Provectus Biopharmaceuticals Inc.

12/12/2019 | Press release | Distributed by Public on 12/12/2019 07:25

Provectus Announces Presentation of Preliminary Results from Phase 1 Trial of PV-10® (rose bengal disodium) for Treatment of Metastatic Uveal Melanoma at ESMO I-O Congress 2019

  • 13 patients treated to date have received single-agent PV-10 or combination of PV-10 and standard of care checkpoint blockade
  • Independent safety profiles of PV-10 and checkpoint inhibition were maintained
  • 32% ORR and 82% DCR of injected visceral hepatic target lesions (2D EASL)

KNOXVILLE, TN, December 12, 2019 -- Provectus (OTCQB: PVCT) today announced that data from the Company's ongoing Phase 1 study of lysosomal-targeting cancer immunotherapy PV-10 (rose bengal disodium) as a single-agent and in combination with standard of care immune checkpoint blockade for the treatment of uveal melanoma metastatic to the liver (NCT00986661, a single-center expansion cohort) were presented at the European Society for Medical Oncology (ESMO) Immuno-Oncology (I-O) Congress 2019, held from December 11-14, 2019 in Geneva, Switzerland. PV-10 is administered percutaneously when targeting primary or metastatic tumors of the liver, such as hepatocellular carcinoma (HCC), metastatic colorectal cancer, metastatic neuroendocrine tumors, and metastatic uveal melanoma (mUM). Intratumoral injection with PV-10 can yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells.1-4

Provectus' ongoing, multi-center, open-label, Phase 1 basket study is evaluating the safety, tolerability, and preliminary efficacy of PV-10 in patients with solid tumors metastatic to the liver. mUM patients are being enrolled into a single-center study cohort at MD Anderson Cancer Center (MDACC) in Houston, Texas. Up to three hepatic tumors can be injected per treatment cycle. Response assessments are performed at Day 28, and then every three months. Patients with multiple injectable visceral hepatic tumors may receive additional PV-10 after Day 28. Eligible mUM patients may also receive standard of care checkpoint blockade during and after treatment with PV-10. This mUM clinical trial work has been led by Sapna Patel, MD, Associate Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine at MDACC.

Preliminary Metastatic Uveal Melanoma Results from the Presentation at ESMO I-O Congress 2019:

  • Baseline characteristics (N=13): 46% men; median age of 61 years; 46% elevated LDH.
  • Disease characteristics: 100% Stage IV M1a-b; 38% of patients were refractory to one or more prior lines of treatment, with 31% having received prior immunotherapy.
  • Treatment summary: 7 patients received 1 cycle of PV-10; 6 patients received 2 cycles; 26 tumors were injected with PV-10.
  • Combination therapy: 9 patients received concomitant standard of care checkpoint blockade (i.e., maintenance anti-PD-1, anti-PD-1 subsequent to PV-10 treatment, or anti-CTLA-4+anti-PD-1 subsequent to PV-10 treatment).
  • Safety: 3 cases of Grade 3/4 transaminitis that resolved to Grade 1 or better within 72 hours; additional Grade 1 PV-10 related events seen in 1 patient each included pink stool, pink urine, photosensitivity, injection site pain, and hyperbilirubinemia; Additional adverse events, such as nausea, headache, myalgias, blurry vision, decreased white blood cells, and fatigue, were attributed to concomitant checkpoint blockade.
  • Preliminary injected target lesion efficacy (n=22): 32% partial response (PR); 32% overall response rate (ORR); 50% stable disease (SD); 82% disease control rate (DCR).

Dominic Rodrigues, Vice Chair of the Company's Board of Directors, said, 'These preliminary safety and efficacy data of PV-10 combination therapy for the treatment of uveal melanoma metastatic to the liver, an immunologically cold and low tumor mutation burden tumor type, indicate that the triplet cancer therapy of PV-10, an anti-CTLA-4 agent, and an anti-PD-1 agent may have a role in an emerging standard of care. Upon assessing survival benefit with this new treatment approach, the next step in PV-10's drug development program for this cancer indication would be a registration-directed clinical trial.'

A copy of the ESMO I-O Congress 2019 poster presentation is available on Provectus' website at https://www.provectusbio.com/media/docs/publications/ESMO-IO-2019-PV-10-poster.pdf.

About PV-10

PV-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).5,6

Tumor Cell Lysosomes as the Seminal Drug Target

Lysosomes are the central organelles for intracellular degradation of biological materials (e.g., the 'stomach' of the cell, the cell's 'trash bin'), 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 functioning7. Cancer progression and metastasis are associated with lysosomal compartment changes8,9, 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, disrupts them, and causes them to die. The physicochemical properties of lysosomes trap PV-10. A lumenal pH of 4.5 to 5.0 is ideal for the conversion of the hydrophilic RB salt into the hydrophobic (lipophilic) lactone version. Provectus1,11, external collaborators5, and other 12-14 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 inducing 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 the Pediatric Oncology Experimental Therapeutics Investigators' Consortium (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 oncolytic destruction of injected tumors (i.e., cell death), mediating several identified immune signaling pathways 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 one currently being investigated that plays an important role in innate immunity. PV-10 is the first cancer drug that may facilitate multiple, temporally-distinct, immune system signaling pathways.15

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 (RB) disodium (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 xanthenes are produced, reducing the formation of previously unknown transhalogenated impurities that exist in commercial grade RB in uncontrolled amounts. The requirement to control these impurities is in accordance with International Conference 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, and 9,839,688, and 10,471,144, with expirations ranging from 2032 to 2035.

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. Potent in vitro and xenograft antitumor activity of a novel agent, PV-10, against relapsed and refractory neuroblastoma.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. Panzarini et al. Timing the multiple cell death pathways initiated by Rose Bengal acetate photodynamic therapy.Cell Death & Disease 2, 169, 2011.

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, 2018).

Contact:

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