On December 12, 2019 Rheos Medicines, a biopharmaceutical company harnessing insights in immunometabolism to create a new class of therapeutics for patients with severe autoimmune disorders, inflammatory diseases and cancer, reported the online publication of a perspective in Cell Metabolism that highlights the rationale and potential of employing principles of immunometabolism to discover and develop novel medicines (Press release, Rheos Medicines, DEC 12, 2019, View Source [SID1234552326]). The article, entitled The Untapped Opportunity and Challenge of Immunometabolism: A New Paradigm for Drug Discovery, was published online today in Cell Metabolism (DOI: 10.1016/j.cmet.2019.11.014).

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Immune cells modulate their energy requirements in response to changes in their environment, which include interactions with pathogens, tumor cells, other immune system cells and molecules such as growth factors and antibodies. The metabolic programs that are induced or inhibited as immune cells respond to such stimuli can drive immune cell activation, differentiation, or suppression. Understanding the mechanisms through which metabolism can dictate the function or fate of immune cells is a new platform for target and biomarker discovery with a goal of identifying new medicines with potential to selectively tune the immune system to amplify or dampen its response. The perspective reviewed the underlying biology of immunometabolism and the new tools to discover and develop novel therapeutics based on this paradigm.

"To exploit this new field of immunometabolism, we have developed and industrialized a platform that comprehensively elucidates the metabolic pathways and targets with potential to control immune cell fate or function, as well as their associated metabolite biomarkers," said Laurence Turka, M.D., Chief Scientific Officer and co-founder of Rheos. "Our approach employs a proprietary integration of metabolomic, transcriptomic, and other data to generate immunometabolism network maps (imMAPs) that characterize immune cell activation and differentiation through a metabolic lens. Our imMAPs have potential to tap currently undiscovered or poorly understood biology and enable development of new therapeutics for a wide range of diseases including autoimmunity and cancer."

Barbara Fox, Ph.D., Chief Executive Officer of Rheos, added, "Immunometabolism has the potential to be the next frontier in drug discovery. Our pioneering product engine has the breadth and power to identify novel metabolic targets across a diverse set of pathways, better understand the metabolic impact of existing therapies and bring the benefits of personalized medicine to autoimmunity. Based on our work to-date, we have initiated drug discovery efforts in a number of programs and we look forward to providing further updates as we continue to make progress."

On December 12, 2019 Silverback Therapeutics, Inc., a biopharmaceutical company developing a pipeline of systemically delivered, locally active therapies, reported the presentation of preclinical data supporting development of its lead ImmunoTAC candidate, SBT6050, at the San Antonio Breast Cancer Symposium (SABCS) (Press release, Silverback Therapeutics, DEC 12, 2019, View Source [SID1234552325]). The data were presented today in Spotlight Oral and Poster Presentations at the Henry B. Gonzalez Convention Center in San Antonio, Texas (Program #PD4-09, Abstract #924).

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"Our preclinical data continue to highlight the potential for single agent clinical activity with SBT6050, even in settings with diminished or absent T cell infiltrates, and now demonstrate the opportunity for enhanced activity in combination with trastuzumab. We are excited to rapidly advance SBT6050 into the clinic."

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The presentation, titled "Preclinical studies support the development of SBT6050, an anti-HER2 antibody conjugated to a potent TLR8 agonist, for treatment of moderate and high HER2 expressing tumors," shows that SBT6050 effectively activates human myeloid cells and drives multiple anti-tumor immune mechanisms in a HER2 dependent manner in vitro, and an SBT6050 mouse surrogate exhibits potent anti-tumor efficacy as a single agent and in combination with trastuzumab in vivo. Unlike other innate immune agonists that have been limited to topical or intratumoral administration, SBT6050 is designed for systemic delivery and tumor-localized activity.

In preclinical studies, robust, durable single agent activity is observed with the SBT6050 mouse surrogate in multiple syngeneic mouse tumor models, including those with low tumor infiltrating lymphocytes, a feature commonly observed in HER2-expressing malignancies. Importantly, the SBT6050 mouse surrogate is curative as a single agent in a human xenograft model lacking T, B, and NK cells, demonstrating the potential of myeloid cells to mediate strong anti-tumor activity. SBT6050 and trastuzumab bind to distinct epitopes on HER2, enabling potential trastuzumab-based combinations in patients. A combination of low dose SBT6050 mouse surrogate with trastuzumab in a HER2-positive human xenograft model greatly enhanced the anti-tumor activity observed with either agent alone. Collectively, these data demonstrate the potential for clinical activity with SBT6050 in HER2-expressing malignancies and highlight development opportunities in clinical combination with trastuzumab.

"SBT6050’s ability to drive a broad spectrum of anti-tumor immune responses through localized and potent activation of human myeloid cells has not been achieved by other cancer immunotherapies," said Valerie Odegard, Ph.D., Silverback’s chief scientific officer. "Our preclinical data continue to highlight the potential for single agent clinical activity with SBT6050, even in settings with diminished or absent T cell infiltrates, and now demonstrate the opportunity for enhanced activity in combination with trastuzumab. We are excited to rapidly advance SBT6050 into the clinic."

Added Naomi Hunder, M.D., Silverback’s senior vice president of clinical development, "Despite advances in treatment options for patients with HER2-expressing tumors, significant unmet medical need remains, and immune checkpoint inhibitors have demonstrated activity in only a subset of these patients. Preclinical data indicate SBT6050 may be useful as a single agent therapeutic or in combination with trastuzumab-based therapies, providing a much needed immunotherapeutic option for patients with HER2-expressing disease. We plan to initiate clinical investigation of SBT6050 in 2020."

About Silverback’s Platform Technology

Silverback’s proprietary technology and integrated R&D approach enables the design and development of ImmunoTAC therapeutics that can be administered systemically but act only at the sites of disease. This approach is designed to spare healthy tissues from unwanted side effects, while modifying disease processes in a targeted and potent manner. Silverback’s platform is useful for developing systemic therapies that can modulate fundamental pathways underlying serious or life-threatening diseases in a targeted manner, in contrast to traditional antibody and small molecule-based approaches that have not been successful due to inadequate activity and/or unacceptable toxicities. Silverback has over 20 patent families directed to the platform and related product candidates.

On December 12, 2019 SCYNEXIS, Inc. (NASDAQ : SCYX) reported the closing of its previously announced underwritten public offering of 38,888,889 shares of common stock and warrants to purchase up to 38,888,889 shares of common stock (Press release, Scynexis, DEC 12, 2019, View Source [SID1234552324])
. Each share of common stock and warrant to purchase one share of common stock were sold at a combined public offering price of $0.90 per share and accompanying warrant. The total gross proceeds to SCYNEXIS from this offering were approximately $35 million, including the exercise of the underwriters’ option to purchase additional warrants, before deducting underwriting discounts and commissions and other estimated offering expenses, and excluding the exercise of any warrants. All of the shares of common stock and warrants were offered by SCYNEXIS.

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H.C. Wainwright & Co. acted as sole book-running manager for the offering. Aegis Capital Corp., Brookline Capital Markets, a division of Arcadia Securities, LLC, Maxim Group LLC and WBB Securities acted as the co-managers for the offering.

The warrants have an exercise price of $1.10 per share and exercise period commencing immediately upon issuance and an expiration date of the earlier of (i) such date that is six months after SCYNEXIS publicly announces the approval from the U.S. Food and Drug Administration for ibrexafungerp for the treatment of vulvovaginal candidiasis and (ii) June 12, 2023. There is no established public trading market for the warrants, and SCYNEXIS does not expect a market to develop.

A shelf registration statement relating to the securities being sold in this offering was filed with the U.S. Securities and Exchange Commission (SEC) on August 31, 2018, and was declared effective on September 14, 2018. The offering is being made only by means of a prospectus supplement and accompanying prospectus. A final prospectus supplement and accompanying prospectus relating to the offering were filed with the SEC and are available for free on the SEC’s website located at View Source When available, electronic copies of the final prospectus supplement and accompanying prospectus relating to the public offering may be obtained by contacting H.C. Wainwright & Co., LLC, 430 Park Avenue, 3rd Floor, New York, NY 10022, or by telephone at (646) 975-6996, or by email to [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On December 12, 2019 Provectus (OTCQB: PVCT) reported that data from the Company’s ongoing Phase 1 study of lysosomal-targeting cancer immunotherapy PV-10 (rose bengal disodium) as a single-agent and in combination with standard of care immune checkpoint blockade for the treatment of uveal melanoma metastatic to the liver (NCT00986661, a single-center expansion cohort) were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno-Oncology (I-O) Congress 2019, held from December 11-14, 2019 in Geneva, Switzerland (Press release, Provectus Pharmaceuticals, DEC 12, 2019, View Source [SID1234552323]). PV-10 is administered percutaneously when targeting primary or metastatic tumors of the liver, such as hepatocellular carcinoma (HCC), metastatic colorectal cancer, metastatic neuroendocrine tumors, and metastatic uveal melanoma (mUM). Intratumoral injection with PV-10 can yield immunogenic cell death in solid tumor cancers that results in tumor-specific reactivity in circulating T cells.1-4

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Provectus’ ongoing, multi-center, open-label, Phase 1 basket study is evaluating the safety, tolerability, and preliminary efficacy of PV-10 in patients with solid tumors metastatic to the liver. mUM patients are being enrolled into a single-center study cohort at MD Anderson Cancer Center (MDACC) in Houston, Texas. Up to three hepatic tumors can be injected per treatment cycle. Response assessments are performed at Day 28, and then every three months. Patients with multiple injectable visceral hepatic tumors may receive additional PV-10 after Day 28. Eligible mUM patients may also receive standard of care checkpoint blockade during and after treatment with PV-10. This mUM clinical trial work has been led by Sapna Patel, MD, Associate Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine at MDACC.

Preliminary Metastatic Uveal Melanoma Results from the Presentation at ESMO (Free ESMO Whitepaper) I-O Congress 2019:

Baseline characteristics (N=13): 46% men; median age of 61 years; 46% elevated LDH.
Disease characteristics: 100% Stage IV M1a-b; 38% of patients were refractory to one or more prior lines of treatment, with 31% having received prior immunotherapy.
Treatment summary: 7 patients received 1 cycle of PV-10; 6 patients received 2 cycles; 26 tumors were injected with PV-10.
Combination therapy: 9 patients received concomitant standard of care checkpoint blockade (i.e., maintenance anti-PD-1, anti-PD-1 subsequent to PV-10 treatment, or anti-CTLA-4+anti-PD-1 subsequent to PV-10 treatment).
Safety: 3 cases of Grade 3/4 transaminitis that resolved to Grade 1 or better within 72 hours; additional Grade 1 PV-10 related events seen in 1 patient each included pink stool, pink urine, photosensitivity, injection site pain, and hyperbilirubinemia; Additional adverse events, such as nausea, headache, myalgias, blurry vision, decreased white blood cells, and fatigue, were attributed to concomitant checkpoint blockade.
Preliminary injected target lesion efficacy (n=22): 32% partial response (PR); 32% overall response rate (ORR); 50% stable disease (SD); 82% disease control rate (DCR).
Dominic Rodrigues, Vice Chair of the Company’s Board of Directors, said, "These preliminary safety and efficacy data of PV-10 combination therapy for the treatment of uveal melanoma metastatic to the liver, an immunologically cold and low tumor mutation burden tumor type, indicate that the triplet cancer therapy of PV-10, an anti-CTLA-4 agent, and an anti-PD-1 agent may have a role in an emerging standard of care. Upon assessing survival benefit with this new treatment approach, the next step in PV-10’s drug development program for this cancer indication would be a registration-directed clinical trial."

A copy of the ESMO (Free ESMO Whitepaper) I-O Congress 2019 poster presentation is available on Provectus’ website at View Source

About PV-10

PV-10 is undergoing clinical study for adult solid tumor cancers, like melanoma and cancers of the liver (including metastatic neuroendocrine tumors and metastatic uveal melanoma). 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 (e.g., the ‘stomach’ of the cell, the cell’s ‘trash bin’), 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 functioning7. 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, disrupts them, and causes them to die. The physicochemical properties of lysosomes trap PV-10. A lumenal pH of 4.5 to 5.0 is ideal for the conversion of the hydrophilic RB salt into the hydrophobic (lipophilic) lactone version. Provectus1,11, external collaborators5, and other researchers12-14 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 inducing autolytic cell death, or death by self-digestion, in Hepa1-6 murine HCC cells can be viewed in this Provectus video of this event (ethidium homodimer [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 the Pediatric Oncology Experimental Therapeutics Investigators’ Consortium (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 oncolytic destruction of injected tumors (i.e., cell death), mediating several identified immune signaling pathways to date, such as the release of danger-associated molecular 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) cleavage and one currently being investigated that plays an important role in innate immunity. PV-10 is the first cancer drug that may facilitate multiple, temporally-distinct, immune system signaling pathways.15

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 (RB) disodium (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. PV-10 drug product is a formulation of 10% w/v 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 pharmaceutical grade RB and related xanthenes are produced, reducing the formation of previously unknown transhalogenated impurities that exist in commercial grade RB in uncontrolled amounts. The requirement to control these impurities is in accordance with International Conference on Harmonisation (ICH) guidelines for the manufacturing of an injectable pharmaceutical. US patent numbers are 8,530,675, 9,273,022, and 9,422,260, with expirations ranging from 2030 to 2031.

The Company’s IP also includes a family of US and international (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.

On December 12, 2019 Molecular Partners AG (SIX:MOLN), a clinical-stage biotech company pioneering the use of DARPin therapeutics to treat serious diseases, reported the continued progress of its pipeline of proprietary therapeutic product candidates in oncology, as well as abicipar in ophthalmology (Press release, Molecular Partners, DEC 12, 2019, View Source [SID1234552322]).

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"We are very proud to present the progress of our company over this past year. We continue to see success of our DARPin platform, from its earliest inception, with abicipar, now on the verge of potential FDA approval, to the newest concepts of attacking previously unreachable targets in cancer, and beyond, with the emergence of our peptide-MHC platform. Our pipeline is set up to provide significant value for patients," said Patrick Amstutz, Ph.D., Chief Executive Officer of Molecular Partners. "Today we will hear from both world-class key opinion leaders as well as our own team highlighting our expertise in drug development and clinical execution and how we will continue to succeed into 2020 and beyond."

During its R&D Day in New York, entitled "Novel Therapeutic Designs Applied," the company will provide updates on its clinical and preclinical programs, including:

Abicipar:

Presentation of recently updated two-year results from CEDAR and SEQUOIA demonstrate that vision gains observed after one year with every 8-week and every 12-week dosing were maintained in the second year (presented at AAO 2019).
Abicipar sustained vision gains in year two with quarterly injections compared to monthly ranibizumab.
MP0250:

As stated at the 61st Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) last week, MP0250 continues to show long-lasting and deepening responses across a variety of patients with multiple myeloma in the relapsed/refractory setting. MP0250 has a novel mechanism of action, designed to target both VEGF and HGF. This design makes MP0250 ideally suited to attack the underlying disease and potentially improve sensitivity, or re-sensitize patients, to existing and emerging treatments.
The company also announced today its intent to evaluate partnering opportunities for MP0250. In conjunction with this endeavor, the company will not start the previously planned clinical trial investigating MP0250 in combination with an IMiD. This is aligned with the company’s corporate strategy to pursue combination data for the most relevant clinical combinations of MP0250, which would be more appropriately determined in collaboration with a partner.
"Given the dynamic landscape of current and emerging treatments for multiple myeloma, along with our strong data recently presented at ASH (Free ASH Whitepaper), we believe that aligning with a partner with an existing hematology franchise will be the best way to accelerate the MP0250 program through the clinic and into the treatment paradigm. In recent discussions with potential collaborators, it is obvious that the time for evaluating this opportunity is now," said Nicolas Leupin, M.D., MBA, Chief Medical Officer of Molecular Partners.

MP0274:

Also discussed today is MP0274, the second-most advanced DARPin drug candidate in the oncology pipeline. It has broad anti-HER activity, inhibiting HER1, HER2 and HER3-mediated downstream signaling via HER2, leading to induction of apoptosis.
The company continues to enroll patients and explore dosing in a phase 1 study.
Current dose levels are presently up to 8mg/kg, and initial data is anticipated in H1 2020.
MP0310 (AMG 506):

MP0310 is a multi-domain DARPin targeting FAP x 4-1BB, designed to activate immune cells specifically in the tumor and not in the rest of the body, potentially delivering greater efficacy with fewer side effects. Preclinical studies of MP0310 have demonstrated immune T-cell activation restricted to solid tumor tissues, and strong CD8 T-cell activation and expansion in vitro and in vivo.
The initial phase 1 study, being conducted by Molecular Partners, was initiated in mid-2019, and dose escalation is underway. Current clinical timelines are on track with initial data expected in H2 2020. In collaboration with Amgen, the clinical program is then expected to expand into additional combination cohorts, to be conducted by Amgen.
Beyond these clinical updates, the company will also detail its growing preclinical pipeline, including the data on FAP x CD40, now designated MP0317, a second multi-specific preclinical DARPin designed for localized activation. In addition to these updates, the company will highlight advances in the DARPin discovery platform, including the advent of peptide-MHC targeting and next-generation T-cell engagers.

In addition to an overview of the Molecular Partners clinical and preclinical pipeline, the R&D Day will feature presentations by the following experts:

Jeremy Wolfe, Practicing Ophthalmology Specialist
Stefan Knop, Department Head Hematology, University of Würzburg, Germany
Jordi Rodon, Associate Professor, Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center
Logistics
The R&D Day for institutional investors, sell-side analysts, investment bankers, and business development professionals will take place at The Yale Club, 50 Vanderbilt Avenue, New York City, from 7:30 am – 10:00 am EST. To RSVP email Seth Lewis at [email protected].
Breakfast starts at 7:30 am EST. The presentations will begin at 8:00 am, followed by a Q&A session.

Audio webcast
The event will be webcast live and will be made available on the company’s website under the Investors section. The replay will be available for 90 days following the presentation.

Financial Calendar
February 6, 2020 Publication of Full-year Results 2019 (unaudited)
April 29, 2020 Annual General Meeting
View Source

About the DARPin Difference
DARPin therapeutics are a new class of protein therapeutics opening an extra dimension of multi-specificity and multi-functionality. DARPin candidates can engage more than five targets, offering potential benefits over those offered by conventional monoclonal antibodies or other currently available protein therapeutics. The DARPin technology is a fast and cost-effective drug discovery engine, producing drug candidates with ideal properties for development and very high production yields.

With their low immunogenicity and long half-life in the bloodstream and the eye, DARPin therapeutics have the potential to advance modern medicine and significantly improve the treatment of serious diseases, including cancer and sight-threatening disorders. Molecular Partners is partnering with Allergan to advance clinical programs in ophthalmology and is advancing a proprietary pipeline of DARPin drug candidates in oncology and immuno-oncology. The most advanced global product candidate in partnership with Allergan is abicipar, a molecule for which phase 3 data have been filed to the respective regulators in both the US and in Europe. Several DARPin molecules for various ophthalmic indications are also in preclinical development. The most advanced DARPin therapeutic candidate wholly owned by Molecular Partners, MP0250, is in phase 2 clinical development for the treatment of hematological tumors. MP0274, the second-most advanced DARPin candidate owned by Molecular Partners, binds to Her2 and inhibits downstream signaling, which leads to induction of apoptosis. MP0274 is currently in phase 1. The company’s lead immuno-oncology product candidate MP0310 is a FAP x 4-1BB multi-DARPin therapeutic candidate designed to locally activate immune cells in the tumor by binding to FAP on tumor stromal cells (localizer) and co-stimulating T cells via 4-1BB (immune modulator). Molecular Partners has closed a collaboration agreement with Amgen for the exclusive clinical development and commercialization of MP0310. The molecule has entered in phase 1 of clinical development in H2 2019. Molecular Partners is also advancing a growing preclinical and research pipeline in immuno-oncology that features its "I/O toolbox" and additional development programs such as novel therapeutic designs to target peptide-MHC complexes. DARPin is a registered trademark owned by Molecular Partners AG.