They ARE out to get me...

My reading of Frank David's March 2nd Forbes article entitled Only The Paranoid Biotechs Will Survive converged interestingly with Peter's presentation at the 8th Annual European Life Science CEO Forum & Exhibition. David wrote:

"The drug industry is surely at a similar “strategic inflection point”. Sales forces are less effective, prices are under constant and increasing assault, and physicians and patients alike are raising the bar for how they define clinical value. (My prior takes here, here, here and here.) High prices and huge sales forces used to prop up even minimally differentiated drugs, especially in big markets like hypercholesterolemia and depression. But today, something is changing: commercial muscle no longer guarantees success unless you also have a compelling clinical benefit. 

But I’d argue we’re in the midst of a “strategic inflection point” that threatens many biotechs’ ability to secure Pharma deals. Whereas the biggest hazard to biotechs in the past was moving too slowly or running out of funds, it’s hard to deny that today, the risk of not demonstrating clinical differentiation is far greater." {Underlined emphasis is mine}

Pembrolizumab. In his presentation Peter noted Merck & Co.'s approved anti-PD-1 therapeutic pembrolizumab (Keytruda) as the control in a planned Phase 1b/2 combination study of PV-10 + immune checkpoint blockade — see Updated presentation slides (March 3, 2015) on the blog's News page.

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Peter has a somewhat "annoying" (because I have to regularly and carefully read, search and sometimes parse them) but mostly helpful (because there often are relevant or germane regulatory, clinical development and commercial bits and bobs in them) habit of placing Easter Eggs of a sort in Provectus' corporate website/investor presentations.

This particular egg referenced Merck's PD-1 drug as the other drug and control in a pairing with PV-10. The "trial" title then would be Pembrolizumab With or Without PV-10 in Unresected Melanoma.

For comparison, Amgen and Merck announced their collaboration and combining of T-Vec and pembrolizumab (MK-3475 at the time) in February 2014 — Amgen's press release is here. The trial protocol of this pairing was filed on ClinicalTrials. gov in September. Recruitment began in December.

If one assumes this egg is not spurious, then Peter's placement was purposefully communicative. While I'm not in a position to opine on whether or not Bristol-Myers will prevail in its lawsuit against Merck U.S. over each other's anti-PD-1 agent, I imagine Craig et al. would not consider doing a trial — with Merck, or by themselves (since the trial size of oncology Phase 1bs can range from 20-25 patients — in a potential future scenario where Bristol-Myers prevails over Merck.

First-in-class. I chuckled when I saw the cover slide of Peter's presentation read "first-in-class halogenated xanthene dye." Before I explain my snorting, it would appear first-in-class means to the FDA (or is defined by the Agency) "...drugs which...use a new and unique mechanism of action for treating a medical condition." Is this another Easter Egg? I believe it is, presumably emanating from further discussions with the FDA.

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Can Drug A be called first-in-class [with its associated mechanism of action ("MOA")] if it is approved for Indication X? If Drug B is approved second for X, is it second-in-class? Or, if A is approved before B, is A then just first-in-class [with MOA]. By this fragile, inexperienced logic, pembrolizumab is a first-in-class PD-1 inhibitor or anti-PD-1 antibody. Is nivolumab second-in-class?

I laughed at the non-FDA contextual use of the entire phrase — first-in-class halogenated xanthene dye — because while pembrolizumab is owned by Merck US, and nivolumab is owned by Bristol-Myers, and Pfizer has a PD-1 inhibitor, and AstraZeneca's for now is labelled MEDI0680, etc., Provectus owns Rose Bengal and related xanthenes (e.g., first-in-class, second-in-class, etc.).

Competition? Amgen will have its FDA PDUFA completion date for T-Vec in October 2015, but the Agency will meet to hold an AdComm meeting in April. In this instance T-Vec is being considered as a monotherapy for advanced melanoma (i.e., the the treatment of patients with injectable regionally or distantly metastatic melanoma).

Interestingly, Amgen filed a trial protocol on ClinicalTrials.gov in November 2014 entitled Phase 2, Open-Label, Single-arm Trial to Evaluate the Correlation Between ORR and Baseline Intratumoral CD8+ Cell Density in Subjects With Unresected Stage IIIB to IVM1c Melanoma With Talimogene Laherparepvec. The trial appears to be taking place in Spain, and may soon begin recruiting. The purpose of the study is to evaluate the correlation between CD8+ cell density and response rate. Cell density (the number of cells per unit volume, such as cells per microliter) presumably plays an important role in immunotherapy effectiveness (i.e., the higher the density, the better the effectiveness). I do wonder whether this density figure, which measures quantity or concentration, also includes a measure of quality too.

In a February 2013 Cancer Watch article entitled Back to Phase 1: Understanding Systemic Effects of PV-10, it was written:

While adoptive cell transfer offers the advantage that enough T cells can be obtained for infusion in all patients, the T-cell receptors transfected into the T cells have a limited antigen-specificity. The strategy works, Dr. Sarnaik said, only about half the time. “We generate large numbers of T-lymphocytes, but we don’t have control over their quality. We think one of the limitations is that the T cells you get out of the tumor just aren’t good enough.” PV-10, however, does cause an immune response, suggesting that a combination treatment may improve the quality of the T-lymphocytes and have a greater impact on the disease. 

When Shari Pilon-Thomas, PhD, also a Moffitt researcher, demonstrated that T-lymphocytes recovered from mice treated with PV-10 do appear to be of a higher quality, as evidenced by stronger tumor reactivity, the stage was set for Dr. Sarnaik’s current 15-patient pilot study. In it, one of two resectable melanoma tumors is injected with PV-10. Both are removed several weeks later. Serum is assessed before and after treatment to look for changes in the infiltration of immune cells. In patients with an immune response, PV-10 therapy can be continued. 

“This is a straightforward study that will give a yes or no answer,” Dr. Sarnaik said. 

Bristol-Myers/Amgen's combination trial that paired ipilimumab and T-Vec. Ipi with or without T-Vec) provided germane information on immunologic signaling (see below, on the right), where PBMC stands for peripheral blood mononuclear cell. PBMCs "...are the populations of immune cells that remain at the less dense, upper interface of the Ficoll layer...PBMCs include lymphocytes (T cells, B cells, and NK cells), monocytes, and dendritic cells."

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My takeaway for this blog post, by returning to David's article, is, again, risk-reward. The potentially vast reward opportunity for Provectus is to effectively demonstrate and communicate that compelling clinical benefit and differentiation.