November 12, 2014

"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.

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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.

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

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