September 19th, 2013
Special Report

Provectus Pharmaceuticals Inc. and PV-10: Rose Bengal as a Novel Cancer Therapeutic

Peter Culpepper Despite all of the advances in diagnosis and treatment, the family of diseases that falls under the umbrella of "cancer" still represents a significant unmet medical need. Consequently, research continues in the discovery and development of therapeutic agents with novel mechanisms of action, wider therapeutic indexes and lower overall toxicities. In this interview with The Life Sciences Report, Peter Culpepper, CFO and COO of Provectus Pharmaceuticals Inc., describes his company's innovative rose bengal formulation and its use as a cancer therapeutic.


Management Q&A: View From the Top

The Life Sciences Report: Rose bengal is commonly known as a dye. Can you tell me about the history of this compound as a therapeutic agent?

PC: Rose bengal is a very unusual compound. It was originally used as a textile dye in the late 1800s, and later found a wide variety of diagnostic applications. There are more than 3,500 peer-reviewed publications describing the use of rose bengal in staining diseased tissue or identifying tissue irregularities.

Provectus Pharmaceuticals Inc. (PVCT:OTCQB) has determined how to use rose bengal therapeutically—the first to do so. In the late nineties, and after more than a hundred years of diagnostic use, we identified rose bengal's therapeutic potential for treating cancers and serious skin diseases by taking advantage of its photosensitivity characteristics.

TLSR: A recently published study by the Moffitt Cancer Center demonstrated that a single injection of PV-10, your rose bengal formulation, may revolutionize melanoma treatment. This could be very significant for Provectus. Can you comment on the results of that study?

PC: Moffitt Cancer Center is one of the National Cancer Institute's 41 comprehensive cancer centers in the U.S. Moffitt is particularly active in melanoma research and has a strong understanding of rose bengal and its safety profile. Beyond this, Moffitt wanted to learn if this agent induced an immune response. This was important because PV-10 is an injectable, and is not delivered systemically.

The Moffitt study established that concentrations of rose bengal will destroy diseased tissue. Furthermore, an immune response follows: The study concluded that when PV-10 ablates, or reduces the growth of directly injected tumors, a robust antitumor T-cell response follows. This was observed in all cancer types studied—not just in melanoma. While Provectus sponsored this study, Provectus is not listed as an author. This is an independent study that proves to the industry that PV-10 works systemically.

TLSR: Regarding toxicity, what makes your rose bengal formulation attractive for development?

PC: Rose bengal operates through a novel mechanism of action. Our formulation, PV-10, is 10% rose bengal in a saline solution, the highest achievable concentration of rose bengal in an injectable. We found that, in this solution, rose bengal is agnostic to any type of cancer. The attractiveness for development is that PV-10 can be used in every cancer that you can get a needle into. It has multi-indication potential and can treat solid tumors in the breast, prostate, bladder and elsewhere.

Rose bengal has been used as a liver diagnostic for decades, and is useful for treating liver cancer. This is important because many cancers metastasize to the liver. Also, because PV-10 is minimally invasive and rose bengal is optically dense, direct injection into solid tumors is straightforward—you can image it as it is being delivered.

"After more than a hundred years of diagnostic use, we identified rose bengal's therapeutic potential for treating cancers and serious skin diseases."

Finally, rose bengal is small molecule, not a biologic. It is synthesized in large quantities in a straightforward manufacturing process. Thus, PV-10 is a cost-effective, multi-indication injectable that can potentially be used in both the pre- and post-surgical arenas, either as a stand-alone or as an adjunct cancer therapy.

TLSR: Going back to your previous statement that PV-10 works by stimulating the immune system, can you describe how that is accomplished?

PC: A study presented at the Eighth World Congress of Melanoma describes the cytotoxicity of unformulated rose bengal, and its ability to preferentially kill diseased tissue over healthy tissue with a wide therapeutic window. The study, titled "Rose Bengal—Phototoxicity Versus Intrinsic Cytotoxicity," concluded that an interplay of cell necrosis and autophagy (in which a cell "digests" itself) is a possible mechanism of action.

We call this interplay "autolysis." Through autolysis, we are forcing cell destruction by delivering enough rose bengal to the tumor site. Following autolysis, work at the Moffitt Cancer Center demonstrates that cellular antigens are exposed to the immune system. The "antigen storm" that follows PV-10-induced autolysis results in the immune system being activated against the cancer. Rapid destruction of the tumor follows.

TLSR: Rose bengal operates in the absence of light-stimulated activity. Can you comment on that?

PC: Rose bengal is unique partly because it has photodynamic characteristics. It can be used as a photodynamic therapy (PDT) agent, as we're demonstrating in the treatment of skin diseases like psoriasis and atopic dermatitis. But rose bengal can used for both PDT and non-PDT applications. For cancer, we don't need light. Rose bengal delivers a pure cytotoxic effect that is safe and well tolerated. It is not metabolized in the body and it has a 30-minute half-life once in the bloodstream. Due to this rapid systemic clearance, intravenous delivery was never able to achieve therapeutic levels. Our therapeutic levels are achieved through direct injection into tumors.

TLSR: How would PV-10 be better than traditional chemotherapeutic agents, antibody-drug conjugates and photodynamic therapy?

PC: PV-10 differs from traditional chemotherapy because of its specificity. There is a wider therapeutic window with rose bengal, compared to chemotherapeutic agents, because it only goes to diseased cells. As a compound, rose bengal does not interact with normal cell membranes. It does, however, interact with cancer cell membranes. Furthermore, rose bengal prefers the lower pH intracellular environment of cancer cells, though it can also prefer higher pH environments. Rose bengal goes different ways in different scenarios, which makes it a very flexible molecule.

"The attractiveness for development is that PV-10 can be used in every cancer that you can get a needle into."

Chemotherapeutic agents are not specific enough to avoid toxicity challenges. Even antibody-drug conjugates don't target individual properties of cells. We're not looking at a particular protein or enzyme, or a particular pathway. Rose bengal destroys cancer cells because it is attracted to cancer cell walls. This is why rose bengal works on every tumor type that we've tried.

TLSR: There are cancers, such as esophageal cancer, that respond very well to photodynamic therapy. Do you envision instances where you would leverage the photodynamic properties of rose bengal as a cancer treatment?

PC: Esophageal cancer could be one example. But there is a complication. Because rose bengal is optically dense, if you have too much in a particular area, it absorbs light and will not facilitate the mechanism that allows cell destruction. Too much rose bengal limits its PDT capability. That's why the concentration of rose bengal in the skin formulation, where we need to take advantage of light, is much less than in the formulation we use inside the body, where we don't need light. Most solid tumors, according to our research and the research of others, react to rose bengal without light.

TLSR: We have talked about melanoma as your initial target indication. How are clinical trials progressing?

PC: We presented final phase 2 data for the use of PV-10 against metastatic melanoma at last year's European Society for Medical Oncology (ESMO) congress. We reported a 51% objective response, a 25% complete response and a 26% partial response. We also found that results improved when patients received all the PV-10 they needed for their lesions. Disease control is very good, and progression-free survival is very good. These results, and additional data, will be presented at this year's European Cancer Congress (ECCO). Finally, the key opinion leaders in the cancer community believe that PV-10 should be developed to approval.

TLSR: Can you comment on what kind of efficacy you're seeing for PV-10 in additional cancers?

PC: The most exciting results on that front would be in primary liver cancer. We have already done a phase 1 study in hepatocellular carcinoma (HCC). These patients have advanced disease, and have already gone through appropriate local therapies, including surgery. Direct injection of PV-10 in the liver lesions of these patients resulted in substantial ablation of the lesions with sustained regression. There is significant durable response, with no evident disease detected during the follow-up period, as determined by CT scan.

Many of the study's subjects—the phase 1 trial was small, involving only six subjects—have been followed for years. Because of its success, the study was expanded to look at safety and efficacy in up to 36 additional patients. Of particular interest are patients on sorafenib, the current standard of care. Our next studies will be designed to look at PV-10 both in addition to, and against, sorafenib.

"The [Moffit Cancer Center] study concluded that when PV-10 ablates, a robust antitumor T-cell response follows."

Following HCC, we have enabling data against breast cancer. We believe there's significant promise in breast cancer because PV-10 can function in the tissue-sparing capacity, much like in the Moffitt study treating melanoma patients. Down the road, we are interested in additional indications, including refractory scalp sarcoma, squamous cell carcinoma, and both pancreatic cancer and ocular melanoma metastasized to the liver.

TLSR: Would you envision being able to treat primary pancreatic cancer, and other difficult cancers like glioblastoma?

PC: We have an investigator who's interested in treating primary lesions in the pancreas. We have seen potential for the immunologic affect of the agent in the pancreas and there's a rationale for direct injection of PV-10 into pancreatic lesions. However, because pancreatic cancer presents with multiple smaller lesions, you have to hope that once you ablate the lesions, the immune system will be appropriately harnessed to assist in the regression of pancreatic cancer that is not directly treated.

In addition to pancreatic cancer, there's a significant interest in bladder cancer and cancers of the head and neck, which are generally very difficult to surgically remove.

TLSR: When do you expect to launch PV-10 for melanoma?

PC: A lot depends on how fast we get regulatory clarity from the FDA, which we expect this year, in 2013. It's fair to say that it would make sense to consider a breakthrough therapy designation. The breakthrough therapy designation could enable us to accelerate the path. Should we obtain breakthrough therapy designation, we could see a PV-10 market entry for melanoma sometime in late 2014. Without the breakthrough therapy designation, we are looking at a standard phase 3 study design, with product launch sometime in 2016.

TLSR: How soon after melanoma would you expect to launch for treatment of additional cancers?

PC: Liver cancer would be our next indication. If we can show, in a pivotal, powered, randomized study, that PV-10 is superior in combination with, or versus, the standard of care, sorafenib, we could have an opportunity for an accelerated path in liver cancer as well, including the breakthrough therapy designation. Furthermore, as indicated in our FDA filings, with an appropriate partner we would be able to leverage considerable additional development resources to advance in additional indications.

TLSR: We talked about how PV-10 works as a potential additive and in synergistic response to other cancer therapies. What kind of market share do you expect for PV-10 as a co-therapy?

PC: When we do the discounted cash flow analysis, we're looking at a maximum penetration of 25% for the different cancer indications. The key opinion leaders want to use PV-10 for surgical candidates, as a monotherapy post-surgery and in combination with other therapies when significant inaccessible disease burden to PV-10 exists. These scenarios cover all the bases, because PV-10 is well tolerated and can be used on either an outpatient basis or for short hospital admissions. We anticipate 35% market penetration for melanoma alone. For at least one third of all stage 3 and stage 4 melanoma patients, lesions can be directly injected.

TLSR: Are there instances where a patient might be a non-responder to PV-10? Do you envision a way to determine if a patient will be a responder versus a non-responder?

PC: Rose bengal and PV-10 are completely agnostic to tumor biomarkers. It doesn't matter if a patient is refractory or naive. It doesn't matter what type of therapy the patient is on. PV-10 responds equally, across the board, to all lesions in all patients.

For some lesions, the morphology is such that the response does depend on lesion size. In these cases, repeat injections may be necessary. If you keep at it, you'll be able to fully ablate all the lesions you can directly access. In this regard, PV-10 is a general tool that is independent of and complementary to personalized medicine.

TLSR: Thank you Peter. I enjoyed our conversation and hope we have the chance to talk again.

PC: I appreciate it as well. Thanks Daniel.

Peter Culpepper, CFO and COO of Provectus Pharmaceuticals Inc., has spent 20 years in the financial field in the U.S. and abroad. His experience includes working with private start-ups, publicly traded global conglomerates, large nonprofits and a national accounting firm. Previous employers include Neptec Inc., a privately held optical networking component manufacturer; Metromedia Company Inc.; and PageNet, the largest wireless messaging company in the world. Culpepper has also taught undergraduate and graduate business courses for the University of Phoenix. He is a licensed certified public accountant in Maryland and Tennessee. His professional affiliations include the American Institute of Certified Public Accountants, Financial Executives International and the Financial Executives Networking Group. Culpepper holds a master's degree in business administration (finance) from the University of Maryland, as well as bachelor's degree in philosophy from the College of William and Mary and an associate's degree in accounting from the Northern Virginia Community College.

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DISCLOSURE:
1) Daniel E. Levy conducted this interview for The Life Sciences Report and provides services to The Life Sciences Report as an independent contractor. He or his family own shares of the company mentioned in this interview: None.
2) Provectus Pharmaceuticals Inc. paid The Life Sciences Report to conduct, produce and distribute the interview.
3) Provectus Pharmaceuticals Inc. had final approval of the content and is wholly responsible for the validity of the statements. Opinions expressed are the opinions of Provectus Pharmaceuticals Inc. and not Streetwise Reports or The Life Sciences Report or its officers.
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