KNOXVILLE, TN, -- Provectus (OTCQB: PVCT) today provided an update on the Company's gastrointestinal (GI) tumor clinical development program for its lead investigational cancer drug PV-10, which is administered percutaneously when targeting primary or metastatic tumors of the liver, such as hepatocellular carcinoma (HCC), metastatic neuroendocrine tumors (mNET), and metastatic uveal melanoma (mUM). Intratumoral injection of oncolytic immunotherapy PV-10 can yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells. 1-5
The Company's oncology drug development strategy includes:
Provectus believes this strategy should quicken the advancement of single-agent PV-10 along a pathway-to-approval in solid tumor cancer indications where there is high unmet need, limited activity from other therapies, and the opportunity to further display a functional immune response from PV-10 treatment, such as for mNET (NCT02693067).
Provectus also believes this approach should permit the Company to develop and advance a combination therapy involving a CI or other drug class along a pathway-to-approval in an indication where there is high unmet need, limited activity from standard of care (SOC) treatment, and the opportunity to display how PV-10 augments clinical response to existing or emerging SOCs, such as for mUM (i.e., combination therapy with anti-CTLA-4 and anti-PD-1 agents) (NCT00986661).
Update #1 (mNET): The Company plans to present further lesion-level (i.e., local) efficacy, preliminary patient-level (i.e., systemic) efficacy, further clinical and biomarker outcome, and preliminary T cell response data from single-agent PV-10 treatment of mNET at a regional annual scientific meeting in the third quarter of 2019 and a global GI-focused medical conference in the first quarter of 2020.
Update #2 (mNET): Investigators and researchers collaborating with Provectus plan to present the design of a Phase 2 mNET study combining PV-10 and an agent from a class of CI drugs at the abovementioned scientific meeting. The Company would seek partial or total sponsored-financial support for this trial.
Update #3 (mNET): The Company is exploring possible collaboration with another group of investigators to develop a Phase 2 mNET study design of PV-10 and an agent from another class of CI drugs. The Company would also seek partial or total sponsored-financial support for this trial.
Dominic Rodrigues, Vice Chair of Provectus' Board of Directors stated, "We believe PV-10 monotherapy treatment of metastatic neuroendocrine tumors has yielded encouraging clinical data of single-agent drug activity that include both local and systemic disease control. Checkpoint inhibitor drugs have thus far shown limited or no monotherapy activity in this non-T cell inflamed and low tumor mutation burden tumor type. While we believe single-agent PV-10 can help fill this unmet medical need, we also think there is a meaningful rationale to combine a tumor-specific immunotherapy like PV-10 with a non-specific immunotherapy like a checkpoint inhibitor drug for this patient population."
Update #4 (mUM): The Company plans to present preliminary lesion- and patient-level efficacy data from PV-10 treatment of mUM at a global immuno-oncology-focused medical conference in the fourth quarter of 2019. mUM patients have received PV-10 monotherapy and PV-10 in combination with two CI drugs, anti-CTLA-4 and anti-PD-1 agents.
Mr. Rodrigues added, "Currently, there is no consensus on standard of care for the treatment of metastatic uveal melanoma. Treatment varies from medical center to medical center. In working with current and prospective principal investigators, we feel strongly that the combination of PV-10 with an anti-CTLA-4 agent and an anti-PD-1 agent, an approach that appears to leverage the unique clinical characteristics of each drug and drug candidate, may benefit this patient population who are in dire need of better therapeutic solutions."
Update #5 (HCC): Provectus has extended its long-standing scientific research relationship with the laboratory of Shari Pilon-Thomas, PhD at Moffitt Cancer Center in Tampa, Florida. A key aim of her new research initiative is to elucidate PV-10's mechanism of action (MOA) in HCC, where the MOA hypothesis is the release of damage associated molecular patterns (DAMPs) from PV-10 treatment. Dr. Pilon-Thomas' team have previously elucidated PV-10's DAMP pathway in both a murine model of and clinical work on cutaneous melanoma.2
Ajay Maker, MD and his team at the University of Illinois at Chicago have previously elucidated a comparable DAMP pathway for PV-10 in colon cancer.3
PV-10, a lysosome-targeting treatment, may trigger several different pathways to achieve the death of cancer. Aru Narendran, MD, PhD and his team at the University of Calgary in Alberta, Canada have shown that PV-10 treatment leads to poly-ADP ribose polymerase (PARP) cleavage and tumor cell apoptosis in refractory neuroblastoma cell lines.5 Dr. Narendran's team is currently pursuing the hypothesis of a third distinct PV-10-mediated cancer cell death pathway through an ongoing scientific research initiative with the Company.
Update #6 (HCC): As of the first quarter of 2019, an analysis of six patients who have received PV-10 monotherapy treatment for HCC displayed a median overall survival of 2.5 years (mean 3.1 years; range 0-8.3+ years).
Mr. Rodrigues concluded, "Dr. Pilon-Thomas and past and present team members at Moffitt Cancer Center have undertaken a significant amount of consequential translational research on PV-10 treatment, ranging from melanoma and breast cancer to monotherapy and combination therapy. This work has resulted in a critical understanding of the drug candidate's underlying medical science and the publication of seminal journal articles. Recent failures by OPDIVO® and KEYTRUDA® to meet primary overall survival endpoints in their respective clinical trials for the treatment of hepatocellular carcinoma highlight the importance of our new mechanism of action study of PV-10 treatment for this disease, which may better help characterize a potential PV-10-checkpoint inhibitor drug combination solution."
PV-10 causes acute oncolytic destruction of injected tumors, releasing DAMPs and tumor antigens that initiate an immunologic cascade where local response by the innate immune system facilitates systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. T cell function can be further augmented by combining PV-10 with CI drugs.
PV-10 is undergoing clinical study for adult solid tumor cancers like melanoma and cancers of the liver (including metastatic neuroendocrine tumors and metastatic uveal melanoma) and preclinical study for pediatric cancers like neuroblastoma5, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma.
Orphan drug designation status has been granted to PV-10 by the U.S. Food and Drug Administration for the treatments of metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.
PV-10 is an injectable formulation of rose bengal disodium (RB) (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein disodium salt), which is a small molecule halogenated xanthene and PV-10's active pharmaceutical ingredient. PV-10 drug product is a bright rose red solution containing 10% w/v RB in 0.9% saline for injection, which is supplied in single-use glass vials containing 5 mL (to deliver) of solution and administered without dilution to solid tumors via intratumoral injection.
Provectus' intellectual property includes a family of US and international patents that protect the process by which pharmaceutical grade RB and related xanthenes are produced, reducing the formation of previously unknown transhalogenated impurities that exist in commercial grade RB in uncontrolled amounts. The requirement to control these impurities is in accordance with International Conference on Harmonisation (ICH) guidelines for the manufacturing of an injectable pharmaceutical. US patent numbers are 8,530,675, 9,273,022, and 9,422,260, with expirations ranging from 2030 to 2031.
Provectus Biopharmaceuticals, Inc. (Provectus or the Company) is a clinical-stage biotechnology company developing a new class of drugs based on an entirely- and wholly-owned family of chemical small molecules called halogenated xanthenes. Information about the Company's clinical trials can be found at the NIH registry, www.clinicaltrials.gov. For additional information about Provectus, please visit the Company's website at www.provectusbio.com.
KEYTRUDA® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Kenilworth, New Jersey, U.S.A.
OPDIVO® is a registered trademark of Bristol-Myers Squibb, New York, New York, U.S.A.
FORWARD-LOOKING STATEMENTS: This release contains "forward-looking statements" as defined under U.S. federal securities laws. These statements reflect management's current knowledge, assumptions, beliefs, estimates, and expectations and express management's current views of future performance, results, and trends and may be identified by their use of terms such as "anticipate," "believe," "would," "could," "estimate," "expect," "intend," "may," "plan," "predict," "project," "will," and other similar terms. Forward-looking statements are subject to a number of risks and uncertainties that could cause our actual results to materially differ from those described in the forward-looking statements. Readers should not place undue reliance on forward-looking statements. Such statements are made as of the date hereof, and we undertake no obligation to update such statements after this date.
Risks and uncertainties that could cause our actual results to materially differ from those described in forward-looking statements include those discussed in our filings with the Securities and Exchange Commission (including those described in Item 1A of our Annual Report on Form 10-K for the year ended December 31, 2018).
Provectus Biopharmaceuticals, Inc.
Heather Raines, CPA
Chief Financial Officer