$PVCT: Fight The Power, Or Play The Game?

Information technology, and some other industries, seems so much easier to invest in than life sciences from the perspective of disruptive technology or approaches being able to fully disrupt. To those to whom this is an obvious statement, you are smarter than me.

My experience and ease with information technology has been to focus on how to use technology, not how or why it works. Don't get me wrong. It was, is and probably will be in my nature to figure out the hows and whys, but a childhood friend of mine years ago framed the situation and solution to me very clearly: (paraphrasing) "Figure out what you're going to do with the box and how much (or whether)/how quickly/how long you'll make doing it, and don't sweat too much how or why the box does what it does."

In the same breath (actually, years later, but I figured it out shortly after the above "epiphany"), he said it's important to have a decent or good understanding of how or why technology works the way it does to keep the inventors of it (e.g., academics, scientists, engineers, etc.) honest -- i.e., be able to call bulls@$% when applicable and appropriate.

How important is understanding "mechanism of action" if PV-10 works: so efficaciously, so broadly, so safely, so easily?

Martin Shkreli wrote in his article on TheStreet.com about Oncothyreon's Stimuvax failure that "A drug's mechanism of action is central to its effect. Do not ignore this! Clinical data can be misleading, innocently biased, meaningless, manipulated and sometimes even downright doctored. However, the question, "How does the drug work?" is always critical." I can understand his point of view, because it you think you understand the MOA (or how or why the technology works the way it does), you're more apt to believe that it does indeed do what you see or read it does.

Working still is working.

This March, we read from Moffitt that, via the titles of Provectus PRs, "mechanism of action data on PV-10 demonstrates therapy induces immunologic response" and "intralesional PV-10 treatment leads to the induction of anti-tumor immunity." Will Moffitt, sometime next year, make more profound statements about PV-10?

Like, PV-10: A robust (strong), durable (long-lasting), portable (vaccine-like) immune-mediated response.

Moffitt est argumentum ad verecundiam. "As a statistical syllogism, the argument has the following basic structure:

• Most of what authority A has to say on subject matter S is correct.
• A says P about subject matter S.
• Therefore, P is correct."

Because if, after further, fuller elucidation of PV-10's immunological mechanism of action characterization, you now like the story, or now feel comfortable you think you know why it does what it does, you're more likely to pay a lot more for it, and drive up the price for the folks who just cared that it worked well and safely.

"Come, Watson, come! The game is afoot. Not a word! Into your clothes and come!"

$PVCT: Blog Reader Question

I really appreciate your posts. Please keep them coming. One issue that I am having with the continued lack of any licensing agreement or income, is if perhaps PVCT is pricing itself unrealistically? I have seen this happen to companies before, when they think they know what their product is worth, but no one else is willing to pay so much for it, and they just go on and on without ever signing anything. They go to their graves secure in the knowledge that no one has taken unfair advantage of them, but without ever cashing in their product which does have genuine value. You wrote that " license interest and discussions are heating up." If this is so, then what I am fearing is not a problem.

Great comments and question, and thank you.

I have had prior experience with management or [particularly] founding teams being unrealistic: about technology, the product, valuation, and other issues. It is frustrating as an investor and shareholder to see intransigence, derived from lack of realism or pragmatism (or both), overtake what started out as a great investment opportunity.

My interactions with Provectus management have not caused me to question their realism as it relates to valuation. Craig and Peter will tell you, quickly, often and repeatedly, they routinely seek out counsel in this area, and enjoy the benefit of several very experienced counselors.

While Craig strikes and has always struck me as fundamentally understanding the value of what the team has innovated, he does not seem to be ideological about valuation. While the check will have to be very large, I do not think him a person desirous of extracting every last dollar from a/the would-be acquirer.

That said, I am struck by management's perspective about the potential impact on valuation of PV-10's immunologic potential. Repeating a portion of a post of mine from a couple of days ago:

The conclusions of the forthcoming immunologic mechanism of action characterization work by Moffitt Cancer Center could be profound. Will Moffitt researchers make full-throated statements regarding PV-10's immunologic potential?

$PVCT.OB: PV-10 -- A Vaccine, or Vaccine-like

Click on the figure to enlarge it.

The abstract and poster from Craig et al.'s participation at the Society for Immunotherapy of Cancer (SITC) 27th Annual Meeting has begun the elaboration of the anti-tumor immune response to PV-10 immuno-chemoablation. This publicly builds upon Moffitt's description of PV-10's immunologic mechanism of action, presented at the 2012 Society of Surgical Oncology Annual Meeting, that confirmed PV-10 chemoablation of melanoma lesions leads to a systemic response and the induction of systemic anti-tumor immunity.

In the SITC abstract (above) Craig et al. hypothesized production of a vaccine- like immune response using a small molecule drug was possible and required:

• An intralesional route of injection that generates rapid, durable tumor destruction via autolysis;
• Rapid clearance of drug from normal tissue; and
• Anti-tumor effects targeted only to tumor tissue.

According to Provectus, PV-10 appeared to meet each of these requirements.

"Treating cancer has historically relied on a trifecta of treatments—surgery, chemotherapy, and radiation—known colloquially as “slash, poison, and burn.” Vaccines have a potential advantage over these three options in that the body’s response is longer lasting (on a scale of years as opposed to weeks or months), which could possibly eradicate the micro-metastases that often linger after standard treatments end. Moreover, cancer vaccines have similar minor side effects to traditional vaccines: inflammation at the injection site and flu-like symptoms." Read more here.

"Cancer vaccines are designed to boost the body’s natural ability to protect itself, through the immune system, from dangers posed by damaged or abnormal cells such as cancer cells. The FDA has approved two types of vaccines to prevent cancer (Gardasil® and Cervarix®): vaccines against the hepatitis B virus, which can cause liver cancer, and vaccines against human papillomavirus types 16 and 18, which are responsible for about 70 percent of cervical cancer cases. The FDA has approved one cancer treatment vaccine for certain men with metastatic prostate cancer (Provenge®)." Read more here.

Click on the figure to enlarge it.

The great anticipation of Moffitt's next presentation(s), purportedly at the AACR Annual Meeting 2013 that will be held April 6-10 in Washington, DC (according to sources external to Provectus), derives from the release of more results and conclusory statements regarding the production of a vaccine-like immune response from PV-10 immuno-chemoablation, and both the preventative and therapeutic vaccine or vaccine-like benefit of the drug.

$PVCT.OB: When Does PV-10 Fail?

"Put enough water onto the fire, and it goes out."

The compassionate use program, where doctors have significantly more flexibility than in the clinical trials to treat and re-treat patients revealed much to Provectus management about what the drug can truly accomplish when it enables the body's own immune system to cure cancer in a patient (and how to better design the pivotal MM Phase 3 trial). Put enough water onto the fire, and it goes out. Regularly treat the patient with enough PV-10 and, over time, the cancer goes away.

Constrained by treatment. As such, some trial failures of PV-10 are not actually failures. Some "failures" occur out of necessity because of the design of the trials. In both the dermatology and oncology studies, management was inhibited by the trial design per regulatory compliance. In the MM Phase 1 and 2 trials, principal investigators were only allowed to inject a few tumors. Nevertheless, you have to be impressed by how well the bystander effect worked given the trial constraints hamstringing the treatment approach. Injecting all accessible tumors with PV-10, of course, would be best. The impact of this is to (a) lower the tumor burden and, thus, the load the patient's immune system has to overcome, and (b) address tumor heterogeneity. Tumors are heterogeneous; that is, they are not all the same antigenically (i.e., what they present to the immune system). So, if the antigens the immune system needs to see are on in one tumor and not another, it is vital to inject PV-10 into as many tumors as possible.

Constrained by time of reporting. Some patients were fine at, say, week XXX; however, the trial design required observation at week X (XXX > X). Efficacy at week XXX, even if higher or better, goes unreported. The patient was listed as a failure.

Constrained by physician implementation. The trial design prevented tumors from being injected more than once: A doctor missed a tumor. There was no ability to retreat to correct the miss. The patient was listed as a failure.

Constrained by patient behavior. It is rumored a PV-10 trial patient flew from the U.S. to Australia in order to participate in the MM Phase 2 trial. His tumors were injected, and they went away. Apparently, it also is rumored that he broke his promise to stay and be observed, and returned home to the U.S. The patient was listed as a failure.

Our immune system can be overwhelmed. As with an infection, doctors use antibiotics to slow it down until the immune system itself can clear it away and cure the patient. If the host cannot help, there is no cure.

Provectus treats cancer like an infectious disease.

Thus, in the case of very late stage disease or very heavy tumor burden disease, more PV-10 is applied at the outset, the drug is applied again and again (i.e., re-treat or throw more water onto the fire), or PV-10 is combined with radiotherapy, chemotherapy or other immunotherapies to stimulate the immune system, reduce the burden and "hold the infection in place" and, eventually, allow the patient's immune system to takeover and finish the task of healing the body.

Failure? Perhaps not so much.

$PVCT.OB Blog Reader Question

I read an old interview (2010) with Craig Dees where he explained the novelty of their
approach in targeting the tumor as opposed to just using a systemic agent that is
(hopefully) more active on the tumor than on the healthy cells. What I was not clear on
is: is this a new philosophic approach, or is it expressed in chemistry? Do they have
some chemical delivery system that is being used to deliver Rose Bengal to the
tumors? Is the novelty of their approach that they are looking for something to target
the tumors directly as opposed to the approach used up to now?

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 Carl Olson 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.

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, systemwide antitumor 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.

Rather than a new philosophic approach, Craig views Provectus' work as the creation of a new paradigm. See The Structure of Scientific Revolutions by Thomas S. Kuhn. "Kuhn argued for an episodic model in which periods of such conceptual continuity in normal science were interrupted by periods of revolutionary science."

People have tried the intra-tumoral route with little or no success. Some approached getting the immune system to act in the manner described above by Dr. Olson. Still others discovered tumor-killing autophagy induced specific, system-wide, antitumor immunity.

Why did others fail to do it well? In Provectus' view, other drugs killed cancers through toxicity rather than tumor tissue specificity, and thus had poor efficacy and problematic side effects. The drugs killed normal tissue, leaked out and systemically poisoned patients, preventing the proper and effective stimulation of the immune system.

PV-10 kills by autophagy and is very much focused only on diseased tissue. According to the company, stimulation of help by the host's anti-tumor defenses appears to be mediated by T-cells and direct actions on antigen-presenting cells. Management thus believes the approach to treating cancer with PV-10 is a new paradigm: Treat cancer like it is an infectious disease. Of course, don't use systemic poisons. Ultimately, however, components of Provectus's approach include pieces of other knowledge assembled to form a whole new approach: A therapy that functions.

$PVCT.OB: Blog Reader Questions

Would a repeat of the study with HCC and melanoma cell lines make sense using pancreatic and breast cancer cell lines? If so, would that be significant to Big Pharma when these 4 studies are viewed collectively?

I think there are some technical challenges, especially with breast cancer. Cancers have to be Major Histocompatibility Complex-matched to the host. Cancer, including mouse cancer, should immediately be killed by the immune system. That is why organ transplants have to be matched as closely as possible. Anti-tumor immunity does not reason. It kills what is not identical to the host.

I do not know of mouse breast cancers lines that would match an immuno-competent host. I think Provectus already has successfully treated naturally occurring breast cancers in mice, and killed human breast cancers produced in mice deficient of anti-tumor immunity (nude mice). I recall Craig showing these pictures in past presentations. I think naturally occurring breast cancer has been treated in dogs. Breast and prostate cancer markets are very hard to penetrate except in very late stage disease, which makes success expensive for Provectus to pursue and achieve in small markets at this tine. Target markets like liver cancer are more accessible.

I think management some pancreatic cancer data in mouse models, ablating pancreatic cancer tumors and again observing the bystander effect. Running more mechanism variants in animal models probably would not add value. One real problem with pancreatic cancer is diagnostic, as it often is very widespread when detected. The immune system can be overwhelmed. For now, it is an open question, and one only answered by trials, as to the value for the company for this disease. A combinational therapy approach probably would have the highest chance of success.

As I previously wrote, I think other types of cancer tumors also have been studied by Moffitt. Mechanism of action is not required for FDA licensure, only safety and efficacy. To secure permission to run trials in humans, Provectus has to demonstrate to regulatory authorities that PV-10 appears safe and has potential benefit, not how it works. The company has run most of its studies with that goal in mind. Other goals have included hoping to improve efficacy or expanding into new indication markets.

As for adding value to Big Pharma, the greatest additional value would be demonstrating safety and efficacy in humans. The vast majority of the melanoma market is not very late stage disease. In the melanoma studies, the majority of the market is lies between early stage 4 and earlier, which is where the MM Phase 3 trial was designed to target. A small percentage of the market is very late stage disease.

Part of Provectus' recent presentation at the SITC 27th Annual Meeting clearly was directed at expanding into the very late stage disease market area by using a combined therapy treatment protocol. I think management believes it is the right thing to do for ethical reasons even though it could gain little in market size.

Work with models should be expanded to and published data should be available for other chemo- and immunotherapy agents (e.g., anti-CTLA 4). The goal would be to demonstrate safety and efficacy in these models with the subsequent goal of asking regulatory authorities for permission to test the combined protocols in humans.

A similar path has been followed in expanding the liver studies in people for late stage disease or disease with heavy tumor burden that might be overwhelming the human immune system. Provectus should have data on the combined therapy (PV-10 + sorafenib) in mice and permission to test the combined therapy in humans, which I think would start as soon as the trial site is able to begin the study.

$PVCT.OB: The Orthogonality Paradigm

Yesterday's PR of Craig et al.'s poster at SITC highlighted additional data that demonstrated the use of PV-10 in combination with systemic chemotherapy. The combination cancer treatments, whether chemotherapy, radiotherapy or immunotherapy, is a growing theme within the medical community. In the case of the work presented at SITC, PV-10, the immuno-chemoablative therapeutic agent, was combined with a systemic chemotherapeutic.

Pre-clinical and clinical data has shown PV-10 generates immunity even in patients afflicted with very late stage cancer. The immune system, however, can be overwhelmed by cancer (and infections). Management thinks the key, for very late stage disease, is to use a chemotherapeutic or another systemic immunotherapeutic agent (like Yervoy/Ipilimumab) to wound the cancer (the infection) just enough so the PV-10-generated immunity can finish it off. Like antibiotics, PV-10 and the application of other therapeutic agents in this manner (i.e., to wound cancer, before PV-10 finishes it off) would not cure anyone. Rather, they hold or bound the infection until the body's natural immune mechanisms can do the job of curing it.

Next up should be the results of combining PV-10 and anti-CTLA-4 system immunotherapeutic agents like Yervoy/Ipilimumab.

Note the importance of Provectus joint patent application with Pfizer for combining local and systemic therapies for enhanced treatment of cancer. More questions arise: How good were the pre-clinical results from combining PV-10 and Yervoy/Ipilimumab? What would the beneficial impact be on very late stage metastatic melanoma cancer patients from this combination? What would the implications be for Bristol-Myers Squibb, and for Pfizer (which retained the right to certain combinations of therapies with tremelimumab?

This Provectus work foreshadows Moffitt's subsequent murine results, having initially reproduced Craig and the team's work and identified the quintessential immune response: a more complete assessment of PV-10's immune-mediated response, demonstration on multiple cancers and in combination with other therapies, and the durability of the immune response (through various challenge studies).

Ultimately, the “orthogonality paradigm” demonstrates PV-10 is orthogonal to (neither impacted by nor having an impact on) other therapeutic agents. This is important because PV-10 would be used first, second and at all times during patient treatment.