant clinical benefit[29]) and Vical’s Allovectin-7 for melanoma in 2013 (no clinical benefit[30]^{, [31]}), as well as comparatively lackluster OS in melanoma for T-Vec in 2014[32]. Allovectin-7’s CRR in its Phase 2 trial for metastatic melanoma was far lower than T-Vec’s, which was much lower than PV-10’s[33]. Second, Provectus originally sought consideration of PV-10 from the FDA for an earlier stage of melanoma when all of it is accessible for injection and overall disease burden is lower (Stage III patients), instead of pursuing advanced melanoma where not all disease is injectable (Stage IV patients) like BCG, Allovectin-7, T-Vec and the systemic immunotherapies.

Whether separately from or together with T-Vec, PV-10 may be the first (or one of the first) locally delivered therapeutic agent to be approved for melanoma. Systemically administered high-dose interleukin-2 was approved in 1998 for advanced melanoma.[34] Against the backdrop of a finalized melanoma Phase 3 protocol and evolving FDA and Big Pharma acceptance of intralesional therapies, there is a meaningful probability of PV-10’s melanoma Phase 3 trial being terminated early for efficacy of the treatment arm over the control. Historical data can be honestly used to determine the likelihood of success. Clear wins on trial endpoints should be acknowledged as former biases fall away.

Clinical development should expand substantially

If early-stage drug development company described Provectus from 2002 to 2015, 2015 marks the beginning of the Company’s transition into a regulatory-focused and data-driven organization. The knowledge base developed and consensus achieved by the FDA’s Division of Oncology Products 2 (“DOP2”)[35] and Provectus of what is necessary and sufficient to approve PV-10 as a monotherapy for loco-regional Stage III melanoma patients should enable the parties to design trial protocols and establish prospective pathways to approval in the future (with the FDA better understanding and having more experience with PV-10’s mechanism, utility and functionality) for a PV-10/immune checkpoint inhibition combination for patients with advanced melanoma, and monotherapy use in patients with hepatocellular carcinoma (“HCC”) and cancer metastatic to the liver.

Combination therapy for advanced melanoma: The second trial of Provectus’ oncology clinical development program that may start in 2015 could be a modest-sized (up to 20 patients), single-arm Phase 1b trial combining PV-10 and Merck’s immune checkpoint inhibitor pembrolizumab for patients with unresectable Stage IIIB to Stage IV advanced melanoma. Provectus may elect to go it alone and use the reimbursable pembrolizumab because of Moffitt’s familiarity with it. Alternatively, the Company could enter into a co-development relationship with this Big Pharma or another one (and its approved or investigational inhibitor). Endpoints would comprise acute safety (of the combination regimen, with PV-10 given first followed by the inhibitor) and objective response rate (“ORR”) (CR + PR) measured at 3 to 4 months.[36] This trial protocol would be agnostic to the inhibitor. Moffitt has completed preclinical combination studies of PV-10 and co-inhibitory blockade (anti-CTLA-4, anti-PD-1, anti-PD-L-1). There should be low or no clinically relevant drug-drug interactions. It is rumored Merck has done due diligence on Rose Bengal through its own murine model work.

Phase 1b/2 studies may streamline drug development and rapidly advance a promising agent demonstrating notable efficacy and sufficient safety through the regulatory process. The initial step (Phase 1b) collects safety and response data from a small number of patients. A successful outcome facilitates subsequent discussions with the FDA about a pivotal trial design for the second step (i.e., a randomized Phase 2 or other aptly named late-stage trial).

Amgen and Bristol-Myers already conducted a Phase 1b trial combining T-Vec and ipilimumab in 19 patients with advanced melanoma.[37] No dose-limiting toxicities and a predominance of Grade 3/4 adverse events were reported. In addition to evidence of immunological signaling, preliminary data suggested higher CRR and ORR than either T-Vec or ipilimumab alone, and earlier responses after ipilimumab initiation during the combination regimen than with ipilimumab alone. In contrast, Moffitt described a greater breadth and depth of T-cell response (CD8+, CD4+, CD3+ and NK) from a single injection of PV-10 in a Phase 1 mechanism study, compared to arguably weaker signaling from repeated, prolonged treatments of T-Vec and ipilimumab. Nevertheless, the results of the T-Vec plus ipilimumab trial inform how an immune system primer (T-Vec) enhances the effectiveness of an immune checkpoint inhibitor (ipilimumab).

Monotherapy for HCC/ metastatic liver cancer (U.S.): A third trial that may be started in 2015 could be a domestic liver cancer one, the design of which is dependent on available data and subsequent guidance from DOP2, the same organization within the FDA responsible for melanoma. Provectus previously completed a liver Phase 1 trial that treated six patients with HCC (five tumors) and a colorectal metastasis from 2009[38] to 2011[39]. The Company has not yet presented or published results from this trial. Presentation is expected this summer. Management previously said tumors were substantially ablated with sustained regression and no disease per positron emission tomography–computed tomography at the patients’ 9- to 15-month check-ups.

In 2012[40] Provectus commenced an expanded Phase 1. The number of treated patients is not yet public. Per the trial’s protocol[41] patients were divided into two cohorts; one received PV-10, and the other both PV-10 and sorafenib. Safety was the primary outcome measure for both liver trials. The second trial had a secondary outcome measure (among others) of ORR of injected and measurable untreated lesions (if present). Sorafenib is the standard of care for patients with more advanced liver cancer or who failed loco-regional therapy.[42] Prior to treating patients in the PV-10-plus-sorafenib cohort, however, Provectus conducted an in vitro study that demonstrated a low risk of clinically relevant drug-drug interaction between Rose Bengal and sorafenib derivatives[43]. This orthogonality assigns the efficacy difference between the two cohorts in the second liver trial solely to PV-10’s clinical benefit. Provectus may seek an expedited pathway to approval via a pivotal trial based on (but not limited to) safety from both liver trials, overall survival observations from the first, measures of ORR from the second, and PV-10/sorafenib orthogonality.

Company management recently said they are assessing potential clinical study of other indications like breast cancer and pancreatic cancer[44]. It is unlikely such work would commence this year given management’s potentially taxed mental bandwidth (management made deliberate choices from the outset regarding operational roles and responsibilities, and these remain unchanged). Provectus’ drug development program also comprises on-going third party research that is rumored to include work on breast, pancreatic and prostate cancer, and renal cell carcinoma. Provectus’ Chief Technology Officer Dr. Wachter commented on this during the Company’s last quarterly conference call:

Dr. Wachter: “I cannot comment on other third-party work that may or may not be underway with regard to non-clinical work with PV-10. Obviously that is something that may be of interest and if it is, and we haven't disclosed this, it’s probably a sensitive nature.”[45]

The oncology clinical development program’s expansion in two key areas — primary and metastatic liver cancer as another approvable indication, and combination therapy for advanced melanoma as an approvable indication expansion — establishes PV-10’s multi-indication viability, broader utility across disease stage spectrum, and greater functionality as a monotherapy and in combination with other treatments as an immune system primer.

Regulatory clarity should facilitate commercial validation

Management has pursued international commercial validation for a couple of years, and over time said licensure discussions have taken place for China, India, Brazil, Russia, Korea, Japan, and the Middle East and North Africa. Completing these deals supplement but should not interfere with a worldwide oncology license for the drug or the eventual sale of the Company to Big Pharma. With an FDA-accepted melanoma Phase 3 protocol finally in hand, a deal or deals may be had with a dominant pharmaceutical company in the respective geography. Provectus currently has a memorandum of understanding for China and its territories with two Sinopharm Group Company subsidiaries, China State Institute of Pharmaceutical Industry and A-THINK Pharmaceutical Co.[46]

If a deal is transacted, a key element of the relationship likely would be the joint undertaking (with the geographic partner) of a Phase 1b/2 trial of PV-10 as a monotherapy versus the particular region’s [loco-regional ablation therapy] standard of care for patients with HCC and metastatic liver cancer. This should require the acceptance of the locally focused protocol by the local regulator, and may be the case with the China Food and Drug Administration (“SFDA” or “CFDA”). Dr. Wachter discussed his perspective of the regulatory pathway in China and the Company’s likely approach to it on the last two Provectus’ quarterly conference calls:

November 2014: “What we have learned in the relatively recent past is with our experience in Asia that it will be necessary going into China to do some additional Phase 1 work and that has colored our design parameters for the next Phase of HCC work to use this 1b-2 approach that I might point out from a prepared comments has been so successful with Amgen and a number of other sponsors in recent years as a way to expedite development of the drug from the Phase 1 safety into a very robust randomized Phase 2 study in a quick fashion.”[47]

March 2015: “So in the part of the world like China which is an interesting case, we might be able to access a large number of patients that would be eligible for the study but for instance the approval process to get the study going, not technical review of the protocol and modifications, I have gone to the agency but just the fundamental review process for conducting a clinical trial where an investigation drug can be very prolonged, often times 12 to 18 months.”⁴⁵

Monotherapy for HCC/ metastatic liver cancer (China): PV-10’s Chinese pathway to approval for liver cancer thus might be the first step of a modest-sized, single-arm Phase 1b trial in 2016 combining PV-10 and a Chinese-favored loco-regional ablation therapy (e.g., transarterial chemoembolization, percutaneous ethanol injection)[48]. Endpoints may comprise acute safety of the combination regimen and hepatic ORR measured at some single digit number of months. A successful outcome could facilitate subsequent discussions with the SFDA/CFDA about a pivotal trial design for a randomized late-stage trial comparing PV-10 and the chosen ablation therapy for OS, among other primary and secondary endpoints.

PH-10 should garner more attention as a very valuable therapeutic asset

By launching a Phase 2 mechanism of action study that started recruiting patients in January and should complete data collection by year-end, existing and prospective investors in the Company are able to better value Provectus’ investigational dermatology compound PH-10. The drug may have an addressable market of all inflammatory dermatoses that could be larger than that of PV-10. Company management has tried to license the drug since at least 2010[49] without success because regulatory clarity had been lacking. This was very likely due to a paucity of data for the regulator and prospective commercial partners, particularly as it relates to near complete absence of toxicity for PH-10. Multiple preclinical toxicity studies should be done:

• Genotoxicity (Ames, Micronucleus and Comet assays),
• Reproductive toxicology (rat DART testing),
• Dermal toxicity and phototoxicity (minipig),
• Dermal carcinogenicity, and
• Chronic toxicity (minipig, rat).

In addition, a key PH-10 patent was issued in March (Topical medicaments and methods for photodynamic treatment of disease[50]), which protects use of the drug for non-dermatology applications (e.g., bladder cancer, oral disease, post-surgery). Observations and conclusions from the toxicity studies, clinical mechanism data and existing clinical data from previous trials should facilitate Agency discussions about consensus pivotal Phase 3 trial designs for psoriasis and/or atopic dermatitis. With regulatory clarity in hand, Company management should be in a much better position to finally achieve a global or regional dermatology license for this asset.

Much more data should be presented or published

Provectus last published new clinical data (about its melanoma Phase 2 trial) at the 2010 annual meeting of the Society for Melanoma Research[51] and new preclinical data (about PV-10 in combination with immune checkpoint inhibition [anti-CTLA-4]) at the 2013 annual meeting of the American Association for Cancer Research (“AACR”).[52] Phase 2 trial results and exploratory analyses were presented at annual meetings of the American Society of Clinical Oncology (“ASCO”), European Society for Medical Oncology (“ESMO”), European Association of Dermato Oncology (“EADO”) and European CanCer Organisation (“ECCO”): ASCO 2009[53], ASCO 2010[54], ESMO 2012[55], ECCO 2013[56], EADO 2014[57], ASCO 2014[58] and ESMO 2014[59].

Moffitt published preclinical data at the 2012 annual meeting of the Society of Surgical Oncology[60], AACR 2013[61] and 2014 annual meeting of the Society for Immunotherapy of Cancer (“SITC”)[62], and clinical data at AACR 2014[63] and ASCO 2014[64]. This cumulative work independently repeated and reproduced the Company’s preclinical and clinical results and claims. Moffitt’s recent work has focused on PV-10’s mechanism. According to Moffitt’s disclosures, Provectus provided only PV-10 to the cancer center for its experiments (a non-author is a paid consultant to the Company).

Additional preclinical and clinical data should be forthcoming this year and next:

• Liver (clinical): Company management said they expect to report data at one or more international conferences this summer, possibly the World Congress on Gastrointestinal Cancer in Barcelona, Spain (April 21 abstract notification) and/or the Annual Conference of the International Liver Cancer Association in Paris, France (late-June abstract notification),

• PV-10’s mechanism (clinical): It’s unclear when and where Moffitt would present and/or publish additional mechanism results. Previous study results were presented at AACR and ASCO 2014,

• PV-10 in combination with immune checkpoint inhibition (preclinical): It’s also unclear when and where Moffitt would present and/or publish additional results of combining PV-10 and co-inhibitory blockade (anti-CTLA-4, anti-PD-1, anti-PD-L-1). Cursory results were presented at SITC 2014, and

• PV-10 in combination with XRT (clinical): Australian researchers should disclose interim clinical data of an investigator-initiated study of 25 patients who received a single injection of PV-10 per lesion followed by XRT. Preliminary study of 3 patients in 2010[65] yielded complete responses without a significant increase in acute radiation reaction.

Mechanism (melanoma [clinical], breast [preclinical]), combination with other treatments (XRT and melanoma [clinical]) and therapies (systemic chemotherapy and liver [preclinical], immune checkpoint inhibition/melanoma [preclinical]), overall survival-focused (liver [clinical]) and interim melanoma Phase 3 (clinical) data affirms PV-10’s proposition that complete response of cancerous tumors after PV-10 injection results in the disease staying away, irrespective of solid tumor indication or disease stage. It’s very likely that late-stage disease, where patients may be overwhelmed by inaccessible tumor burden, requires the additional use of XRT or immune checkpoint inhibition to reduce this burden before the PV-10-stimulated immune system finishes the job.

Favorable pharmaceutical industry trends should provide valuation tailwinds

Provectus achieved a sizeable measure of regulatory clarity it previously lacked. I framed this necessary step in my September 2013 investment letter[66]:

“When regulatory clarity is achieved, it would be FDA validation of the local agent's systemic properties and benefit. When more clinical trials are conducted and regulatory clarity is achieved for other indications, regional and/or worldwide license transactions are consummated, and the investment community is more aware of the drug and the Company, Provectus' market capitalization should substantially increase from its current valuation. The share price should enjoy significantly more upside from there when acquisitive global pharmaceutical companies, having fully embraced PV-10's immense oncology value proposition for their respective business franchises, pay up for this unique, fully owned, cancer treatment asset.”

Key clinical trends have overtaken the pharmaceutical industry in regards to treating cancer: the tumor microenvironment as the route of delivery, supercharging T-cells to better harness the immune system, and de facto combination therapy for late-stage disease.

Immune checkpoint inhibition (so called “releasing the brakes”) no longer is the panacea it initially was believed to be for harnessing the immune system to treat late-stage cancer, the pharmaceutical industry’s historic and current focus. After well more than a decade of development and hundreds of millions if not billions of cumulative dollars in expenditure by Big Pharma, the FDA approved anti-CTLA4 therapeutic ipilimumab in 2011 for advanced melanoma, and next generation anti-PD-1 therapeutics pembrolizumab and nivolumab burst onto the scene at ASCO 2013 and were first approved in 2014 for advanced melanoma. Non-specific immunotherapies require a dynamic tumor antigen expression process — front-end radiation therapy, targeted chemotherapies or intralesional therapies like T-VEC and PV-10 — to optimally potentiate the body’s T-cells against the inciting cancer. That is, they require the “engine to be started” and/or the “gas pedal to be stepped on” because the car itself may be unable to move or is moving very slowly (i.e., make non-immunogenic tumors immunogenic, and immunogenic ones more so). Without a viable front-end (immune system primer), the back-end (immune checkpoint inhibition) is limited.

Big Pharma oncology franchises are separating into three categories: those with immune checkpoint inhibition that admit the need for a primer (e.g., Bristol-Myers, Merck, Novartis, Roche), those who do not fully admit such need (e.g., AstraZeneca), and those who have a stimulatory compound (e.g., Amgen), an inhibitor (e.g., Pfizer) or neither (e.g., J&J) and know they require a matching set to remain relevant in oncology. Outside of PV-10 there is an inventory of various co-stimulatory and agonist agents (e.g., anti-CTLA-4, anti-CD137, anti-OX40, anti-CD27, IL-2, IL-12, vaccines, IFN-α, GM-CSF, anti-CD40, Toll-like receptors[67]) that can start the engine and/or step on the gas pedal. Each has advantages and disadvantages with regard to cost, safety and level of antigen expression individually and in combination with a co-inhibitory or antagonist partner. PV-10’s unique functional and approvable blend of low cost, high safety, high expression, and orthogonality may offer the perfect way to prime the immune system[68].

Other relevant Big Pharma trends include obviously bulging balance sheet cash amounts and emptying drug pipelines.

Provectus is on the cusp of meriting a “Phase 3 badge.”[69] Small biotechnology companies whose drug candidates present compelling value propositions based on well-defined patient populations, notable clinical value and advantageous economic value[70]  — and have achieved regulatory clarity — should see dramatically increased market capitalizations, and have presented to them lucrative buy-out options commensurate with the breadth and depth of their propositions. I believe Provectus will be one of these companies:

• The Company’s drug compounds have compelling clinical and business value propositions. Regulatory clarity has been achieved. Commercial validation should follow,

• The first pathway to oncology approval is set,

• The oncology clinical development program should expand this year,

• A regional geographic license for PV-10 should follow in China and/or India, along with a local liver trial involving PV-10,

• Inflammatory dermatoses therapeutic PH-10 finally should garner more attention,

• More data should be presented and published this year, and

• Favorable pharmaceutical industry trends should further improve Provectus’ M&A valuation prospects.

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[1] www.pvct.com

[2] Gnehm R.Ueber Tetrachlorphtalsäure. Justus Liebigs Annalen der Chemie 1887; 238:318–338

[3] Feenstra RPG and Tseng CG. What is actually stained by rose bengal? Arch Ophthalmol 1992; 110:984-993.

[4] Sjögren H. (1933) Zur Kenntnis der Keratoconjunctivitis sicca (Keratitis filiformisbeiHypofunktion der Tränendrüsen). Acta Ophthalmol 1933; 11 suppl. 2:1-151.

[5] Delprat GD. Studies on liver function: Rose Bengal elimination from the blood as influenced by liver injury. Archives of Internal Medicine 1923; vol. 32:401-410.

[6] http://www.ncbi.nlm.nih.gov/pubmed/?term=%22rose+bengal%22

[7] http://www.ncbi.nlm.nih.gov/pubmed/?term=%22rose+bengal%22+cancer

[8] Ito A, Watanabe H, Naito M, Aoyama H, Nakagawa Y, Fujimoto N. Induction of thyroid tumors in (C57BL/6N x C3H/N)F1 mice by oral administration of 9-3',4',5',6'-tetrachloro-o-carboxyphenyl-6-hydroxy-2,4,5,7-tetraiodo-3-isoxanthone sodium (Food Red 105, Rose Bengal B). J Natl Cancer Inst 1986 Jul; 77(1):277-81.

[9] http://www.pvct.com/news/PT-August-2010.pdf

[10] http://www.pvct.com/presentation/corporate/img6.html

[11] Moffitt, 4th European Post-Chicago Melanoma/Skin Cancer Meeting (2014)

[12] Rose Bengal, PV-10 and PH-10’s active pharmaceutical ingredient, has an established FDA safety profile for prior human use as an intravenous hepatic diagnostic (Robengatope®) and topical ophthalmic diagnostic (Rosettes® and Minims®)

[13] Thompson, Agarwala et al., Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma, Annals of Surgical Oncology (2014)

[14] http://www.pvct.com/publications/SPTAACR2013-Final.pdf

[15] Provectus website, page: Clinical Trials and Compassionate Use/PV-10 for Melanoma

[16] http://eorder.sheridan.com/3_0/display/index.php?flashprint=3356

[17] http://www.pvct.com/publications/SITC-Poster-23Oct12.pdf

[18] http://www.pvct.com/news/MelanomaRes-v20-n1/index.html

[19] http://www.pvct.com/publications/AACR-Poster-10-Apr-2013.pdf

[20] http://www.pvct.com/publications/SITCposter2014.pdf

[21] Illustrative examples: Moffitt Cancer Center, Various; Zamani Taghizadeh Rabe et al., Rose Bengal suppresses gastric cancer cell proliferation via apoptosis and inhibits nitric oxide formation in macrophages, Journal of Immunotoxicology (2014); Tan et al., Novel use of Rose Bengal (PV-10) in two cases of refractory scalp sarcoma, ANZ Journal of Surgery (2013); Koevary, Selective toxicity of rose bengal to ovarian cancer cells in vitro, International Journal of Physiology, Pathophysiology and Pharmacology (2012)

[22] http://www.pvct.com/news/PVCT-TRANS-CONF-CALL-3-12-2015.pdf

[23] http://www.pvct.com/publications/ASCO-Poster-2014.pdf

[24] http://www.pvct.com/publications/Provectus-ESMO-2014-09-28.pdf

[25] https://clinicaltrials.gov/archive/NCT02288897/2015_03_12

[26] https://www.federalregister.gov/articles/2014/10/08/2014-23965/prescription-drug-user-fee-act-patient-focused-drug-development-request-for-comments

[27] http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/10/WC500005222.pdf

[28] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3571061/

[29] http://www.skincancer.org/publications/the-melanoma-letter/spring-2012-vol-30-no-1/PV-10

[30] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323546/

[31] http://www.fiercebiotech.com/press-releases/vical-phase-3-trial-allovectinr-fails-meet-efficacy-endpoints

[32] http://www.fiercebiotech.com/story/amgens-viral-cancer-vaccine-misses-its-survival-goal-melanoma-phiii/2014-04-04

[33] See table, http://provectuspharmaceuticalsinc.blogspot.com/p/why-im-long-provectus.html

[34] http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/HealthProfessional/Page9#_693

[35] http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm093907.htm

[36] http://seekingalpha.com/article/2999576-provectus-biopharmaceuticals-pvct-q4-2014-results-earnings-call-transcript

[37] http://meetinglibrary.asco.org/content/128142-144

[38] http://www.pvct.com/pressrelease.html?article=20091001

[39] http://www.pvct.com/pressrelease.html?article=20110127

[40] http://www.pvct.com/pressrelease.html?article=20120927

[41] https://clinicaltrials.gov/ct2/show/NCT00986661?term=Provectus&rank=4

[42] http://theoncologist.alphamedpress.org/content/15/suppl_4/42.full

[43] http://eorder.sheridan.com/3_0/app/orders/3356/article.php

[44] http://www.sec.gov/Archives/edgar/data/315545/000119312515088039/d862762d10k.htm

[45] http://seekingalpha.com/article/2999576-provectus-biopharmaceuticals-pvct-q4-2014-results-earnings-call-transcript

[46] http://www.pvct.com/pressrelease.html?article=20141114

[47] http://seekingalpha.com/article/2667675-provectus-biopharmaceuticals-pvct-q3-2014-results-earnings-call-transcript

[48] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1422461/

[49] http://www.pvct.com/pressrelease.html?article=20100107

[50] http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=provectus&OS=provectus&RS=provectus

[51] https://www.pvct.com/news/PV-10_Presentation_Sydney-Nov-2010.pdf

[52] http://www.pvct.com/publications/AACR-Poster-10-Apr-2013.pdf

[53] http://www.pvct.com/publications/ASCO_Poster-2009.pdf

[54] http://www.pvct.com/publications/ASCO_Poster-2010.pdf

[55] http://www.pvct.com/publications/PVCT-ESMO-2012-Poster.pdf

[56] http://www.pvct.com/publications/Provectus-ECCO-2013.pdf

[57] https://www.pvct.com/news/PV-10-EADO-2014-May.pdf

[58] http://www.pvct.com/publications/ASCO-Poster-2014.pdf

[59] http://www.pvct.com/publications/Provectus-ESMO-2014-09-28.pdf

[60] http://www.pvct.com/publications/Paul-Toomey-PV10-SSO-2012.pdf

[61] http://www.pvct.com/publications/SPTAACR2013-Final.pdf

[62] http://www.pvct.com/publications/SITCposter2014.pdf

[63] http://www.pvct.com/pressrelease.html?article=20140306

[64] http://meetinglibrary.asco.org/content/132288-144

[65] http://www.pvct.com/news/MelanomaRes-v20-n1/index.html

[66] http://seekingalpha.com/article/1710182-why-im-long-provectus-pharmaceuticals

[67] http://www.sciencedirect.com/science/article/pii/S1074761313002963

[68] http://ecancer.org/news/5790-provectus-outlines-path-forward-for-pv-10.php

[69] http://www.thestreet.com/story/12696926/1/the-feuerstein-ratain-rule-update-still-perfect-predicting-small-cap-cancer-drug-failure.html

[70] http://obroncology.com/obrgreen/article/Ensuring-a-Compelling-Value-Proposition-in-Oncology