On June 222, 2020 Verastem, Inc. (Nasdaq:VSTM) (also known as Verastem Oncology), a biopharmaceutical company committed to developing and commercializing new medicines for patients battling cancer, reported results from a study that provides preclinical proof-of-concept for combining VS-6766, its RAF/MEK inhibitor, with defactinib, its focal adhesion kinase (FAK) inhibitor, for the treatment of metastatic uveal melanoma (UM), the most prevalent eye cancer among adults (Press release, Verastem, JUN 22, 2020, View Source [SID1234561357]). The data comprise one of four virtual posters with Verastem authors being presented today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Annual Meeting II, which is taking place June 22-24, 2020.

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Uveal melanoma arises from the melanin-producing cells in the eye, similar to how it arises in cutaneous melanoma. While it’s considered rare, primary UM metastasizes in 50% of patients with only 8% of patients surviving 2 years after development of metastatic disease.1 Previously, MEK inhibitors, including selumetinib and trametinib, have failed to show substantial clinical benefit for patients with metastatic uveal melanoma.2,3 Indeed, no current therapies improve overall survival for metastatic UM and there is a high unmet need for novel therapies.4

In the current preclinical study, FAK inhibition (FAKi; e.g., defactinib) demonstrated synergistic growth-inhibitory effects in UM cells when combined with a MEK inhibitor (MEKi) or the investigational RAF/MEK inhibitor VS-6766. Additionally, MEKi increased phosphorylation of FAK, suggesting the need for FAK blockade in combination with MEKi for more complete antitumor effect. Accordingly, FAKi combination with MEKi induced apoptotic cell death leading to rapid tumor regression in UM xenografts, whereas the MEKi or FAKi as single agents showed tumor growth inhibition but failed to showed tumor shrinkage. Furthermore, the FAKi/MEKi combination was successful at reducing tumor burden in liver metastasis UM models.

"The study identified and reinforced FAK as a viable pathway to inhibit downstream from the GNAQ pathway, which is constitutively active in UM," said J. Silvio Gutkind, PhD, Distinguished Professor of Pharmacology and Associate Director for Basic Science at UC San Diego Moores Cancer Center, and senior investigator of the study. "We observed that co-targeting of FAK and RAF/MEK signaling led to tumor collapse in UM xenograft and liver metastasis models in vivo. Based on the encouraging results of this study, we are excited to work toward clinical testing of defactinib with VS-6766 for patients with metastatic uveal melanoma."

"These data build on a growing body of evidence that underscore the potential of the VS-6766/defactinib combination for treatment of a variety of solid tumors with significant medical need," said Brian Stuglik, Chief Executive Officer of Verastem Oncology. "We will continue to evaluate the combination in metastatic uveal melanoma along with rapidly advancing our broader clinical development program in solid tumors."

The combination of VS-6766 and defactinib is being evaluated in patients with Low Grade Serous Ovarian Cancer (LGSOC), and KRAS mutant non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) in the ongoing investigator-initiated Phase I trial. The company also plans to support a Phase II investigator-initiated study of the combination of VS-6766 and defactinib in uveal melanoma anticipated to begin in late 2020.

Details for all abstracts selected for presentation at the AACR (Free AACR Whitepaper) 2020 Virtual Meeting II are as follows:

Title: FAK and MEK co-targeting: A new multimodal precision therapy for GNAQ-driven uveal melanoma
Lead author: Justine S. Paradis
Poster #: 6406/30
Session: PO.ET06.05
Date and Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. EDT
URL: View Source!/9045/presentation/5323

Title: The dual PI3K-δ/PI3K-γ inhibitor duvelisib inhibits signaling and proliferation of solid tumor cells expressing PI3K-δ and/or PI3K-γ
Lead author: Silvia Coma
Poster #: 663/10
Session: PO.ET06.06
Date and Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. EDT
URL: View Source!/9045/presentation/1880

Title: Single cell expression analysis of PIK3 genes to direct solid tumor treatment with the dual PI3K-δ,γ inhibitor duvelisib
Lead author: Samantha Hidy
Poster #: 1552/3
Session: PO.TB06.02
Date and Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. EDT
URL: View Source!/9045/presentation/7806

Title: PEGylated recombinant human hyaluronidase, PEGPH20, significantly enhances the anti-tumor activity of the combination of focal adhesion kinase Inhibitor and anti-PD-1 antibody by targeting CXCR4-expressing myeloid cells in a murine model of PDAC
Lead author: Arsen Osipov
Poster #: 1588/9
Session: PO.TB06.04
Date and Time: Monday, June 22, 2020; 9:00 a.m. to 6:00 p.m. EDT
URL: View Source!/9045/presentation/7864

About VS-6766

VS-6766 (formerly known as CH5126766, CKI27 and RO5126766) is a unique inhibitor of the RAF/MEK signaling pathway. In contrast to other MEK inhibitors in development, VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors. The combination of VS-6766 and the focal adhesion kinase (FAK) inhibitor defactinib is currently being investigated in an investigator-initiated Phase 1 dose escalation and expansion study. The expansion cohorts are currently ongoing in patients with KRAS mutant advanced solid tumors, including low grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).6 The ongoing clinical study of the VS-6766/defactinib combination is supported by single-agent Phase 2 studies which investigated defactinib in KRAS mutant NSCLC7 and VS-6766 in KRAS mutant NSCLC and LGSOC.5

About Defactinib

Defactinib (VS-6063) is an oral small molecule inhibitor of FAK and PYK2 that is currently being evaluated as a potential combination therapy for various solid tumors. The Company has received Orphan Drug designation for defactinib in ovarian cancer and mesothelioma in the US, EU and Australia. Preclinical research by Verastem Oncology scientists and collaborators at world-renowned research institutions has described the effect of FAK inhibition to enhance immune response by decreasing immuno-suppressive cells, increasing cytotoxic T cells, and reducing stromal density, which allows tumor-killing immune cells to enter the tumor.8,9 Additionally, in both preclinical and clinical studies, FAK activation has been shown to occur as a potential resistance mechanism in response to MEK inhibitor treatment, and synergy of a FAK inhibitor with a RAF/MEK inhibitor has been shown in several preclinical models. The combination of defactinib and VS-6766 is currently being investigated in an investigator-initiated Phase 1 dose escalation and expansion study. The expansion cohorts are currently ongoing in patients with KRAS mutant advanced solid tumors, including low grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC).6 The ongoing clinical study of the VS-6766/defactinib combination is supported by single-agent Phase 2 studies which investigated defactinib in KRAS mutant NSCLC7 and VS-6766 in KRAS mutant NSCLC and LGSOC.8 Defactinib is also in clinical testing in combination with pembrolizumab for treatment of patients with pancreatic cancer, NSCLC and mesothelioma.10

About COPIKTRA (duvelisib)

COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells. PI3K signaling may lead to the proliferation of malignant B-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.11,12,13 COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. COPIKTRA is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), for which it has received Fast Track status and Orphan Drug Designation, and is being investigated in combination with other agents through investigator-sponsored studies.14 For more information on COPIKTRA, please visit www.COPIKTRA.com. Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

On June 22, 2020 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported preclinical studies highlighting the potential for its lead drug candidate, repotrectinib, to increase the effectiveness of KRAS-G12C and MEK inhibitors in cancer models, and for its next-generation ALK inhibitor candidate, TPX-0131, to overcome ALK-resistant mutations (Press release, Turning Point Therapeutics, JUN 22, 2020, View Source [SID1234564369]).

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The studies were included as part of three poster presentations at today’s virtual annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

"Feedback reactivation and bypass signaling may limit the efficacy of KRAS-G12C and MEK inhibitors against KRAS-driven tumors, and our encouraging preclinical data shows how repotrectinib has the potential to increase the anti-tumor effects by inhibiting SRC, FAK and JAK2 signaling," said Athena Countouriotis, M.D., president and chief executive officer. "We look forward to building upon these preclinical combination studies as we explore the potential for repotrectinib to address a broad set of oncogenic-driven solid tumors.

"In addition, we are excited to share for the first time preclinical data for our fourth drug candidate, TPX-0131, a next generation ALK inhibitor in IND enabling studies. We are encouraged by TPX-0131’s preclinical potency against both wildtype ALK and the most common resistant mutations."

Jessica Lin, M.D., Attending Physician in the Center for Thoracic Cancers at Massachusetts General Hospital Cancer Center and Henri and Belinda Termeer Center for Targeted Therapies, and Instructor in Medicine at Harvard Medical School said: "Resistant mutations following treatment with approved ALK inhibitors remain a challenge for patients, especially the difficult to treat G1202R/del solvent front mutation which can occur in up to 42 percent of patients who develop a resistance mutation, and compound mutations that develop after the recently approved agent Lorbrena. The preclinical potency of TPX-0131 against these mutations suggests that it warrants further study."

Repotrectinib Combination Studies
The preclinical antitumor activities of repotrectinib in combination with proxy molecules for AMG510, an investigational KRAS-G12C inhibitor, and trametinib, an approved MEK inhibitor were highlighted for the first time in two poster presentations. The studies show repotrectinib’s inhibition of SRC, FAK and JAK2 at therapeutically relevant concentrations, which in combination with AMG510 or trametinib demonstrated a synergistic effect over the single agent by reducing tumor cell growth and enhancing tumor cell death. The repotrectinib-trametinib combination studies were replicated across panels of KRAS mutant non-small cell lung, colorectal and pancreatic cancer cell lines that harbor a spectrum of KRAS mutations.

The frequently mutated Kirsten Rat Sarcoma (KRAS) viral oncogene is associated with a broad range of human cancers, including approximately 25 percent of non-small cell lung, 45 percent of colorectal and 75 percent of pancreatic cancers. Therapeutic targeting of KRAS has proven challenging, in part due to resistance and adaptive upregulation of alternative signaling pathways that promote tumor cell survival, as well as concurrent secretion of various cytokines and growth factors.

In preclinical models, repotrectinib inhibits SRC and FAK signaling, a key pathway for oncogenic resistance, and JAK2, a driver of cytokine secretion pathways.

TPX-0131, a Next-Generation ALK Inhibitor
TPX-0131 has been internally designed with a compact macrocyclic structure to bind completely within the ATP binding site of ALK. In preclinical studies, TPX-0131 potently inhibits wildtype ALK and numerous ALK mutations, in particular the clinically observed G1202R solvent-front mutation and G1202R/L1196M compound mutation.

In cell proliferation assays presented at AACR (Free AACR Whitepaper), TPX-0131 exhibited greater potency against wildtype ALK as compared to proxy molecules for approved front-line ALK inhibitors crizotinib, alectinib, brigatinib and ceritinib, and comparable potency to a proxy molecule for approved ALK inhibitor, lorlatinib. TPX-0131 demonstrated more than 100-fold greater potency against the G1202R solvent-front mutation as compared to proxy molecules for the approved ALK inhibitors. Additionally, TPX-0131 is the most potent inhibitor against a range of EML4-ALK compound mutations while prior generation ALK inhibitors tested have shown moderate to no activity.

Anaplastic lymphoma kinase- (ALK) driven tumors are estimated to represent up to 7 percent of driver oncogenes in non-small cell lung cancer and in one study of patients who develop a resistance mutation, G1202R was reported in approximately 42 percent of patients, and compound mutations have been reported in approximately 35 percent of patients who developed resistance following treatment with lorlatinib.

The three posters presented today are:

Title: Repotrectinib increases effectiveness of KRAS-G12C inhibitors in KRAS-G12C mutant cancer models via simultaneous SRC/FAK/JAK2 inhibition
Abstract Number: 1958

Title: Repotrectinib increases effectiveness of MEK inhibitor trametinib in KRAS mutant cancer models via simultaneous SRC/FAK/JAK2 inhibition
Abstract Number: 1957

Title: TPX-0131: A next generation macrocyclic ALK inhibitor that overcomes ALK resistant mutations refractory to current approved ALK inhibitorsbstract Number: 5226

On June 22, 2020 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, taking place June 22-24, 2020 (Press release, MacroGenics, JUN 22, 2020, View Source [SID1234561287]).

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"We are pleased to present data at this year’s AACR (Free AACR Whitepaper) that highlight three platform technologies upon which multiple molecules are being developed at MacroGenics. We are presenting preclinical data for MGC018, our investigational antibody-drug conjugate targeting B7-H3, that provide evidence for an immune-mediated anti-tumor mechanism, as well as a rationale for clinical investigation of this molecule in combination with checkpoint blockade. Separately, we are presenting data from our novel Fc-engineered, bispecific DART molecule that binds CD25 and CTLA-4 that is capable of depleting tumor-infiltrating regulatory T cells with high specificity in vitro," said Ezio Bonvini, M.D., Senior Vice President and Chief Scientific Officer of MacroGenics. "Finally, one of the clinical investigators for flotetuzumab, our investigational CD123 x CD3 DART molecule, will be presenting preclinical data from his research with this molecule during an oral Education Session."

AACR II Presentations

MGC018, a duocarmycin-based antibody-drug conjugate targeting B7-H3, exhibits immunomodulatory activity and enhanced antitumor activity in combination with checkpoint inhibitors

Poster Session: PO.ET07.01 – Cell Surface Antigens and Receptors as Drug Targets

MGC018 is an investigational antibody-drug conjugate targeting B7-H3 that has shown preliminary anti-tumor activity in an ongoing Phase 1 dose escalation study in patients with advanced solid tumors. The poster presented at AACR (Free AACR Whitepaper) describes preclinical data suggesting that MGC018 can promote immune surveillance or stimulate immune responses to dying cancer cells that led to immunological memory, and when combined with checkpoint blockade may enhance anti-tumor activity.

These studies used a mouse model system designed to evaluate anti-tumor activity in an intact and functioning immune system. In this in vivo model, MGC018 demonstrated targeted activity against tumors expressing human B7-H3. Mechanistically, in vitro data suggested that MGC018 induced immunogenic cell death of target cells with the translocation of calreticulin to the cell surface during apoptosis. In addition, treatment with MGC018 in this model system led to an increased infiltration of T cells into the tumor microenvironment. Depleting these T cells attenuated the anti-tumor activity by MGC018, demonstrating their role in mediating response. Furthermore, MGC018 combined with an anti-PD-1 antibody enhanced anti-tumor activity observed in this study. Finally, mice that had achieved a complete response to initial treatment with MGC018 with or without checkpoint blockade survived longer when re-challenged with tumor without subsequent treatment compared to mice that had not received treatment with MGC018, suggesting immunological memory.

Investigational CD25 x CTLA-4 bispecific DART molecule for depletion of tumor infiltrating Tregs via an enhanced Fc-dependent effector mechanism

Poster Session: PO.IM02.23 – Therapeutic Antibodies 1

The poster presented at AACR (Free AACR Whitepaper) described a preclinical bispecific CD25 x CTLA-4 DART molecule containing an Fc region engineered to enhance clearance of target cells by antibody-dependent cellular cytotoxicity. This molecule was designed to deplete tumor-associated regulatory T cells co-expressing CD25 and CTLA-4 to reduce immune suppression mediated by these cells but preserve effector T cell function. CD25 is the alpha subunit of IL-2 receptor and CTLA-4 is a molecule involved in regulatory T cell function.

In vitro studies showed that the Fc-engineered bispecific CD25 x CTLA-4 DART molecule depleted regulatory T cells, with minimal effect on effector T cells. This depletion of regulatory T cells was shown to occur through an Fc-dependent mechanism, as a control CD25 x CTLA-4 DART molecule with an inactivated Fc domain had no effect in this assay. In addition, the bispecific CD25 x CTLA-4 DART molecule preserved cytotoxic T cell effector function in vitro compared to a combination of Fc-engineered monoclonal antibodies independently targeting CD25 and CTLA-4.

Immune escape after bone marrow transplantation: Hiding in plain sight

Educational Session: ED52 – Immunotherapy, Immune Evasion in Myeloid Malignancies, and Therapeutic Implications

John F. DiPersio, M.D., Ph.D., from Washington University School of Medicine in St. Louis, will present an overview of his research related to immune evasion and mechanisms of relapse after allogeneic hematopoietic cell transplantation (allo-HCT). The presentation will include preclinical data on flotetuzumab (MGD006), an investigational CD123 x CD3 bispecific DART molecule, suggesting a potential role for this molecule in treating patients with acute myeloid leukemia whose disease is relapsing after allo-HCT.

Date: June 24, 2020
Time: 5:30 – 5:50pm ET
Location: AACR (Free AACR Whitepaper) Virtual Annual Meeting II at www.aacr.org

The posters will be available on the Events & Presentations page on MacroGenics’ website at View Source

On June 22, 2020, Revolution Medicine Presented a corporate presentation (Presentation, Revolution Medicines, JUN 22, 2020, View Source [SID1234561310]).

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On June 22, 2020 Provectus (OTCQB: PVCT) reported that data from ongoing preclinical study of investigational autolytic cancer immunotherapy PV-10 (rose bengal disodium) is being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2020 Virtual Annual Meeting II, held online June 22-24, 2020 (Press release, Provectus Biopharmaceuticals, JUN 22, 2020, View Source [SID1234561326]). This PV-10 research has been led by Aru Narendran, MD, PhD and his team of researchers at the University of Calgary in Alberta, Canada (UCalgary).

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Dr. Narendran and his colleagues studied the effects of PV-10 treatment on primary cells and cell lines derived from pediatric leukemia patients. UCalgary showed that PV-10 treatment led to STING dimerization and the release of interferon gamma (IFNγ), indicating a potential immune activation mechanism of PV-10. UCalgary further showed that heat shock proteins (HSPs), which chaperone misfolded or abnormally folded proteins, associated with STING dimerization in PV-10-treated cells, indicating a mechanism that may lead to enhanced STING activation following PV-10 treatment.

A copy of the AACR (Free AACR Whitepaper) poster presentation is available on Provectus’ website at View Source

"The essence of cancer is the struggle for survival of these abnormal cells in the body. Over the course of their existence, cancer cells acquire multiple cellular pathways that become active or inactive in order for cancer to have a survival advantage against our immune system. This struggle changes the biology of cancer cells, which may have a direct impact on the activity of anticancer drugs within these cells," Dr. Narendran said. "We observed these very dynamics from our research on PV-10 and pediatric leukemia cells. Classic STING activation does not occur through PV-10 treatment. Rather, STING forms a dimer complex following PV-10 treatment, which may potentially lead to effective immune activation and anticancer activity."

Dr. Narendran added, "Our PV-10 research has enabled us to show, we believe for the first time, that heat shock proteins, which play important roles in the survival of cancer cells, are involved in STING activation. We also believe the involvement of heat shock proteins with STING is an important observation that requires further study."

Dominic Rodrigues, Vice Chair of Provectus’ Board of Directors, said "We are grateful to Dr. Narendran, his team, and the University of Calgary for their consequential research on PV-10 to better understand the basic biology of cancer. This seminal discovery of PV-10-induced alterations of the STING pathway, which plays a pivotal role in innate immunity, contributes to an increasing body of knowledge about how and why PV-10 may function as an immunotherapy across a growing number of cancer types."

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

PV-10 causes acute autolytic destruction of injected tumors (i.e., cell death), mediating the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens that 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.

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 stringent 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 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.