Provectus Announces Presentation of Initial Results from Phase 1B Trial

Provectus recently announced that data from the company’s ongoing Phase 1b/2 study of lysosomal-targeting cancer immunotherapy PV-10 (rose bengal disodium) in combination with KEYTRUDA (pembrolizumab) for the treatment of checkpoint inhibition-refractory advanced cutaneous melanoma patients were presented at the 16^th International Congress of the Society for Melanoma Research (SMR 2019 Congress), held in Salt Lake City, Utah from November 20-24, 2019. Intralesional (aka intratumoral) injection with PV-10 can yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells.

A first expansion cohort of the Phase 1b portion of the study began enrolling patients with metastatic melanoma who were checkpoint inhibition-refractory (the “Checkpoint-Refractory Cohort”) in December 2018 (NCT02557321). The Checkpoint-Refractory Cohort extended an exploratory group of refractory patients enrolled into the main cohort of this study, which primarily enrolled patients naïve to checkpoint inhibition (the “Checkpoint-Naïve Cohort”). 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. Objective 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).

Initial Checkpoint-Refractory Results from the Presentation at SMR 2019 Congress:

• Baseline characteristic: median age of 77 years (range 54-90); compared to the median age of 69 years (range 28-62) of the Checkpoint-Naive Cohort.
• Disease characteristics: 50% Stage IV M1b-d; 50% of patients were refractory to single-agent and dual-agent checkpoint inhibition treatment (KEYTRUDA, YERVOY^® [ipilimumab], or OPDIVO^® [nivolumab] and YERVOY).
• Treatment summary: PV-10 was limited to 5 cycles.
• Safety: adverse events were consistent with the established patterns for the single-agent use of each drug; 1 patient withdrew due to an adverse reaction to KEYTRUDA.
• Overall patient efficacy (BORR, RECIST 1.1): 20% objective response rate (ORR) and 40% disease control rate (DCR); 2 of 10 patients were not evaluated (NEV).
• Durability: median OS and DSS were not reached; median progression-free survival (PFS) of 4.9 months.
• Changes in peripheral blood biomarkers:
• Initial correlative results for these highly checkpoint inhibition-refractory patients were consistent with prior evidence of immune activation by PV-10 in checkpoint inhibition-naïve patients, both as a single-agent and in combination with KEYTRUDA.
• PV 10 combination therapy-treated Checkpoint-Refractory Cohort patients exhibited a damage-associated molecular pattern (DAMP) profile similar to the DAMP profile of checkpoint inhibition-naïve patients receiving single-agent PV-10 (NCT01760499).

Dominic Rodrigues, Vice Chair of the Company’s Board of Directors, said, “Cancer cells are highly dependent on lysosomal function. PV-10 selectively accumulates in cancer cell lysosomes upon contact, disrupts them, and causes the cancer cell to die. This autolytic immunogenic cell death primes and educates the immune system to yield a precise, tumor-specific, T cell response. This PV-10-induced, educated, tumor-specific, T cell response can be boosted by checkpoint blockade for the treatment of solid tumor cancers.”

Mr. Rodrigues added, “These initial data of PV-10 combination therapy for the treatment of what is effectively an immunologically cold tumor type, checkpoint inhibition-refractory cutaneous melanoma, further demonstrate that immune system activation can be initiated or re-initiated by PV-10 treatment. We believe PV-10 can serve as the necessary partner for the checkpoint inhibitor class of drugs to improve clinical response and treatment durability for cancer patients across a wide range of tumor types.”

A copy of the poster presentation is available on Provectus’ website at https://www.provectusbio.com/media/docs/publications/SMR2019_PV-10-MM_1201_CI_Refractory-web.pdf.

Provectus has shown that PV-10 selectively accumulates in the lysosomes of only cancer cells upon contact, disrupts them, and causes the cancer cells to die, a mechanism that has been reproduced by external collaborators. Provectus, external collaborators, and independent researchers have further shown that PV-10 treatment (RB application) can trigger each of the three major and distinct lysosomal cell death pathways of apoptosis, autophagy, and necrosis, and does so in a disease-dependent manner.

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 patterns (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 a third pathway 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.

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), and preclinical study for pediatric solid tumor cancers (like neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma) and pediatric blood cancers (like leukemia).

Orphan drug designation 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.

PV-10 is an injectable formulation of rose bengal disodium (RB) (4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein disodium salt), which is a small molecule halogenated xanthene and PV-10’s active pharmaceutical ingredient. PV-10 drug product is a bright rose red solution containing 10% w/v RB in 0.9% saline for injection, which is supplied in single-use glass vials containing 5 mL (to deliver) of solution and administered without dilution to solid tumors via intratumoral injection.

Provectus’ intellectual property (IP) includes a family of US and international 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 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 a US patent application number is 15/804,357 (allowed, but not yet awarded), 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.