A More Aggressive Pathway To Approval for $PVCT

A meme making the rounds yesterday relates to an August 2010 article in knoxvillebiz.com about Provectus entitled "Knox company enters clinical trial stage for cancer drug." In it, Eric is quoted as saying of the FDA "If we had an ironclad explanation of this bystander effect that they could understand that it was…real and…why it was occurring, they would be more amenable to a more aggressive pathway to approval."

There was a great deal of consternation regarding my comment in my "$PVCT: A Slow, Hot, Smoky Summer Monday" post that recent information purports to suggest that, as late as last week, more time was needed to submit the breakthrough therapy ("BTD") application. Related frustration later was voiced by some shareholders about the special protocol assessment ("SPA"), the process for which appeared further elongated when management wrote in May in the annual CEO letter that it had every reason to believe the SPA would be achieved in 2013. As recently as March, in Dr. Andtbacka's presentation at the HemOnc Today conference in New York, a presentation slide indicated the MM Phase 3 trial under SPA would begin enrolling patients in mid-2013.

Peter would neither address Craig's comments about BTD (and other topics) after the annual general meeting in June nor my comment above (when other shareholders queried him about it). He also sidesteps SPA and BTD application submission questions, pointing out to shareholders (and the general public) that Provectus will not discuss specifics of the SPA process beyond what management has said in press releases and various corporate and investors presentations on the website and elsewhere.

More specifically, Peter will not address the topic of whether Provectus has or has not applied for the SPA and BTD. He did communicate Provectus expects to work with the FDA to get the SPA, and that the company is considering and very optimistic about BTD because management has been speaking with the FDA all along about accelerated approval ("AA").

I'm not convinced Provectus has submitted the BTD application, but I think the delay is due more to reconfiguration than having to fill a substance gap. When I recently asked Peter if the company had all the information and data necessary to complete the BTD application (i.e., did management feel it had answered all of the FDA's questions about PV-10), he replied it did. In truth, Eric is the only person at Provectus with a "real-time" view on the situation and process with the FDA, but I take Peter's reply to me to be as much of a current snapshot as one could obtain.

Is the right question to ask "when will the SPA and BTD submissions be made" (or, has the SPA and/or BTD application been submitted)? These are questions on the minds of most shareholders. It's clear to me management understands they have not completed the SPA process as quickly as they or shareholders would have liked. Everyone wants the ultimate milestone reached; namely, the SPA and, now, BTD.

I think the better question is to ask "what's needed (or what's left information- or data-wise) to get PV-10 approved." In my "For $PVCT, it's the FDA's move" post, I queried what remains. Safety and efficacy has been established beyond question. MOA, at least from a murine model perspective, has been explained and is understood. Proof of systemic properties and benefit has been shown. I also spelled out potential regulatory clarity outcomes: the SPA, AA, BTD (several options) and outright approval. It's no longer about whether the drug should be approved, but rather how it should be approved.

Segue to another Provectus article that also recently made the rounds again, February 2013's Cancer Watch's "Back to Phase 1: Understanding Systemic Effects of PV-10." In it, Moffitt's Dr. Amod Sarnaik said the cancer research center's focus "...is on discerning the presence of immune cell infiltrate in untreated tumors after PV-10 injections into other lesions. “We are really interested in harnessing immune cell infiltrate as a form of treatment,” he said, noting also that while creating cancer vaccines has been thought of traditionally as one of the Holy Grails of cancer research, cancer vaccines have turned out to be not strong enough to generate an adequate immune response." The literature suggests a a link between the immune infiltrate in several human carcinoma types and prognosis and response to therapy (2011). Later, the potential prognostic and/or predictive role of the immune infiltrate in this setting attracted attention (2012). The concept here is that tumor-infiltrating leucocytes ("TILs") may possess true predictive potential in cancer patients, where in some clinical settings the immune infiltrate can reliably predict if a specific patient will respond to therapy or not (Senovilla L et al. Oncoimmunology [2012, 1(8):1323-1343]). Later, in the same Cancer Watch article, Dr. Sarnaik said of Moffitt's Phase 1 feasibility study, "This is a straightforward study that will give a yes or no answer," which simply means Moffitt and he want to confirm what they already have seen pre-clinically (Moffitt's posters at SSO 2012 and AACR 2013) and in Provectus' prior clinical studies. One wonders if Moffitt's quantification of the significance of the immune-mediated response might further the belief in the independent predictive quality of PV-10-derived immune cell infiltrate for long-term survival of cancer patients.

Which brings me back to the meme I used to open this post. By completing the feasibility study, it would seem Moffitt would have provided the FDA with the "ironclad explanation of the bystander effect" sought by Provectus in 2010. Which then leads to contemplating the resulting "more aggressive pathway to approval." AA, BTD or outright approval? It's no longer about whether the drug should be approved, but rather how it should be approved. When Craig presented in town to biotech and life sciences industry folks, and some investment management people, in early-June, he said the FDA had asked Provectus to submit a BTD application.

If it's not a question of when was the SPA and/or BTD submitted, I think it's a question of when was (and what proportion of) Moffitt's feasibility study data (was) transmitted to the FDA. This remaining item should be what's left, or what remains. Interim results already have been generated. By early-June, before ASCO, the bulk of the work had been completed.

I read Peter's "very optimistic" stance by Provectus about BTD relates to the outcome management thinks is possible or probable. Perhaps they know the outcome, or at least have a good to very good idea about it. As of June 28, the FDA's CDER's performance on breakthrough requests was 98%, where where action was taken within 60 days of receipt of a request for BTD. It's possible for the so-called clock to be shorter than the planned time frame.

If, at best, management surmises the regulatory clarity outcome, or range of outcomes -- outcomes that in all likelihood clearly define the path and time to approval (the "time value of money" to both Big Pharma and life sciences investors) -- it would seem rational to not strike a regional transaction until the regulatory veil has been lifted. Two Chinese, one Indian and one Japanese pharmaceutical companies very recently entered into confidential disclosure agreements ("CDAs") with Provectus. I don't have a sense at the moment about the names of the Indian and Japanese firms, but I think one of the Chinese companies is Hisun-Pfizer Pharmaceutical. China economics for Pfizer continues to interest me: 25% of PV-10 sales if Provectus strikes a deal with a Chinese pharmaceutical company by virtue of owning/receiving that royalty figure, 49% if the Provectus partners with Hisun-Pfizer, and 100% if Pfizer goes it alone in China (since Hisun-Pfizer was established to produce branded generics).