On June 9, 2020 Provectus (OTCQB: PVCT) reported that the Indian Patent Office (IPO) has granted the Company’s patent application for the combination of investigational autolytic cancer immunotherapy PV-10 and systemic immunomodulatory therapy, such as immune checkpoint blockade (CB) (Press release, Provectus Biopharmaceuticals, JUN 9, 2020, View Source [SID1234560940]). Pfizer, Inc. is a co-assignee on this award. The Company’s cancer combination therapy patent estate provides intellectual property (IP) protection in a number of countries in Asia, Europe, and North America into the 2030s.

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New IPO patent 337563 is associated with a family of US patents, including 9,107,887, which is entitled "Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer" and was awarded by the United States Patent and Trademark Office (USPTO) in 2015, and 9,808,524, 9,839,688, and 10,471,144, which were awarded by the USPTO from 2017 to 2019.

The new 2020 IPO patent award for cancer combination therapy follows the Company’s IPO patent 297453, which was awarded in 2018 and protects Provectus’ proprietary manufacturing process used to produce the active pharmaceutical ingredient (API) in the Company’s current and prospective investigational drug products. IPO patent 297453 is associated with a family of US composition of matter and process patents, including 8,530,675, which is entitled "Process for the Synthesis of 4,5,6,7-tetrachloro-3′,6′-dihydroxy-2′,4′,5′,7′-tetraiodo-3H-spiro[isobenzofuran-1,9-xanthen]-3-one (Rose Bengal) and Related Xanthenes" and was awarded by the USPTO in 2013, and 9,273,022 and 9,422,260, which were awarded by the USPTO in 2016.

The Company is also pleased to announce that it received application number 20200138942 from the USPTO for a fifth cancer combination therapy patent application filing, which is based on the abovementioned patent family and includes the combination of PV-10 and two systemic immunomodulatory therapies, such as an anti-CTLA-4 agent (e.g., Yervoy) and an anti-PD-1 agent (e.g., Opdivo). The Company is the sole assignee for this new cancer combination therapy patent application.

The triplet immunotherapy combination of PV-10, Yervoy, and Opdivo for the treatment of uveal melanoma metastatic to the liver (mUM) in patients naïve to CB and refractory to single-agent and combination therapy CB was the subject of the Company’s poster presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Virtual Scientific Program, held online May 29-31, 2020, entitled "Percutaneous hepatic injection of rose bengal disodium (PV-10) in metastatic uveal melanoma." This study, led by Sapna Patel, MD, Associate Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine of The University of Texas MD Anderson Cancer Center (MDACC), is enrolling patients into a single-center cohort at MDACC of up to 25 mUM patients.

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 tumors of the liver (such as hepatocellular carcinoma, metastatic colorectal cancer, metastatic neuroendocrine tumors, and mUM). 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 can be enhanced by combining CB with PV-10.4

About PV-10

PV-10 is an investigational new drug 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 myelocytic leukemia)7,16.

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.8 Cancer progression and metastasis are associated with lysosomal compartment changes9,10, which are closely correlated with (among other things) invasive growth, angiogenesis, and drug resistance11.

PV-10 selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus1,12, external collaborators6, and other researchers14,15,17 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 PARP cleavage5 and, now, stimulator of interferon genes (STING), which plays an important role in innate immunity16. PV-10 is the first cancer drug that may facilitate multiple, complementary, immune system signaling pathways.17

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.

On June 9, 2020 Voltron Therapeutics, Inc. reported that it has entered into a Sponsored Research Agreement (SRA) with the Vaccine and Immunotherapy Center (VIC) of the Massachusetts General Hospital (MGH). Leveraging VaxCelerate, a self-assembling vaccine (SAV) platform licensed exclusively to Voltron Therapeutics by Partners HealthCare, the goal of the collaboration is to optimize the dosing and development of potent compounds that inhibit tumor growth in mice in the treatment of Human Papilloma Virus (HPV) induced malignancy and Ovarian cancer (Press release, Voltron Therapeutics, JUN 9, 2020, View Source;immunotherapy-center-at-the-massachusetts-general-hospital-to-advance-the-development-of-a-personalized-cancer-vaccine-301073035.html [SID1234560957]).

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In prior research, the SAV, when combined with a checkpoint inhibitor in a model of HPV-induced cancer, demonstrated a significant improvement in survival over either agent alone or combined. Based on these preliminary findings, several aspects of the protein core of the vaccine construct were re-engineered to optimize its ability to bind targets on cancer cells. These new Voltron Therapeutics sponsored preclinical studies set out to underscore the SAV’s safety and efficacy track record and position it for human trials.

Dr. Mark Poznansky, Director, Vaccine and Immunotherapy Center, MGH stated, "The self-assembling vaccine, co-invented with my colleague Dr. Jeffrey Gelfand, has been designed to be highly adaptable, designed for safety and allows for seamless modifications in order to target specific proteins found in tumor cells. Leveraging the protein HSP70, we are able to determine the quantity and timing of vaccination that best induces T-cell responses and explore the maximized benefit from vaccine induced anti-tumor immunity."

The SAV program has intellectual property surrounding composition of matter. The vaccine incorporates a heat shock protein that activates the immune system, bound to targeting peptides. The base core technology relies on synthesizing the heat shock protein with Avidin. Biotinylated immunogenic peptides are then bound to the HSP to customize the vaccine.

"Voltron Therapeutics is excited to continue our groundbreaking work with the VIC by supporting ongoing research dedicated to our Oncology program and the advancement of the VaxCelerate platform to develop vaccines to fight a range of cancers," said Pat Gallagher, Chief Executive Officer, Voltron Therapeutics. "The resources at the VIC and MGH to support vaccine development and innovation are instrumental in helping us advance this important work. We are hopeful that further development, pre-clinical testing and additional proof of concept results could lead to first in human trials in 2021 and ultimately make a significant and lasting difference in the treatment of cancer patients."

Additionally, Voltron Therapeutics has closed on $3.5 million in a Series-A Preferred funding round. The funds raised will be used to accelerate the development of SAV technology and expansion of the Company’s vaccine portfolio.

"This funding for Voltron Therapeutics will allow the company to conclude preclinical work as it moves toward human trials with the self-assembling vaccine," added James Ahern, Founder of Laidlaw Venture Partners, and member of the Voltron Therapeutics Board of Directors. "We at LVP are committed to continuing to support Voltron as it progresses the SAV portfolio into clinical development, with financial sponsorship and leverage of our expert network."

Voltron Therapeutics and MGH have a longstanding relationship for the development of vaccines to fight infectious diseases and cancer. Recently, Voltron Therapeutics announced a separate joint agreement to advance an application of the VaxCelerate platform to develop a vaccine designed to protect patients at risk of Coronavirus (COVID-19) infection. This vaccine will be entering animal testing this quarter. Currently, preclinical data exists in two different infectious disease settings with encouraging results. The COVID-19 vaccine could be in humans by late 2020/early 2021.

On June 9, 2020 Oasmia Pharmaceutical reported that it will publish its Year End Report for the financial year 2019/2020 on June 18, 2020, at 08.00 am CET (Press release, Oasmia, JUN 9, 2020, View Source [SID1234560923]).

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The company will hold a conference call and an online presentation on the same day at 10.00 am (CEST). The call will be hosted by Francois Martelet, CEO, and Michael af Winklerfelt, CFO. The presentation will be in English.

The conference call will be broadcast live on the web via the link: View Source

On June 9, 2020 Oncology Venture A/S (Nasdaq First North Stockholm: OV.ST) ("OV" or the "Company") reported that it has called upon Global Corporate Finance (GCF) to invest SEK 10 million in a directed shared issue in accordance with the Company’s share subscription agreement with GCF (Press release, Oncology Venture, JUN 9, 2020, View Source [SID1234560941]). The draw-down notice was issued to GCF on June 9, and the share subscription price shall be calculated as 95% of the daily volume weighted average price (VWAP) of the Company’s shares for the five consecutive trading days following the date of the draw down notice.

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The investment is the first investment tranche of up to a total of five such tranches Oncology Venture may request from Global Corporate Finance (New York City, NY, U.S.). Each investment tranche can total up to SEK 10 million.

On June 9th, 2020 Lycia Therapeutics, Inc. exited stealth mode with a $50 million commitment from founding investor Versant Ventures (Press release, Lycia Therapeutics, JUN 9, 2020, View Source [SID1234560925]). Proceeds are being used to develop lysosomal targeting chimeras, or LYTACs, as therapeutics for a broad set of currently intractable cell surface targets.

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"I look forward to working closely with the team to advance the science and explore the broader applications to developing effective therapeutics for intractable cancers and many other challenging diseases."

Interest in the field of protein degradation continues to grow, as classical approaches to developing small molecule and biologic therapeutics have proven to be ineffective on many disease-relevant targets. This is especially the case for extracellular and secreted proteins that have inaccessible active sites, complex and challenging molecular structures, and other limiting factors.

"Our understanding of the biological pathways and targets relevant to certain diseases has far outreached our ability to develop effective therapeutic modalities," said Lycia CEO Aetna Wun Trombley, Ph.D. "LYTACs offer the promise of targeting a wider array of proteins on the cell surface or in the extracellular compartment. Many of these have been linked to cancer, autoimmune and other serious diseases."

Targeting extracellular proteins with LYTACs

Versant established Lycia in 2019 within the firm’s San Diego-based Inception labs in collaboration with academic founder Carolyn Bertozzi, Ph.D., professor of chemistry and HHMI investigator at Stanford University. The initial aim was to develop and validate a drug discovery platform.

The LYTACs platform leverages decades of work in the field of lysosomal biology. In a 2019 publication, Dr. Bertozzi’s team at Stanford demonstrated that a cation-independent receptor called CI-M6PR could be exploited to capture and drag extracellular proteins into cells, trafficking them to the lysosome for destruction.

In addition to CI-M6PR, Lycia has now extended this approach and leveraged other tissue-specific internalizing receptor systems to further expand the technology’s therapeutic potential.

"Our understanding of multiple receptor systems including M6PR offered Lycia the opportunity to take the protein degradation field in a new direction," said Dr. Bertozzi. "I look forward to working closely with the team to advance the science and explore the broader applications to developing effective therapeutics for intractable cancers and many other challenging diseases."

Relevance to numerous diseases and modalities

With the Inception team, Lycia has been able to validate, optimize and expand this approach. Confirmatory studies have shown targeted degradation of cell surface proteins such as EGFR, PD-L1, as well as secreted proteins like ApoE4. Collectively these results suggest that LYTACs can potentially serve as effective therapeutics for a wide range of difficult-to-treat conditions. Further work continues to target other membrane proteins, including receptor tyrosine kinases, and pathogenic immune complexes in circulation.

Moreover, the platform has the potential to extend the reach of other modalities including gene therapy, which cannot be chronically dosed due to the production of autoantibodies. The platform can be exploited to develop a LYTAC binder able to capture and drag the autoantibodies into a lysosomal trafficking pathway.

Advisors and operating plans

The Lycia team will work alongside experienced entrepreneurs and leading scientists who have made important contributions in the field and bring relevant experience to the company.

Carolyn Bertozzi, Ph.D., who chairs Lycia’s Scientific Advisory Board, is the Anne T. and Robert M. Bass Professor of Chemistry and Professor of Chemical & Systems Biology and Radiology at Stanford University, and an Investigator of the Howard Hughes Medical Institute. Dr. Bertozzi’s research interests span the disciplines of chemistry and biology with an emphasis on studies of cell surface glycosylation pertinent to disease states. She is an elected member of the Institute of Medicine, National Academy of Sciences, and American Academy of Arts and Sciences. She has been awarded the Lemelson-MIT Prize, the Heinrich Wieland Prize, and a MacArthur Foundation Fellowship, among many others.

Randy Schekman, Ph.D., is an investigator of the Howard Hughes Medical Institute and a Professor of Cell and Developmental Biology in the Department of Molecular and Cell Biology at the University of California at Berkeley. He was awarded the Nobel Prize in Physiology or Medicine in 2013.

Mark M. Davis, Ph.D. is the Director of the Stanford Institute for Immunology, Transplantation and Infection (ITI), a Professor of Microbiology and Immunology and a Howard Hughes Medical Institute Investigator at Stanford University. He received a B.A. from Johns Hopkins University and a Ph.D. from the California Institute of Technology. Dr. Davis is well known for identifying many of the T-cell receptor genes, which are responsible for the ability of these cells to recognize a diverse repertoire of antigens. His current research focuses on obtaining a systems level understanding of the human immune system.

Brian Druker, M.D., is Professor of Medicine and Director of the OHSU Knight Cancer Institute and the JELD-WEN Chair of Leukemia Research. His research focuses on activated tyrosine kinases with an emphasis on their role in cancer. His work resulted in Gleevec, the first drug to target the molecular defect of a cancer while leaving healthy cells unharmed. He has been recognized with numerous awards, including the Warren Alpert Prize from Harvard Medical School, the Lasker-DeBakey Award for Clinical Medical Research, the Japan Prize in Healthcare and Medical Technology, and most recently, the 2018 Tang Prize in Biopharmaceutical Science.

Alanna Schepartz, Ph.D., is the T.Z. and Irmgard Chu Distinguished Chair in Chemistry and Professor of Molecular and Cell Biology at the University of California at Berkeley. Her research spans the fields of chemical and synthetic biology. A primary focus is to uncover the chemistry that drives complex cellular processes and apply this knowledge to design or discover molecules – large and small – that possess unique or useful properties.

Monther Abu-Remaileh, Ph.D., is Assistant Professor of Chemical Engineering at Stanford University. His lab is focused on identifying novel pathways that enable cellular and organismal adaptation to metabolic stress and changes in environmental conditions, as well as how these pathways go awry in human diseases such as cancer, neurodegeneration and metabolic syndrome, in order to engineer new therapeutic modalities.

Laurent Fischer, M.D., who is an independent member of Lycia’s Board of Directors, was senior vice president and head of the liver therapeutic area at Allergan. Before that, he was CEO of Tobira Therapeutics, which Allergan acquired in 2016 for $1.7 billion. Dr. Fischer has held numerous CEO roles at biotechnology companies, as well as senior leadership positions at large pharmaceutical companies. He has been involved in the launch of multiple drugs.

Lycia will be headquartered in the San Francisco Bay Area and will continue collaborating with the San Diego-based Inception team during the startup phase. With this financing, the company plans to build out its foundational LYTAC platform, develop an internal pipeline, and will also consider discovery-stage partnerships to fully exploit the potential of this novel approach.

"The team at Lycia has begun to translate recent insights on the utility of targeted lysosomal trafficking into a new class of therapeutics," said Clare Ozawa, Ph.D., Versant managing director and a Lycia board member. "With this financing, we hope to build on this progress and to generate a broad pipeline of development candidates."

About Lycia Therapeutics, Inc.

Lycia Therapeutics, Inc. is a biotechnology company using its lysosomal targeting chimeras (LYTACs) platform to discover and develop first-in-class therapeutics that degrade extracellular and membrane-bound proteins that drive a range of difficult-to-treat diseases, including cancers and autoimmune conditions. Lycia was established in 2019 within founding investor Versant Ventures’ San Diego-based Inception Discovery Engine, and now is headquartered in the San Francisco Bay Area. Visit www.lyciatx.com for more information.

About Versant Ventures

Versant Ventures is a leading healthcare venture capital firm committed to helping exceptional entrepreneurs build the next generation of great companies. The firm’s emphasis is on biotechnology companies that are discovering and developing novel therapeutics. With $3.2 billion under management and offices in the U.S., Canada and Europe, Versant has built a team with deep investment, operating and R&D expertise that enables a hands-on approach to company building. Since the firm’s founding in 1999, more than 75 Versant companies have achieved successful acquisitions or IPOs. Versant is currently investing out of its seventh fund, Versant Venture Capital VII, a $600 million global biotech fund closed in December 2018. In parallel the firm co-invests out of its Canadian strategic fund Versant Voyageurs I and its later-stage biotech opportunity fund Versant Vantage I. For more information, please visit www.versantventures.com.