Provectus Biopharmaceuticals Expands Sponsored Research Collaboration with University of Calgary (Canada) to Investigate Oral Administration of Rose Bengal Disodium for Cancer Treatment

Thursday August 13, 2020
  • University of Calgary researchers have successfully demonstrated initial, in vivo proof-of-concept, oral rose bengal disodium treatment for blood cancer
  • Researchers will now investigate oral treatment for high-risk adult solid tumor cancers

KNOXVILLE, TN, August 13, 2020 (GLOBE NEWSWIRE) - Provectus (OTCQB: PVCT) today announced that the Company has expanded its sponsored research program with Aru Narendran, MD, PhD, Professor, Departments of Pediatrics, Oncology, Biochemistry & Molecular Biology, and Physiology & Pharmacology at the Cumming School of Medicine of the University of Calgary in Calgary, Alberta, Canada.

Under ongoing collaboration with Provectus, the Narendran research team has produced preliminary findings that show oral dosing of the Company's current Good Manufacturing Practice (cGMP) rose bengal disodium (RBD) is effective and well tolerated in an in vivo pediatric leukemia murine model. Data from this work are currently being prepared for publication.

As part of today's announced sponsored research expansion, the Narendran team will now investigate oral dosing of cGMP RBD in in vivo murine models for the treatment of refractory adult solid tumors that are high-risk phenotypes and have high metastatic potential. These cancer types will include head and neck, breast, pancreatic, liver, and colorectal.

The Narendran research team will also evaluate the potential prophylactic efficacy of oral cGMP RBD dosing to prevent or delay the initiation of malignancies in established in vivo murine models predisposed to developing cancer.

Provectus' cGMP RBD is a pharmaceutical-grade drug substance produced by the Company's quality-by-design (QbD) manufacturing process to exacting regulatory standards that avoids the formation of uncontrolled impurities currently present in commercial-grade rose bengal. The Company's cGMP RBD manufacturing process is protected by composition of matter and manufacturing patents as well as trade secrets.

"Provectus' prior and ongoing clinical work, which has treated more than 400 cancer patients in single-agent and combination therapy settings via intralesional administration, has established the safety, activity, mechanistic, and immunomodulatory profile of our proprietary, pharmaceutical-grade rose bengal disodium," Dominic Rodrigues, Vice Chair of the Company's Board of Directors added. "Oral administration of a new rose bengal disodium formulation for cancer treatment is a potential novel drug product for Provectus and the logical outgrowth of the Company's expansive medical science platform and strong clinical foundation."

About Rose Bengal Disodium

cGMP RBD is 4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein disodium, which is a small molecule halogenated xanthene and Provectus' proprietary lead compound. Administered by intralesional (IL) (aka intratumoral) injection, PV-10® is the Company's investigational autolytic immunotherapy drug product and a formulation of cGMP RBD drug substance. The Company manufactures RBD using a patented process designed to meet stringent modern global quality requirements for pharmaceuticals and pharmaceutical ingredients (cGMP).

By targeting tumor cell lysosomes, RBD 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 RBD.4

IL PV-10 is undergoing clinical study for adult solid tumor cancers, such as relapsed and refractory cancers metastatic to the liver and metastatic melanoma. IL PV-10 is also undergoing preclinical study for relapsed and refractory pediatric solid tumor cancers (e.g., neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma)5,6.

New formulations of cGMP RBD are undergoing preclinical study for relapsed and refractory pediatric blood cancers (such as acute lymphocytic leukemia and acute myelomonocytic leukemia)7,8.

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.9 Cancer progression and metastasis are associated with lysosomal compartment changes10,11, which are closely correlated (among other things) with invasive growth, angiogenesis, and drug resistance12.

RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus1,13, external collaborators6, and other researchers14,15,16 have independently shown that RBD 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 this event (ethidium homodimer [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

Tumor Autolytic Death via PV-10: PV-10 causes acute autolytic destruction of injected tumors (via autolytic cell death), mediating the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens; release of these signaling factors may initiate an immunologic cascade where local response by the innate immune system may facilitate 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. Mediated immune signaling pathways may include an effect on STING, which plays an important role in innate immunity8.

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.

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. Swift et al. In Vitro Activity and Target Modulation of PV-10 Against Relapsed and Refractory Pediatric Leukemia 2018 ASH Annual Meeting, Blood 132 2018 (suppl; abstr 5207).
  8. Thakur 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. 2020 AACR VAM II, pending (abstr 5393).
  9. Piao et al. Targeting the lysosome in cancer. Annals of the New York Academy of Sciences. 2016; 1371(1): 45.
  10. Nishimura et al. Malignant Transformation Alters Intracellular Trafficking of Lysosomal Cathespin D in Human Breast Epithelial Cells. Pathology Oncology Research. 1998; 4(4): 283.
  11. Gocheva et al. Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes & Development. 2006; 20(5): 543.
  12. Fehrenbacher et al. Lysosomes as Targets for Cancer Therapy. Cancer Research. 2005; 65 (8): 2993.
  13. Wachter et al. Imaging Photosensitizer Distribution and Pharmacology using Multiphoton Microscopy. Proceedings of SPIE 4622, 112, 2002..
  14. Koevary Selective toxicity of rose Bengal to ovarian cancer cells in vitro. International Journal of Physiology, Pathophysiology and Pharmacology 4(2), 99, 2012.
  15. 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.
  16. Luciana et al. Rose Bengal Acetate photodynamic therapy-induced autophagy. Cancer Biology & Therapy, 10:10, 1048, 2010.

Trademark

PV-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 and Provectus' Quarterly Report on Form 10-Q for the quarter ended June 30, 2020.

Contact:

Provectus Biopharmaceuticals, Inc.
Heather Raines, CPA
Chief Financial Officer
Phone: 866-594-5999

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