Provectus Biopharmaceuticals Receives Notice of Allowance for Adult Solid Tumor Cancer Combination Therapy Patent

Provectus recently announced the United States Patent and Trademark Office (USPTO) has allowed US patent (USP) application 16/678,133, which covers the use of intralesional (aka intratumoral) PV-10, an injectable formulation of Provectus’ proprietary small molecule rose bengal disodium (RBD), in concomitant combination with two immune checkpoint inhibitors (eg, PV-10 + an anti-CTLA-4 agent + an anti-PD-(L)1 agent) for the treatment of adult solid tumor cancers, such as melanoma, breast cancer, primary and metastatic liver cancers, prostate cancer, and small cell and non-small cell lung cancer.

The allowed patent application is the fourth continuation of USP 9,107,887, Provectus’ foundational cancer combination therapy patent granted by the USPTO in 2015. It is also related to USP 9,808,524, USP 9,839,688, and USP 10,471,144, which are also continuations. Provectus is the sole assignee on the allowed patent application.

Dominic Rodrigues, Vice Chair of the Company’s Board of Directors, said “This pending new patent further expands and enhances our intralesional oncology drug development program by protecting, in particular, the concomitant combination of PV-10 and the duo of anti-CTLA-4 and anti-PD-1 agents for the treatment of solid tumor cancers beyond melanoma, for which the combination of ipilimumab and nivolumab has been approved. There is emerging evidence of major differences in how the combination of anti-CTLA-4 and anti-PD-1 drugs acts on T cell populations and thus immune response, compared with either monotherapy.”

Mr. Rodrigues added “Provectus has shown that single-agent PV-10 treatment of melanoma may lead to the maturation of immature T cells into functional ones, and that the anti-tumor activity of these T cells may be enhanced by the blockade of the PD-1 regulatory pathway. The Company’s clinical study of metastatic uveal melanoma is focused on showing that these T cells can be further enhanced, potentially synergistically so, by the blockade of both the CTLA-4 and PD-1 pathways.”

Intralesional (IL) administration of PV-10 for the treatment of solid tumor cancers can yield immunogenic cell death within hours of tumor injection, and induce tumor-specific reactivity in circulating T cells within days. This IL PV-10-induced functional T cell response may be enhanced and boosted in combination with immune checkpoint blockade (CB). In CB-refractory advanced cutaneous melanoma, IL PV-10 may restore disease-specific T cell function, which may also be prognostic of clinical response. IL PV-10 has been administered to over 450 patients with cancers of the skin and of the liver. It is administered under visual, tactile or ultrasound guidance to superficial malignancies, and under CT or ultrasound guidance to tumors of the liver.

RBD is 4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein disodium, a halogenated xanthene and Provectus’ proprietary lead molecule. 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.

An IL formulation (ie, by direct injection) of cGMP RBD drug substance, cGMP PV-10, is being developed as an autolytic immunotherapy drug product for solid tumor 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.

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.

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.

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 also undergoing preclinical study as potential treatments for multi-drug resistant (MDR) bacteria, such as Gram-negative bacteria.

Topical formulations of cGMP RBD are also undergoing preclinical study as potential treatments for diseases of the eye, such as infectious keratitis.

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.

Cancer cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning. Cancer progression and metastasis are associated with lysosomal compartment changes, which are closely correlated (among other things) with invasive growth, angiogenesis, and drug resistance.

RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus, external collaborators, and other researchers 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.

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.

ODD status has been granted to RBD by the US FDA for metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

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 (eg, 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 (i.e., 16/678,133).

Provectus Biopharmaceuticals, Inc. 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 National Institutes of Health (NIH) registry, www.clinicaltrials.gov. For more information, visit www.provectusbio.com.