Moffitt Cancer Center

How does a paradigm shift in a highly regulated industry like pharmaceuticals? Change happens through acceptance and adoption. How does a disruptive technology disrupt in a highly regulated industry like pharmaceuticals? Acceptance and adoption by the governing regulatory body, the FDA, needs to occur, and it facilitates (invites) the disruption. Ultimate validation for Provectus only comes with an Agency stamp, which should begin with attaining a breakthrough therapy designation for PV-10 Provectus says it would request in 1Q14 and for which it would expect a response within 60 days of FDA receipt.

There is no doubt of Big Pharma's challenge: "More innovation. Better innovation. Affordable innovation." "Breakthrough must be seen through the eye of the patient (user), not the scientist. Gleevec is a breakthrough… so is Augmentin, Zocor, Aranesp, Humulin. Lipitor is not a breakthrough" (Source: The State of Pharmaceutical Innovation, Bernard Munos, InnoThink Center For Research in Biomedical Innovation, July 2012). Entrenched incumbents in a highly regulated environment with substantial balance sheets facing their so-called Kodak moment can draw out the inevitable. It takes is time..."This thing all things devours; Birds, beasts, trees, flowers; Gnaws iron, bites steel; Grinds hard stones to meal; Slays king, ruins town, And beats mountain down."

Until we learn more about the regulatory path to approval, what more has Moffitt Cancer Center to say about PV-10?

When I wrote in my September 2013 investment letter PV-10 exemplifies innovation over incrementalism, meaningful over marginal, productized technology over hypothetical, and changing the world over accepting the status quo, with not an insignificant amount of serendipity over contrivance...[i]n sum...the quintessential essence of a paradigm shift in the treatment of cancer, I refer to the disruptive nature of this life sciences technology from a user (patient) perspective: very safe, very effective, very inexpensive. The speed of adoption and acceptance (assuming first and foremost a regulatory embrace) relies on the breadth and depth of the customer (user (patient)) value proposition, and the convergence of the swirling winds of change impacting the industry's operating environment. As a giant pharmaceutical company, you no longer can sustain a business that charges tens and tens and tens and...of thousands of dollars for oncology drugs that fail to offer more than nominal tumor destruction, fail to meaningfully prevent recurrence, and fail to meaningfully overcome drug resistance.

While Provectus' stated path to initial approval in the U.S. for PV-10 would be locally advanced cutaneous melanoma, Moffitt's translational research work on the drug has been "...to find out more about how PV-10 works in melanoma tumors...[and] changes in the body's immune cells (cells that fight infection and illnesses) after PV-10 is given, both inside the melanoma tumors and circulating in the blood." As a patient, enrolling in Moffitt's Phase 1 feasibility study is not about seeking a clinical trial to successfully treat your affliction (NCCN guidelines suggest seeking a clinical trial as a treatment option for certain stages of melanoma). Rather, this pilot study is about agreeing to be experimented on by Moffitt researchers, presumably for the betterment of others (what Moffitt learns about PV-10 could help many more patients). One would hope the enrolled patients beneficially exit the trial having received sufficient successful PV-10 treatment (after researchers have literally extracted the information they desire and require).

Moffitt's August 2013 press release revealed their preliminary understanding of PV-10's "one shot one kill ability:" Single Injection May Revolutionize Melanoma Treatment, Moffitt Study Shows. If enough PV-10 is injected into a melanoma tumor -- the volume of PV-10 for injection (the amount in milliliters) should be proportional to the volume of the tumor -- the tumor is destroyed. For other indications, like liver or breast cancer, I imagine the surrounding organ or body tissue would influence the required drug volume. For example, PV-10 per unit volume of melanoma tumor should be different than PV-10 per unit volume of breast tumor because the makeup of skin tissue should be different than the makeup of breast tissue.

PV-10 is both a targeted therapy, and an immunotherapy. As a targeted therapy, it quickly destroys the tumor into which it is injected through its rapid ablative effect, which is the basis for the company's regulatory approval value proposition (locally advanced cutaneous melanoma). As an immunotherapy, the drug generates a systemic tumor-specific immune response in which Moffitt is interested and that has formed the basis for the center's work to date (and which would provide additional data and knowledge to expand the label over time). Although immunotherapies win over targeted therapy because of long tails, there is value to combining their benefits. It's great if your drug does both.

When we last heard from Moffitt (aside from their August 22 PR), pre-clinical murine study work, the center concluded: "...intralesional PV-10, in addition to reducing the growth of a directly injected tumor, leads to the induction of a robust anti-tumor T cell response and supports the use of PV-10 to induce systemic anti-tumor immunity for the treatment of metastatic melanoma and breast cancer."

Moffitt last presented PV-10-related results at the April 2013 Annual Meeting of the American Association for Cancer Research: PV-10 Data Presented by Moffitt Cancer Center Researchers Examines Induction of Systemic Immune Response in Multiple Tumor Types (prior to that, the March 2012 annual meeting of the Society of Surgical Oncology). The 2014 AACR meeting runs from April 5-9. I imagine we may learn more about the center's pre-clinical and clinical work. While unlikely because Moffitt's clinical work is a Phase 1 study, there of course is the 2014 Annual Meeting of the American Society of Clinical Oncology from May 30-June 3.

Click to enlarge the figure.

What's next?

I'm sure Moffitt researchers are interested in a lot of things as it relates to PV-10. The February 2013 Cancer Watch article about the Phase 1 study noted: "The focus at Moffitt, Dr. Sarnaik continued, 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." Producing lots of T-lymphocytes isn't the issue or challenge. Producing lots of good to great ones is. I imagine Moffitt succeeded in getting their "yes" or "no" answer. I also am curious whether the center is looking at a PV-10 injection into a tumor as an in vivo (in the body) adoptive cell (T-cell) transfer "mini-reactor." Ex vivo (out of the body) adoptive cell transfer ("ACT") therapy is expensive, and limited for now to centers with the expertise and resources (like the NCI, MD Anderson, Moffitt).

At AACR 2013, Provectus also presented a poster entitled Combination of PV-10 Immuno-chemoablation and Systemic Anti-CTLA-4 Antibody Therapy in Murine Models of Melanoma, concluding that for "visceral or other inaccessible disease the combination of PV-10 with CTLA- 4 blockade has important potential for synergy." Given PV-10, according to the company, has no known toxicity nor no known resistance, its combination with PD-1 drugs, among other immunomodulatory agents, may allow these drugs to better function by overcoming the body's eventual resistance to them. Perhaps Moffitt may discuss this as well.

One of my favorite songs...