Provectus Biopharmaceuticals Announces Presentation of Full Study Data from Metastatic Neuroendocrine Cancer Phase 1 Trial of PV-10® at American Society of Clinical Oncology (ASCO) 2021 Annual Meeting

     — Systemic disease control achieved in heavily pre-treated liver cancer patients
     — 83% DCR; median PFS of 9.2 months; median OS of 22.5 months; half of patients undergoing response follow-up
     — Monotherapy PV-10 treatment mounts adaptive immune response

KNOXVILLE, TN, June 04, 2021 (GLOBE NEWSWIRE) -- Provectus (OTCQB: PVCT) today announced that preliminary full study data from the Company’s Phase 1 clinical trial of investigational cancer immunotherapy PV-10 (rose bengal disodium) for the treatment of neuroendocrine tumors (NET) metastatic to the liver (mNET) refractory to somatostatin analogs (SSAs) and peptide receptor radionuclide therapy (PRRT) (NCT02693067) is be presented at the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting, held June 4-8 online.

Highlights from the mNET Presentation at ASCO 2021:

• Baseline and disease characteristics
  • 12 patients; 50% male; median age of 66 years (range 47-79)
  • Primary tumor sites: 7 small bowel (58%), 2 pancreas (17%), 1 caecal (8%), and 2 unknown (17%)
  • NET grades: 5 Grade 1 (42%) and 7 Grade 2 (58%)
  • Refractory to SSA and PRRT; symptomatic progressive disease
• PV-10 treatment summary
  • Median of 1 hepatic NET lesion injected (range 1-4); median of 1 injection cycle (range 1-4); 8 patients (75%) received 1 PV-10 treatment
• Safety
  • Mild-to-moderate post-procedure pain reported by most patients
  • Grade 3 photosensitivity reaction in 1 patient, Grade 3 elevation of hepatic enzymes in 1 patient, and carcinoid flare in 2 patients
• Injected lesion efficacy (RECIST 1.1)
  • 42% partial response (PR) and 42% objective response rate (ORR)
• Patient-level efficacy (RECIST 1.1)
  • 83%^a disease control rate (DCR)
  • Progression-free survival (PFS): median 9.2 months (range 1.0-41.8)
  • Overall survival (OS): median 22.5 months (range 5.5-41.8); 6 patients (50%) undergoing response follow-up at the data cut-off of April 30, 2021
• Immune response
  • Upregulation of NK cells and activated CD4+ T cells was observed in peripheral blood collected 7 and 28 days post-PV-10 injection
• Biomarkers and quality of life (QOL)
  • Chromogranin A levels remained stable in 10 patients (83%)
  • QOL assessments showed stable or improved carcinoid symptoms and global health status in most patients
    

^a Typographical error on the poster

A copy of the poster is available on Provectus’ website at https://www.provectusbio.com/media/docs/publications/ASCO-2021-Phase-1-NET-Poster-4115.pdf.

This clinical trial, a single-center study at The Queen Elizabeth Hospital (TQEH) in Adelaide, Australia that completed enrollment in 2020, is led by Tim Price, MBBS, DHlthSc (Medicine), FRACP, Head of Clinical Oncology Research and Chair of the combined Hematology and Medical Oncology Unit at TQEH and Clinical Professor in the Faculty of Medicine at the University of Adelaide. The primary endpoint of the trial is safety. Secondary endpoints include ORR of injected target and measurable bystander lesions, target lesion somatostatin receptor expression, and biochemical response. Disease response assessments are conducted by independent review using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Six patients in the first cohort each received one percutaneously-administered injection of PV-10 to one target lesion per treatment cycle. Patients in the six-person second cohort can receive PV-10 injections of multiple lesions per cycle.

Dominic Rodrigues, Vice Chair of the Company’s Board of Directors, said, “The vast majority of patients with neuroendocrine cancer present with liver metastases, and their prognosis is poor. PV-10 treatment of these hepatic tumors in heavily pre-treated patients resulted in durable systemic clinical benefit and evidence of immunotherapeutic activity in an otherwise immunologically cold tumor type.”

Mr. Rodrigues added, “Provectus’ PV-10 development program for visceral hepatic tumors, led by more recent clinical study of neuroendocrine cancer and uveal melanoma, has not elicited any safety concerns and provided encouraging evidence of local and systemic response and disease control in refractory patient populations. Numerous liver metastases of defined tumor types have been treated in this program, including hepatoma, colorectal, lung, pancreatic, ovarian, cutaneous melanoma, breast, neuroendocrine, and uveal melanoma.”

About PV-10

Intralesional (IL) administration of PV-10 for the treatment of solid tumor cancers can yield immunogenic cell death within hours of tumor injection, and induce tumor-specific reactivity in circulating T cells within days.^1,2,3 This IL PV-10-induced functional T cell response may be enhanced and boosted in combination with immune checkpoint blockade (CB).⁴ In CB-refractory advanced cutaneous melanoma, IL PV-10 may restore disease-specific T cell function, which may also be prognostic of clinical response. IL PV-10 has been administered to over 450 patients with cancers of the skin and of the liver. It is administered under visual, tactile or ultrasound guidance to superficial malignancies, and under CT or ultrasound guidance to tumors of the liver. Systemic administration of PV-10 is also undergoing preclinical study as prophylactic and therapeutic treatments for refractory and high-risk adult solid tumor cancers, and as a treatment for relapsed and refractory blood cancers.

About Rose Bengal Disodium

RBD is 4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein disodium, a halogenated xanthene and Provectus’ proprietary lead molecule. Provectus' current Good Manufacturing Practices (cGMP) RBD is a proprietary 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. Provectus' RBD and cGMP RBD manufacturing process are protected by composition of matter and manufacturing patents as well as trade secrets.

An IL formulation (i.e., by direct injection) of cGMP RBD drug substance, cGMP PV-10, is being developed as an autolytic immunotherapy drug product for solid tumor cancers.

IL PV-10 is also undergoing preclinical study for relapsed and refractory pediatric solid tumor cancers, such as neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma.^5,6

A topical formulation of cGMP RBD drug substance, PH-10^®, is being developed as a clinical-stage immuno-dermatology drug product for inflammatory dermatoses, such as atopic dermatitis and psoriasis. RBD can modulate multiple interleukin and interferon pathways and key cytokine disease drivers.⁷

Oral formulations of cGMP RBD are undergoing preclinical study for relapsed and refractory pediatric blood cancers, such as acute lymphocytic leukemia and acute myelomonocytic leukemia.^8,9

Oral formulations of cGMP RBD are also undergoing preclinical study as prophylactic and therapeutic treatments for high-risk adult solid tumor cancers, such as head and neck, breast, pancreatic, liver, and colorectal cancers.

Different formulations of cGMP RBD are also undergoing preclinical study as potential treatments for multi-drug resistant (MDR) bacteria, such as Gram-negative bacteria.

Topical formulations of cGMP RBD are also undergoing preclinical study as potential treatments for diseases of the eye, such as infectious keratitis

Tumor Cell Lysosomes as the Seminal Cancer 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.¹⁰ Cancer progression and metastasis are associated with lysosomal compartment changes^11,12, which are closely correlated (among other things) with invasive growth, angiogenesis, and drug resistance¹³.

RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus^2,14, external collaborators⁵, and other researchers^15,16,17 have independently shown that RBD triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Cancer Cell Autolytic Death via RBD: RBD-induced autolytic cell death, or death by self-digestion, in Hepa1-6 murine hepatocellular carcinoma (HCC) cells can be viewed in this Provectus video of the process (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, with a duration of approximately one hour). Exposure to RBD 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 of the process, with 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 in neuroblastoma cells to show that lysosomes are disrupted upon exposure to RBD.⁵

Tumor Autolytic Death via RBD: RBD 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 immunity.⁹

Orphan Drug Designations (ODDs)

ODD status has been granted to RBD by the U.S. Food and Drug Administration for metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

Intellectual Property

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 cGMP RBD and related halogenated xanthenes are produced, avoiding the formation of previously unknown impurities that exist in commercial-grade rose bengal 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 RBD and CB (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 (i.e., 16/678,133), which has been allowed.

About Provectus

Provectus Biopharmaceuticals, Inc. (Provectus or the Company) is a clinical-stage biotechnology company developing immunotherapy medicines for different disease areas based on an entirely- and wholly-owned family of small molecules called halogenated xanthenes. Information about the Company’s clinical trials can be found at the National Institutes of Health (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. Krueger et al. Immune Modulation by Topical PH-10 Aqueous Hydrogel (Rose Bengal Disodium) in Psoriasis Lesions. Psoriasis Gene to Clinic, 8^th International Congress, Br J Dermatol 177.
8. 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).
9. 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, (abstr 5393).
10. Piao et al. Targeting the lysosome in cancer. Annals of the New York Academy of Sciences. 2016; 1371(1): 45.
11. Nishimura et al. Malignant Transformation Alters Intracellular Trafficking of Lysosomal Cathespin D in Human Breast Epithelial Cells. Pathology Oncology Research. 1998; 4(4): 283.
12. Gocheva et al. Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes & Development. 2006; 20(5): 543.
13. Fehrenbacher et al. Lysosomes as Targets for Cancer Therapy. Cancer Research. 2005; 65 (8): 2993.
14. Wachter et al. Imaging Photosensitizer Distribution and Pharmacology using Multiphoton Microscopy. Proceedings of SPIE 4622, 112, 2002.
15. Koevary. Selective toxicity of rose Bengal to ovarian cancer cells in vitro. International Journal of Physiology, Pathophysiology and Pharmacology 4(2), 99, 2012.
16. 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.
17. Luciana et al. Rose Bengal Acetate photodynamic therapy-induced autophagy. Cancer Biology & Therapy, 10:10, 1048, 2010.
    

Trademarks

PV-10^® and PH-10^® are registered trademarks of Provectus, Knoxville, Tennessee, U.S.A.

FORWARD-LOOKING STATEMENTS: The information in this press release may include “forward-looking statements,” within the meaning of U.S. securities legislation, relating to the business of Provectus and its affiliates, which are based on the opinions and estimates of Company management and are subject to a variety of risks and uncertainties and other factors that could cause actual events or results to differ materially from those projected in the forward-looking statements. Forward-looking statements are often, but not always, identified by the use of words such as “seek,” “anticipate,” “budget,” “plan,” “continue,” “estimate,” “expect,” “forecast,” “may,” “will,” “project,” “predict,” “potential,” “targeting,” “intend,” “could,” “might,” “should,” “believe,” and similar words suggesting future outcomes or statements regarding an outlook.

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated or that such agents as products will achieve any particular revenue levels.

Due to the risks, uncertainties, and assumptions inherent in forward-looking statements, readers should not place undue reliance on these forward-looking statements. The forward-looking statements contained in this press release are made as of the date hereof or as of the date specifically specified herein, and Provectus undertakes no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except in accordance with applicable securities laws. The forward-looking statements are expressly qualified by this cautionary statement.

Risks, uncertainties, and assumptions include those discussed in the Company’s filings with the SEC, including those described in Item 1A of the Company’s Annual Report on Form 10-K for the year ended December 31, 2020 and Provectus’ Quarterly Report on Form 10-Q for the quarter ended March 31, 2021.

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Contact:

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