"These murine studies support combination therapy with IL PV-10 and co-inhibitory blockade."

Provectus issued a press release, filed an associated 8-K and made available Moffitt Cancer Center's PV-10-related poster from the 29th annual meeting of the Society for Immunotherapy of Cancer ("SITC") Monday. Of the conclusions provided by Moffitt, it struck me the key one was the first:

Moffitt affirmed there is a clinical rationale and value proposition, based on pre-clinical murine model work, to undertake a study (studies) combining PV-10 and each/any of the anti-PD-L1, -PD1 and -CTLA4 therapeutic agents.

❐ Moffitt's initial murine model work investigating PV-10 as a monotherapy -- "Intralesional Injection of Melanoma with Rose Bengal Induces Regression of Untreated Synchronous Melanoma In a Murine Model," Society of Surgical Oncology Annual Meeting, March 2012, and "Intralesional Injection with PV-10 Induces a Systemic Anti-tumor Immune Response in Murine Models of Breast Cancer and Melanoma," American Association for Cancer Research Annual Meeting, April 2013 -- demonstrated:

• Regression in both injected and un-injected melanoma tumors,
• Anti-tumor immunity (T-cell generation & activity), and
• Increased survival (in mice).

❐ Moffitt followed up their mousie work with a human feasibility study of PV-10 as a monotherapy -- "Assessment of immune and clinical efficacy after intralesional PV-10 in injected and uninjected metastatic melanoma lesions," American Society of Clinical Oncology Annual Meeting, June 2014 -- that demonstrated:

• Regression in both injected and un-injected melanoma tumors, and
• Anti-tumor immunity (T-cell generation & activity).

❐ Moffitt continued their murine model work investigating PV-10 in combination with each of three categories of checkpoint inhibitors (anti-PD-L1, -PD1, -CTLA4) -- "Efficacy of Intralesional Injection with PV-10 in Combination with Co-Inhibitory Blockade in a Murine Model of Melanoma," Society for Immunotherapy of Cancer Annual Meeting, November 2014 -- that demonstrated:

• Regression in both injected and un-injected melanoma tumors,
• Anti-tumor immunity (T-cell generation & activity), and
• Increased survival (in mice).

All of Moffitt's work, murine and human, involved a single intralesional injection of PV-10 per injected lesion. It would appear what Moffitt is doing with PV-10 the way they are doing it is procedural, meaning the cancer center is trying to better understand PV-10's tumor-specific immunity with scientific experimental methods, rather than with specific clinical or clinically translational approaches at this time. Ultimately, it seems Moffitt wanted to know if PV-10 worked, found out it did, then wanted to know how well it worked, and then found out how much it did -- as a single agent, and in combination with other agents.

All Moffitt posters -- SSO 2012, AACR 2013, ASCO 2014, SITC 2014 -- have been exclusively co-authored by Moffitt researchers/employees. It is interesting to note Provectus, it appears, freely allowed the cancer center to undertake this work without, it would seem, involvement or interference. I imagine the company, in addition to providing PV-10 drug product to Moffitt, compensates or pays or contributes funding to the cancer center and/or researchers in some form or fashion, like other biopharmaceutical companies do.

○          ○          ○          ○          ○          ○          ○

The Methods section of Moffitt's SITC 2014 poster was sparse on experimental method detail, as was the Methods section of their AACR 2013 poster. As such, we will have to wait for an/the associated peer-reviewed paper that would describe the method(s) of the SITC work (as their 2013 PLOS One paper did for the AACR poster and work); specifically, the modifications the cancer center made to their PV-10 injection approach (contrasted with the AACR work's approach) to elicit and elucidate the value of PV-10 in combination with checkpoint inhibitors.

The 2013 "monotherapy" poster/paper appeared to show relatively greater interferon gamma production relative to control than the 2014 "combination therapy" poster did. PV-10's propensity to completely destroy and/or dramatically reduce injected and un-injected tumors -- the subject of Moffitt's August 2013 Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows press release-- must have required modifications to the experimental design in order to facilitate the combination therapy murine model work (i.e., don't kill the tumor completely but "partially kill" it so as to observe and measure the subsequent effect of a checkpoint inhibitor on PV-10-damaged-but-not-destroyed-tumor), such as treating part of a large tumor, reducing PV-10 dose per volume, or diluting the concentration of the drug.

○          ○          ○          ○          ○          ○          ○

Peter noted in the company's third quarter 10-Q:

We also have begun to consider co-development transactions with one or more pharmaceutical or biotech companies to combine PV-10 with immunology agents such as those referred to as immune checkpoint inhibitors...Furthermore, the strategy of the Company for the benefit of stockholders is a series of partnerships followed by an acquisition of the Company along the lines of Celgene-Abraxis, although there can be no assurance that such partnerships or acquisition will occur. An interim transaction could be a co-development deal like Roche-NewLink, Bristol-Celldex or AstraZeneca-Incyte. {Underlined emphasis is mine.}

NewLink published preclinical combination study work (their drug + anti-PD1/PD-L1 antibodies) at AACR 2014 (April)*, co-conducted by NewLink employees and Georgia Regents University Research Institute researchers/employees.

• The company licensed their drug to Genentech/Roche in October 2014.

* "The current preclinical studies suggest a mechanistic rationale for a combining IDO pathway

inhibitors with agents targeting the PD-1/PD-L1/PD-L2 pathway."

Celldex published preclinical combo work (their drug + checkpoint blockade therapies) at SITC 2013 (November)*, conducted by Celldex employees.

• The company announced a combination collaboration of their drug with Bristol-Myers' PD-1 agent in May 2014.

* "These studies...support the initiation of combination trials with conventional and immune-based therapies."

Incyte filed a protocol for combining its subject drug with Bristol-Myers' anti-CTLA-4 agent Yervoy in 2012. From what I can gather (and I may be wrong) the trial of the combination therapy was initiated alone by Incyte (I cannot find any publication of preclinical work that may have preceded this trial). At an ASCO 2014 presentation of a Phase 1/2 melanoma study, principal investigators (that included Moffitt Cancer Center's Dr. Jeffrey Weber, M.D., Ph.D.) noted "[p]reclinical data support antitumor synergy for INCB024360 when administered with an antibody antagonist to checkpoint receptors," referencing a October 2013 (submitted)/February 2014 (published) SITC journal paper* (the paper, however, does not present preclinical combo work on the subject drug but another related Incyte compound), co-conducted by Celldex employees and the University of Chicago researchers/employees

• The company announced combination collaborations of their drug with Merck's PD-1 agent in February 2014, AstraZeneca's PD-L1 agent in May 2014, and Bristol-Myers' PD-1 agent also in May 2014.

* "These three combinations are attractive to pursue clinically..."

○          ○          ○          ○          ○          ○          ○

Provectus published preclinical combination study work (PV-10 + anti-CTLA-4 mouse antibodies) in April at AACR 2013. Moffitt published their preclinical combination study work (PV-10 + anti-PD-L1, -PD1, and -CTLA4) in November at SITC 2014, of course.

The company should have sufficient data to establish the rationale for a combination study with a Big Pharma partner:

• Preclinical from Moffitt's poster, and additional material not included on it,

• Clinical, perhaps, and in context, from Moffitt's human feasibility study ("Six of 8 patients had metastatic disease refractory to previous ipilimumab, anti-PD-1 and/or vemurafenib therapy"), and

• Clinical, possibly, from Provectus' compassionate use program ("CUP"), where patients previously on checkpoint inhibitors who recurred from these may have sought help from PV-10 (Phase 2 patients were refractory to a median of 6 previous interventions, including immunotherapy (21%)).

Arriving at an agreement on business terms of a so-called co-development deal is/will be another story; however, this information should be the hard data of PV-10's immunological activity (most of it generated independently of Provectus by Moffitt) that may facilitate a discussion, or two, with Big Pharma.

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.

ASCO 2013 Immunotherapy Highlights Covered by $PVCT-$PFE's Combination Therapy Patent Application

Sally Church, writer of the Pharma Strategy Blog, notes ASCO 2013 will bring new data on immunotherapy agents called checkpoint regulatory inhibitors.

All of these groups of compounds are covered by Provectus' joint patent application with Pfizer for the combination of PV-10 and other therapies. All of the above drugs have been combined with PV-10 by Moffitt.

@adamfeuerstein: What Wall Street's Watching at ASCO (The Burrill Report)

This podcast, featuring Adam Feuerstein, senior columnist for TheStreet.com, is worth hearing. Click on this link: The Burrill Report (May 28, 2013): What Wall Street's Watching at ASCO.

Notes:

• ASCO 2013 likely will be about so-called "second generation" immunotherapies: anti-PD-1 and anti-PDL-1 agents. Ipilimumab (and, I suppose, vemurafenib) were/are first generation,
• Combination therapies, like ipi + nivo (both Bristol-Meyers drugs), have potential utility if/because you get synergism,
• Cancer disguises itself or is cloaked from the immune system? Craig's view (when treating cancer like an infectious disease) is the immune system is overwhelmed by cancer, not hidden or disguised from it. I don't think this is a semantic difference. Uncloaking, better distinguishing, etc. suggest artificial solutions or constructs.
• Key abstracts include Amgen's T-Vec.

Anything positive about T-Vec enhances the view the pharmaceutical industry has about intralesional agents in general.  So, we all should root for T-Vec. That said, if Amgen's compound bombs, the view still remains that intralesional agents are back, and PV-10 is the leader of the pack.

The "Immuno-Oncology" Market That Encompasses $PVCT & PV-10

On May 15, a Wall Street Journal article highlighted middle market investment bank Leerink Swann's of immuno-oncology addressable market as an annual $20 billion figure. A week later, Citigroup analyst Andrew Baum was quoted by Reuters sizing the market as $35 billion a year over the next 10 years for, where this category of drugs would be used in some way in the management of up to 60% of all cancers. I think the immuno-oncology category includes immuntherapies broadly, but it's possible the above estimates are inclusive only of anti-CTLA-4, anti-PD1 and anti-PDL-1 (and the like) agents.

I Think it's a Good Time to be a $PVCT Shareholder

Shareholders are closer to the end-game for the stock than to their journey's beginning. The company's  life sciences technology is head and shoulders above its peers. The lead compound presents a compelling clinical value proposition capable, perhaps, of indeed shifting the paradigm of cancer treatment (and treatment of inflammatory skin disorders). The drug already is productized, with a product business proposition to match that of the underlying technology. Provectus appears to be nearing transparency regarding regulatory clarity for oncology. The company also appears to be nearing certain license deals that will provide initial market validation. In sum, management, Provectus and its shareholders are nearing the end-game.

Provectus' technology is a game changer, productized to effect the change, and can be delivered and scaled to profit from the change to come.

The technology, PV-10 for oncology, is an effective local treatment capable of as effectively treating distant disease and visceral metastases. The drug, through expression of antigens in context in tumors into which PV-10 is injected fortifies the immune system against cancerous agents. Immunization occurs because PV-10's chemoablation causes rapid, complete, durable necrosis of tumor lesions.

"Scientists have been trying for decades to understand why the body's immune system didn't see cancer cells as the enemy and attack them. Recent discoveries revealed that tumors are adept at cloaking themselves by hijacking the body's own mechanism for preventing the system's T-cells, the infection- and disease-fighting cells of the immune system, from running amok against healthy tissue."

The above quote from Wall Street Journal (WSJ) article New Cancer Drugs Harness Power of Immune System (5/15/13) is not quite on-point. Rather, the quote below from Bloomberg article Human Immune-Boosting Cancer Drugs Seen Extending Lives (5/12/13) is more to the point.

"Now many believe that by strengthening the immune system’s ability to identify and kill cancer cells, they can broaden the attack so it will fight any dangerous malignancy. “You’re setting up a fair fight” with the disease, said Nils Lonberg, a senior vice president at Bristol-Myers, in a telephone interview. “The immune system is just as adaptable as the cancer.”"

How do you strengthen the immune system? Medical science has done it before with infectious diseases. Immune systems can be overwhelmed and, thus, are unable to help the human body fight back. Antibiotics themselves do not cure patients of infectious diseases that have afflicted them. Rather, the immune system cures the hosts with the help of antibiotics. Treating infectious diseases requires that antibiotics should have near absolute specificity for the infectious agent. Tough infections require multiple agents.

I think it's a good time to be a Provectus shareholder.

The volume of the conversations about immunotherapy has grown much, much louder. Take Xconomy's Luke Timmerman's article Genentech Follows Fast at ASCO as Cancer Immunotherapy Picks Up (5/15/13) for example.

"Genentech made its name in cancer by creating targeted antibody drugs that zero in on tumor cells while mostly sparing healthy tissue. Now it’s seeking to compete in the next wave of cancer immunotherapies, which are designed to spark the immune system to attack tumors like a virus."

Or take NBC's Nightly News report Immunotherapy targets cancer cells with remarkable results (5/15/13).

"Cancer cells typically put up a chemical shield to protect against the body’s disease-fighting T cells. But immunotherapy can break down the shield and let the T cells get to work."

The more the biopharmaceuticals industry, investing community and general public talk about immunotherapy, the better the environment or atmosphere for PV-10 and Provectus to flourish.

From the same WSJ article above: "More broadly, Leerink [Swann, a middle market investment bank] believes the "immuno-oncology" drug market could amount to a $20 billion category annually, putting it on a par with the cholesterol-lowering statin market at its height."

From dendritic cells (Dendreon's Provenge) to antitumor antibodies (Bristol-Myers' anti-CTLA-4 agent Yervoy) to immune checkpoint blockades (ASCO 2013's anti-PD1 and anti-PDL-1 agents):

"The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology...[t]he pillars of human cancer therapy have historically been surgery, radiotherapy, and chemotherapy, but a fourth modality of immunotherapy has been well documented since 1890..." (Kirkwood et al.).

Big Pharma is tacking closer to the ultimate goal, but they mostly still are sailing wide of the objective.

"If the new generation of immune therapies lives up to its promise, “this is going to be a paradigm shift for treating cancer,” said Merck senior vice president Gary Gilliland in an interview. “We are pretty good at shrinking tumors, but not good at getting rid of them. Immune therapy is a way to begin to approach that.”"

Yes, Big Pharma is pretty good at shrinking cancerous tumors, but not yet good enough at making them go away.

Craig's postulation that you treat cancer like you treat an infectious disease requires a/the drug treatment to possess near absolute specificity for diseased tissue (spare normal tissue and clear rapidly from it) and induce a host response (combined apoptosis-autophagy of treated targets because intralesional delivery produces a “vaccine-like” systemic effect that enhances normal human body defenses) over a very wide range of activity (broad spectrum antibiotic-like)


PV-10 chemoablation causes rapid, complete, durable necrosis of tumor lesions.

I think it's a good time to be a Provectus shareholder.

The general discourse at the moment about immunotherapies, however, is far from well understood or a consensus. Take last week's exchange on Adam Feuerstein's Twitter feed @adamfeuerstein below.

Feuerstein had been explaining the fundamental bear case for Vical's Allovectin-7, but aside from perhaps some valid trial design questions, his "red flags" included a lack of positive statements by melanoma experts and institutional healthcare investors as well as a lack of immune-related toxicity by Allovectin-7. Church is not a fan of immune-related toxicity because of the long-term dangers of altering the immune system in order to use it. All of this despite the on-point replies of other respondents: directing T-cells to attack tumors rather than a broad uncontrolled response, the beauty of local treatment is limited toxicity, revolutionary if the local treatment works on visceral mets, etc.

Many monoclonal immunotherapies do cause terrible toxicities, which are related not just related to "taking the brakes off" the immune system. Their target antigens are not only on/in the immune cells they wish to suppress. Just like chemotherapy agents, immunotherapy agents also can cause collateral damage with more adverse side effects like cancer and death.

The nature of the conversation Feuerstein, Church and the others need to have has to be deeper and more substantive. It's too simplistic to say Allovectin-7 does or will not work. Whether it's Allovectin-7 or talimogene laherparepvecone (T-Vec, formerly OncoVEX), or PV-10 itself, one has to balance positive effects with side effects. Think of it as a biological signal-to-noise ratio. One can titer up dosages until one sees bad things happen.

I think Pfizer probably refused to do this with its anti-CTLA-4 agent tremelimumab, which is why it has a greater failure record in clinical trials than it's Bristol-Myers' ipilimumab. Bristol-Myers probably had a higher tolerance for "bad things to happen" in order to suss out the optimal or near-optimal signal-to-noise or benefit-to-side-effect ratio.

Remind yourself of Provectus' combination therapy work at AACR 2013 utilizing PV-10 and a systemic anti-CTLA-4 antibody. The highest dose of the latter killed the murine subjects more quickly. Lower doses were less effective but also less dangerous. Interestingly, the results the company concluded that while PV-10 is highly effective when all existing tumor is accessible for injection, for visceral or other inaccessible disease the combination of PV-10 with CTLA-4 blockade has important potential synergy. Nevertheless, the apparent toxicity at high doses of the anti-CTLA-4 antibody markedly reduced the effect of the antibody alone and the combination of PV-10 and the antibody.

If an immunotherapy is working, there has to be some response (e.g., inflamation, redness, blistering, itching, etc.). These "side effects" come with the territory, and merely are signs the immune system is now in the game. So, while one indeed is generating a toxic response by recruiting the immune system, the key is focusing this toxicity as much as possible.

The problem with Yervoy, and perhaps immunotherapies like anti-PD-1, anti-PDL-1 agents and other treatments, is the collateral damage they cause to the body. PV-10's great strength has been and is its ability to the target only what it kills and kill only what it targets. Another strength is the drug's ability to generate a very specific, targeted, immune response with very little collateral damage to anything but the tumor itself. So, some blistering occurs, body temperature rises, etc. Nothing more.

I think it's a good time to be a Provectus shareholder.

Still, regulatory clarity has to become transparent. Is it an MM Phase 3 trial under SPA powered for for a 6-month progressional free survival for PV-10 vs. 2-month plus PFS for the comparator DTIC?Or is it breakthrough designation therapy and accelerated approval or another accelerated pathway?

Further still, commercial validation through one or more meaningful license transactions (global, regional, dermatology) is required. For example, will it be Hisun-Pfizer Pharmaceuticals in China? Or another company or entity? The Hisun-Pfizer joint venture was established in 2012 to sell off-patent medicines in China and other emerging markets. But economics are economics. Pfizer's 49% equity ownership and thus 49% ownership of any PV-10 sales in China would be a strong inducement to widening the entity's mandate through a license deal with Provectus.

Who will it be in India? In Japan? When will PH-10 be licensed, and to whom?

Provectus is squarely in the eye of key cancer patient advocates. The company participated in Melanoma Research Alliances' (MRA's) Fifth Annual Scientific Retreat in February. In April Peter joined MRA's President and CEO Wendy Selig, LiveSTRONG's President and CEO and Provectus corporate advisory board member Doug Ulman, Moffitt Cancer Research Center's Dr. Shari Pilon-Thomas and some media for dinner.

Key opinion leaders like Moffitt's Dr. Jeff Weber and Dr. Vernon Sondak and Pfizer's Dr. Craig Eagle are enthused about PV-10 as both a monotherapy and combination therapy.

More data is on the way. And data is driving and will drive the deals.

Yes, I think it's a good time to be a Provectus shareholder.

$PVCT CEO Letter: PV-10 selective, does not harm healthy tissue, safe, effective, multi-indication, monotherapy, sequenced/combination therapy

This probably is the most communicative portion of the annual CEO letter, describing PV-10's clinical value proposition (a critical component of my investment thesis, and really for any investment thesis involving Provectus):

• Selectively targets and destroys cancer cells without harming surrounding healthy tissue (efficacy),
• Continues to demonstrate its local and systemic benefits (efficacy),
• Excellent safety profile (safety), and
• Potential applicability in multiple cancer indications (platform drug).

Building awareness in the medical and medical researcher community, particularly among key opinion leaders (KOLs), as a means of advancing PV-10 as a new paradigm for cancer treatment, has been a key component of Provectus' business strategy, starting as far back as Australia's Professor John Thompson, MD and the first PV-10 clinical trial for metastatic melanoma. PV-10’s unique characteristics and safety profile are attracting the attention of clinicians at nationally recognized medical research institutions. For example, I heard a recent rumor [as yet unvalidated] a high profile Memorial Sloan-Kettering Cancer Center researcher (and, thus, presumably a KOL) commented that PV-10 will be the future of cancer treatment.

...safe and effective as a monotherapy,...as an adjunct...and in combination... In addition to being, again, safe and effective (efficacious) as a monotherapy, the letter highlights PV-10's orthogonal nature and, thus, significant potential in appropriately pairing it with traditional chemotherapeutic, immunomodulatory (in the same general class as immunomodulatory agents like ipilimumab, tremelimumab, PD-1, PDL-1, etc.) and metabolic (the same general class as inhibitors) agents. "Combination" does not just mean giving PV-10 and another drug at the same, such as PV-10 and ipilimumab/Yervoy, together, but also "sequencing" (i.e., give PV-10 first, then give drug no. 2). I heard from some in Europe (Paris) [but cannot confirm] that Moffitt Cancer Center's Jeffrey Weber spoke about PV-10, both monotherapeutically and combinatorially, in meetings.