KNOXVILLE, TN, April 16, 2020 (GLOBE NEWSWIRE) — Provectus (OTCQB: PVCT) today said that data from its clinical trial of autolytic cancer immunotherapy PV-10 (rose bengal disodium) as a single-agent and in combination with immune checkpoint blockade for the treatment of primary or metastatic tumors of the liver (NCT00986661) was uploaded to the SIR 2020 ePoster Gallery of the canceled Society of Interventional Radiology (SIR) 2020 Annual Scientific Meeting, which was originally scheduled to be held March 28-April 2, 2020 in Seattle, Washington.
SARS-CoV-211 note: Provectus' ongoing clinical trials continue to enroll new patients, and patients who have been enrolled and treated on these trials still receive care.
Small molecule-based PV-10 is administered by percutaneous intratumoral injection to primary or metastatic tumors of the liver, such as hepatocellular carcinoma (HCC), metastatic colorectal cancer (mCRC), metastatic neuroendocrine tumors, and metastatic uveal melanoma (mUM). Intratumoral injection with lysosomal-targeting PV-10 yields immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells.2-5
This multicenter, open-label, Phase 1 basket study is evaluating PV-10's safety, tolerability, and preliminary efficacy in unresectable cancers of the liver. PV-10 is administered under image guidance to one to three tumors of 1.0 to 4.9 cm in diameter. Response assessments (Computed Tomography [CT], Magnetic Resonance Imaging [MRI], and/or Positron Emission Tomography [PET]) are performed at day 28, and then every 12 weeks. Patients with additional injectable disease may receive further PV-10 injection after day 28. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and European Association of the Study of the Liver (2D-EASL) criteria were used to evaluate response of injected tumors; 2D-EASL response assessment measures only viable tumor tissue. PV-10 is radiopaque, which facilitates disease treatment and response follow-up.
Updated Hepatic Tumor Results from the Presentation at SIR 2020:
Dominic Rodrigues, Vice Chair of the Company's Board of Directors, said, "These single-agent PV-10 and combination therapy data further support our drug development strategy and specific plans of developing a registrational study of the combination of PV-10, ipilimumab, and nivolumab for the treatment of uveal melanoma metastatic to the liver as well as a Phase 2 study of the combination of PV-10 and an anti-PD-(L)1 agent for first- and/or second-line treatment of hepatocellular carcinoma."
A copy of our poster presentation is available on Provectus' website at https://www.provectusbio.com/media/docs/publications/SIR-2020.PV-10.PosterID-509.30-Mar-2020.pdf.
On March 4th, SIR and SIR Foundation leadership cancelled the SIR 2020 Annual Scientific Meeting. SIR asked all presenters to upload their presentations to the SIR 2020 ePoster Portal.
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).6,7
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 functioning8. Cancer progression and metastasis are associated with lysosomal compartment changes9,10, which are closely correlated with (among other things) invasive growth, angiogenesis, and drug resistance11.
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. Provectus2,12, external collaborators6, and other 13-15 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-10.6
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.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.
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.
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.
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).
Provectus Biopharmaceuticals, Inc.
Heather Raines, CPA
Chief Financial Officer