On June 1, 2020 Provectus (OTCQB: PVCT) reported that updated data from the first cohort of the Company’s neuroendocrine tumors (NET) metastatic to the liver (mNET) Phase 1 study of investigational autolytic cancer immunotherapy PV-10 (rose bengal disodium) were published as an abstract as part of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Virtual Scientific Program, held online May 29-31, 2020 (Press release, Provectus Biopharmaceuticals, JUN 1, 2020, View Source [SID1234560733]).

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Small molecule-based PV-10 is administered either by cutaneous intratumoral (IT) injection to superficial melanoma and non-melanoma skin cancer tumors (such as basal cell carcinoma, Merkel cell carcinoma, and squamous cell carcinoma) or by percutaneous IT injection to visceral primary and metastatic hepatic tumors (such as hepatocellular carcinoma, metastatic colorectal cancer, mNET, and metastatic uveal melanoma). By targeting tumor cell lysosomes, 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 may be enhanced by combining immune checkpoint blockade (CB) with PV-10.4

This single-center Phase 1 study is being conducted at The Queen Elizabeth Hospital in Adelaide, Australia to evaluate the potential safety, tolerability, and preliminary efficacy of single-agent PV-10 treatment in symptomatic mNET patients (NCT02693067) refractory to systemic somatostatin analogues (SSA) and peptide receptor radionuclide therapy (PRRT). The primary endpoint of the trial is safety; secondary endpoints include objective response rate (ORR) of injected target and measurable bystander lesions, target lesion somatostatin receptor expression, and biochemical response. Response assessments were conducted using Response Evaluation Criteria in Solid Tumors (RECIST) criteria and by independent review. Six patients in the first cohort each received one percutaneously-administered IT injection of PV-10 to one target lesion per treatment cycle. Patients in the second cohort can receive PV-10 injection of multiple lesions per cycle; enrollment of this cohort is nearing completion.

Highlights from the mNET Presentation at ASCO (Free ASCO Whitepaper):

Baseline characteristics (N=6): 67% male; median age of 65 years (range 47-72).
Disease characteristics
Primary tumor site: small bowel (50%), pancreas (33%), and caecal (17%)
NET grades: Grade 1 (83%) and Grade 2 (17%)
All patients were refractory to SSA and PRRT
PV-10 treatment summary: Median of 1 cycle (mean 1.7, range 1-4)
Safety: Post-procedure pain, carcinoid flare, and nausea
Injected target lesion efficacy (RECIST 1.1): 50% partial response (PR), 50%ORR
Patient-level efficacy (RECIST 1.1)
83%a disease control rate (DCR)
Progression-free survival (PFS): Not reached by computerized tomography (CT) scan (range 2.4-25.3+ months); 6.1 months by positron emission tomography (PET) scan
Overall survival (OS): >22.5 months; 50% ongoing response follow-up (range 18.1-33.8 months OS) at the January 2020 data cut-off
a Typographical error in the abstract

A copy of the abstract, which was first published on May 13th, is available on the ASCO (Free ASCO Whitepaper) website at View Source .

About PV-10

PV-10 is an investigational new drug undergoing clinical study for adult solid tumor cancers, like melanoma and cancers of the liver (including mNET 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).5,6

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.7 Cancer progression and metastasis are associated with lysosomal compartment changes8,9, which are closely correlated with (among other things) invasive growth, angiogenesis, and drug resistance10.

PV-10 selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus1,11, external collaborators6, and other researchers13,14,16 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 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 from POETIC using relapsed and refractory human pediatric neuroblastoma cells to show that lysosomes are disrupted upon exposure to PV-10.5

Immune Signaling Pathways: PV-10 causes acute autolytic destruction of injected tumors (i.e., cell death), mediating several identified immune signaling pathways studied 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) cleavage5 and stimulator of interferon genes (STING), which plays an important role in innate immunity15. PV-10 is the first cancer drug that may facilitate multiple, complementary, 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.

Drug Product

Rose bengal disodium (RB) (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. The Company manufactures RB using a patented process designed to meet strict modern global quality requirements for pharmaceuticals and pharmaceutical ingredients (Good Manufacturing Practice, or GMP). PV-10 drug product is an injectable formulation of 10% w/v GMP 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 IT 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.