When Provectus Biopharmaceuticals Chairman, CEO and co-founder Dr. Craig Dees, PhD, talks about his company’s investigational cancer drug, PV-10 (made from centuries old Rose Bengal), he points to a history of reproducible therapeutic features, and reproduced preclinical and clinical results by multiple clinicians and researchers in multiple cancer indications. Craig refers to reproducibility as the hallmark of Western science. If a scientist cannot repeat an experiment’s outcome, and if another scientist cannot replicate that result, the veracity of the original work and claims made from it may be questionable.
When Provectus Biopharmaceuticals Chairman, CEO and co-founder Dr. Craig Dees, PhD talks about his company’s investigational cancer drug PV-10 (made from centuries old Rose Bengal), he points to a history of reproducible therapeutic features, and reproduced preclinical and clinical results by multiple clinicians and researchers in multiple cancer indications. Craig refers to reproducibility as the hallmark of Western science. If a scientist cannot repeat an experiment’s outcome, and if another scientist cannot replicate that result, the veracity of the original work and claims made from it may be questionable.
In drug research and development, though, there has been long-running and widespread lack of reproducibility. A 2011 Wall Street Journal article highlighted “This is one of medicine's dirty secrets: Most results, including those that appear in top-flight peer-reviewed journals, can't be reproduced.”
A 2012 Reuters story expanded on the two studies mentioned in the Journal article “During a decade as head of global cancer research at Amgen, C. Glenn Begley identified 53 "landmark" publications – papers in top journals, from reputable labs – for his team to reproduce. Begley sought to double-check the findings before trying to build on them for drug development. Result: 47 of the 53 could not be replicated”
Some in the pharmaceutical industry may not care about irreproducible work. Drs. Arturo Casadevall, MD, PhD and Ferric Fang, MD observed in their 2010 paper that most scientists are not interested in reproducing the work of others, and therefore “only rarely is the reproducibility of such work tested or known. In fact, the emphasis on reproducing experimental results becomes important only when work becomes controversial or called into doubt.”
In Rose Bengal, PV-10’s active pharmaceutical ingredient, Provectus’ co-founders discovered a small molecule lying around in plain sight of Big Pharma for more than 130 years. Explaining how PV-10 worked was a secondary consideration for Craig, who fervently believed Provectus had a ready-made drug product from the outset that worked very well.
His fact-based belief, however, belied the arduous, not so straightforward, lengthy and opaque FDA drug approval process all drug companies must traverse, irrespective of Craig’s further belief that approval did not require explanation of mechanism. More daunting was the reality of attempting to bring to market the chemical-oriented cancer therapy of this forgotten compound that had not only an unappreciated treatment delivery route (intratumoral or intralesional), but also two unrecognized mechanisms of action (one local and one systemic).
Provectus had to generate more data that further argued for PV-10’s clinical value proposition. Another was to conclusively demonstrate the reproducibility of Rose Bengal therapeutic benefit.
Provectus presented preliminary full study data of its Phase 2 trial of PV-10 in patients with advanced melanoma at the Melanoma 2010 Congress. Final data were presented at the European Society for Medical Oncology 2012 Congress. A 2015 peer-reviewed article about the data was published in the Annals of Surgical Oncology which stated “ For target lesions, the best overall response rate was 51%, and the complete response rate was 26%. Median time to response was 1.9 months, and median duration of response was 4.0 months, with 8% of patients having no evidence of disease after 52 weeks.”
Eric, who has led all aspects of Provectus’ clinical development program, met with the FDA in 2010 for the first of three end-of-Phase 2 meetings related to the company’s melanoma work (the others were held in 2011). He was told a consensus Phase 3 trial randomized against a control was necessary. Eric continued to collaborate with the FDA on PV-10’s initial pathway to approval, ultimately reaching a 2013 agreement with the Agency on the indication of locally advanced cutaneous melanoma (Stage III disease). Despite denying Provectus’ request in 2014 for breakthrough therapy designation for this indication, the FDA subsequently allowed the company’s pivotal Phase 3 trial that began treating patients in 2015. The hypothesis of this trial is that the spread of melanoma from Stage III to Stage IV may be forestalled or prevented if all disease is treated with PV-10.
Provectus presented preliminary initial study data of the company’s Phase 1 trial of PV-10 in patients with hepatocellular carcinoma and cancer metastatic to the liver at the 2015 European Society for Medical Oncology World Congress on Gastrointestinal Cancer “For the first analysis of five patients (six tumors) who had longer-term assessment, two patients showed no evidence of disease at more than 40 months follow-up according to RECIST and EASL criteria… Furthermore, at up to 54 months follow-up 10 out of the initial 13 patients were alive, with one death due to cardiac comorbidity, one to serious adverse events and one to HCC progression.”
Returning to melanoma, in 2015, Provectus began a Phase 1b trial combining PV-10 and Merck & Co.’s approved immune checkpoint inhibitor Keytruda (pembrolizumab) in patients with advanced melanoma (Stage IV disease). The approach of this combination study, where not all tumor burden is accessible to PV-10 injection, would be for the latter to enhance the systemic immune response generated by the former. PV-10 elicits a functional anti-tumor T-cell response in patients, while Keytruda increases the anti-tumor function of their T cells.
Starting in 2010, Eric also commenced a parallel effort to elucidate PV-10’s dual mechanisms of action. During an ASCO 2010 investor presentation, Eric presented about the bystander effect, which is a tumor-specific response brought on by PV-10 treatment. He sought to have a translational cancer research organization undertake arm’s length reproduction of Craig’s original murine model work, and what was being clinically observed in human trials, to independently establish PV-10’s bona fides. This work commenced in 2011 when Provectus agreed to have Tampa, Florida’s H. Lee Moffitt Cancer Center & Research Institute carry out this necessary initial research (after also considering MD Anderson Cancer Center in Houston, Texas). In 2014, Eric added the University of Illinois at Chicago to his list of stringers.
At the 2012 annual meeting of the Society for Immunotherapy of Cancer, Craig, Tim, Eric and others presented data that showed PV-10 (10% Rose Bengal in 0.9% saline) has been used to chemoablate a wide variety of tumors in human clinical trials and in animal patients when delivered by intralesional (IL) injection. At the 2013 annual meeting of the American Association for Cancer Research, Moffitt Cancer Center presented that intralesional injection (IL) of PV-10 has led to regression of injected lesions as well as distant metastases. At the 2015 annual meeting of the Society of Surgical Oncology, the University of Illinois at Chicago presented early phase studies using intratumoral injection of PV-10 (10% Rose Bengal) have shown regression of in-transit melanoma deposits and non-treated bystander lesions..
Moffitt Cancer Center and the University of Illinois independently, and independently from each other, reproduced Craig’s original work. Other affiliated and independent researchers around the world have noted the cancer-fighting benefits of Rose Bengal. Their observations and conclusions have been consistent with those of Craig (US), Moffitt Cancer Center (US) and the University of Illinois (US) as well as Delprat (US) and Ito (Japan): Koevary (2012, ovarian cancer cells, US), Nascimento et al. (2013, melanoma cells, Australia), Tan et al. (2013, clinical refractory scalp sarcoma, Australia), Zamani et al. (2014, gastric cancer cells, Iran), and Panzarini et al. (2014, cervical cancer cells, Italy).
Provectus management has some way to go in their stewardship of the company to converge its market capitalization with its intrinsic value. There should be no disagreement, however, about the veracity of their claims about Rose Bengal/PV-10 and its therapeutic benefits for the treatment of solid tumor cancer. After all, Craig, Tim and Eric’s original work achieved [global] reproducibility, the hallmark of Western science.
 Scientists' Elusive Goal: Reproducing Study Results, Gautam Naik, The Wall Street Journal, December 2, 2011
 In cancer science, many "discoveries" don't hold up, Sharon Begley, Reuters, March 28, 2012
 Drug development: Raise standards for preclinical cancer research, Begley et al., Nature 483, 531–533 (29 March 2012)
 Reproducible Science, Casadevall et al., Infect Immun. 2010 Dec; 78(12): 4972–4975
 PV-10 is the drug product. Rose Bengal is the drug substance.
 Provectus Reports Full Phase 2 Study Data on PV-10 for Metastatic Melanoma, November 5, 2010
 Immuno-chemoablation of metastatic melanoma with intralesional rose bengal, European Society for Medical Oncology 2012 Congress, October 2012
 Phase 2 Study of Intralesional PV-10 in Refractory Metastatic Melanoma, Thompson et al., Annals of Surgical Oncology, July 2015, Volume 22, Issue 7, pp 2135-2142
 Provectus Reports on Successful End-of-Phase 2 Meeting with U.S. FDA and Gains Clarity for Licensure of PV-10 for Metastatic Melanoma, April 29, 2010
 Provectus's PV-10 Path to Initial Approval in U.S. Now Clear Per FDA Meeting Minutes, January 24, 2014
 Provectus Biopharmaceuticals Inc. Reaffirms Its Commitment to Bringing PV-10 to Market Notwithstanding FDA Decision on Breakthrough Therapy Designation, May 23, 2014
 Provectus Biopharmaceuticals Opens Patient Enrollment; Begins Phase 3 International FDA Comparative Clinical Trial of PV-10 for Melanoma, April 15, 2015
 Provectus Biopharmaceuticals' Data on PV-10 for Chemoablation of Liver Cancers Presented at ESMO 17th World Congress on Gastrointestinal Cancer, July 2, 2015
 ESMO GI: PV-10 shows potential in hepatocellular carcinoma and metastatic liver disease, Janet Fricker, ecancernews, July 7, 2015
 ASCO 2010 Investor Briefing Presentation, Clinical Program Overview, Provectus, Dr. Eric Wachter, PhD, slide 39 of 55
 Ibid, slide 42 of 55
 Intralesional injection with PV-10 induces a systemic anti-tumor immune response in murine models of breast cancer and melanoma, Pilon-Thomas et al., Cancer Res. April 15, 2013 73; 1248.
 Intralesional Injection of Rose Bengal Induces an Anti-tumor Immune Response and Potent Tumor Regressions in a Murine Model of Colon Cancer, 2015 Society of Surgical Oncology Annual Cancer Symposium, March 2015: abstract
 Selective toxicity of rose bengal to ovarian cancer cells in vitro. Koevary, Int J Physiol Pathophysiol Pharmacol. 2012;4:99–107
 Rose Bengal - Phototoxicity versus intrinsic cytotoxicity [abstract]. Nascimento et al. Journal der Deutschen Dermatologischen Gesellschaft. 2013;11
 Novel use of Rose Bengal (PV-10) in two cases of refractory scalp sarcoma. Tan et al., ANZ J Surg. 2013;83:93
 Rose Bengal suppresses gastric cancer cell proliferation via apoptosis and inhibits nitric oxide formation in macrophages. Zamani et al., J Immunotoxicol. 2014;11:367–375
 Rose Bengal Acetate PhotoDynamic Therapy (RBAc-PDT) Induces Exposure and Release of Damage-Associated Molecular Patterns (DAMPs) in Human HeLa Cells. Panzarini et al., (2014) PLoS ONE 9(8): e105778
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