Provectus Biopharmaceuticals Highlights Stage IV M1d Patient Outcome from Combination Therapy Trial of PV-10® and KEYTRUDA® for Checkpoint-Refractory Advanced Cutaneous Melanoma at ESMO Virtual Congress 2020

Monday September 21, 2020
  • Complete response of all injected lesions
  • Regression of non-injected inguinal node, lung, and brain metastases
  • Expanded data set of trial subject provided

KNOXVILLE, TN, September 21, 2020 (GLOBE NEWSWIRE) - Provectus (OTCQB: PVCT) today highlighted the clinical outcome of a Stage IV M1d patient (Subject 0602) in the Company's Phase 1b/2 study of small molecule autolytic cancer immunotherapy PV-10, an injectable formulation of Provectus' proprietary rose bengal disodium (RBD), in combination with KEYTRUDA (pembrolizumab) for the treatment of advanced cutaneous melanoma in patients refractory to immune checkpoint blockade (CB). Preliminary response, safety, and immune correlative data from this CB-Refractory Cohort were previously presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020, held online from September 19-21, 2020.

This combination therapy study first enrolled and treated CB-naïve patients in its main cohort (CB-Naïve Cohort). A subsequent expansion cohort, the subject of this ESMO poster presentation, enrolled and treated CB-refractory patients (CB-Refractory Cohort).

Intralesional (IL) (aka intratumoral) administration of PV-10 for the treatment of solid tumors with PV-10 can yield immunogenic cell death and induce tumor-specific reactivity in circulating T cells.1-3 This IL PV-10-induced functional T cell response may be enhanced and boosted in combination with 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.

ESMO 2020 Presentation CB-Refractory Patient Highlights (Subject 0602):

  • 74-year old male with Stage IV M1d (N3) disease
  • Refractory to BRAF-MEK, CB, and twice-radiotherapy brain treatments
  • Multiple metastases
    • Injectable subcutaneous (SQ) lesions
    • Distant metastatic sites: inguinal lymph nodes, lung, and cerebellum
  • IL PV-10 treatment
    • 9 cycles to the injectable SQ lesions over a 5-month period
    • Median dose 0.32 mL PV-10 per cycle (range 0.15-2.46 mL)
  • At 28 weeks of treatment
    • Complete response of injected lesions
    • Overall: Partial response by RECIST 1.1 with regression of all non-injected metastatic sites

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.

A copy of a slide presentation about Subject 0602's clinical outcome is available on Provectus' website at https://www.provectusbio.com/media/docs/publications/ESMO-2020_CB_refractory_patient.pdf.

A copy of the poster presentation of this CB-Refractory Cohort is available on Provectus' website at https://www.provectusbio.com/media/docs/publications/ESMO-2020-Zager-PV-10-Pembro-in-CB-Refractory-Pts.pdf.

About the Phase 1b/2 Combination Therapy Trial (NCT02557321)

A first expansion cohort of the Phase 1b portion of the study began enrolling patients with metastatic cutaneous melanoma who were CB-refractory in December 2018. This CB-Refractory Cohort extended an exploratory group of refractory patients enrolled into the study's main cohort, which primarily enrolled CB-naïve patients. Patients with at least one injectable lesion and who were candidates for KEYTRUDA were eligible. Eligible subjects received the combination treatment of PV-10 and KEYTRUDA every three weeks for up to five cycles (i.e., over a period of up to 12 weeks), followed by only KEYTRUDA every three weeks for up to 24 months. The primary endpoint for the Phase 1b trial was safety and tolerability. ORR and progression-free survival were key secondary endpoints (both assessed via RECIST 1.1 after five treatment cycles, and then every 12 weeks thereafter).

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. The Company manufactures cGMP RBD using a patented process designed to meet stringent modern global quality requirements for pharmaceuticals and pharmaceutical ingredients.

An intralesional (IL) formulation (i.e., by direct injection) of cGMP RBD drug substance, cGMP PV-10®, is being developed as a clinical-stage autolytic immunotherapy drug product for solid tumor cancers. 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 relapsed and refractory adult solid tumor cancers, such skin and liver cancers.

IL PV-10 is also undergoing preclinical study for relapsed and refractory pediatric solid tumor cancers, such as neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma5,6.

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 drivers7.

Oral formulations of cGMP RBD are undergoing preclinical study for relapsed and refractory pediatric blood cancers, such as acute lymphocytic leukemia and acute myelomonocytic leukemia8,9.

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

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 changes11,12, 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. Provectus1,14, external collaborators5, and other researchers15,16,17 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 (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 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.

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 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, 8th International Congress, British Journal of Dermatology 177. /li>
  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, pending (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.

KEYTRUDA® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Kenilworth, New Jersey, 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, 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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