On September 17, 2020 Provectus (OTCQB: PVCT) reported that 2-year landmark survival, response, and safety data from 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 naïve to immune checkpoint blockade (CB) will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020, held online from September 19-21, 2020 (Press release, Provectus Biopharmaceuticals, SEP 17, 2020, View Source [SID1234565298]).

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Intralesional (IL) (aka intratumoral) administration of PV-10 for the treatment of solid tumor cancers 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

ESMO 2020 Presentation Summary Data of this CB-Naïve Cohort:

2-year Survival Analysis
62% overall survival (OS) (55% for KEYTRUDAa alone)
Median OS not reached (median OS not reached for KEYTRUDAa alone)
65% disease-specific survival (DSS); median DSS for all patients not reached; 23.5-month median DSS for Stage IV M1c patients
Safety
Consistent with the established patterns for single-agent use of each drug; principally grades 1 and 2 injection site reactions for PV-10; principally grades 1 to 3 immune-mediated reactions for KEYTRUDA
Synergy of approved and investigational first-line cutaneous melanoma combination therapies: Schmidt et al. (JAMA Netw Open 2020b) have proposed a Bliss independent activity model to analyze observed combination therapy overall response rates (ORRs) and a Z score to measure the difference between observed and calculated ORRs. The higher the Z score, the greater the contribution of the combination therapy. Provectus calculated a Z score of 25% for the PV-10+KEYTRUDA combination. Other first-line (i.e., CB-naïve) advanced cutaneous melanoma combination therapy Z scores include:b

15.5% for OPDIVO+YERVOY, 23.4% for KEYTRUDA+YERVOY,
-0.8% for KEYTRUDA+epacadostat (IDO-1), 30% OPDIVO+epacadostat,
13.5% for KEYTRUDA+IMLYGIC (oncolytic virus), and
13% for OPDIVO+bempegaldesleukin (interleukin-2)c.
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.

Dominic Rodrigues, Vice Chair of the Company’s Board of Directors said, "These two-year survival landmark data support the clinical value of PV-10 in combination with immune checkpoint blockade in a predominantly Stage IV melanoma patient population, including those with extensive visceral disease. These data illustrate a stable, non-overlapping safety profile over time; highlight substantial, efficient, upfront tumor destruction by PV-10 directly against injected disease burden; and appear to be the result of a strong, PV-10-induced, tumor-specific, functional T cell response.2 Taken together,PV-10’s clinical and mechanistic attributes may better leverage the strengths of checkpoint blockade for the durable treatment benefit of melanoma patients."

A copy of the poster presentation is available on Provectus’ website at View Source

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

The Phase 1b portion of the study completed enrollment of 23 patients with metastatic cutaneous melanoma in April 2018 at clinical sites in the U.S.; of these patients, 21 were naïve to checkpoint inhibition treatment. 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, with no further PV-10 administered after week 12), followed by only KEYTRUDA every three weeks for up to 24 months. The primary endpoint for the Phase 1b trial was safety and tolerability. Overall response rate 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 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. 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, including a T cell mediated immune response against treatment refractory and immunologically cold tumors.1-3 Adaptive immunity can be enhanced by combining 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 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 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 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.