Provectus Announces Presentation of Updated Data from

Treatment refractory, immunologically cold, hepatic tumor type
37% reduction and 83% stabilization of treated disease (2D-EASL)
Overall survival of 11 months for checkpoint inhibition-naïve patients; 11.4 months for checkpoint inhibition-refractory patients

KNOXVILLE, TN, June 01, 2020 (GLOBE NEWSWIRE) -- Provectus (OTCQB: PVCT) today is pleased to announce that updated data from the Company's expansion cohort of patients with uveal melanoma metastatic to the liver (mUM) in its Phase 1 cancers of the liver “basket study” of investigational autolytic cancer immunotherapy PV-10 (rose bengal disodium) were presented at the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program, held online May 29-31, 2020. Lead author, Sapna Patel, MD, Associate Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine of The University of Texas MD Anderson Cancer Center (MDACC), is also the lead principal investigator of this single-center cohort at MDACC.

Small molecule-based PV-10 is administered either by cutaneous intratumoral (IT) injection to superficial melanoma and non-melanoma skin cancer tumors (such as basal cell carcinoma, Merkel cell carcinoma, and squamous cell carcinoma) or by percutaneous IT injection to visceral primary and metastatic hepatic tumors (such as hepatocellular carcinoma, metastatic colorectal cancer, metastatic neuroendocrine tumors, and mUM). By targeting tumor cell lysosomes, PV-10 treatment may yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells and a T cell mediated immune response against treatment refractory and immunologically cold tumors.^1-3 Adaptive immunity can be enhanced by combining immune checkpoint blockade (CB) with PV-10.⁴

This ongoing, multi-center, open-label, Phase 1 study is evaluating the safety, tolerability, and efficacy of PV-10-based treatment in patients with solid tumors metastatic to the liver (NCT00986661). PV-10 is administered to one or more designated hepatic tumors. Response assessments using European Association of the Study of the Liver (2D-EASL) criteria are performed at Day 28, and then every three months. Patients with additional injectable tumors and/or unresponsive injected tumors may receive additional PV-10 after Day 28. This study is now enrolling patients into a single-center cohort at MDACC of up to 25 uveal melanoma patients with hepatic metastases. Eligible patients may also receive standard of care CB during and after treatment with PV-10.

Highlights from the Presentation at ASCO:

Baseline characteristics (N=14): % men; median age of 62 years (range 32-81)
Treatment summary: 3 patients received single-agent PV-10; 3 patients received the combination of PV-10 and an anti-PD-1 (Keytruda^® or Opdivo^®); 8 patients received the triplet combination of PV-10, an anti-CTLA-4 agent (Yervoy^®), and an anti-PD-1 agent (Opdivo)
Safety: Adverse events (AEs) were consistent with each agent’s established pattern single agent and/or combination settings
- AEs attributed to PV-10 were transient and included Grade 3/4 transaminitis that resolved within 72 hours, injection site pain, photosensitivity, and pink discoloration of skin, urine or feces
- AEs attributed to CB included nausea, decreased white blood cell (WBC) count, and fatigue
Injected target lesion efficacy (n=24, 2D EASL):
- 8% complete response (CR), 29% partial response (PR), 37% overall response rate (ORR)
- 46% stable disease (SD), 83% disease control rate (DCR)
Overall survival (OS):
- CB-naïve (9 patients): median OS of 11 months (range 5.7-24.7 months); 5 patients alive at 6.4-24.7 months
- CB-refractory (5 patients): OS of 11.4 months (range 6.9-17.5 months); 2 patient alive at 9.4 and 17.5 months
- Single-agent PV-10 (3 patients): OS of 7.9 months; 1 CB-naïve patient alive with PR at 24.7 months

“These data continue to establish PV-10’s safety profile as a single-agent and as part of immunotherapy combinations and triplet combinations with checkpoint blockade for the treatment of hepatic disease. Furthermore, in this immunologically cold cancer, we have shown that PV-10 treatment of metastatic uveal melanoma tumors led to the reduction or stabilization of most treated disease, which is associated with promising patient survival. We are very encouraged by Dr. Patel’s work and thankful for her clinical leadership in uveal melanoma, a rare disease of major unmet medical need,” said Dominic Rodrigues, Vice Chair of the Company's Board of Directors. “We are grateful to the patients, their families, their health care providers, and our academic partner who have all devoted and contributed so much to making this important study possible.”

A copy of the ASCO poster presentation is available on Provectus' website at https://www.provectusbio.com/media/docs/publications/ASCO_2020_MUM.20May2020.pdf.

About PV-10

PV-10 is an investigational new drug undergoing clinical study for adult solid tumor cancers, like melanoma and cancers of the liver (including metastatic neuroendocrine tumors and mUM). 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).^5,6

Tumor Cell Lysosomes as the Seminal Drug Target

Lysosomes 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 Lysosomes

Cancer cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning.⁷ Cancer progression and metastasis are associated with lysosomal compartment changes^8,9, which are closely correlated with (among other things) invasive growth, angiogenesis, and drug resistance¹⁰.

PV-10 selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus^1,11, external collaborators⁶, and other researchers^13,14,16 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-10.⁵

Immune 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 PARP cleavage⁵ and, now, stimulator of interferon genes (STING), which plays an important role in innate immunity¹⁵. PV-10 is the first cancer drug that may facilitate multiple, complementary, immune system signaling pathways.¹⁶

Orphan 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 Product

Rose 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. The Company manufactures RB using a patented process designed to meet strict modern global quality requirements for pharmaceuticals and pharmaceutical ingredients (Good Manufacturing Practice, or GMP). PV-10 drug product is an injectable formulation of 10% w/v GMP 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 IT 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 GMP RB and related halogenated xanthenes are produced, avoiding 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; US patent application numbers include 20200138942.

About Provectus

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.

References

	1.	Wachter et al. Functional Imaging of Photosensitizers using Multiphoton Microscopy. Proceedings of SPIE 4620, 143, 2002.

	2.	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.

	3.	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.

	4.	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.

	5.	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.

	6.	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).

	7.	Piao et al. Targeting the lysosome in cancer. Annals of the New York Academy of Sciences. 2016; 1371(1): 45.

	8.	Nishimura et al. Malignant Transformation Alters Intracellular Trafficking of Lysosomal Cathespin D in Human Breast Epithelial Cells. Pathology Oncology Research. 1998; 4(4): 283.

	9.	Gocheva et al. Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes & Development. 2006; 20(5): 543.

	10.	Fehrenbacher et al. Lysosomes as Targets for Cancer Therapy. Cancer Research. 2005; 65 (8): 2993.

	11.	Wachter et al. Imaging Photosensitizer Distribution and Pharmacology using Multiphoton Microscopy. Proceedings of SPIE 4622, 112, 2002.

	12.	Koevary. Selective toxicity of rose Bengal to ovarian cancer cells in vitro. International Journal of Physiology, Pathophysiology and Pharmacology 4(2), 99, 2012.

	13.	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.

	14.	Luciana et al. Rose Bengal Acetate photodynamic therapy-induced autophagy. Cancer Biology & Therapy, 10:10, 1048, 2010.

	15.	Narendran et al. Association of heat shock proteins as chaperone for STING: A potential link in a key immune activation mechanism revealed by the novel anti-cancer agent PV-10. 2019 AACR Annual Meeting, pending (abstr 8165).

	16.	Panzarini et al. Timing the multiple cell death pathways initiated by Rose Bengal acetate photodynamic therapy. Cell Death & Disease 2, 169, 2011.

Trademarks

PV-10^® is a registered trademark of Provectus, Knoxville, Tennessee, U.S.A.

Keytruda^® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Kenilworth, New Jersey, U.S.A.

Yervoy^® and Opdivo^® are registered trademarks of Bristol Myers Squibb Company, 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,” “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

Provectus Announces Presentation of Updated Data from Metastatic Uveal Melanoma Cohort of Phase 1 PV-10® Study at American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program

Tags