On July 22, 2020 Provectus (OTCQB: PVCT) reported that data from an ongoing clinical trial of investigational autolytic cancer immunotherapy PV-10 (rose bengal disodium) in combination with immune checkpoint blockade for the treatment of advanced cutaneous melanoma (NCT02557321) will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress, to be held online from September 19-21, 2020 (Press release, Provectus Biopharmaceuticals, JUL 22, 2020, View Source [SID1234562251]).

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The abstracts accepted for electronic poster presentations are entitled:

"A phase 1b study of rose bengal disodium and anti-PD-1 in metastatic cutaneous melanoma: results in patients naïve to immune checkpoint blockade" (#4281), and

"A phase 1b study of rose bengal disodium and anti-PD-1 in metastatic cutaneous melanoma: initial results in patients refractory to checkpoint blockade" (#4397).
Presentation details will be announced closer to the ESMO (Free ESMO Whitepaper) Virtual Congress 2020.

An injectable pharmaceutical product, PV-10 is a proprietary formulation of the Company’s current Good Manufacturing Practice (cGMP) rose bengal disodium (RB). This pharmaceutical-grade RB is produced by Provectus’ multi-step, quality-by-design (QbD) manufacturing process to exacting, modern regulatory standards that avoids the formation of previously unknown impurities present in commercial-grade rose bengal in uncontrolled amounts. The Company’s RB manufacturing process is protected by composition of matter and manufacturing patents as well as trade secrets.

About PV-10

By targeting tumor cell lysosomes, investigational new drug PV-10 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 checkpoint blockade (CB) with PV-10.4

PV-10 is undergoing clinical study for adult solid tumor cancers, such as relapsed and refractory cancers metastatic to the liver and metastatic melanoma. 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 and 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 with (among other things) invasive growth, angiogenesis, and drug resistance12.

PV-10 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 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 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 event (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; 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 in 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.

Investigational Drug Product

RB is 4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium, a small molecule halogenated xanthene and PV-10’s active pharmaceutical ingredient. The Company manufactures RB using a patented process designed to meet stringent modern global quality requirements for pharmaceuticals and pharmaceutical ingredients (cGMP). PV-10 drug product is an injectable formulation of 10% w/v cGMP 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 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.