"Intralesional rose bengal as an ablative immunotherapy for hepatic tumors"

Abstracts from the 26th Annual Conference of APASL (February 15th to 19th) are available here, including that of Provectus (shown below).

Click to enlarge. Right-hand side text.

Click to enlarge. Left-hand side text, and top right image.

PV-10's Pharmaceutical Alpha

In investment management, there are several measures of risk-return (aka risk-reward), including alpha, beta and Sharpe Ratio (see, for example, Forbes' Measuring Risk With Alpha, Beta and Sharpe Ratio by Richard Loth). Most investment professionals and retail investors do not outperform the market. Most investment funds, mutual, hedge or otherwise, after fees and expenses (and, more often than not, before too) do not generate alpha.

Alpha measures the value an investment manager adds to his or her fund portfolio. Warren Buffett, Jim Simmons, Ray Dalio, etc. established their reputations by generating lots of alpha for notable periods of times. Beta measure volatility. A beta greater than 1 means a portfolio (or security) will be more volatile than the market (less than 1 means less volatile, and equal to 1 means the same volatility). Many hedge funds generate high beta; that is, when the market goes up they go up higher, and when the market goes down they go down more. Some funds are low beta ones; they go up less when the market goes up and go down less when the market goes down. "Investors would most likely prefer a high alpha and a low beta." Sharpe Ratio measures risk-adjusted performance, and "...tells investors whether an investment's returns are due to smart investment decisions or are the result of excess risk."

While far from a perfect analogy, many or most of the pharmaceutical industry's oncology drugs generate beta. Few, if any, generate real alpha. Most have forgettable Sharpes. Layer on the cost of treatment (i.e., mutual fund costs or hedge fund fees and expenses), only the most effective drugs (i.e., the very best investment managers) deliver a compelling patient (i.e., investor) value proposition.

As I have written before on the blog before, and continue with the above analogy:

• Pharmaceutical Risk = Safety,
• Pharmaceutical Return = Efficacy, and
• Pharmaceutical Fees & Expenses = Treatment Cost.

PV-10 for melanoma (or any of the solid tumor cancers for which it likely should have great potential) is like a very high alpha, very low beta, very inexpensive-to-own fund.

Safe. Efficacious. Broad spectrum of use. Low cost.

✩     ✭     ✩     ✭     ✩

January 28th press release: Provectus Announces PV-10's Assessment for Drug-Drug Interaction Potential is Subject of Article Published by Xenobiotica

Byline: Demonstrates Risk of Clinically Relevant Drug-Drug Interactions with Rose Bengal is Low

Key Statement:

• "The published research indicated that the risk of PV-10 causing clinically relevant drug-drug interactions is likely minimal."
• "Sorafenib is a competitive inhibitor of cytochrome P450 (CYP) drug metabolism enzymes and is reliant on the UDP-glucuronosyltransferase (UGT) pathway for efficient clearance. CYP and UGT enzymes help to biotransform small lipophilic drugs like sorafenib into water-soluble excretable metabolites."
• "As we discuss our clinical results with regulatory authorities, we continue to be intensely committed to building all sections of the prescribing information for a future package insert for PV-10."

The paper's Discussion section helps to place the conclusion of low risk of clinically relevant or significant drug-drug interaction in context, and discusses what is known, what can by hypothesized, what is not known, and what requires or deserves more work. The paper and the PR begin to reveal more of PV-10's orthogonality (drug-drug interaction) potential. My posts on orthogonality are here, here, here and here.

Orthogonal, as you know, refers to the the idea of perpendicular, non-overlapping, independently varying or uncorrelated items. Two lines at right angles to each other are perpendicular, or orthogonal. X, Y and Z axes conventions reflect axes perpendicular (or orthogonal) to each other.

I think there are at least two key takeaways from this work and PR. First, clinical trial outcome. Sorafenib, co-developed and co-marketed as Nexavar by Bayer and Onyx Pharmaceuticals (acquired by Amgen in August 2013) is the standard of care for the treatment of advanced hepatocellular carcinoma. The company currently is running an expanded liver cancer Phase 1 trial comparing sorafenib (cohort 1) to PV-10 plus sorafenib (cohort 2). Sorafenib/Nexavar is not a very good drug, but it remains the go-to-solution for physicians for this disease.

By demonstrating low clinically relevant drug-drug interaction, all or most of the difference in efficacy between cohort 1 and 2 should be attributed, positively (more efficacy in 2 than 1) or negatively (less efficacy in 2 than 1), to PV-10. The trial is permitting a single intralesional injection of PV-10 in patients with either recurrent hepatocellular carcinoma (HCC) or cancer metastatic to the liver. Success data (higher efficacy in cohort 2 v. cohort 1), likely measurements should include overall response (complete, partial, stable) of injected tumors, would inform the FDA and impress Big Pharma, particularly if they are even remotely close to what was demonstrated for locally advanced cutaneous melanoma. Provectus has not updated the market on its liver cancer Phase 1 trial save this old information from its current website presentation.

Click the figure to enlarge it.

This biochemistry work published today is very useful for when the company shows its expanded liver trial efficacy results and analysis to the FDA and Pfizer, er, Big Pharma.

Second, market opportunity. "Three fourths of worldwide liver cancer cases in males and two thirds in females occur in the fifteen Asian countries." Sorafenib is not well liked in Asia for its utility (more so than in the U.S.). Sorafenib/Nexavar's price certainly is not liked there either. Nevertheless, the drug is the standard of care, until it is not.

"The drug, which is particularly effective on late-stage kidney and liver cancer, costs approximately $69,000 per year in India, so in March 2012 an Indian court granted a license to an Indian company to produce to the drug at a 97 percent discount" (quote source, and for the two quotes below, is here) "Nexavar costs approximately $96,000 per year in the United States, but Bayer assures “western patients” that they can have access to the drug for a $100 copay." [Bold and underlined emphasis is mine.] "In an interview with Bloomberg Businessweek, Bayer CEO Marijn Dekkers said that his company’s new cancer drug, Nexavar, isn’t “for Indians,” but “for western patients who can afford it.”"

A generic version of Nexavar may hurt Bayer/Amgen. PV-10 reducing Nexavar to near obsolescence certainly won't kill Bayer/Amgen, but the companies certainly will miss the sales (and that will impact earnings to an extent balance sheet financial engineering cannot fix). For example, in the U.S., $96,000 per year for Sorafenib/Nexavar, or a $20,000-30,000 "one shot, one kill," single use (multiple injections, if necessary) 100 mL vial of PV-10. The issue of treatment cost, in the U.S. and around the world, is far from resolved. The market opportunity for liver cancer for PV-10 still remains a very, very large addressable market times PV-10's likely very large market share times some price per treatment.

The lack of drug-drug interaction makes possible the combination of PV-10 and other drug therapies (chemotherapy, immunotherapies). That's, um, Pfizer and Provectus' joint patent application (Combination of Local and Systemic Immunomodulative Therapies for Enhanced Treatment of Cancer), which should be fully approved later this year.

This biochemistry work published today, assuming expanded liver cancer Phase 1 study data is consistent with other PV-10 liver and other cancer indication tumor results and more work conducted on combination therapies including PV-10 is successful, should open very significant market opportunities for Provectus and PV-10

$PVCT #AACR2013 Thoughts...

Two summary thoughts from today's release of the AACR abstracts, one by Moffitt and one by Provectus, follow.

Moffitt
The first one derives from the second to last sentence of Moffitt's abstract: "In total, these studies support the induction of tumor-specific T cell-mediated immunity after single treatment with IL-PV-10 in multiple histologic subtypes."

"Multiple histologic subtypes," an extremely comprehensive statement, refers to all cancer indications tested by Moffitt: breast, melanoma, ... Tumor specific immunity was achieved in multiple indications.

Chemoablation via PV-10 ablation causes antigenization, and antigenization causes immunization.

Wachter et al.
The second thought comes from the last sentence of the company's abstract: "The rapid reduction in tumor burden and tumor specific immunologic stimulation provided by PV-10 may complement the immune stimulation of anti-CTLA-4 antibodies such as ipilimumab without increased toxicity."

You will recall I wrote earlier:

The crux of the matter is that PV-10, as a local agent, needs to show systemic potential for life science investors, Big Pharma and the FDA to view the drug as clinically relevant. This is the local agent "burden of proof." There must be systemic potential to be relevant for treating cancer after surgery, where cancer is viewed by definition as a systemic disease. PV-10 is an drug with tremendous local efficacy and before unseen systemic benefit (even more so than systemic agents). 

But PV-10 still is a local agent. 

The mindset of the industry -- medical oncologists and hematologist-oncologists, but not surgeons -- is that a local agent has to be combined with a systemic agent to be relevant.  The industry does not yet realize how much of an impact PV-10 will be just as a local agent. All it can currently understand is that PV-10 works, and harnesses the immune system in novel manner. It is obvious to industry PV-10 will get even better systemic results when combined with other agents, or, other agents will get better results when combined with PV-10.

"PV-10 may complement the immune stimulation of anti-CTLA-4 antibodies...without increased toxicity:" Provectus further elucidates the concept of PV-10 orthogonality to systemic therapies; in this case, systemic immunotherapy in the form of anti-CTLA4 agents like Bristol Myers' ipilimumab (Yervoy) in murine model work. Ipilimumab gets better results when combined with PV-10, with no increased toxicity.

Orthogonality: In geometry, two lines (vectors) are orthogonal if they are perpendicular; that is, they form a right angle. Our three dimensions -- the x-, y- and z-axes -- are orthogonal because each is at right angles with the others: non-overlapping, uncorrelated, or independent of each other. In computer science, orthogonality is "a system design property which guarantees that modifying the technical effect produced by a component of a system neither creates nor propagates side effects to other components of the system." (Source: Wikipedia).

Previously, the company demonstrated orthogonality (in pre-clinical work that led up to the upcoming human trial) with systemic chemotherapy agent sorafenib (in the case of liver cancer/HCC). Sorafenib gets better results when combined with PV-10, with no increased toxicity.

Later, Provectus provided results of orthogonality with [inexpensive] systemic chemotherapy agent 5-fluorouracil ("5-FU") in murine model work. 5-FU gets better results when combined with PV-10, with no increased toxicity.

$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.