On June 22, 2020 Medigene AG (Medigene, FSE: MDG1), a clinical stage immuno-oncology company focusing on the development of T cell immunotherapies, reported insights from preclinical studies on its PD1-41BB switch receptor at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II taking place from 22 – 24 June 2020 (Press release, MediGene, JUN 22, 2020, View Source;s%20scientists%20demonstrated%20that%20the,especially%20against%20solid%20tumor%20cells.&text=One%20prominent%20inhibitory%20axis%20exploited,T%20cell%20activity%20in%20tumors. [SID1234561330]). The e-poster is available online today on the first day of the virtual conference as well as on Medigene’s website.

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Medigene’s scientists demonstrated that the PD1-41BB switch receptor significantly improves the functional activity of T cell receptor-modified T cells (TCR-Ts) especially against solid tumor cells. Many solid tumors create a "hostile" microenvironment that suppresses immune cell attack, enabling tumors to survive and grow. To this end, tumor cells employ so-called "checkpoint mechanisms" to impede T cell activity. One prominent inhibitory axis exploited by tumors, the PD1-PDL1 pathway, is known to shut down T cell activity in tumors. Medigene’s PD1-41BB molecule is designed to convert the PD-1 "stop" signal induced by tumor cells to a "go" command by switching signals inside the T cells to activation, thereby overcoming the PD1-PDL1 inhibitory checkpoint blockade.

Prof. Dolores Schendel, Chief Executive Officer and Chief Scientific Officer of Medigene: "In preclinical studies we could show that the addition of the PD1-41BB switch receptor to our TCR-Ts strongly enhances the antigen-specific functions of the TCR-Ts against solid tumors.

"Based on these promising results, we believe that the PD1-41BB switch receptor will ultimately enable our TCR-Ts to be more active in patients with solid tumors which have previously been very difficult to treat due to multiple mechanisms of immunosuppression. Furthermore, exploiting the PD1-PDL1 pathway to increase TCR-T activity through our switch receptor can be done in a targeted, localized manner, thereby avoiding the challenges of systemic side-effects that accompany treatment with existing checkpoint inhibitors."

Presentation Details:

Poster #3231 "The chimeric co-stimulatory receptor PD1-41BB enhances the function of T cell receptor (TCR)-modified T cells targeting solid tumors"

(E-poster with an audio description)

Session Adoptive Cell Therapy 3

Link to abstract https://bit.ly/3g3Q44H

Date 22 June 2020, 9:00 am – 06:00 pm (EDT)

Download www.medigene.com/technologies/abstracts
About Medigene’s PD1-41BB switch receptor:

Checkpoint inhibition via PD1-PDL1 pathway: Solid tumor cells are known to be sensitive to killing by activated T cells. Tumor cells can escape this killing activity by expressing inhibitory molecules, so-called ‘checkpoint proteins’, such as Programmed Death Ligand 1 (PD-L1) on their surface. When this occurs, activated T cells which express PD-1, the natural receptor for PD-L1, are inactivated. The expression of PD-L1 by tumors represents an adaptive immune resistance mechanism that can lead to tumor survival and growth.

The 4-1BB co-stimulatory signaling pathway: Effective T cell immune responses to antigens typically require costimulatory signals to be received alongside the primary antigenic stimulation via the T cell receptor (TCR). The intracellular signaling domains of the 4-1BB protein offer a well-characterized pathway to positively enhance T cell responses.

Medigene’s PD1-41BB switch receptor takes advantage of the binding of PD-1 on the T cells to PD-L1 on tumors. In the switch receptor, the inhibitory signaling domain of PD-1 has been substituted with the activating signaling domain of 4-1BB. As a result, the switch receptor then delivers an activating signal to the TCR-T cells (not the usually inhibitory signal of PD-1). This enables the PD1-41BB-modified TCR-T cells to proliferate strongly in the presence of PD-L1-positive tumor cells and to mediate greater killing of tumor cells upon repeated exposure. Additionally, signals mediated through the switch receptor also enhance metabolic fitness of TCR-T cells, enabling better function in conditions of low levels of glucose or high levels of the immunosuppressive factor TGF-ß, two conditions that are characteristic of strongly hostile tumor microenvironments.

On June 22, 2020 OncoSec Medical Incorporated (the "Company" or "OncoSec") (Nasdaq: ONCS), a company developing late-stage intratumoral cancer immunotherapies, reported that new data further demonstrating the power of OncoSec’s next-generation interleukin-12 (IL-12) plasmid (TAVOPLUS) therapeutic when combined with a T cell stimulator (TAVOPLUS-CD3) or an enhanced chemokine gradient (TAVOPLUS-CXCL9) (Press release, OncoSec Medical, JUN 22, 2020, View Source [SID1234561329]). These product candidates, coupled with the new low-voltage electroporation gene delivery system, represent a promising approach for treating patients with a variety of solid tumors. The data were presented today during two late-breaking poster presentations at the American Association for Cancer (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II being held from June 22-24, 2020.

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"Multiple studies have used intratumoral plasmid IL-12 (TAVO) to treat solid tumor indications with a demonstrable clinical benefit due to this cytokine’s ability to drive deep and durable immune responses," said Christopher Twitty, Ph.D., OncoSec’s Chief Science Officer. "The new preclinical data exhibited in both AACR (Free AACR Whitepaper) presentations highlights the evolution of OncoSec’s IL-12-based platform. Incorporation of a chemokine gradient and a polyclonal T cell stimulator with the enhanced IL-12 backbone of TAVOPLUS holds significant potential in the treatment of solid tumors. We believe these data provide a strong rationale for filing an Investigational New Drug application and we are excited to advance TAVOPLUS into clinical development."

The following posters were presented during the session titled, "Late-Breaking Research: Immunology 2":

Title: "Intratumoral electroporation of plasmid-encoded IL-12 and membrane-bound anti-CD3 increases tumor immunogenicity and augments the function of T cell subsets"
Poster Number: 14
Abstract Number: LB-390

Study Highlights:

Compared to IT-tavo-EP, TAVO+-αCD3 enhances T cells engagement with tumor cells and augments T cell killing function in preclinical cancer models by:

Increasing expressor memory T cells, which may extend anti-tumor response from treatment.
Increasing activated T cells in peripheral blood, which may enhance anti-tumor response throughout the body.
Increasing antigen specific T cells anti-tumor activity, which leads to enhanced cancer cell recognition by T cells.
Restoring the exhausted, non-active T cells’ anti-tumor activity, which leads to re-energized cancer cell killing activity.
Title: "Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of CXCL9 synergizes with IL-12 gene therapy (TAVO) to elicit robust anti-tumor immunity"
Poster Number: 20
Abstract Number: LB-396

Study Highlights:

Data demonstrated that IL-12, in concert with CXCL9 (a potent chemokine), leads to brisk infiltration of T cells and efficient remodeling of the tumor microenvironment, making tumors more susceptible to treatment.
This new product candidate thus builds upon OncoSec’s plasmid based immunotherapeutic platform by augmenting the effects of IL-12 with the inclusion of CXCL9.
Study showed that combining intratumoral TAVO with a DNA-encoded, locally secreted CXCL9, significantly improves anti-PD1 response, thus providing an approach to extend the benefit of PD-1 blockade to more patients.
The full abstracts presented at the AACR (Free AACR Whitepaper) Virtual Meeting II are available online at www.aacr.org and the posters are available on OncoSec’s website at www.oncosec.com.

On June 22, 2020 Precigen, Inc., a biopharmaceutical company specializing in the development of innovative gene and cell therapies to improve the lives of patients, reported preclinical data for its innovative investigational PRGN-3005 UltraCAR-T in patients with advanced, recurrent platinum resistant ovarian, fallopian tube or primary peritoneal cancer has been published as an e-poster and accompanying audio presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II (Press release, Precigen, JUN 22, 2020, View Source [SID1234561328]). The e-poster presentation titled PRGN-3005 UltraCAR-T: Multigenic CAR-T Cells Generated Using Non-viral Gene Delivery and Rapid Manufacturing Process for the Treatment of Ovarian Cancer (Abstract 6593) is part of the Immunology/Adoptive Cell Therapy session and is accessible on the AACR (Free AACR Whitepaper) e-poster website.

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Traditional methods for CAR-T cell manufacturing involve the use of viral vectors and ex vivo cell expansion at centralized manufacturing facilities, contributing to potentially high costs and extended waiting periods. Precigen’s UltraCAR-T platform, in contrast, is based upon a non-viral multigene delivery system combined with a rapid, decentralized manufacturing process without ex vivo expansion. Following isolation of the patient’s own T cells after blood draw, non-viral gene transfer occurs overnight at the medical center’s cGMP facility. The next day, UltraCAR-T cells are infused into the patient.

PRGN-3005 is an autologous CAR-T treatment simultaneously expressing three gene products, which results in a uniform, homogenous CAR-T cell therapy: 1) CAR to specifically target the unshed portion of Mucin 16 (MUC16), which is overexpressed on over 80% of ovarian tumors with limited expression found in healthy tissues; 2) membrane-bound IL-15 (mbIL15) to provide improved UltraCAR-T persistence and maintenance of preferred stem cell like memory phenotype; and 3) a kill switch to eliminate the CAR-T cells, if needed.

Preclinical data demonstrate the specificity and efficacy of using the rapidly manufactured PRGN-3005 UltraCAR-T cells for the treatment of ovarian tumors. Specifically, a single administration of PRGN-3005 showed significantly superior expansion and preferred memory phenotype of UltraCAR-T in vivo and significantly superior efficacy compared to traditional CAR-T resulting in all PRGN-3005 treated mice becoming tumor-free. Furthermore, rechallenging these tumor-free mice three months later with ovarian tumors for a second time (to simulate tumor relapse) led to the elimination of tumor burden without additional PRGN-3005 UltraCAR-T treatment. These data demonstrate the potential of UltraCAR-T cells to persist long-term in vivo, prevent CAR-T cell exhaustion, and mount a durable anti-tumor response with the ability to continue to respond upon tumor rechallenge.

"We are pleased to be able to share the preclinical data for PRGN-3005 that led to the IND clearance and initiation of the Phase I study," said Helen Sabzevari, PhD, President and CEO of Precigen. "Our preclinical results demonstrate that PRGN-3005 UltraCAR-T administered one day after non-viral gene transfer has superior anti-tumor efficacy and persistence compared to traditional CAR-T cells and represents a promising opportunity for ovarian cancer treatment. We look forward to sharing the first clinical data for PRGN-3005 in the second half of 2020."

Based on these preclinical results, the FDA approved the IND application, and the first-in-human PRGN-3005 Phase I clinical trial for advanced ovarian cancer is currently under way (clinical trial identifier: NCT03907527). The PRGN-3005 UltraCAR-T Phase I clinical study is an open-label, dose escalation study to evaluate the safety and maximal tolerated dose of PRGN-3005 UltraCAR-T delivered by intraperitoneal infusion (IP) or intravenous infusion (IV). The study population includes patients with advanced stage (III/IV) recurrent ovarian, fallopian tube, and primary peritoneal cancer who are platinum-resistant and have progressed after receiving standard-of-care therapies or are not eligible to receive available therapies with known clinical benefit.

About Ovarian Cancer
Worldwide, nearly 300,000 women are diagnosed with ovarian cancer every year1 with approximately 22,000 of them in the US2. Since early ovarian cancer is often without obvious symptoms, the disease is frequently diagnosed at an advanced stage where cancer has spread to distant parts of the body, such as the liver or lungs2,3. Five-year survival rates depend on stage and type of ovarian cancer with rates decreasing for advanced stage cancers that have spread to distant parts of the body3.

Precigen: Advancing Medicine with Precision
Precigen (Nasdaq: PGEN) is a dedicated discovery and clinical stage biopharmaceutical company advancing the next generation of gene and cell therapies using precision technology to target urgent and intractable diseases in our core therapeutic areas of immuno-oncology, autoimmune disorders, and infectious diseases. Our technologies enable us to find innovative solutions for affordable biotherapeutics in a controlled manner. Precigen operates as an innovation engine progressing a preclinical and clinical pipeline of well-differentiated unique therapies toward clinical proof-of-concept and commercialization. For more information about Precigen, visit www.precigen.com or follow us on Twitter @Precigen and LinkedIn.

Precigen’s UltraCAR-T Therapeutic Platform
Precigen’s UltraCAR-T platform has the potential to disrupt the CAR-T treatment landscape by increasing patient access through shortening manufacturing time, decreasing manufacturing-related costs, and improving outcomes using advanced approaches for precise tumor targeting and control of the immune system. The platform brings several key advancements: 1) Non-viral gene transfer using multigenic vectors for expression of multiple effector genes leads to better precision and control of tumor targeting and eliminates the need for virus; 2) Sustained persistence and desired phenotype of infused UltraCAR-T helps address T-cell exhaustion, a common issue with current CAR-T therapies; 3) T-cell control by incorporation of kill switch technology to potentially improve the safety profile; and 4) Rapid manufacturing of UltraCAR-T cells using our proprietary non-viral gene transfer process, which eliminates the need for ex vivo propagation, thus dramatically reducing wait times for patients from weeks to one day after gene transfer.

Trademarks
Precigen, UltraCAR-T, and Advancing Medicine with Precision are trademarks of Precigen and/or its affiliates. Other names may be trademarks of their respective owners.

On June 22, 2020 Myovant Sciences (NYSE: MYOV), a healthcare company focused on redefining care for women and for men, reported that its New Drug Application (NDA) for once-daily, oral relugolix (120 mg) for the treatment of men with advanced prostate cancer has been accepted for Priority Review by the U.S. Food and Drug Administration (FDA) (Press release, Myovant Sciences, JUN 22, 2020, https://investors.myovant.com/news-releases/news-release-details/myovant-sciences-announces-priority-review-and-fda-acceptance [SID1234561327]).

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"We are delighted that the FDA has accepted for Priority Review our New Drug Application for relugolix, bringing us one step closer to providing a one pill, once a day potential new treatment option to men with advanced prostate cancer," said Lynn Seely, M.D., chief executive officer of Myovant Sciences. "As recently published in the New England Journal of Medicine, relugolix demonstrated superior efficacy and a 54% lower risk of major adverse cardiovascular events compared to the current standard of care, leuprolide acetate injections, in the Phase 3 HERO study."

The FDA grants Priority Review to applications for potential therapies that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications. The FDA has set a target action date of December 20, 2020 under the Prescription Drug User Fee Act (PDUFA). In its acceptance letter, the FDA also stated that it is currently not planning to hold an advisory committee meeting for this application. If approved, relugolix would be the first and only oral gonadotropin-releasing hormone (GnRH) receptor antagonist treatment for men with advanced prostate cancer.

In May 2020, Myovant submitted a separate NDA for once-daily, oral relugolix combination tablet (relugolix 40 mg, estradiol 1.0 mg, and norethindrone acetate 0.5 mg) for women with heavy menstrual bleeding associated with uterine fibroids. A Marketing Authorization Application for relugolix combination tablet in women with moderate to severe symptoms associated with uterine fibroids is also under review by the European Medicines Agency.

About the Phase 3 HERO Program in Advanced Prostate Cancer
Myovant’s Phase 3 clinical program for advanced prostate cancer consisted of a randomized, open-label, parallel-group, multinational clinical study designed to evaluate the safety and efficacy of relugolix in over 900 men with androgen-sensitive advanced prostate cancer who required at least one year of continuous androgen deprivation therapy. Men were randomized 2:1 to receive a single loading dose of relugolix 360 mg followed by relugolix 120 mg once daily, or to treatment with leuprolide acetate 3-month depot injection, respectively.

Relugolix met the primary efficacy endpoint, with 96.7% of men treated with relugolix achieving sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks versus 88.8% of men treated with leuprolide acetate. Relugolix also met all six key secondary endpoints, demonstrating superiority to leuprolide acetate in rapid and profound suppression of testosterone and PSA response, in addition to improved testosterone recovery after discontinuation of treatment. Men in the relugolix group had a 54% lower risk of major adverse cardiovascular events (MACE) compared to men in the leuprolide acetate group (2.9% vs. 6.2%, respectively). In men with a reported history of MACE, the relugolix group had 80% fewer MACE events reported compared to the leuprolide acetate group (3.6% vs. 17.8%, respectively). The overall incidence of adverse events in the relugolix and leuprolide acetate groups was comparable (92.9% vs. 93.5%, respectively).

Data from an additional key secondary endpoint, castration resistance-free survival, are expected in the third quarter of 2020.

About Prostate Cancer
Prostate cancer is the second most prevalent form of cancer in men and the second leading cause of death due to cancer in men in the U.S. Cardiovascular mortality is the leading cause of death in men with prostate cancer and accounts for 34% of deaths in men with prostate cancer in the U.S. More than three million men in the U.S. are currently living with prostate cancer, and approximately 190,000 men are estimated to be newly diagnosed in 2020. Advanced prostate cancer is prostate cancer that has spread or come back after treatment and may include men with biochemical recurrence (rising PSA in the absence of metastatic disease on imaging), locally advanced disease, or metastatic disease. Front-line medical therapy for advanced prostate cancer typically involves androgen deprivation therapy, which reduces testosterone to very low levels, commonly referred to as castrate levels. GnRH receptor agonists, such as leuprolide acetate, are depot injections and the current standard of care for androgen deprivation therapy. However, GnRH receptor agonists may be associated with mechanism-of-action limitations, including the potentially detrimental initial surge in testosterone levels that can exacerbate clinical symptoms, which is known as clinical or hormonal flare, and delayed testosterone recovery after the drug is discontinued. Approximately 210,000 men are treated with androgen deprivation therapy with a GnRH agonist or antagonist each year.

About Relugolix
Relugolix is a once-daily, oral gonadotropin-releasing hormone (GnRH) receptor antagonist that reduces production of testicular testosterone, a hormone known to stimulate the growth of prostate cancer, and ovarian estradiol, a hormone known to stimulate the growth of uterine fibroids and endometriosis. Myovant is developing relugolix as a monotherapy tablet (120 mg once daily) for men with advanced prostate cancer. Myovant is also developing a relugolix combination tablet (relugolix 40 mg, estradiol 1.0 mg, and norethindrone acetate 0.5 mg) for women with uterine fibroids and for women with endometriosis.

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.