September 2, 2014

A China Tale, and Process

From the traditional folksong of Tiger Woman,
adapted by Laurence Yep
From Peter's first trip to China in November 2012 when he began to engage Chinese pharmaceutical companies for a regional partnership, to Eric and Peter's recent trip in August 2014 (the former's first) to sign a memorandum of understanding ("MOU") with one of them, Provectus principals have made five trips to China. These also include February, September and December 2013. 

The November 2012 trip comprised introductory meetings with companies of varying size and geographic scope. Subsequent follow-ups with some additional initial get-togethers too, essentially trips in 2013, comprised gradually more serious meetings with a short-list of more interested companies and increasing senior levels of their leadership. These introductions were facilitated by a number of individuals, agents and third parties that included strategic advisory board members, Network 1 Financial, and Maxim Group. Potential partners have interacted with Provectus in the interim via e-mail and phone, and conducted due diligence via the company's electronic data room. The culmination of these efforts and trips resulted in a first MOU for a China regional partnership with two subsidiaries of Sinopharm Group in August.

Generally speaking, an MOU is to a licensing deal or business relationship what a term sheet is to a venture capital investment and a letter of intent ("LOI") is to an acquisition: formalizations and acknowledgements of serious discussions towards the above mentioned ends, frameworks or outlines of business-investment-acquisition terms, conditions, rights, etc., and lists or mentions of other customary and perfunctory ifs, ands or buts.

Provectus noted in their press release:
During the next three months, the parties will seek to enter into a definitive licensing contract, subject to additional negotiation, due diligence, and any required regulatory and corporate approvals. The parties will further address the details of the license; the use of the technology from Provectus to Sinopharm A-THINK in China; the process for commercialization; and payments to Provectus (upfront, milestone and royalties). Provectus intends to manufacture PV-10 in the USA and Sinopharm A-THINK will distribute PV-10 in China. {Underlined emphasis is mine}
I'm reminded of our corporate venture capital process back in the day (our process flow is below), which I believe is a reasonable facsimile of Provectus' process and the process from Sinopharm's perspective in this situation.
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Preliminary analysis/assessment. Prior to Peter's trip, third parties introducers would have pre-submitted information about Provectus, PV-10, summary and previously public information about pre-clinical and clinical data, regulatory interactions, etc. to potential Chinese pharmaceutical company partners for their analysis and assessment, and to gauge any interest to learn more.

Management team meeting(s). The parties would have had an initial meeting, and potentially or eventually other more serious ones.

Due diligence. Although the graph above is linear and discrete in its steps, some actions are undertaken in parallel and are continuous, like due diligence, even after engagement is formalized. The potential licensee-investor-acquirer conducts due diligence in advance of and after the initial management team meeting, and as more meetings are conducted. As Provectus mentioned on several of its conference calls this year, Chinese companies (among others) have visited the electronic data room to review the various different types of documents stored there.

Due diligence of course goes beyond reading introductory collateral material, meeting management, and visiting data rooms. It extends to on-site visits of the business (Provectus), where clinical work is carried out (e.g., St. Luke’s Cancer Network, Moffitt Cancer Center) and with the people carrying this work out (e.g., Dr. Sanjiv Agarwala, M.D., Moffitt personnel), and other relevant and germane people, companies and institutions, and places. I imagine these due diligence activities are to come.

Term sheet negotiations. At some point, interest rises to a level where the parties can discuss price expectations and their associated structure, terms and conditions. If the parties can reach sufficient preliminary consensus they feel could ultimately lead to a transaction (but with no certainty nor obligation [unless they elect to bind themselves] to do so), they enter into or agree to an MOU-term sheet-LOI. As the jargon goes, MOUs are agreed to by the parties, while term sheets and LOIs are extended by one party to the other.

Negotiations of definitive agreements. When continuing due diligence is satisfactorily wrapped up, should the consensus remains the consensus, and if the broad and not so broad strokes of the MOU-term sheet-LOI are conveyed to definitive agreements, a definitive license-investment-purchase agreement may be struck for signing.

Deal closing. Documents are signed. Signatures are swapped. Money, securities, licenses, etc. change hands.

The process.

MOUs can be serious documents, and they can be far from serious. Sometimes also known as "Barney agreements" (i.e., "I love you, you love me") during the dot com era, Internet companies would enter into them with more established companies or other like venture-backed firms in hopes of demonstrating or simply giving the illusion of progress, business value creation, and rationale for increased valuation.

In the past management has garnered license and acquisition interest, in hand or through conversation, but nothing that rose to the level of both seriousness (met price expectations) and tangibleness (was on paper). For example*:
  • Galderma's rumored 2010 interest in Provectus' dermatology business (on paper, but not serious),
  • A Big Pharma's rumored 2011 interest to buy the intralesional drug compound company (not serious, and not on paper),
  • Orbimed and Domain Associates-backed Eddingpharm's rumored 2013 interest to license PV-10 for sale in China and its territories (on paper, but not serious), and
  • The above Big Pharma's rumored 2014 interest to acquire Provectus for twice its 2011 bid (still not serious enough, and still not on paper).
Provectus' MOU with Sinopharm is the first serious commercial interest the company has tangibly garnered. Tangibly serious because (i) it met management's price expectations as translated into potential payments to Provectus (i.e., upfront, milestone and royalties) and (ii) it was on paper.

To what, if anything, will/could the MOU between Provectus and the Sinopharm subsidiaries lead? The easiest way to answer this question of course is to wait and see if/when a license deal transaction is consummated between the parties. In the interim, I look at the situation this way: Provectus agreed to sign a document that formalized their discussions with Sinopharm towards the end of consummating a license deal and business relationship with the Chinese healthcare company under a framework of financial and business terms and conditions that may good to great [for Provectus], and we should know by mid-November or earlier if the parties ultimately do something together.

Finally, I wanted to comment on some of the verbiage in the MOU PR:
The MOU contains customary provisions regarding confidential information, publicity, and intellectual property, and is non-binding upon the parties (except for certain non-material provisions). The MOU shall continue in effect until the earliest of the replacement of the MOU with a definitive agreement, one month prior written notice by either Provectus or Sinopharm, or ninety days from the signing of the MOU.
In order to facilitate my comments, I also provided a sample or model venture capital investment term sheet below, which I utilized during my corporate venture capital investment days.


Click to enlarge. Sample venture capital investment term sheet, page 1.
Click to enlarge. Sample venture capital investment term sheet, page 2.
Click to enlarge. Sample venture capital investment term sheet, page 3.
Click to enlarge. Sample venture capital investment term sheet, page 4.
Click to enlarge. Sample venture capital investment term sheet, page 5.
Click to enlarge. Sample venture capital investment term sheet, page 6.
Click to enlarge. Sample venture capital investment term sheet, page 7. 
Click to enlarge. Sample venture capital investment term sheet, page 8.
Click to enlarge. Sample venture capital investment term sheet, page 9 (of 9).
Provectus' MOU PR naturally did not discuss "price," or payments to Provectus (upfront, milestone and royalties). Management would not have signed an MOU if those elements were neither to their liking nor codified (summarily or specifically) in the document. The first page of a term sheet (i.e., page 1 above) or the first paragraph of an LOI, aside from pleasantries, typically addresses the headline numbers of a prospective deal. I previously have commented on this blog about Provectus' price expectations for a China partnership. One wouldn't have expected the company to detail price agreements with Sinopharm in either the PR or the associated 8-K filing. Additional MOUs maybe forthcoming, and there may be competitive interest. Then again, there may not be dueling interest that pushes price upwards, and I would presume Provectus then would be comfortable with price as outlined in the Sinopharm MOU (with perhaps some further wrangling to finalize agreement on the timing of payments).

The MOU PR discussed "customary provisions regarding confidential information, publicity, and intellectual property," some of which find commonality with the venture capital investment term sheet (i.e., page 7, Confidentiality). Later versions of my terms sheets included sections dealing with publicity, and intellectual property (of the target company) as and when appropriate.

MOUs, term sheets and LOIs are broadly binding (i.e., material and non-material provisions) when the parties agree to be so bound, or when one party wants the other party to be bound and the other party agrees to such binding. Usually, as illustrated by the sample or model term sheet above, these relationship documents generally aren't binding in any meaningful way (to allow an out for either party, but many times the the one wanting to partner, invest or purchase). For non-material binding provisions see page 8, Binding Provisions. For outs, see page 7, Conditions to Closing.

As the MOU PR noted, the term sheet often references the definitive investment (or securities purchase) agreement that replaces the MOU or term sheet. See page 7, Purchase Agreement or page 1, introduction, for example.

Term sheets often include a target closing date (see page 7, Closing Date) by which time the parties hope or seek to complete their negotiations to consummate a transaction (i.e., finalize definitive agreements, sign them, exchange whatever). The parties mutually agree on a timeframe; however, the closing date is not set in stone and can be mutually modified through subsequent revisions to the term sheet (in large part to maintain exclusivity until a transaction is done). Provectus MOU PR noted a ninety-day period, which should be the target or contemplated closing date.

Exclusivity clauses almost always are part of terms sheets and LOIs to provide sufficient timing for the parties (especially the motivated one) to consummate a transaction. They may be part of an MOU in terms of the transaction (i.e., Sinopharm may exclusively negotiate with Provectus until such time as a deal is done, or the parties part ways). I imagine if the MOU had an exclusivity clause, the MOU PR would have mentioned it (not saying anything about it says something too). Exclusivity certainly may be part of the business terms; in this case it is: "Sinopharm-CSIPI and Sinopharm A-THINK desire to obtain an exclusive license to commercialize PV-10 within [the People's Republic of] China territory, and PVCT is willing to grant such license to Sinopharm."

* Listen to Provectus' echo chamber long enough, do some due diligence and, pardon the pun, connect some dots, and you eventually make out what the original voice that started the echo said or meant to convey. And while it doesn't mean a hill of beans if it's not translated into share price, the sound nevertheless is informative and instructive.

August 31, 2014

Potential Catalysts

Potential catalysts through 1Q15 could include:
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Commencing enrollment of its pivotal late-stage trial for melanoma (locally advanced unresectable/unresected cutaneous melanoma) is a key milestone and important catalyst for Provectus because the eventual outcome should provide clarity about the prospects for PV-10's regulatory validation (i.e., the drug's initial pathway to approval).

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

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

August 22, 2014

Notepad

1. DAMPs. Following up on my Damage-Associated Molecular Patterns, and Immunogenic Cell Death (August 21, 2014) news item, I'm curious (fascinated) by PV-10's potential role in immunogenic cell death, and thus the release and surface expression of damage-associated molecular patterns ("DAMPs"). DAMPs "..link the dying tumor cell with innate immunity, culminating in adaptive anticancer memory responses."

The recent paper by Panzarini et al. (2014), Rose Bengal Acetate PhotoDynamic Therapy (RBAc-PDT) Induces Exposure and Release of Damage-Associated Molecular Patterns (DAMPs) in Human HeLa Cells, observed that key DAMPs -- ATP, HSP70, HSP90, HMGB1 and CRT -- were exposed and/or released after treatment of cell lines with Rose Bengal acetate and photodynamic therapy. I understand this work involved using PDT and a functional RB derivative, and was carried out on cell lines; however, what interests me about it is the study's goal, which was to determine if RB could trigger apoptosis and autophagy -- cell death -- and thus expose and/or release pivotal DAMPs.

Very interestingly, in my view, the researchers also noted their data represented the fourth demonstration of the exposure of the HSP90 DAMP by indication and third demonstration by drug compound: "In fact, exposure of HSP90 was shown only in lung cancer [36] and myeloma [37] treated with Bortezomib and in bladder cancer cells treated with capsaicin [38]." Bortezomib is a proteasome inhibitor (Millennium Pharmaceuticals [Velcade]/Venus Remedies [Cytomib]). Capsaicin is a neurotoxin and active component of chili peppers.

Moffitt previously showed PV-10 (Rose Bengal) in their murine model work released HMGB1.

2. Innate and Adaptive Immunity. As I wrote above, DAMPs, or their impact once exposed and/or released, form a bridge between the body's innate and adaptive immune systems (or non-specific and specific, respectively). See my blog post PV-10 is not bigger than Mother Nature for a discussion of the immune system; "The immune system protects organisms from infection with layered defenses of increasing specificity."

In 1994, "[t]wo papers appearing in the same year presaged the deeper understanding of innate immune reactivity, dictating the subsequent nature of the adaptive immune response. The first...speculated...free radical-mediated reperfusion injury-was seen to contribute to the process of innate and subsequent adaptive immune responses. The second...suggested the possibility that the immune system detected "danger", through a series of what we would now call damage associated molecular pattern molecules (DAMPs), working in concert with both positive and negative signals derived from other tissues." {Underlined emphasis is mine}
  • Land W, Schneeberger H, Schleibner S, et al. (January 1994). "The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants." Transplantation 57 (2): 211–7.
  • Matzinger P (1994). "Tolerance, danger, and the extended family." Annu. Rev. Immunol. 12: 991–1045.
I've written that PV-10 harnesses the immune system, rather than restraining, blocking, manipulating, etc. parts of it. Note that Chen & Mellman (2013) title step 3 of their cancer immunity cycle illustration "Priming and activation." {Underlined emphasis is mine}

3. It's A Small World. The authors of the RBa-PDT paper come from Italy's University of Salento, and do not appear to have any disclosures related to Provectus. While the company has engaged certain principal investigators and their respective hospitals in Australia and the United States, as well as Moffitt Cancer Center, there is a body of work from researchers espousing Rose Bengal's potential as a cancer therapeutic who are currently or not at all unaffiliated (or appear to be unaffiliated) with the company. They are, among others (representative papers below):
4. Amgen's talimogene laherparepvec ("T-Vec"). Related to Amgen's T-Vec, the FDA announced a November 6th advisory committee ("AdComm") meeting (Cellular, Tissue and Gene Therapies Advisory Committee) to discuss the draft guidance for industry entitled "Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products." Does this bode well or poorly for T-Vec in regards to its ease of administration and use, or lack thereof?

5. Info. An interview with Peter formed the basis for today's Seeking Alpha article Provectus' Latest Developments Spark Investor Interest -- CFO/COO Culpepper Explains Why. Of note to me was his answer to the interviewer's question "What is the anticipated market trajectory for PV-10?"
Peter: "We anticipate PV-10 phase 3 for melanoma to be one path for PV-10 approval. We anticipate also combining PV-10 to treat patients with disease inaccessible to direct injections. We also anticipate treating primary liver cancer patients in an upcoming randomized phase 2 study and seeking an expedited approval path in that important indication as well."
Taking this response at face value would suggest the upcoming (anticipated) liver Phase 2 trial would be for primary liver cancer (hepatocellular carcinoma), and not include cancers metastatic to the liver. A subsequent or concurrent study might examine this aspect of liver cancer, but the contemplated Phase 2 trial would not, or so it seems to me. Liver cancer of course is a very large unmet need in Asia. One would hope Eric garnered the feedback he required [from his recent Asia trip] to finalize and file the liver Phase 2 trial protocol.

August 17, 2014

Immune Surveillance

Following up on my Juxtaposition blog post, there is the potential for a melanoma combination therapy Phase 1 (or 1b)/2 trial of PV-10 and a checkpoint inhibitor, which management briefly discussed on their 2Q14 conference call.
Eric: As Pete mentioned earlier, we're also looking beyond single-agent therapy with PV-10 to address the needs of patients with more extensive disease, particularly those with visceral tumors that are not injectable. One attractive and complementary approach may be to combine PV-10 with a systemic immunotherapy, such as an immune checkpoint protein inhibitor. Immune checkpoint protein inhibitors, such as anti-CTLA4, anti-PD-1, and anti-PD-L1 agents, are an important advance in the treatment of melanoma and other cancers, another subject of intense development in our industry. 
However, while these drugs represent an important step forward, like any drug they are not perfect and they might be improved. As was clearly presented by the medical oncology community earlier this summer at ASCO, using an agent like PV-10 to prime the immune system could be synergistic in combination with such a systemic agent. 
Our patent application on this strategy was published in 2012 and we've been vigorous by pursuing this approach since. The nonclinical research we first presented at the Society for Immunotherapy of Cancer Annual Meeting in 2012, together with ongoing translational clinical research on PV-10's mechanism of action that we were sponsoring at Moffitt Cancer Center and our own Phase 2 data, provide a rationale for combination testing of PV-10. 
This development track, separate from the Phase 3 study I discussed earlier, could represent a path forward for patients with significant disease burden not amenable to intralesional injection, and is a possible candidate for co-development with one or more pharmaceutical or biotech companies. {Underlined emphasis is mine}
Eric wouldn't insert statements about this topic into his comments until and unless at least minimally substantive progress has been made towards this end. He first addressed a combination study via St. Luke’s Cancer Center and Temple University's and principal investigator Dr. Sanjiv Agarwala, M.D.'s presentation at the 10th European Association of Dermato-Oncology (EADO) congress in May ("Commencement of combination studies in Stage IV disease in second half of 2014"). The reality of a combination study/trial probably is dependent on the partnering pharmaceutical company's, the one with the checkpoint protein inhibitor to be combined with PV-10, interest in and willingness to:
  • At a minimum, run and shoulder the cost of a trial, aside from Provectus's minimal expense to provide PV-10 drug product,
  • At a minimum (more than likely) make a one-time payment to Provectus, such as was the case in Bristol-Meyers' collaboration with Celldex Therapeutics, and
  • Forego meaningful rights of first somethings, unless the partner fully compensates Provectus for this ask.
I summarized a number of previously announced and/or conducted combination studies in my Combinations (July 24, 2014) news items under the blog's News tab.
Click to enlarge.
Click to enlarge.
Although Provectus management has understood and communicated the potential for combination therapy involving PV-10 for the treatment of metastatic melanoma, noting this on the 2Q14 conference call (i.e., the Provectus-Pfizer patent application, the SITC 2012 poster presentation), they historically have not prioritized this potential regulatory pathway, and have been disinterested in and unwilling to allocate resources to conduct a typical combination study where companies share trial costs and the "non-CTLA-4/PD-1" (i.e., non-Bristol-Myers or Merck) partner conducts (sponsors) the trial.

There is no certainty a trial comes together, but it would appear Provectus is engaged in the kind of basic or fundamental conversations, data sharing and expectation setting necessary to contemplate a combination study and develop the associated relationship between the parties involved.

The consensus of melanoma key opinion leaders appears to be that “[t]he future lies in combinational approaches with drugs from the new melanoma landscape” (e.g., intralesional therapies, BRAF inhibitors, ipilimumab, anti-PD-1 antibodies). Moffitt Cancer Center's pre-clinical work combining PV-10 with other approved and investigational immunotherapeutic agents more than likely would be, and would have to be, the driving force behind any clinical combination study focused on metastatic melanoma patients with visceral disease (i.e., Stage IV M1b-c). The cancer center already has alluded to the completion and results of this pre-clinical work, which should form the rationale for a future clinical trial or trials, at ASCO 2014 by concluding "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma," and again at the 4th European Post-Chicago Melanoma & Skin Cancer Meeting 2014 by concluding "[p]reclinical data suggest PV-10 would be a good candidate to evaluate in conjunction with available systemic therapies and new agents in development."

I previously wrote about historical pre-clinical and some clinical work on PV-10 in combination with other treatments (systemic chemotherapy [pre-clinical], systemic immunotherapy [pre-clinical], radiotherapy [clinical]) in my "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma" blog post.

A potential clinical trial combining PV-10 with a checkpoint inhibitor should be viewed in the context of other clinical trials and studies Provectus expects  hopes to commence in 2014 and/or 2015:
  • Melanoma, PV-10: Phase 3 trial, locally advanced unresectable/unresected cutaneous melanoma, 2H2014,
  • Dermatology, PH-10: Phase 1 trial, mechanism of action/feasibility study, 2H2014 (my estimate),
  • Liver cancer, PV-10: Phase 2/3 trial, locally advanced, unresectable/unresected liver cancer (my speculation of the trial title), 1H2015 (my estimate); the trial also should include liver tumors caused by primary non-liver cancers (i.e., cancers metastatic to the liver), and
I do not believe a deal between Provectus and a pharmaceutical company (and its checkpoint inhibitor), the first step towards an eventual clinical trial, would be consummated until Moffitt's preclinical combination study data is more broadly communicated. Meaning, neither Bristol-Myers nor Merck, for example, would even contemplate acceding to Provectus deal expectations until and unless Moffitt substantiates their above mentioned conclusions with very compelling data (i.e., together PV-10 makes your drug much better than your drug alone).

I think the venue for the cancer center's communication will be the 29th Annual Meeting of the Society of Immunotherapy for Cancer, November 6-9, 2014. Provectus first addressed combination treatment at the 2012 annual SITC meeting concluding the co-administration of PV-10 immuno-chemoablation with other systemic therapy could yield potent synergy in uninjected tumors.

But, more than just the pre-clinical drug combination study results, I also am very interested in other aspects of Moffitt's work, and Dr. Jeffrey Weber, M.D., Ph.D.'s comprehensive views on the utility and use of PV-10.

First, what is the basis for Weber's comment "PV-10 might offer the perfect way to prime the immune system?" Dr. Weber has said (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.

Second, what is PV-10's role and participation in each step of the cancer immunity cycle (Chen & Mellman, 2013)? Under the blog's PV-10, and the Cancer Immunity Cycle tab I illustrate PV-10's involvement in steps 1 (release of cancer cell antigens), 2 (cancer antigen presentation), 3 (priming and activation) and 7 (killing of cancer cells). And although Dr. Weber has said (paraphrasing) one should prioritize which steps are the most important (presumably in order to determine how to utilize what agents in combination and why; for example, impacting on endothelial cells have been less promising as a therapeutic than many of the other steps), I'd like to understand Moffitt's view on PV-10's involvement in steps 4 (trafficking of T cells to tumors), 5 (infiltration of T cells into tumors) and 6 (recognition of cancer cells by T cells).

And third, what are Weber's thoughts about PV-10 in the context of or in regards to immune surveillance? Immune surveillance theory is:
The concept that the immune system protects the host against cancer was first posited by Ehrlich in 1909 (1) and modified in the 1950s by Burnet and Thomas (2, 3), who proposed that it was instrumental in eliminating precancerous or cancerous cells, through a “surveillance” function. However, the concept fell out of favor when studies in the 1980s indicated that tumors failed to develop more rapidly in nude mice (which lack T cells and B cells, but not NK cells) than in wild-type mice. It was resurrected in the 1990s, when a body of evidence emerged indicating that immunodeficient mice were at greater risk for spontaneous tumor development (4). These studies led to further refinement of the theory, now referred to as “cancer immunoediting,” encompassing three phases: elimination, equilibrium, and escape. (J Clin Invest. 2007;117(5):1130–1136. doi:10.1172/JCI32136)
In a February article of The American Journal of Managed Care, Weber said:
"Well, the Holy Grail of cancer immunology is to create a cancer vaccine. Provenge was the first and only cancer vaccine that was ever approved. But that is truly the mantra, that is, the immune system is the ultimate way to perform targeted therapy. So immunotherapy is targeted therapy, and its hallmark is memory." {Underlined emphasis is mine} 
And: "There are certainly data to suggest that this idea of immune surveillance is indeed valid. On the other hand, people on immunosuppressants don’t always present with 30 different types of solid tumors. Transplant patients often develop squamous skin cancers, especially virally related squamous skin cancers. So there are data to suggest that we always have immune surveillance to prevent cancer from developing." 
And: "You can divide immunotherapies into 4 or 5 categories: these include chemicals like cytokines; antibodies…cells, which are not really well developed; vaccines, which is always the Holy Grail to try to vaccinate someone against his or her own cancer. You’ve got 1 approved vaccine. One of the antibodies, which are the most exciting and promising, is approved. That’s ipilimumab, the anti-CTLA4 antibody. In terms of the cytokines, in 1996 and 1998 IL-2, interleukin-2, was approved for kidney cancer and for melanoma. The cell therapy is immature, and you will hear a lot more about the antibodies coming up in the next couple of years." {Underlined emphasis is mine} 
Recall that Moffitt said, following their initial murine model work, that:
"These murine studies confirm that PV-10 chemoablation results in both a direct effect on injected lesions as well as a systemic response that leads to regression of uninjected subcutaneous and lung lesions. Intralesional PV-10 treatment leads to the induction of tumor-specific immunity." (AACR 2013) {Underlined emphasis is mine} 
And that Provectus concluded at SITC 2012, by virtue of murine model work:
Chemoablation with PV-10 results in the induction of tumor-specific immunity. Immunodeficient mice exhibited no anti-tumor effect on re-challenge. Adoptive transfer of immunity only occurred following chemoablation in donor mice. Tumor-specific, long-term immunity and adoptive transfer implicate immune cell mediation. This immuno-chemoablative response to PV-10 is tantamount to “in situ vaccination.” (SITC 2012) {Underlined emphasis is mine} 

          August 10, 2014

          Juxtaposition

          Provectus held its second quarter conference call on Thursday. A transcript is here. Some of my initial takeaways are below. I open, however, with a brief aside about at least two indications on which management thinks it may commence trials in 2H14.

          Locally advanced, unresectable (unresected) cutaneous melanoma, the subject of a Phase 3 trial, does not kill you. Its spread, however, eventually does. Putting it perhaps too simplistically, the tumor on your skin may not immediately kill you; however, its unchecked or unsuccessfully treated spread should at some point. It is the nature of the indication, melanoma's virulence and subsequent metastasis, that presumably has created seemingly idealogical differences and skepticisms over using local agents and therapies to treat what otherwise is considered a systemic disease.

          On the other hand, locally advanced unresectable (unresected) liver cancer, the subject of what should be a Phase 2 randomized control trial ("RCT"), can kill you. Simplistically, the tumor on your liver may or probably will kill you before its spread does. Perhaps also too simplistically, the spread of a primary (non-hepatocellular carcinoma, or non-HCC) cancer to the liver (i.e., a cancer metastatic to the liver) probably kills you faster than the primary cancer in its non-liver location. Using local agents and therapies (i.e., ablation therapies) is much more easily accepted.

          PV-10's initial pathway to approval, using it to treat locally advanced, unresectable cutaneous melanoma, recognizes an alternative way, with this particular compound, to treat melanoma: stop its spread. A subsequent pathway would be to explore PV-10's role in combination with a checkpoint protein inhibitor (as an immune system primer and activator) to, after melanoma has spread, defeat its metastasis. It would seem that as much as PV-10's rapid local ablative properties are of interest to certain parts of the medical community, its potentially robust immunological properties are of greater interest to other parts.

          Expanding PV-10's opportunities for approval, this time using it to treat locally advanced, unresectable liver cancer is more straightforward, more acceptable, and more understandable in its benefit. Injecting PV-10 into a tumor on the liver to make it go away would seem much more of a victory to some than injecting the drug into a melanoma tumor on the skin to make it also go away. As a result, PV-10's immunologic benefit would seem to some (and I make a very thin straw-man argument here) greater or more important for melanoma than for liver cancer, even if PV-10 injection in a tumor on the liver metastasized from another primary cancer demonstrates regression or remission of this cancer from whence it came.

          Process similarities between the two indications (and hoped for/sought after labels) of locally advanced, unresectable cutaneous melanoma and locally advanced, unresectable liver cancer include working with the FDA's Division of Oncology Products 2 ("DOP2") and, as Eric noted:
          Any combination studies in the liver are likely to follow similar development strategies to those outlined earlier for melanoma and rely on much of the same foundational science.
          A. Melanoma Phase 3 Trial (PV-10)

          When will the trial protocol be filed, and when could the trial start? On the conference call Eric said:
          We've indicated previously that we plan to commence the study this year and this work is allowing us to put the finishing touches on the protocol before it undergoes final review in the next few weeks by key melanoma investigators and consultants in clinical operations and regulatory affairs. 
          And: As I outlined in my earlier comments, we're working to address both long-term and recent guidance from the agency, and particularly the recent guidance provided via our interactions with the agency since December concerning the relevance of symptom assessment in our patient population, those patients with locally advanced cutaneous melanoma. We're working with leading partners in this area to finalize this aspect of our study design and expect to send our protocol out for review by our team of CROs, regulatory consultants and investigators in coming weeks. 
          And: So to reiterate, we expect to commence the Phase 3 melanoma study by the end of the year, including filing the protocol with the agency and starting patient enrollment at sites already using PV-10 under our expanded access protocol.
          I previously initially assumed (projected) a September start to the trial and a partial quarter of recruitment, enrollment and treatment ("accrual"), with a full 4Q14 quarter of accrual in my July 10th 2014 Annual CEO Letter (pt. 1) blog post. Later I revised this to an end of September start, and thus assumed a full 4Q14 quarter of accrual in my July 31st MD Anderson, More Cash, Checkpoint Protein Inhibitor Combinations blog post. There is the risk of "trial start creep," perhaps similar or analogous to the creep in the company's pursuit of a special protocol assessment ("SPA") for a pivotal melanoma Phase 3 trial. Is it different this time, or is it the same?

          I think it's different because with the SPA Eric said, finally and beginning with the May 23rd conference call, he did not have (i.e., was not in agreement with the FDA on) the right patient population for the trial (i.e., the right indication), the right endpoints, and the right drug supply. "Right" means high likelihood of trial success:
          Click to enlarge. June 19th conference call
          Whereas, presumably now, he does have it right: the right patient population (no uninjectable disease; i.e., akin to the all lesions treated sub-group of the Phase 2 trial), the right endpoints, and sufficient modernized drug supply.

          Eric still is finalizing the Phase 3 protocol because he hasn't completed one piece of it (or is putting "the finishing touches" on it): the third secondary endpoint of Patient Reported Outcomes ("PROs") to assess impact on lesion pain and other skin symptoms:
          Furthermore, our endpoints with complete response rate should allow us to highlight one of the key features of PV-10, and we'll measure patient reported outcomes to better characterize the relationship between complete response and symptoms of locally advanced cutaneous melanoma, such as pain and bleeding. 
          We're working with several leading CROs with specialized expertise in the assessment of patient reported outcomes to show that our planned assessments are rock-solid. This is an important but complex topic and the experience of these expert groups is allowing us to put into place the final missing pieces of our protocol. 
          And: So to summarize so far, we are finalizing the process of combining our expertise gained from years of clinical testing of PV-10, inputs from meetings with our scientific advisors, investigators and advocates in the field, and design input from multiple CROs having specialized expertise in key areas such as assessment of patient reported outcomes, radiologic and clinical image management, bio-statistics, clinical data management, and so on, to ensure that we have a robust protocol that can address the needs of licensure. 
          We are also adopting, to the extent possible, important design elements from successful pivotal trials of other drugs recently approved in melanoma and other cancers that address issues pertinent to pivotal testing in PV-10. These include details on scheduling of response assessments, handling of issues pertinent to our comparative drugs, and the collection and interpretation of patient reported outcome. {Bold and/or underlined emphasis is mine}
          It's clear (at least to me) Eric feels he can adequately predict the outcome of the Phase 3 trial for the primary and first two secondary endpoints of progression free survival ("PFS"), complete response [rate] ("CR") and overall survival ("OR").
          I can't really speculate on what effect size we anticipate seeing in Phase 3. Classically, there is a phenomena of effect size compression and the effect of the drug is smaller progressing from Phase 1 to Phase 2 and then again from Phase 2 to Phase 3. We've seen the opposite so far going from Phase 1 to Phase 2. I don't know if that is necessarily going to be a continuing trend, but it certainly is directionally favorable. We will be using fully conforming RECIST assessments in the Phase 3 study versus modified RECIST assessment. So, really it's not directly comparable. 
          Having said, we do expect to see a very high rate of complete response consistent with the patients in the Phase 3 study where we treated all in existing disease, we'll be treating all existing disease in our Phase 3 patients and so we can use that group from Phase 2 as a model. {Underlined emphasis is mine.}
          Company and investigator medical conference presentations over time periodically present and discuss various response and survival results: objective response (and components: CR, partial response, stable disease), PFS, OS, disease specific survival ("DSS"), etc. (although the presented data should be a fraction of the total, frustrating, secretive, and most assuredly intellectually inconsistent in the founders' thinking as it is). This means, in my view, that Eric believes he can adequately predict the trial's outcome, and more than reasonably project or "guess" the mean/median and confidence intervals of the primary endpoint PFS and secondary endpoints CR and OS of patients in the PV-10 arm should beat statistically significantly/not overlap those of the patients in the comparator (systemic chemotherapy dacarbazine) arm.

          What remains, or what may have recently been completed, could be assuring the approach to PRO assessments are "rock-solid." Eric's comment of "We are also adopting, to the extent possible, important design elements from successful pivotal trials of other drugs recently approved in melanoma and other cancers that address issues pertinent to pivotal testing in PV-10" likely refers to, for example, the use of the Skindex survey Genentech used in vismodegib trials and approval for locally advanced or metastatic basal cell carcinoma.

          The timing of the filing of the Phase 3 protocol, and thus the commencement of the trial itself, may be as early as after its "final review in the next few weeks by key melanoma investigators and consultants in clinical operations and regulatory affairs," or having observed Eric's process over time, meticulous, deliberate and seemingly lacking in urgency as it may appear, filing and enrollment could occur later than I previously assumed (e.g., September, end-of-September). For now, I'll stick with the end of September until such time as I have to revise my viewpoint.

          When the trial starts v. How the trial ends. Loosely speaking (writing), I don't think Eric cares as much about when the trial starts as he does about whether he can adequately predict the outcome of the trial, and thus how (and when) the trial ends or could end.

          B. Liver Phase 2 trial (PV-10)

          Getting to a deal in China (or India), let alone closing one, should be a function of or tied to finalizing, and thus filing, a Phase 2 trial protocol for a presumably pivotal RCT:
          Peter: This is a gray topic and we are actively discussing with potential partners in both India and China in particular when to enter into a transaction, but I think conservatively it does make sense for a protocol for both melanoma and liver that's appropriate for those respective countries to be in place prior to at least a transaction be consummated. It's possible that MoU could be signed in advance, but conservatively I think it makes sense for say you as an investor, Dr. Gollum, or any to see that protocol filed on clinicaltrials.gov and then you could make a logical assumption from there, once the Phase 3 melanoma study or the Phase 2 liver that Eric touched on has been filed, that that makes sense for potential global partner or geographic partners. Eric can comment.
          Like the final piece of getting to a final melanoma Phase 3 protocol is addressing possibly the last piece of PRO assessment, the final piece of getting to a final liver Phase 2 protocol probably is addressing the respective liver cancer needs of geographic populations:
          Eric: Follow-up of our initial patients at one or more conferences and in the literature in coming months, and we're assessing strategies to accelerate transition to Phase 2 testing in a randomized controlled trail, either alone or in combination with systemic therapy. Any combination studies in the liver are likely to follow similar development strategies to those outlined earlier for melanoma and rely on much of the same foundational science.
          And: As the CTO, I cover both clinical development and intellectual property portfolio of the Company and I'll point out that in those sorts of scenarios, it's almost certain any protocol that we entered into in Asia would be an international protocol because there are certain implications of a single country of protocol and intellectual property rights. So, you can expect that that would be one of the aspects of such protocol.
          For example, the final piece needed to fall in place might be deciding, in advance consultation with key liver cancer investigators and consultants in clinical operations and regulatory affairs (prior to his trip) as well as with prospective geographic partners (during it), whether to (i) compare sorafenib and sorafenib + PV-10 with separate American/Western European and Asian cohorts because of different etiologies, or (ii) undertake a "Western" study of PV-10 in combination with systemic therapy (sorafenib) and an "Eastern" study of PV-10 versus an ablation therapy (like percutaneous ethanol injection). I imagine Eric should return from his trip next week to China with, I hope, sufficient and final perspective on how to complete and file the design of the Phase 2 trial upon his return and after reviewing it with his team of investigators and consultants.

          I'll address the PH-10 mechanism of action study and a potential melanoma combination therapy Phase 1 (or 1b)/2 trial involving PV-10 and a checkpoint inhibitor in a subsequent blog post or news item.

          July 31, 2014

          MD Anderson, More Cash, Checkpoint Protein Inhibitor Combinations

          MD Anderson surgical oncologist and Provectus principal investigator Dr. Merrick Ross' paper Intralesional therapy with PV-10 (Rose Bengal) for in-transit melanoma, published in peer-reviewed Journal of Surgical Oncology, was made broadly available by the company today.
          Abstract: Rose Bengal is a novel injectable agent that has been evaluated as a rational treatment strategy for melanoma patients with recurrent unresectable local/regional metastases accessible for intralesional injection. PV-10 (10% Rose Bengal) has completed phase 1 and phase 2 multi-center clinical trials demonstrating significant local/regional disease control and also responses in non-injected regional bystander lesions and distant metastases. The published results of studies that have assessed PV-10 are presented, and the rationale for combining its use with recently approved immunotherapeutic agents is discussed.
          See the link to the paper here. The digital version provided by Provectus on its website reached the maximum number of users/views allowed (i.e., too many views), however. The company will have to up this number for more folks to read it. I discussed the paper when it was first published online; see blog news item Journal Publication (February 11, 2014) under the Archived News tab.

          A blog reader further highlighted his takeaways from Ross' paper:
          • "In addition to an excellent safety profile, encouraging results were observed, including effective local tumor ablation, bystander responses in un‐injected lesions, and unexpectedly prolonged delays in disease progression, particularly in patients who were observed to have local tumor destruction. These latter observations suggested an induced systemic immune response elicited by the tumor ablation."
          • "These observations suggest that tumor necrosis may lead to a robust specific anti‐tumor host immune response. The effects of released tumor antigens on nearby antigen presenting cells may facilitate the presentation of specific antigenic targets to circulating T and B cells. The potential for chemokine release and local inflammation in response to granulocyte destruction may enhance the host response. Interestingly, spontaneous involution of untreated tumors was observed in a mouse hepatocellular homograft model and closely correlated with effective ablation of injected target tumors. These observations support the induction of a tumor‐specific host immune response."
          • "Furthermore, unexpected long‐term survival was observed in the patients achieving a response compared to similarly staged patients receiving other therapeutic modalities. These observations strongly support the concept that effective tumor ablation can elicit an effective anti‐tumor systemic response."
          • "Because of easy access to the local/regional disease, intralesional agents have been studied, but only recently with the rigor of formal prospective trials. IL PV‐10, is well tolerated, easy to administer, and based on Phase 1 and 2 data has an established and excellent safety profile, and results in meaningful responses in injected lesions and untreated bystander lesions. IL PV‐10 compares favorably with the published experience with the vast majority of other injectable agents in terms of side effects and local disease control."
          I also add:
          Further study of PV‐10 is certainly warranted either in the context of a phase 3 trial, or as a phase 1/2 study in combination with the checkpoint blocking agents or vaccines. The goal of these phase1/2 trials would be to document the safety of these novel combinations and demonstrate enhanced local/regional response and disease control as well as an augmentation of the systemic anti‐tumor responses. The success of such trials would further advance the melanoma treatment landscape.
          Dr. Ross has been involved with the company for several years, and MD Anderson has been a compassionate use program ("CUP") site on and off since about 2009. Interestingly, it only was since March 2014 (around the time Provectus announced it had submitted its breakthrough therapy designation application ["BTD"]) that the cancer center was named a CUP site on clinicaltrials.gov. See my blog post Provectus Submits Application to FDA for Breakthrough Therapy Designation. As I noted in blog news item Various (July 30, 2014)MD Anderson noted Provectus' CUP in its August 2014 Melanoma Horizons newsletter, following ASCO 2014 and BTD denial.

          Per my blog news item Provectus increases cash balance (July 31, 2014) it would appear the company has increased the amount of cash on its balance sheet, by virtue [I believe] of management writing "Cash on hand supports planned operations until 2016" (rather than its previous comment as late as July 28th of "Cash on hand supports planned operations until 2015"). In my blog post 2014 Annual CEO Letter (pt. 1) I wrote:
          Without consideration of the melanoma Phase 3 trial, the projected cash balance should look something like the below. At a projected $2.5 million average quarterly burn, Provectus would approach its accounting firm BDO LLC's minimum cash threshold figure of about $4 million in the 4Q15 timeframe (potential fund raising would occur before that so the threshold is not met of course).
          Click to enlarge.
          We should find out the source of the additional cash (I assume quarterly burn rate guidance has not changed of course) during the company's quarterly earnings conference call on August 7th. I speculate it originates from executive compensation repayment; however, the question is whether ~$4.5 million or $9 million was repaid. A lower projected burn rate (ex-pivotal melanoma Phase 3 trial expenses) than the $2.5 million quarterly figure [in order to compare apples-to-apples above] also could allow for the change in the corporate website presentation cash burn message (i.e., until 2015) without an increase in cash on hand. In blog news item Revisiting Cash On Hand (July 15, 2014) I wrote:
          Provectus' June 12th 8-K detailing the settlement of the shareholder derivative lawsuit noted a date of July 24th for a hearing on the terms of the proposed settlement. Depending on how much is paid back by management (i.e., ~$4.5 million or ~$9 million), the additional cash should provide further runway for the company to reach the trial's interim readout and make its case to the Agency for filing the NDA. Below, for example, I assume these monies are paid back in 3Q14. Without consideration of the melanoma Phase 3 trial, the projected cash balance would look something like the below. At a projected $2.5 million average quarterly burn, Provectus would approach its accounting firm BDO LLC's minimum cash threshold figure of about $4 million in the 1Q16 timeframe, assuming repayment of the lower amount (the higher payment obviously provides at least an additional quarter of runway).
          Click to enlarge.
          With combining oncology drugs all the rage in 2014, FierceBiotech's John Caroll wrote this week in his article Immuno-oncology partnering-palooza continues with Genentech, AstraZeneca deals:
          "AstraZeneca has managed to be included in the pioneering group of players working on immune checkpoint inhibitors, which prominently features competing teams from Bristol-Myers Squibb ($BMS) (nivolumab), Merck ($MRK) (pembrolizumab) and Roche ($RHHBY) (the rival PD-L1 drug MPDL3280A.) Merck has been the leader in the partnering arena, executing a long lineup of collaborations. But all the players see combo treatments as the big second wave in R&D, with immuno-oncology treatments dismantling the protective screen cancer cells use to hide from the immune system and other drugs spurring an attack."
          Where is Provectus and PV-10 in this partnering-palooza? Management's plan A was and still is to pursue a monotherapy path for PV-10, which finally appears to be unresectable locally advanced cutaneous melanoma for which I think the Phase 3 trial should commence enrollment at the end of September.

          The plan B path to approval, albeit a very reticent one in the past, was to allow PV-10 to be combined with checkpoint inhibitors, initially anti-CTLA-4 agents (early on tremelimumab before it was out-licensed by Pfizer to AstraZeneca/MedImmune in 2011, later following approval ipilimumab) but now anti-PD-1 agents (at the moment both Bristol-Myers' nivolumab and Merck's pembrolizumab). Moffitt Cancer Center as recently as ASCO 2014 said/wrote in/on their PV-10-related abstract/poster: "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma." Moffitt later repeated the statement at a presentation during the 4th European Post-Chicago Melanoma Meeting: Interdisciplinary Global Conference on News in Melanoma. One of management's reservations has been paying for or materially contributing to the expense of such a combination study. The checkpoint inhibitors range in cost from $100,000 to over $200,000; see my blog news item % CR per thousand dollars of treatment cost (February 6, 2014) under the blog's Archived News tab. The total cost of treatment for several treatment courses over whatever prescribed time period for a combination study would be much more (the above costs are for a single course). There also are investigator, site and other customary costs of running a trial. If management were to agree to combine PV-10 with, say, nivolumab or pembrolizumab, they presumably would require (unless their current stance is materially different from their historical one) the partner to pay for most if not all of the study's cost save for Provectus' contribution of PV-10 drug product.

          Moffitt's Dr. Jeffrey Weber, M.D., Ph.D. is a notable proponent of combination therapy (quotes below are from a December 2013 interview/article):
          • "If you use [BRAF drugs] sequentially, it isn’t as good as using them in combination. The way to deal with metastatic melanoma is to hit it hard upfront rather than treat them, wait for resistance, then try to overcome resistance. So the best way to approach treatment is to hit them hard, hit them quick, and hit them often. Melanoma is a difficult disease, and backing off is a sure-fire way to not benefit the patient."
          • "I think community oncologists should also consider patients for combination BRAF inhibitor trials—not just treat them on vemurafenib, but consider them for a trial of combination therapy. The combination therapies are all investigational, of course. You can always treat someone with vemurafenib, but they are almost always going to progress. So why not try to do something where they may not progress? And I would send patients for combination ipilimumab/PD-1 trials, because it turns out that the combination, despite a fair amount of toxicity, has a very impressive response rate. Many patients become complete responders, which is very encouraging. I think there are many good combination therapy trials under way, as well as trials with adoptive cell therapy, that look very promising to me."
          • "If you combine blocking of CTLA-4 in the mouse with some sort of vaccine strategy, tumors could be cured. In fact this was seen in some tumors that otherwise were very difficult to treat in the mouse model. This was studied around 2001, and initial studies were at the National Institutes of Health and in Los Angeles, where I was at the time."
          I think the "tough" part of any combination study is to finalize the sequencing of PV-10 and the partnered checkpoint inhibitor. I wrote about likely combinations in my blog post Combinations & Permutations, Sequencing. Weber's important Big Pharma relationships include Bristol Myers and Merck. For combination study relationships to be struck with Provectus for PV-10, I would presume Moffitt's pre-clinical work on combining the drug with checkpoint protein inhibitors will have to be front and center, Dr. Weber and Moffitt will have to play a key (primary) role in carrying the work out, there would have to be strong interest on the part of prospective partners, and small or little expense would have to be incurred by Provectus.

          July 26, 2014

          Combinations & Permutations, Sequencing

          Provectus' upcoming, presumably pivotal, Phase 3 trial for unresectable, locally advanced cutaneous melanoma is a potential pathway to approval for PV-10. Management noted in their July 8th annual CEO letter that: "Our development plans for PV-10 stem from the results of our phase 2 study. In that trial, tumors were no longer detectable in 50% of patients with locally advanced cutaneous melanoma who had all of their existing lesions injected. Results from these patients support the potential of PV-10 as a single agent, and provide rationale for a phase 3 randomized controlled trial in patients with unresectable, locally advanced cutaneous melanoma."

          Management went on to write: "Provectus is not alone in advocating for an intralesional approach in the treatment of cancer. For melanoma patients with recurrent or in-transit disease confined to their skin this approach has been used to treat patients for many years, as evidenced by guidelines published by the National Comprehensive Cancer Network (NCCN Guidelines®) defining the standard of care for cancer treatment in the United States. Intralesional injection with BCG and certain immunomodulatory agents, local ablation, topical therapy for superficial lesions and regional radiotherapy are consensus interventions for these patients, while systemic therapy remains an option and participation in a clinical trial is the preferred option. We believe that, in this context, PV-10 is well positioned to show superiority in phase 3 testing as a single agent."

          Click to enlarge.
          Percent of Cases by Stage at Diagnosis: Melanoma of the Skin
          According to the Melanoma Research Foundation, "[m]elanoma that occurs on the skin, called cutaneous melanoma, is the most common type of melanoma." The Phase 3 trial should enroll primarily or exclusively Stage IIIB and IIIC melanoma patients, where the goal, for this patient population, is to clearly demonstrate PV-10's superiority to consensus and other interventions. PV-10, however, is applicable to localized and regional melanoma (i.e., earlier stages), where in due course the drug should demonstrate superiority to surgery and other appropriately suggested interventions. PV-10's sparing of tissue -- injected tumors (i.e., diseased tissue) go away, but healthy tissue is spared -- together with its efficacy should provide a compelling value proposition and alternative to surgery. Localized and regional melanoma, according to the National Cancer Institute, represents 90-95% of melanoma of the skin cases by stage. First and foremost, however, the contemplated Phase 3 trial must be run and the initial pathway to approval achieved.

          Beneficial options for patients with distant or metastasized cancer -- in this case, metastatic melanoma -- have dramatically increased in number (and thus choice) and improved in efficacy; however, there obviously still remains a sizable unmet need because the narrative has changed over the last several years from monotherapeutic approaches to treatment (particularly, after each one fails, is to pursue another approach) to combining treatments (whether two treatments are delivered concurrently, or treatments are knowingly delivered sequentially). The goals of combination therapy is to delivery more efficacy and to overcome resistance. I suppose the goal of any cancer therapy is to delivery better efficacy than what came before it, and to overcome resistance (or recurrence), and thus prolong survival.

          And that's where the industry's thinking has evolved, by embracing the cancer immunity cycle to progress towards harnessing the body's immune system to fight cancer and thus better deliver on the promise of better efficacy and overcoming resistance. In this case, sequencing the delivery of a permutation of treatments (drugs, therapies) is what constitutes combination.
          Click to enlarge.
          Eggermont (2012) writes: "The immune system can be leveraged to fight cancer via four broad, overlapping strategies, comprising priming/boosting of the immune system, T-cell modulation, reducing immunosuppression in the tumour microenvironment and enhancing adaptive immunity." As the author further write: "As immunotherapies function by distinct mechanisms, it is possible that their combination with other treatment modalities may be synergistic."

          What does Moffitt Cancer Center's Dr. Jeffrey Weber think? At a minimum he thinks:
          • Injectable therapies are making a comeback, where one would use an intralesional agent to prime the immune system of a patient with late stage and/or visceral disease, and then boost it with a checkpoint protein inhibitors (or combination of inhibitors). Unfortunately, he sees Amgen's T-Vec as limited ("I see this as a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipilimumab, or a combination of those."). See 'Pretty Darn Impressive' PD-1 Data in Melanoma, Ribas and Weber, June 12, 2014.
          • Moffitt's Phase 1 feasibility study of PV-10 provided "...more and more evidence that you are altering both local and systemic immunity in a positive way. It also provides a rationale for combination trials of PV-10 with check point protein inhibitors, such as ipilimumab, pembrolizumab and nivolumab. PV-10 might offer the perfect way to prime the immune system."
          • In response to my question of how to assess the utility or value of an agent or compound as an immune system primer: "Simply its ability to synergize with the immune agent in question in terms of clinical effect when given prior to the second agent...the priming agent would simply add to the effect of the immune agent, when used at the same dose and schedule."
          The priming agent above would be PV-10 (or T-Vec), while the immune agent would be one of the checkpoint inhibitors.

          Weber previously said he is hard pressed to see a systemic role for IL therapies like T-Vec in patients with significant disease burden and visceral M1c disease. Stages IIIB-C and IV M1a patients could be treated with IL therapy. To expect, however, significant clinical and biologic systemic benefit (affect) with any IL therapy -- as we now know them -- in patients with significant disease burden and visceral M1c disease is very low. For now, for him and those he seeks to help, he sees PV-10's role, it would appear, as a potentially powerful (dare I say perfect) immune system primer to help patients with significant disease burden and visceral M1c disease. In addition to its role as a monotherapy for cutaneous melanoma, management wrote in its annual CEO letter about PV-10's role as part of a sequenced combination therapy for metastatic melanoma: "And for those patients who do not have all disease accessible to injection, medical oncologists have stated that using an agent like PV-10 to prime the immune system could be synergistic in combination with a systemic agent."

          Management previously recognized of the benefit and value of combining PV-10 with other treatments and therapies:
          • 2006 patent and Foote et al., 2010 regarding PV-10 plus radiotherapy;
          • Dees et al., SITC 2012 regarding co-administration of PV-10 and other systemic therapy (i.e., systemic chemotherapy);
          • 2012 patent regarding PV-10 plus systemic immunomodulative therapy; and,
          • Wachter et al., AACR 2013 regarding PV-10 plus anti-CTLA-4 antibody therapy.
          Moffitt previously concluded for AACR 2014 that "IL PV-10 may be rationally combined with systemic immunotherapy for the treatment of metastatic melanoma," and the same for ASCO 2014. Moffitt and Weber would seem to be key clinical players (i.e., site, lead/sole principal investigator) in any combination study.

          Management, however, historically has been reticent to pursue combination therapy on their own dime (or spend significantly on it), aside from providing the drug for study, unless someone else (i.e., another company) stepped up to the plate. The situation appears to have changed, per their comments on recent conference calls regarding potential combination studies and related relationships. Experience would suggest (because of the aforementioned comments they made "now") the phone rang, Provectus picked it up, and management listened to what the party(ies) on the other end had to say. The company typically has not talked publicly about things until there is sufficient activity (with of course no certainty of closure or timing thereof) to warrant comment.

          Utilizing the table I prepared in my July 24th Combinations news item (see below),...
          Click to enlarge.
          Click to enlarge.
          ...Weber's support and contemplated use of PV-10 (and his industry associations and relationships), and other due diligence, likely, potential or possible interest (or lack thereof) is:
          • Anti-CTLA-4: Bristol-Myers, obviously, but unlikely. Although an approved drug, it would appear anti-PD-1 agent nivolumab ultimately will supersede it (together with other PD-1 and PD-L1 agents), and PV-10 is potentially a more powerful priming and activation agent vis a vis steps in the cancer immunity cycle in order to combine with a PD-1 or PD-L1 agent.
          • Anti-PD-1: Bristol-Myers and/or Merck.
          • Anti-PD-L1: AstraZeneca, potentially. Roche is more likely to engage in combination studies utilizing investigational agents in its own pipeline that represent the distinct cycle steps, and thus not look to outside parties yet for combinations.
          Grading any so-called co-development deal should Provectus be able to enter into one, more so than merely the design of the clinical studies, would be based on (among other things):
          • Who pays for the trial (aside from, and above and beyond Provectus contributing drug product),
          • Who conducts, operates (and sponsors) the trial,
          • Whether Provectus, like Celldex, would receive an upfront payment, and if so how much,
          • What exclusivity might constrain PV-10 to combine with other agents, and
          • What right of first something(s) might accompany a co-development deal.