Hypothesis: Intralesional PV10 induces systemic immunity in humans

Provectus issued a press release today and made an associated 8-K filing (that included another item) regarding Moffitt Cancer Center's Dr. Vernon Sondak, MD's presentation in Munich, Germany, Provectus Biopharmaceuticals' Data on PV-10 as Treatment for Melanoma Presented at 5th European Post-Chicago Melanoma / Skin Cancer Meeting. The company made Dr. Sondak's presentation available; the link is here.

I believe the key takeaway comes from the 19th slide in the deck, which clearly and simply states [what I think is] the ultimate goal of Moffitt's research work on PV-10: to prove or disprove the hypothesis that intralesional PV10 induces systemic immunity in humans [for melanoma].

Click to enlarge. Slide no. 19. New 2015 slide (v. 2014)

The other slide of note [to me], and that I was struck by, was the presentation's final slide (of "The Moffitt PV-10 Team").

Click to enlarge. Slide no. 21. New 2015 slide (v. 2014)

Below I compare Sondak's 2014 presentation to his 2015 one, which in the early going are ostensibly the same. A shareholder who attended last year's presentation sent me pictures of it.

Disclosures

Click to enlarge. 2014

Click to enlarge. 2015: Slide no. 2

Potential Applications

Click to enlarge. 2014

Click to enlarge. 2014

Click to enlarge. 2015: Slide no. 3

Click to enlarge. 2015: Slide no. 4

Properties of the Ideal Agent

Click to enlarge. 2014

Click to enlarge. 2015: Slide no. 5

New in 2015: Sondak included a "history of" slide, which speaks to Rose Bengal lying around in plain sight of Big Pharma for about 75 years before Provectus' cofounders "re-discovered" it, and the drug substance/drug product's safety and specificity (i.e., Pharmacology).

Click to enlarge. 2015: Slide no. 6

Properties of PV-10

Click to enlarge. 2014 

Click to enlarge. 2014

Click to enlarge. 2015: Slide no. 7

Click to enlarge. 2015: Slide no. 8

Click to enlarge. 2015: Slide no. 9

New in 2015: A picture of Melanoma Institute Australia and the University of Sydney's Dr./Prof. John Thompson, MD with PV-10 (Rose Bengal) on his face?

Click to enlarge. 2015: Slide no. 10 

Click to enlarge. 2014

Click to enlarge. 2014

Click to enlarge. 2014

Click to enlarge. 2014

Click to enlarge. 2015: Slide no. 12

Click to enlarge. 2015: Slide no. 13

Click to enlarge. 2015: Slide no. 11

Click to enlarge. 2015: Slide no. 14

New in 2015: Summary/overview slides of Moffitt's work to assess systemic immunity from intralesional therapy, in mice and humans (noting whether and where such work was or was not published in a peer-reviewed journal).

Click to enlarge. 2015: Slide no. 15

Click to enlarge. 2015: Slide no. 16

Click to enlarge. 2015: Slide no. 17

Click to enlarge. 2015: Slide no. 18

Click to enlarge. 2015: Slide no. 19. Notable, as discussed above

Conclusions

Click to enlarge. 2014

Click to enlarge. 2015: Slide no. 20

Final Slide

Sondak's final June 2014 presentation slide was telling, given the FDA's May 2014 denial of Provectus' application for breakthrough therapy designation for PV-10 (in locally advanced cutaneous melanoma), and that he made that presentation well before the Agency's April 2015's advisory committees overwhelming vote in favor of Amgen's talimogene laherparepvec ("T-Vec") having an overall favorable benefit-risk profile for the treatment of injectable regionally or distantly metastatic melanoma (for the latter, see blog post The first guy through the wall).

Click to enlarge. 2014

In June 2015, however, there are smiling faces:

Click to enlarge. 2015: Slide no. 21

Recall Eric said on Provectus' May 7th 1Q15 conference call:

"We really can't speculate on the direct implications of the T-VEC decision other than to say that clearly the regulatory environment is continuing to change what the agency identified deficiencies in the T-VEC package. And this may come as significant review questions when the agency finalizes the review of potential decision to approve or not approve the BLA, the application for approval for that my logic may have relevance for us going forward. That being said, the end points that were used for the T-VEC pivotal study were different than the ones that we used in Phase 2 study. And more importantly, the T-VEC Phase 3 study, pivotal study was larger, so have more patients than we have in the Phase 2 study. I would speculate that we can see that what was clearly very strong headwinds a year ago are maybe abating here in Washington and that presumably bodes well for future success with PV-10." {Underlined emphasis is mine}

N.B. Provectus did not make Dr. Sondak's 2014 presentation at the 4th European Post-Chicago Melanoma / Skin Cancer Meeting available last year. For whatever reason (e.g., perhaps Eric is more comfortable and confident now than he was then*), Provectus' Chief Technology Officer Dr. Eric Wachter, PhD appears to have allowed the company's Chief Operating Officer/Chief Financial Officer Peter Culepper to press release the 2015 presentation.

* If true and in the absence of more explanation directly from him on this, then my reaction is that such feeling(s) is(are) are disrespectful to Provectus shareholders and representative of an intellectually inconsistent sub-process.

Moffitt

H. Lee Moffitt Cancer Center & Research Institute has issued strongly worded press releases related to recent pre-clinical and clinical cancer trial work and research successes.

Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows

August 22, 2013, Tampa, Fla. – A new study at Moffitt Cancer Center could offer hope to people with melanoma, the deadliest form of skin cancer. Researchers are investigating whether an injectable known as PV-10 can shrink tumors and reduce the spread of cancer. PV-10 is a solution developed from Rose Bengal, a water-soluble dye commonly used to stain damaged cells in the eye. Early clinical trials show PV-10 can boost immune response in melanoma tumors, as well as the blood stream.

Moffitt Cancer Center Instrumental in FDA Approval of Revolutionary Two-Drug Combo to Treat Advanced Melanoma

January 23, 2014, Tampa, Fla. – Moffitt Cancer Center researchers have laid the groundwork for a revolutionary new combination therapy for the treatment of advanced melanoma – melanoma that cannot be removed surgically or has spread to other areas of the body. The newly FDA-approved therapy, Mekinist (trametinib) in combination with Tafinlar (dabrafenib), is one of the biggest advancements in melanoma treatment in the past 30 years.

Moffitt Cancer Center Plays Pivotal Role in FDA Approval of New Anti-PD-1 Inhibitor Keytruda for Metastatic Melanoma

September 4, 2014, Tampa Fla. – The U.S. Food and Drug Administration (FDA) announced the approval of a new cancer immunotherapy today to treat patients with metastatic melanoma, Keytruda (pembrolizumab) by Merck & Co.

Quotes and statements from Moffitt about PV-10

Click to enlarge.

Properties of PV-10

Presentation statements about PV-10 by Moffitt Cancer Center's Dr. Vernon Sondak on Friday, June 27th at the 4th European Post-Chicago Melanoma Meeting.

1. Simple to store, handle and use and reuse

2. Modest local toxicity and minimal to no systemic toxicity

3. Rapid and complete induction of necrosis/antigen release in injected lesions

4. Excellent healing of the injected site after tumor necrosis

5. Reliable and reproducible induction of regional and systemic immune effects capable of destroying occult tumor cells, "bystander lesions" and distant metastatic lesions regardless of prior treatments

[My note: An occult tumour is one that is hidden, or so small that it can't be found, even by the most detailed scans. His disclosures included that he is a compensated consultant for Provectus, Merck, Bristol-Myers, GlaxoSmithKline, Amgen and Novartis, and that Provectus provided support to Moffitt for research related to his presentation.]

$PVCT in Paris?

2013 Annual Paris Melanoma Conference & Moffitt's Dr. Jeffrey Weber, MD, PhD (see post below). So what? Here's what:

1. Dr. Weber appears to be about combination therapies of all sorts. Read Melanoma: is immunotherapy the future?, an interview of Dr. Weber by Jenaid Rees, Commissioning Editor of Expert Review of Dermatology. The article does not mention PV-10 by name. Reading the interview, however, gives you a very good sense of his professional interest (combination therapies).

2. Dr. Weber presentation at this Paris melanoma conference is about combination therapies. Dr. Sondak, a senior leader at Moffitt, has been very involved with Provectus. To what extent is Dr. Weber (the leadership at Moffitt) involved in or sees further professional development, success and/or legacy building through translational research into and the work of combining PV-10 with anti-CTLA4 agents, anti-PD-1 agents, systemic chemotherapies, other systemic immunotherapies, and on and on...?

3. At a Paris melanoma conference, several industry folks will be gathered. I don't where in Europe Peter is, but Paris probably is on his itinerary. If you're an industry professional, particularly focused on M&A, corporate development, business development or R&D, you owe it to your company to, at the very least, seek Provectus out and speak with them (Pete).

Video -- Matastasectomy: Does it make sense in the setting of effective systemic therapy?

I found this video presentation from Dr. Argarwala's 2013 HemOnc Today Melanoma Conference this past March in New York interesting: Matastasectomy: Does it make sense in the setting of effective systemic therapy? by Moffitt Cancer Center's Dr. Vernon Sondak. Provectus some time back had initially facilitated my ability to communicate and interact with Dr. Sondak.

In the presentation, he contrasts and compares surgery PFS and survival times and their respective percentages (PFS6, OS12) to results of various systemic treatment therapies.

Intralesional therapy like PV-10 is the best treatment option for patients who are not amenable to surgery. There undoubtedly will be interest in the pre-operative use of intralesional therapy, but traditional thinking suggests such interest would be on a research basis for the foreseeable future. 

Surgical oncologists, however, including several key opinion leaders, think intralesional therapy PV-10 already is viable for pre-operative use, whether the patient is or is not amenable to surgery.

$PVCT: Waiting for MoffittCancerCenter (@MoffittNews)

I previously wrote that: I asked Pete for his perspective on it in the context of management's work with the FDA. Regulatory approval is a complex topic, especially as it relates to local agent PV-10 versus systemic ones. PV-10 as a local agent is a reality that has driven management's MM Phase 3 trial design more than anything else. The key to the FDA, according to Peter, is proving "clinical relevance." This certainly means meeting endpoints, but it also means whether a drug should be approved or not. PV-10 needs to be clinically relevant to be approved. Provectus' Phase 3 trial design discussed with the FDA would support PV-10 as being "clinically relevant."

With two days left, the blog's poll -- What company achievement will have the greatest impact on share price in Q1? -- has 13% of participants voting for Moffitt's data. I previously wrote that I don't think Moffitt's full effect will be felt this quarter. That does not mean I think Moffitt is not important. It appears Moffitt is crucial to Provectus, PV-10 and Rose Bengals' story.

Management will not say where, when and what Moffitt will say about the cancer center's follow-up mouse work to SSO (recall here and here), and whether some of Moffitt's human trial work results will be available concurrently with the mouse work.

So, we wait...

Peter says "Everyone, and I mean everyone, wants to better understand the systemic benefit of PV-10." With that, I assume "everyone" includes the FDA. Management's silence on Moffitt's results as well as the timing and venues of their presentation and publication suggest to me the FDA, Big Pharma and serious life sciences investors also have not seen Moffitt's full data-set.

In Provectus' CEO Letter last April, management discussed how Moffitt's work was "...fundamental for full characterization of PV-10's systemic benefit and may provide pivotal support for accelerated approval in the U.S." Accelerated approval is a real possibility, given the basis for seeking such is the import of Moffitt's work.

Moffitt weighing in on PV-10's clinical relevance and the timing of these comments should give us great insight into whether and when the management might state it is appropriate to seek accelerated approval based on discussions with the FDA.