June 24, 2012

Munich, And Beyond

Provectus' clinical data to date paints a very clear and very promising treatment picture of injected lesions. Inject PV-10 directly into a melanoma lesion (i.e., deliver the drug intralesionally), and the lesion shrinks a lot. Injected lesions shrink a lot of the time. The preliminary objective response of the metastatic melanoma Phase 2 trial, both complete and partial response, was 49% (55% for unresectable Stage 3 and early-Stage 4 (i.e., M1a), which is the target patient population for the label management seeks for PV-10 from the FDA). The trial's local-regional control, comprised of complete and partial response and stable disease, was 77%; here again, loco-regional application is part of the desired label. There is no doubt the FDA thinks PV-10 should be used as a local agent to treat metastatic melanoma. With an SPA in hand, patients and their doctors will be a major step closer to broadly accessing the drug for local treatment of melanoma.

Craig frames Provectus' approach to treating cancer in the following way: the harder you punch the immune system, the greater the response. He references a lecture by a veterinary virologist who showed a picture of a cow with a basketball-sized papilloma hanging from its stomach. The professor said, paraphrasing: "Cut that off aseptically and cleanly, and it will grow back every time. Tear it off, make it bleed, kick dirt into the wound, and it will never come back." Shock the heck out of the immune system with tissue destruction (wake it up), break tolerance and encourage a large-scale release of tumor antigens into the system so they can be seen in context. 

The clinical data to date also has provided a perspective on PV-10's effect on bystander lesions. If injected lesions had a positive objective response, patients' bystander lesions did as well: preliminarily, a 67% objective response and 72% loco-regional control. To many, the "problem" is the available data does not provide a clear picture of the reduction of patients' overall disease burden. It is not possible to tell from the Phase 2 clinical data if PV-10 provided an overall clinical benefit. It's one thing to clear up an injected lesion, but it's another thing to positively impact cancer that has spread to other parts of the body, like internal organs or lymph nodes.

What does the final data for the metastatic melanoma Phase 2 trial show? Did injected lesion response rates improve over preliminary results? If so, how much and why [did they improve]Did bystander lesion response rates improve over preliminary results? If so, how much and whyWhat was the response from the overall disease burden? How long did responses; how durable were responses? Munich results should be available on Tuesday.

Dirt (in the story above), like a vaccine adjuvant, riles up the immune system causing it to attack. Much of what Provectus  is doing is treating cancer like an infectious disease, and recruiting immune system help. There's another explanation, besides "PV-10 did not work," for non- or poorly responsive injected lesions and bystander lesions that responded poorly or did not respond at all. PV-10's mechanism of immune response is an autophagy-induced, system-wide anti-tumor one. Sufficiently inject the lesion (or tumor); induce autophagy and shrink or eliminate the lesion; and, induce the immune system, via the antigens released from successfully treating the injected lesion(s), to successfully treat bystander lesions and remote cancerous locations. In other words, effectively punch the target lesion enough so the immune system can more effectively punch cancer around the patient's body enough. Proper action. Beneficial reaction.

In their first model, Moffitt treated C57BL/6 mice with PV-10 and saw 3 of 5 mice with 3 or less lung metastases (3, 0 and 1, respectively) while all control mice treated with PBS had over 250 lung metastases. Moffitt's goals were to see if PV-10 produced a systemic response, since any such response for an intralesional (local regional) agent is unheard of, and, more importantly, understand the nature of tumor-specific immunity and the interferon gamma production assessment.

If they wanted to (i.e., if the goal of the work was to cure the mice), Moffitt could have gone 5-for-5, by injecting more drug directly, with additional re-treatments, or simply more in general.

The Munich presentation and Moffitt's work marks the beginning of a much better understanding by the broader market (e.g., FDA, big pharma, key opinion leaders, medical community, serious life sciences investors, etc.) of the vast potential for systemic benefit PV-10 delivers to patients.

Perhaps even the beginning of the end-game?

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