Provectus Announces PV-10® Liver Cancer Presentation in ePoster Gallery of Society of Interventional Radiology (SIR) 2020 Annual Scientific Meeting

KNOXVILLE, TN, April 16, 2020 (GLOBE NEWSWIRE) — Provectus (OTCQB: PVCT) today said that data from its clinical trial of autolytic cancer immunotherapy PV-10 (rose bengal disodium) as a single-agent and in combination with immune checkpoint blockade for the treatment of primary or metastatic tumors of the liver (NCT00986661) was uploaded to the SIR 2020 ePoster Gallery of the canceled Society of Interventional Radiology (SIR) 2020 Annual Scientific Meeting, which was originally scheduled to be held March 28-April 2, 2020 in Seattle, Washington.
SARS-CoV-2¹note: Provectus’ ongoing clinical trials continue to enroll new patients, and patients who have been enrolled and treated on these trials still receive care.Small molecule-based PV-10 is administered by percutaneous intratumoral injection to primary or metastatic tumors of the liver, such as hepatocellular carcinoma (HCC), metastatic colorectal cancer (mCRC), metastatic neuroendocrine tumors, and metastatic uveal melanoma (mUM). Intratumoral injection with lysosomal-targeting PV-10 yields immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells.^2-5This multicenter, open-label, Phase 1 basket study is evaluating PV-10’s safety, tolerability, and preliminary efficacy in unresectable cancers of the liver. PV-10 is administered under image guidance to one to three tumors of 1.0 to 4.9 cm in diameter. Response assessments (Computed Tomography [CT], Magnetic Resonance Imaging [MRI], and/or Positron Emission Tomography [PET]) are performed at day 28, and then every 12 weeks. Patients with additional injectable disease may receive further PV-10 injection after day 28. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and European Association of the Study of the Liver (2D-EASL) criteria were used to evaluate response of injected tumors; 2D-EASL response assessment measures only viable tumor tissue. PV-10 is radiopaque, which facilitates disease treatment and response follow-up.Updated Hepatic Tumor Results from the Presentation at SIR 2020:Baseline characteristics (N=32): 44% male; median age of 66 years (range 32-89).Disease characteristics: HCC (7 patients), mCRC (6), mUM (13); other metastases included lung carcinoma (2), cutaneous melanoma (1), breast carcinoma (1), ovarian adenocarcinoma (1), and pancreatobiliary adenocarcinoma (1)Safety summary: Treatment-emergent serious adverse events attributed to PV-10 were observed in 6 patients (5 patients experienced transient CTCAE Grade 3 events that resolved with sequalae; 1 patient experienced Grade 5 thrombus)Treatment summary: 49 injected tumors (46 interventional procedures); 1 tumor injected twiceTumor treatment patterns, response characteristics, and patient status:HCC: 10 evaluable injected lesions by mRECIST, 30% object response rate (ORR), 90% disease control rate (DRR); 8 evaluable by 2D-EASL, 75% ORR, 100% DCR; 4 of 7 patients alive (range 0-112 months)mCRC: 6 evaluable injected lesions by mRECIST, 67% DCR; ; 5 evaluable by 2D-EASL, 60% ORR, 60% DCR; 2 of 6 patients alive (3-97+ months)mUM: 10 of 13 patients alive (4.6-22.7 months)Patient survival characteristics:HCC: median overall survival (OS) and disease-specific survival (DSS) not reachedmCRC: median 26.8 months OS and DSS (range 3-97+)mUM: median OS and DSS not reached; initial follow-up <24 monthsDominic Rodrigues, Vice Chair of the Company’s Board of Directors, said, “These single-agent PV-10 and combination therapy data further support our drug development strategy and specific plans of developing a registrational study of the combination of PV-10, ipilimumab, and nivolumab for the treatment of uveal melanoma metastatic to the liver as well as a Phase 2 study of the combination of PV-10 and an anti-PD-(L)1 agent for first- and/or second-line treatment of hepatocellular carcinoma.”A copy of our poster presentation is available on Provectus’ website at https://www.provectusbio.com/media/docs/publications/SIR-2020.PV-10.PosterID-509.30-Mar-2020.pdf.On March 4^th, SIR and SIR Foundation leadership cancelled the SIR 2020 Annual Scientific Meeting. SIR asked all presenters to upload their presentations to the SIR 2020 ePoster Portal.About PV-10PV-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). PV-10 is also undergoing preclinical study for pediatric solid tumor cancers (like neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma) and pediatric blood cancers (like leukemia).^6,7Tumor Cell Lysosomes as the Seminal Drug TargetLysosomes are the central organelles for intracellular degradation of biological materials, and nearly all types of eukaryotic cells have them. Discovered by Christian de Duve, MD in 1955, lysosomes are linked to several biological processes, including cell death and immune response. In 1959, de Duve described them as ‘suicide bags’ because their rupture causes cell death and tissue autolysis. He was awarded the Nobel Prize in 1974 for discovering and characterizing lysosomes, which are also linked to each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.Building on the Discovery, Exploration, and Characterization of LysosomesCancer cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning.⁸ Cancer progression and metastasis are associated with lysosomal compartment changes^9,10, which are closely correlated with (among other things) invasive growth, angiogenesis, and drug resistance¹¹.PV-10 selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cell to die. Provectus^2,12, external collaborators⁶, and other researchers^13-15 have independently shown that PV-10 (RB) triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.Cancer Cell Autolytic Death via PV-10: PV-10 induced autolytic cell death, or death by self-digestion, in Hepa1-6 murine HCC cells can be viewed in this Provectus video of the event (ethidium homodimer 1 [ED-1] stains DNA, but is excluded from intact nuclei; lysosensor green [LSG] stains intact lysosomes; the video is provided in 30-second frames; the event has a duration of approximately one hour). Exposure to PV-10 triggers the disruption of lysosomes, followed by nucleus failure and autolytic cell death. Identical responses have been shown by the Company in HTB-133 human breast carcinoma (which can be viewed in this Provectus video; this event has a duration of approximately two hours) and H69Ar human multidrug-resistant small cell lung carcinoma. Cancer cell autolytic cell death was reproduced by research collaborators from POETIC using relapsed and refractory human pediatric neuroblastoma cells to show that lysosomes are disrupted upon exposure to PV-10.⁶Immune Signaling Pathways: PV-10 causes acute autolytic destruction of injected tumors (i.e., cell death), mediating several identified immune signaling pathways studied to date, such as the release of danger-associated molecular pattern molecules (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. Other mediated immune signaling pathways that have been identified include poly-ADP ribose polymerase (PARP) cleavage and, now, stimulator of interferon genes (STING), which plays an important role in innate immunity. PV-10 is the first cancer drug that may facilitate multiple, complementary, immune system signaling pathways.¹⁶Orphan Drug Designations (ODDs)ODD 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.Drug ProductRose bengal disodium (RB) (4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium salt) is a small molecule halogenated xanthene and PV-10’s active pharmaceutical ingredient. PV-10 drug product is a formulation of 10% w/v RB in 0.9% saline, supplied in single-use glass vials containing 5 mL (to deliver) of solution, and administered without dilution to solid tumors via intratumoral injection.Intellectual Property (IP)Provectus’ IP includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the process by which pharmaceutical grade RB and related halogenated xanthenes are produced, reducing the formation of previously unknown impurities that exist in commercial grade RB in uncontrolled amounts. The requirement to control these impurities is in accordance with International Council 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.The Company’s IP also includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the combination of PV-10 and systemic immunomodulatory therapy (e.g., anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents) for the treatment of a range of solid tumor cancers. US patent numbers are 9,107,887, 9,808,524, 9,839,688, and 10,471,144, with expirations ranging from 2032 to 2035.About ProvectusProvectus 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.References1. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the respiratory illness coronavirus disease 2019 (COVID-19).2. Wachter et al. Functional Imaging of Photosensitizers using Multiphoton Microscopy. Proceedings of SPIE 4620, 143, 2002.3. Liu et al. Intralesional rose bengal in melanoma elicits tumor immunity via activation of dendritic cells by the release of high mobility group box 1. Oncotarget 7, 37893, 2016.4. Qin et al. Colon cancer cell treatment with rose bengal generates a protective immune response via immunogenic cell death. Cell Death and Disease 8, e2584, 2017.5. Liu et al. T cell mediated immunity after combination therapy with intralesional PV-10 and blockade of the PD-1/PD-L1 pathway in a murine melanoma model. PLoS One 13, e0196033, 2018.6. Swift et al. Potent in vitro and xenograft antitumor activity of a novel agent, PV-10, against relapsed and refractory neuroblastoma. OncoTargets and Therapy 12, 1293, 2019.7. Swift et al. In vitro and xenograft anti-tumor activity, target modulation and drug synergy studies of PV-10 against refractory pediatric solid tumors. 2018 ASCO Annual Meeting, J Clin Oncol 36, 2018 (suppl; abstr 10557).8. Piao et al. Targeting the lysosome in cancer. Annals of the New York Academy of Sciences. 2016; 1371(1): 45.9. Nishimura et al. Malignant Transformation Alters Intracellular Trafficking of Lysosomal Cathespin D in Human Breast Epithelial Cells. Pathology Oncology Research. 1998; 4(4): 283.10. Gocheva et al. Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes & Development. 2006; 20(5): 543.11. Fehrenbacher et al. Lysosomes as Targets for Cancer Therapy. Cancer Research. 2005; 65 (8): 2993.12. Wachter et al. Imaging Photosensitizer Distribution and Pharmacology using Multiphoton Microscopy. Proceedings of SPIE 4622, 112, 2002.13. Koevary. Selective toxicity of rose Bengal to ovarian cancer cells in vitro. International Journal of Physiology, Pathophysiology and Pharmacology 4(2), 99, 2012.14. Zamani et al. Rose Bengal suppresses gastric cancer cell proliferation via apoptosis and inhibits nitric oxide formation in macrophages. Journal of Immunotoxicology, 11(4), 367, 2014.15. Luciana et al. Rose Bengal Acetate photodynamic therapy-induced autophagy. Cancer Biology & Therapy, 10:10, 1048, 2010.16. Panzarini et al. Timing the multiple cell death pathways initiated by Rose Bengal acetate photodynamic therapy. Cell Death & Disease 2, 169, 2011.TrademarksPV-10^® is a registered trademark of Provectus, Knoxville, Tennessee, 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,” “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. No claims with respect to PV-10, Provectus’ investigational drug for oncology, or PH-10, the Company’s investigational drug for dermatology, are intended regarding safety or efficacy in the context of any forward-looking statements made in this press release.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, 2019).###Contact:Provectus Biopharmaceuticals, Inc.
Heather Raines, CPA
Chief Financial Officer
Phone: (866) 594-5999