October 15, 2015

Still Standing

“PV-10 is interesting because of its simple, entertaining background. You know, not derived from some obscure Amazonian rainforest plant. It’s telling us about a fundamental mechanism. So it’s a bit like the Wright Brothers and persistence. In 1903, a couple of bicycle mechanics with a rickety canvas box kite and a petrol engine solve the problem of controlled, powered flight because they found an error in the lift equation. Once the problem or mechanism was worked out, everyone was in the air and 66 years later we had 747s and were on the moon. PV-10 has that dramatic translational capacity in my view.”
Comments by an Australian researcher familiar with but not involved in Dees et al.’s work (edited by me slightly to read better)

Rose Bengal (aka Rose Bengal disodium) is a small molecule that laid around in the plain sight of the global biotechnology and pharmaceutical industries for about 85 years before scientists formerly from the U.S. Department of Energy’s Oak Ridge National Laboratory re-discovered it during their search for the ideal cancer killer. Rose Bengal is a water-soluble industrial dye created in Germany in 1882, and a non-biologic whose two-prong approach to fighting cancer (dual mechanisms of action) derives from its physical chemistry.

Rose Bengal’s first recorded medical use was noted in 1914, when it was added to Safranin Victoria Yellow for the treatment of ocular pneumococcal infection.[1] In 1998 Provectus Biopharmaceuticals’ founders Dr. Craig Dees, PhD (Chairman and CEO), Dr. Timothy Scott, PhD (President) and Dr. Eric Wachter, PhD (CTO) identified Rose Bengal as an attractive candidate for preventing the growth and spread of cancer tumors,[2] and possibly even defeating the disease altogether.

Rose Bengal is the active pharmaceutical ingredient in both PV-10 and PH-10. Provectus’ advanced investigational oncology drug compound is PV-10, an injectable 10% solution of Rose Bengal in saline. The company’s investigational dermatology drug compound is PH-10, a topical a 0.001% to 0.01% gel of Rose Bengal.

An American physician, G.D. Delprat, MD, observed his experience of a Rose Bengal test for liver function: “It was with some hesitation in 1923, that we injected this dye into our first human subject. The patient, a Chinaman with a carcinoma of the pancreas with complete biliary obstruction, showed no toxic effects after the intravenous injection of 100 mg. of the dye. In fact, while observing with interest the injection of this beautifully colored “medicine” he stated that he felt much better and wanted more. Frequent injections on this patient gave no toxic effects and led to the subsequent injection of some two to three hundred others.”[3]

The compound’s therapeutic benefits remained hidden until the 1986 when it was given to mice by Japanese researchers while investigating whether red food dye No. 105 (also made from Rose Bengal) caused cancer. Instead, they observed dose-dependent survival increases in the mice.[4] The researchers, however, did not advance their observations into formal cancer studies and trials of the compound.

Rose Bengal’s medical properties have been established in the clinic, adults and children[5], and the literature, as well as with the FDA. The compound was noted as a stain for visualizing corneal ulcers in 1919[6] and a marker for impaired liver function in 1923[7]. Currently there are more than 3,800 Rose Bengal references in the U.S. National Institutes of Health's National Library of Medicine’s PubMed Central database.[8] The compound has [non-therapeutic] FDA safety profiles as an intravenous hepatic diagnostic called Robengatope® and a topical ophthalmic diagnostic called Rosettes® or Minims®.

Some consider the Holy Grail of cancer therapy to be the achievement of durable anti-tumor immunity in patients. That is, killing cancer cells in such a way that suitably robust data (relevant antigens, appropriate signals to dendritic and other antigen-presenting cells) are delivered to the immune system. The body (the immune system) then can produce anti-tumor T cells in sufficient quantity and quality that destroy cancer “today,” and if it returns “tomorrow.”

But like Arthurian Grail stories of yore, the journey to find cancer’s grail has ranged far and wide, from radiation, chemotherapy, and targeted therapies to immunotherapies, and intralesional agents injected directly into cancerous tumors, to combinations and permutations of them. The journey has been replete with failure. Yet, the search for cancer’s grail still fosters never-ending hope of one day raising the cup.

Dees, Scott and Wachter hypothesized a patient’s own immune system could bestow immunity against his or her cancer if the tumor was killed properly. They believed patients could achieve durable anti-tumor immunity by killing tumors:
  1. Directly,
  2. Specifically,
  3. Completely,
  4. Comprehensively,
  5. Quickly, and
  6. Safely.
Dees et al. have spent the better part of two decades educating much of the biopharmaceutical industry and its ecosystem about the merits of their approach to fighting cancer. Dees frames therapeutic outcomes of Rose Bengal use in the context of reproducibility, whether preclinical or clinical, study or trial, generated by the company, a clinical investigator or a third-party researcher, affiliated or unaffiliated with Provectus. He reminds that reproducibility the hallmark of Western science. If a scientist or researcher cannot repeat the outcome of an experiment, and another researcher or scientist cannot replicate the result, one should be skeptical about the veracity of the original work and claims made from it.

Rose Bengal’s track record of reproducible therapeutic features as well as preclinical and clinical results by multiple parties in multiple cancer indications in multiple species is noteworthy. For example, two different research entities (Moffitt Cancer Center in Tampa, Florida in 2013[9], and the University of Illinois at Chicago in 2015[10]) separately and independently reproduced Dees et al.’s two-prong cancer killing approach of, initially or first, tumor ablation and, subsequently or second, tumor-specific immune responses in multiple solid tumor cancers (in preclinical mouse models).

If they are ultimately successful in demonstrating Rose Bengal’s therapeutic benefits to the satisfaction of the FDA (and a Big Pharma acquirer at a commensurate valuation), Dees, Scott and Wachter’s legacy must include their steadfastness in pursuing their own philosophy for defeating the disease in the face of the regulator and industry that did not readily understand, embrace or believe the idea that a local agent could deliver meaningful, systemic, clinical benefit to cancer patients.

1) Directly

The cancer tumor is not so much a patient’s enemy as it could be his or her “frenemy” (both friend and enemy). Dees et al. viewed the tumor as essential to making good on the promise of anti-tumor immunity, believing tumors were repositories of a cancer patient’s known knowns, known unknowns and unknown unknowns. The immune system needed to gain access to this information (in antigenic structure and biological context) in order to effectively fight back. There arguably is more we don’t know about the immune system than we know about it. Dees’ philosophy in regards to Mother Nature’s creation (the immune system), as a result, was to help rather than change or tinker with it.      
2015 Lasker Award winner Dr. James Allison, PhD[11], whose research eventually resulted in the development of immune checkpoint inhibitor and systemic immunotherapy ipilimumab (an anti-CTLA-4 therapeutic now called Yervoy and marketed by Bristol-Myers Squib), believed cancer tumor shrinkage was the successful byproduct of doing something right to the immune system. That is, releasing the immune system’s so-called brakes that block CTLA-4, thereby enabling T cells to fight the tumor.

Dees, on the other hand, thought that harnessing the immune system in the right way to fight cancer was the successful byproduct of properly destroying the tumor.

Dees, Scott and Wachter believed intratumoral or intralesional injection of the right compound into cancer tumors or lesions (local delivery), rather than oral or intravenous administration (systemic delivery), would deliver the right information in the right format and the right way to the immune system. But intralesional oncology therapies had previously failed to demonstrate they could provide meaningful, systemic, clinical benefit to cancer patients for more than 40 years.[12]

Repeated failure by others meant skepticism of the veracity and about the success of Dees et al.’s approach and their chosen candidate Rose Bengal. Skepticism remains high in many quarters of the industry’s ecosystem. The FDA and global pharmaceutical industry R&D groups appear to have mostly forgotten about the history and promise behind intralesional oncology therapy even though William Coley, acknowledged by many as the father of cancer immunotherapy, injected dead bacteria (conceptually a vaccine) into cancerous tumors and cancer metastases in the late-1800s.[13]

That may have changed somewhat with the modest success and, more importantly, regulatory progress of Amgen’s intralesional agent talimogene laherparepvec (“T-Vec”)(aka oncolytic immunotherapy or an oncolytic virus). In April 2015 a joint meeting of the FDA’s Cellular, Tissue and Gene Therapies Advisory Committee and Oncologic Drugs Advisory Committee voted 22-to-1 in favor of T-Vec’s benefit-risk profile for the treatment of injectable regionally or distantly metastatic melanoma, and thus supported traditional FDA approval of the compound.[14] Physician panel members concluded the reduction of injected cancer tumors equated to clinical benefit. T-Vec, however, is far from an ideal intralesional candidate because of a questionable Phase 3 trial primary endpoint (durable response rate), a questionable Phase 3 trial comparator (GM-CSF), and an unresolved issue of viral shedding (imagine becoming infected by and/or immune to the very treatment you are taking or giving).

Interestingly, Allison appears to have evolved his position towards Dees’ prioritization of cause-and-effect in regards to the tumor and immune system (Dees: tumor then immune system versus Allison: immune system then tumor). In 2014 the former co-filed a patent application of an oncolytic virus and its combination with both agonist and antagonist immune agents.[15]

2) Specifically

Although route of delivery is a critical facet of Dees et al.’s approach to fighting cancer, success is made dramatically more so with the right compound of course. One that is capable of being very, very specific. One that consistently, comprehensively and repeatedly distinguishes between normal and abnormal tissue while at the same time inhibiting or preventing the growth and spread of cancer tumors. Rose Bengal’s medical bona fides include more than a century of use in the clinic and research laboratory as both diagnostic and staining agents.

But its therapeutic potential for oncology (where Rose Bengal acts in a upregulating manner) and dermatology (where, quizzically, it acts in a downregulating manner), had never been systematically explored until Dees et al. began their journey of rediscovery in 1998.

A very underappreciated aspect of Rose Bengal’s clinical value proposition is the ability for the body to re-grow healthy, replacement tissue over tumor sites destroyed by the injection of the compound into them. Rose Bengal might be the anti-scalpel.

3) Completely

According to President and Director of Fred Hutchinson Cancer Research Center and former Merck & Co. senior vice president Dr. Gary Gilliland, MD, PhD, “[Big Pharma is] pretty good at shrinking tumors, but not good at getting rid of them.”[16] The immunotherapy the Merck team and he brought to market in what he termed record time[17], anti-PD-1 drug pembrolizumab (aka Keytruda), has a complete response (“CR”) rate indistinguishable from predecessor ipilimumab in advanced melanoma: 1%[18] vs. 0.2-1.5%[19]. Keytruda competitor nivolumab (aka Opdivo) had a 3% CR in advanced melanoma.[20]

The pharmaceutical industry lauds the achievement of better objective response (“OR”) rates. OR comprises CR (tumor destruction) and partial response (“PR”)(tumor shrinkage). Big Pharma hasn’t cracked the code on CR, as part of a more successful approach to fighting cancer. Tumor shrinkage seems more prevalent than tumor destruction with systemic immunotherapies thus far. Excitement over OR presumably derives from the general belief that good OR in cancer patients may lead to good progression-free survival (“PFS”), which may lead to good overall survival (“OS”)(for which PFS can be a surrogate).

Consistently high rates of CR may be more predictive and prognostic of PFS and OS, and thus, potentially, grail-worthy durability. Rose Bengal’s ability to completely destroy tumors was documented in the subgroup of patients in Provectus’ metastatic melanoma Phase 2 trial who had all of their refractory Stage III disease treated. This subgroup group achieved 50% CR (71% OR).[21] Moreover, only one or two injections of the compound typically were required to achieve CR.[22]

A higher threshold of CR achievement for PV-10 would be Provectus’ Phase 1b/2 trial program of combining Rose Bengal with an immune checkpoint inhibitor in patients with advanced melanoma (aka Stage IV patients). A phase 1b study of T-VEC and ipilimumab in patients with previously untreated, unresectable, advanced melanoma achieved 33% CR.[23]

Rose Bengal has completely ablated (destroyed) many different types of cancers, irrespective of disease presentation. The compound’s ablative agnosticism is well documented: melanoma, breast cancer, ovarian cancer, gastric cancer, and sarcoma.[24]

4) Comprehensively

Of course, it is not enough to kill just one tumor. You have to kill as many of them as you can that are accessible to injection. In doing so Rose Bengal may help the immune system kill a broader diverse array of cancer tumors and cells that cannot be reached with a needle or that you cannot see. The more tumors you inject and completely destroy, the more antigens can be presented in proper structure and biological context to the immune system.

The difference in complete response melanoma patients achieved varied depending on the proportion of their disease directly treated by injection. In Provectus’ melanoma Phase 2 trial mentioned above (where treatment was limited by study protocol), patients who had all of their refractory disease treated with Rose Bengal achieved 50% CR. Those with untreated bystander lesions, however, achieved 23% CR. Patients who had up to 10 untreated lesions achieved 14% CR. Patients with either lesions that were too numerous to count or Stage IV disease inaccessible to injection had no CR.

Moffitt Cancer Center’s Dr. Vernon Sondak, MD, a paid consultant to Provectus, has described PV-10 as the ideal intralesional agent, in no small part due to its “reliable and reproducible induction of regional and systemic immune effects capable of destroying occult tumor cells, “bystander lesions” and distant metastatic lesions regardless of prior treatments.”[25]

The melanoma component of Provectus’ clinical development program has two fundamentally different pathways to approval. In April 2015 the company commenced its pivotal Phase 3 trial of PV-10 versus systemic chemotherapy in patients with unresectable locally advanced melanoma (Stage III patients).[26] The trial’s hypotheses are two-fold: whether complete response of injected tumors is tantamount to elimination of disease symptoms and whether PV-10 can forestall or prevent the spread of the disease from Stage III to Stage IV. If you make the tumor go away, don’t the symptoms go away too? Success with Stage III patients, and consequently with earlier stages of melanoma, Dees et al.’s vision was to replace a surgical oncologist’s scalpel with a Rose Bengal needle.

In September 2015 Provectus initiated a Phase 1b/2 trial program combining PV-10 with an immune checkpoint inhibitor (Keytruda) in patients with advanced melanoma (Stage IV) by filing the associated study protocol. Late-stage disease indicates with tumors typically inaccessible to injection. A PV-10-checkpoint inhibitor combination presents the medical oncologist with a more effective approach to reducing tumor burden (PV-10 where accessible by injection, a checkpoint inhibitor where inaccessible to injections) until the immune system can re-establish itself to finish the job Mother Nature intended it to do.

5) Quickly

Quickly means having the drug processed through and excreted from the body in short order. Rose Bengal (PV-10) is not metabolized in the body. The compound has a half-life measured in single digit hours, irrespective of indication.[27][28] Compare this to systemic immunotherapies like Yervoy, Keytruda and Opdivo that have half-lives of 15.4[29], 26[30] and 26.7[31] days, respectively. It’s no wonder systemic immunotherapy safety profiles are lacking.

Speed also matters when it comes to overcoming cancer resistance or tolerance to therapeutics and therapies. According to Provectus PV-10 does not rely on a single pathway to work and has no known resistance. Fast complete responses not only mean not having to poison the immune system (and the body) with the artificial material you used to kill the cancer, it also may mean cancer doesn’t have the chance to mount any substantive defense or return in more virulent versions.

6) Safely

Safety is both a goal and a hoped for outcome that more often than not is sacrificed in favor of incremental or fleeting efficacy. Specificity should ensure safety because the drug is delivered directly to (into) the target (the tumor). The body or even parts of it need not be bathed in radiation. The bloodstream need not be filled with oral or intravenous chemotherapies or present-day immunotherapies.

From the outset Dees et al. only wanted to harness the immune system, not tinker with or change it. Rather than believing they could improve on Mother Nature’s construct, they thought she was fully capable of fighting cancer (if only overwhelmed at times by heavy tumor burden as the disease approached its later or end stages).


Provectus’ founders hold that tumors are the gateways to solving cancer’s riddle.

Antigens generated from destroying tumors caused by Rose Bengal injections are presented to the body’s cells responsible for selecting the best and most relevant antigens. These presentations encourage cancer-killing cells to replicate themselves throughout the body. Tumor antigens have to be viewed in context. Physical tumor destruction techniques such as heating or freezing tissue destroy fragile antigens and disrupt their relevant contextual structures. Disruption of cell membranes and removal of lipids, proteins, and complex carbohydrates destroy the antigens’ context, which is the very thing to what immune system cells respond. Thermal destruction denatures potential antigens, changing their chemical structure so that they are no longer representative of the tumor cell. In order to work rapid destruction of tumors must preserve both antigenic structure and biological context.

There were numerous failed manned flight attempts before the Wright brothers proved it could be done. 

[1] Feenstra RPG and Tseng CG. Arch Ophthalmol 1992; 110:984–993
[2] “Antineoplastic:” inhibiting or preventing the growth and spread of tumors or malignant cells, http://www.merriam-webster.com/dictionary/antineoplastic
[4] Ito A, Watanabe H, Naito M, Aoyama H, Nakagawa Y, Fujimoto N. J Natl Cancer Inst 1986 Jul; 77(1):277–81
[5] E.g., Pediatric application of the radioiodine (1-131) Rose Bengal in hepatic and biliary system disease, William E. White, John S. Welsh, Daniel C. Darrow, and Thomas M. Holder
Pediatrics 1963; 32:2 239-250
[6] Norn MS. Acta Ophthalmol 1970;48(3):546-559
[7] Delprat GD. Arch Int Med 1923; 32(3):401–410
[12] Intralesional Therapy for Metastatic Melanoma, Sanjiv S. Agarwala, MD, The Melanoma Letter. 2012;30(1):5-7.

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