On November 4, 2021 EpiVax, Inc. ("EpiVax") reported an important commercial licensing agreement with Maruho Co., Ltd. ("Maruho") for EpiVax’s patented Tregitope technology (Press release, EpiVax, NOV 4, 2021, View Source [SID1234594558]). This marks an exciting step for Maruho and EpiVax towards continued expansion of the Tregitope program and translation to the clinic.

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Tregitopes are immune-modulating peptides derived from human immunoglobulin. Tregitopes were first discovered in 2008 by EpiVax co-founders Dr. Anne De Groot and William Martin. EpiVax has since validated many more Tregitopes and has developed a strong Tregitope patent estate. With a wide range of therapeutic applications, Tregitopes can be co-formulated or fused to proteins to induce antigen-specific tolerance. EpiVax is currently licensing Tregitope for additional indications with commercial and academic partners. More information on the EpiVax Tregitope Platform is available here.

Similar to intravenous immunoglobulin G (IVIG) therapy, Tregitopes engage regulatory T cells and downregulate inflammation in a wide range of disease models. This mechanism of action has been studied in academic collaborations at McGill University, Harvard Medical School, and undisclosed commercial partners. There have been many peer-reviewed publications on the Tregitope platform in recent years. A full list can be found here.

Maruho will be able to leverage their Tregitope license to enhance their in-house therapeutic development strategies for autoimmune conditions. Annie De Groot MD, CEO/CSO of EpiVax, said "This agreement reflects the potential for Tregitopes, natural Treg epitopes that help regulate immune responses, to be used for the treatment of conditions that afflict patients around the world".

On November 4, 2021 Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL) reported a summary of corporate accomplishments and reports its third quarter 2021 financial results (Press release, Synta Pharmaceuticals, NOV 4, 2021, View Source [SID1234594573]).

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Paul Friedman, M.D., Chief Executive Officer of Madrigal, stated, "Throughout the third quarter, the Madrigal team continued to progress MAESTRO-NASH, the pivotal serial liver biopsy study and a key component of the Phase 3 program for resmetirom for patients with non-alcoholic steatohepatitis, NASH. We remain on track to complete the double-blind portion of our Phase 3 non-invasive imaging and biomarker study, MAESTRO-NAFLD-1, and report topline data by year-end, with additional topline data rollout in early 2022. We will also be presenting additional data from the open-label portion of this study at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting on November 12-15th."

Becky Taub, M.D., Chief Medical Officer and President of Research & Development at Madrigal stated, "Data from the recently completed 52 week open-label arm of the MAESTRO-NAFLD-1 study will be presented at AASLD and provides our most informed insights to date regarding the effects of resmetirom in presumed NASH patients, using a variety of non-invasive tests relevant to clinical practice. The double-blinded MAESTRO-NAFLD-1 and MAESTRO NASH studies readouts over the forthcoming months will further inform our understanding of how to identify and monitor NASH patients with significant fibrosis."

Dr. Taub added, "In October, in recognition of Liver Awareness Month, we announced our alliance with the Fatty Liver Foundation, a leading patient advocacy organization focused on the diagnosis, treatment and support of individuals with non-alcoholic fatty liver disease or NAFLD and NASH. Our alliance with the Foundation is in support of their NAFLD Screening Fund and aligns with our commitment to advance the use of non-invasive techniques to improve the diagnosis and staging of NAFLD and NASH and identify people at risk of NASH earlier in the course of their disease."

Several abstracts summarizing data from the open-label arms of the MAESTRO-NAFLD-1 study have been accepted for presentation at AASLD’s The Liver Meeting 2021. Madrigal will host a webcast and conference call on Tuesday, November 16th at 8.00 AM ET to summarize and discuss the data that are being presented.

AASLD Presentations

Friday, November 12, 2021: Late-breaker Poster Presentation (abstract #LP21)
Biomarkers, imaging and safety in resmetirom 52 week non-cirrhotic NASH Phase 3 clinical trial, completed open-label arm of MAESTRO-NAFLD-1
Friday November 12, 2021: Poster Presentation (abstract #1922)
Liver volume reduction in resmetirom treated non-cirrhotic and cirrhotic NASH patients
Friday, November 12, 2021 (1:00-2:00pm EST): Virtual Product Theatre
Live presentation by Manal Abdelmalek, MD, Professor of Medicine, Duke University School of Medicine and Mazen Noureddin, MD, Director, Cedars-Sinai Medical Center, Karsh Division of Gastroenterology and Hepatology entitled: NASH with Fibrosis: Updates from the MAESTRO Phase 3 Clinical Program
Sunday, November 14, 2021: Oral Presentation (4:00pm EST) (abstract #118)
Presentation by Mazen Noureddin, MD, Director, Cedars-Sinai Medical Center, Karsh Division of Gastroenterology and Hepatology entitled: Utilization of the MAST (MRI-PDFF-MRE-AST) score to predict NASH on liver biopsy in MAESTRO-NASH and access response to resmetirom in MAESTRO-NAFLD-1
Leadership Team Expanded

Stephen Dodge, PharmD, MBA, has joined Madrigal as Senior Vice President and Global Head of Medical Affairs. Prior to joining Madrigal, Dr. Dodge was Senior Vice President, Cholestasis Program Head at Intercept Pharmaceuticals. Prior to Intercept, he held a number of leadership positions in medical affairs at Merck, Novo Nordisk and Novartis. His experience includes over 20 new product launches in new therapeutic areas, spanning over 20 years, with 10 years in liver and GI diseases. Dr. Dodge received an MBA from Washington University in St. Louis, his PharmD – Doctor of Pharmacy from the University of The Pacific School of Pharmacy and a B.S., Biology from California State University.

Kia Motesharei, PhD, has joined Madrigal as Senior Vice President Business & Corporate Development. Dr. Motesharei’s 20 plus years of industry experience includes over 100 business development transactions and corporate strategy initiatives including therapeutic product licensing and alliances, R&D collaborations, commercial product partnerships, royalty financing and M&A activities with companies in the United States, Europe, Japan, China, Latin America and the Middle East. Prior to joining Madrigal, Dr. Motesharei was Chief Business and Strategy Officer at NeuBase Therapeutics. Since 2004, he has held similar positions with Akcea Therapeutics, EMD Serono (Merck KGaA), Dyax Corporation, Genfit, and Activx Biosciences. Dr. Motesharei completed his Postdoctoral training as a National Institutes of Health fellow at The Scripps Research Institute and received his Doctorate degree from UCLA.

Financial Results

As of September 30, 2021, Madrigal had cash, cash equivalents and marketable securities of $299.1 million, compared to $284.1 million at December 31, 2020. The increase in cash and marketable securities was due to net proceeds of $151.2 million from sales of common stock via our at-the-market (ATM) program, partially offset by cash used to support operations of $135.9 million.

Operating expenses were $63.2 million and $177.9 million for the three and nine month periods ended September 30, 2021, compared to $58.8 million and $147.1 million in the comparable prior year periods.

Research and development expenses for the three and nine month periods ended September 30, 2021 were $54.9 million and $152.3 million, compared to $53.3 million and $131.4 million in the comparable prior year periods. The increase is attributable primarily to additional activities related to the Phase 3 clinical trials, and an increase in head count.

General and administrative expenses for the three and nine month periods ended September 30, 2021 were $8.3 million and $25.6 million, compared to $5.5 million and $15.8 million in the comparable prior year periods. The increase is attributable primarily to increases in commercial preparation activities, including an increase in headcount and an increase in non-cash stock compensation.

Interest income for the three and nine month periods ended September 30, 2021 was $0.1 million and $0.3 million, compared to $0.8 million and $3.9 million in the comparable prior year periods. The decrease in interest income was due primarily to decreased interest rates.

About Resmetirom
Thyroid hormone, through activation of its β-receptor in hepatocytes, plays a central role in liver function impacting a range of health parameters from levels of serum cholesterol and triglycerides to the pathological buildup of fat in the liver. Thyroid hormone receptor (THR)-β action in the liver is key to proper function of the liver, including regulation of mitochondrial activity such as breakdown of liver fat and control of the level of normal, healthy mitochondria. Patients with NASH have reduced levels of thyroid hormone activity in the liver with resultant impaired hepatic function, in part due to the inflamed state of the liver that causes degradation of thyroid hormone.

To exploit the thyroid hormone receptor (THR)-β pathway for therapeutic purposes in liver and cardio-metabolic diseases, it is important to avoid activity at the THR-α receptor, the predominant systemic receptor for thyroid hormone that is responsible for activity outside the liver including in heart and bone. The lack of selectivity of older thyromimetic compounds, chemically-related toxicities and undesirable distribution in the body led to safety concerns. Madrigal recognized that greater selectivity for thyroid hormone receptor (THR)-β and liver targeting might overcome these challenges and deliver the full therapeutic potential of THR-β agonism. Resmetirom has been shown to be highly selective based on 1) THR-β receptor functional selectivity based on both in vitro and in vivo assays and 2) specific uptake into the liver, its site of action, virtually avoiding any uptake into tissues outside the liver. In short- and long- term human and animal studies, resmetirom has been confirmed to be safe and devoid of activity at the THR-α receptor and without impact on bone or cardiac parameters. Resmetirom does not impact the thyroid axis hormones, including the central thyroid axis. Madrigal believes that resmetirom is the first orally administered, small-molecule, liver-directed, truly β-selective THR agonist.

About the Phase 3 Registration Program for the Treatment of NASH (Non-alcoholic steatohepatitis)
Madrigal is currently conducting two Phase 3 Clinical trials, MAESTRO-NASH and MAESTRO-NAFLD-1, to demonstrate the safety and efficacy of resmetirom for the treatment of NASH.

MAESTRO-NASH is a Phase 3 multi-center, double-blind, randomized, placebo-controlled study of resmetirom in patients with liver biopsy confirmed NASH and was initiated in March 2019. The study targets enrollment of 900 patients with biopsy-proven NASH (fibrosis stage 2 or 3, at least 450 fibrosis stage 3), randomized 1:1:1 to receive resmetirom 80 mg once a day, 100 mg once a day, or placebo. After 52 weeks of treatment a second biopsy is performed. The primary surrogate endpoint on biopsy will be NASH resolution, with at least a 2-point reduction in NAS (NASH Activity Score), and with no worsening of fibrosis. Two key secondary endpoints are liver fibrosis reduction of at least one stage, with no worsening of NASH on liver biopsy, and lowering of LDL-cholesterol [ClinicalTrials.gov/NCT03900429]. Madrigal announced achievement of the planned target enrollment on June 30, 2021.

The first 900 patients in the MAESTRO-NASH study will continue on therapy after the initial 52-week treatment period; and up to another 1,100 patients are to be added using the same randomization plan and the study is expected to continue for up to 54 months to accrue and measure hepatic clinical outcome events including progression to cirrhosis on biopsy (52 weeks and 54 months) and hepatic decompensation events.

MAESTRO-NAFLD-1 is a 52-week Phase 3 multi-center, double-blind, randomized, placebo-controlled study of resmetirom, and was initiated in December 2019 in patients with non-alcoholic fatty liver disease (NAFLD), presumed NASH. The primary endpoint for this study is to evaluate the safety and tolerability of resmetirom. Completion of enrollment of over 1,200 patients into the study was announced in November 2020. Top-line data from the study is targeted by end of year 2021.

Patients in MAESTRO-NAFLD-1 are randomized 1:1:1 to receive resmetirom 80 mg once a day, 100 mg once a day, or placebo. MAESTRO-NAFLD-1 also includes a 100 mg resmetirom open label arm. 52 week data were presented from the open label arm at The International Liver Congress 2021 in June and demonstrated that resmetirom is safe and well-tolerated at 100mg per day [view press release here]. MAESTRO-NAFLD-1 (unlike MAESTRO-NASH), does not include a liver biopsy and represents a "real-life" NASH study. NASH or presumed NASH is documented using historical liver biopsy or non-invasive techniques including FibroScan and magnetic resonance imaging, proton density fat fraction (MRI-PDFF) respectively. Using non-invasive measures, MAESTRO-NAFLD-1 is designed to provide incremental safety information to support the NASH indication as well as provide additional data regarding clinically relevant key secondary efficacy endpoints to better characterize the potential clinical benefits of resmetirom on cardiovascular and liver related endpoints. These key secondary endpoints include LDL-cholesterol, apolipoprotein B and triglyceride (TG) lowering; reduction of liver fat as determined by MRI-PDFF; and reduction of PRO-C3, a NASH fibrosis biomarker. [ClinicalTrials.gov/NCT04197479]. Additional secondary and exploratory endpoints will be assessed including reduction in liver enzymes, FibroScan scores and other fibrosis and inflammatory biomarkers.

Data from the 52 week portion of MAESTRO-NASH, together with data from MAESTRO-NAFLD-1 and other data, including safety parameters, will form the basis for a potential subpart H submission to FDA for accelerated approval for the treatment of NASH.

On November 4, 2021 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for patients with cancer, reported that three oral and five poster presentations for the Company’s induced pluripotent stem cell (iPSC) product platform were accepted for presentation at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held from December 11-14, 2021 (Press release, Fate Therapeutics, NOV 4, 2021, View Source [SID1234594366]). The Company also plans to host a virtual investor event on Tuesday, December 14.

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The oral presentations will include updated Phase 1 clinical data of FT596, the Company’s universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master iPSC line engineered with three anti-tumor functional modalities: a proprietary chimeric antigen receptor (CAR) optimized for NK cell biology that targets B-cell antigen CD19; a novel high-affinity, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies; and an IL-15 receptor fusion (IL-15RF) that augments NK cell activity. The Company previously reported interim Phase 1 clinical data of FT596 as monotherapy and in combination with rituximab for the treatment of relapsed / refractory B-cell lymphoma. As of the data cutoff date of June 25, 2021, in the second and third dose cohorts (90 million cells and 300 million cells, respectively) of the single-dose monotherapy and combination regimens, 10 of 14 patients (71%) achieved an objective response, including seven patients (50%) that achieved a complete response, on Day 29 as assessed by PET-CT scan per Lugano 2014 criteria. Treatment with FT596 was well tolerated, with two reported low-grade adverse events (one Grade 1, one Grade 2) of cytokine release syndrome (CRS) and no reported adverse events of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GVHD).

The poster presentations will include updated Phase 1 clinical data of FT516, the Company’s universal, off-the-shelf NK cell cancer immunotherapy derived from a clonal master iPSC line engineered to express a novel hnCD16 Fc receptor. The Company previously reported interim Phase 1 clinical data of FT516 in combination with rituximab for the treatment of relapsed / refractory B-cell lymphoma. As of the data cutoff date of July 7, 2021, in the second and third multi-dose cohorts (90 million cells per dose and 300 million cells per dose, respectively), eight of 11 patients (73%) achieved an objective response, including six patients (55%) that achieved a complete response, on Day 29 of the second FT516 treatment cycle as assessed by PET-CT scan per Lugano 2014 criteria. Five of the 11 patients (45%) maintained their response without further therapeutic intervention, including four patients that remained in complete response (4.6-9.5 months) and one patient that remained in partial response (6.1 months). The multi-dose, multi-cycle treatment regimen was well tolerated, and no adverse events of CRS, ICANS, or GVHD were reported.

Additional presentations will include an oral presentation describing preclinical and clinical translational data of FT596; a poster presentation describing the making of the clonal engineered master iPSC line for FT819, which is created from a single iPSC that has a novel CD19-targeted 1XX CAR construct integrated into the T-cell receptor alpha constant (TRAC) locus; a poster presentation describing the preclinical activity of a novel multiplexed-engineered, dual CAR NK cell product candidate targeting B-cell maturation antigen (BCMA) and the alpha-3 domain of MICA/B in models of multiple myeloma; and a poster presentation describing the preclinical activity of multiplexed-engineered, iPSC-derived T cells incorporating three distinct tumor-targeting modalities (CAR, TCR and hnCD16).

Oral Presentations

Safety and Efficacy of FT596, a First-in-Class, Multi-Antigen Targeted, Off-the-Shelf, iPSC-Derived CD19 CAR NK Cell Therapy in Relapsed / Refractory B-Cell Lymphoma
Publication Number: 823
Session Name: 704. Cellular Immunotherapies: Expanding Targets and Cellular Sources for Immunotherapies
Presentation Date / Time: Monday, December 13, 2021; 4:30 PM
Room: Georgia World Congress Center, Georgia Ballroom 1-3
Off-the-Shelf, Multiplexed-Engineered iPSC-Derived NK Cells Mediate Potent Multi-Antigen Targeting of B-Cell Malignancies with Reduced Cytotoxicity Against Healthy B Cells
Publication Number: 407
Session Name: 703. Cellular Immunotherapies: Basic and Translational II
Presentation Date / Time: Sunday, December 12, 2021; 10:30 AM
Room: Georgia World Congress Center, B405-B407
Arming of iPSC-Derived NK Cells Expressing a Novel CD64 Fusion Receptor with Therapeutic Antibodies Represents a Novel Off-the-Shelf, Antigen-Targeting Strategy for Cancer
Publication Number: 406
Session Name: 703. Cellular Immunotherapies: Basic and Translational II
Presentation Date / Time: Sunday, December 12, 2021; 10:15 AM
Room: Georgia World Congress Center, B405-B407
Poster Presentations

Phase I Study of FT516, an Off-the-Shelf, iPSC-Derived NK Cell Therapy, in Combination with Rituximab in Patients with Relapsed / Refractory B-Cell Lymphoma
Publication Number: 3873
Session Name: 704. Cellular Immunotherapies: Clinical: Poster III
Presentation Date / Time: Monday, December 13, 2021; 6:00 PM
Room: Georgia World Congress Center, Hall B5
Clinical Manufacture of FT819: Use of a Clonal Multiplexed-Engineered Master Induced Pluripotent Stem Cell Line to Mass Produce Off-the-Shelf CAR T-Cell Therapy
Publication Number: 1766
Session Name: 711. Cell Collection and Processing: Poster I
Presentation Date / Time: Saturday, December 11, 2021; 5:30 PM
Room: Georgia World Congress Center, Hall B5
Combination of Three Unique Anti-Tumor Modalities Engineered into iPSC-Derived T Cells Demonstrate a Synergistic Effect in Overcoming Tumor Heterogeneity and Cancer Escape
Publication Number: 2793
Session Name: 703. Cellular Immunotherapies: Basic and Translational: Poster II
Presentation Date / Time: Sunday, December 12, 2021; 6:00 PM
Room: Georgia World Congress Center, Hall B5
Dual Chimeric Antigen Receptor Approach Combining Novel Tumor Targeting Strategies Circumvents Antigen Escape in Multiple Myeloma
Publication Number: 1718
Session Name: 703. Cellular Immunotherapies: Basic and Translational: Poster I
Presentation Date / Time: Saturday, December 11, 2021; 5:30 PM
Room: Georgia World Congress Center, Hall B5
Off-the-Shelf, iPSC-Derived CAR NK Cells Multiplexed-Engineered for the Avoidance of Allogeneic Host Immune Cell Rejection
Publication Number: 2795
Session Name: 703. Cellular Immunotherapies: Basic and Translational: Poster II
Presentation Date / Time: Sunday, December 12, 2021; 6:00 PM
Room: Georgia World Congress Center, Hall B5
The accepted abstracts are available online through the ASH (Free ASH Whitepaper) conference website (www.hematology.org/Annual-Meeting/Abstracts/).

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 350 issued patents and 150 pending patent applications.

About FT516
FT516 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered to express a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies. CD16 mediates antibody-dependent cellular cytotoxicity (ADCC), a potent anti-tumor mechanism by which NK cells recognize, bind and kill antibody-coated cancer cells. ADCC is dependent on NK cells maintaining stable and effective expression of CD16, which has been shown to undergo considerable down-regulation in cancer patients. In addition, CD16 occurs in two variants, 158V or 158F, that elicit high or low binding affinity, respectively, to the Fc domain of IgG1 antibodies. Numerous clinical studies with FDA-approved tumor-targeting antibodies, including rituximab, trastuzumab and cetuximab, have demonstrated that patients homozygous for the 158V variant, which is present in only about 15% of patients, have improved clinical outcomes. FT516 is being investigated in a multi-dose Phase 1 clinical trial as a monotherapy for the treatment of acute myeloid leukemia and in combination with CD20-targeted monoclonal antibodies for the treatment of advanced B-cell lymphoma (NCT04023071). Additionally, FT516 is being investigated in a multi-dose Phase 1 clinical trial in combination with avelumab for the treatment of advanced solid tumors resistant to anti-PDL1 checkpoint inhibitor therapy (NCT04551885).

About FT596
FT596 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three anti-tumor functional modalities: a proprietary chimeric antigen receptor (CAR) optimized for NK cell biology that targets B-cell antigen CD19; a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies; and an IL-15 receptor fusion (IL-15RF) that augments NK cell activity. In preclinical studies of FT596, the Company has demonstrated that dual activation of the CAR19 and hnCD16 targeting receptors enhances cytotoxic activity, indicating that multi-antigen engagement may elicit a deeper and more durable response. Additionally, in a humanized mouse model of lymphoma, FT596 in combination with the anti-CD20 monoclonal antibody rituximab showed enhanced killing of tumor cells in vivo as compared to rituximab alone. FT596 is being investigated in a multi-center Phase 1 clinical trial for the treatment of relapsed / refractory B-cell lymphoma as a monotherapy and in combination with rituximab, and for the treatment of relapsed / refractory chronic lymphocytic leukemia (CLL) as a monotherapy and in combination with obinutuzumab (NCT04245722).

About FT819
FT819 is an investigational, universal, off-the-shelf, T-cell receptor (TCR)-less CD19 chimeric antigen receptor (CAR) T-cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line, which is engineered with the following features designed to improve the safety and efficacy of CAR19 T-cell therapy: a novel 1XX CAR signaling domain, which has been shown to extend T-cell effector function without eliciting exhaustion; integration of the CAR19 transgene directly into the T-cell receptor alpha constant (TRAC) locus, which has been shown to promote uniform CAR19 expression and enhanced T-cell potency; and complete bi-allelic disruption of TCR expression for the prevention of graft-versus-host disease. FT819 demonstrated antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines comparable to that of primary CAR T cells, and persisted and maintained tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia (Valamehr et al. 2020). FT819 is being investigated in a multi-center Phase 1 clinical trial for the treatment of relapsed / refractory B-cell malignancies, including B-cell lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia (NCT04629729).

On November 4, 2021 IGM Biosciences, Inc. (Nasdaq: IGMS), a clinical-stage biotechnology company focused on creating and developing engineered IgM antibodies, reported its financial results for the third quarter ended September 30, 2021 and provided an update on recent developments (Press release, IGM Biosciences, NOV 4, 2021, View Source [SID1234594394]).

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"IGM continues to validate and expand the IgM platform through the clinical development of IGM-2323, our CD20 x CD3 T cell engager IgM antibody for the treatment of B cell proliferative diseases, IGM-8444, our Death Receptor 5 (DR5) agonist IgM antibody for the treatment of solid and hematologic cancers, and the establishment of our infectious diseases and autoimmunity and inflammation business units," said Fred Schwarzer, Chief Executive Officer of IGM Biosciences. "We plan to continue to expand our clinical development efforts, and by the end of 2022 we expect to be actively pursuing the clinical development of four oncology product candidates, led by two Phase 2 clinical studies of IGM-2323."

"We are encouraged by the emerging data from the clinical testing of IGM-2323 in our most fully explored titration dose cohort, 100 mg, where we have seen multiple complete responses in both diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), and we look forward to sharing the initial data from this 100 mg dose cohort at our American Society of Hematology (ASH) (Free ASH Whitepaper) presentation in December," said Chris Takimoto, M.D., Ph.D., F.A.C.P., Chief Medical Officer of IGM Biosciences. "While the number of patients we have treated at 100 mg is relatively small, we believe that the planned Phase 2 expansion studies could potentially provide the basis for accelerated review and approval. As a first step, consistent with the spirit of the U.S. Food and Drug Administration’s (FDA) Project Optimus, we plan to test doses of 100 mg and 300 mg in two separate randomized ‘pick the winner’ Phase 2 studies of 30 patients at each dose level, one in DLBCL and one in FL. We plan to then expand the Phase 2 studies at the optimal dose, while including the prior data from that dose for purposes of potential registration. While our safety profile at 600 mg and 1000 mg is consistent with lower doses and very encouraging, we do not plan to continue to explore doses higher than 300 mg for purposes of greater efficacy in either DLBCL or FL."

Pipeline Updates

IGM-2323 (CD20 x CD3)

Plans to initiate potentially registrational Phase 2 study. IGM reported plans to commence two potentially registrational Phase 2 studies to assess the safety and efficacy of two doses of IGM-2323, 100 mg and 300 mg, in patients with DLBCL and FL, one Phase 2 study in DLBCL and one Phase 2 study in FL. Each Phase 2 multicenter, open-label study will take place in two stages. In the first stage, cohorts of 30 patients at each dose level (100 mg and 300 mg) will be randomized in a ‘pick the winner’ design in both DLBCL and FL, respectively. The optimal dose arm in each Phase 2 clinical trial will then be expanded to additional patients in the second stage, potentially providing the basis for accelerated review and approval of IGM-2323, assuming the clinical data support that expansion.
Data from Phase 1 trial evaluating IGM-2323 selected for oral presentation at 2021 ASH (Free ASH Whitepaper) Annual Meeting and Exposition, being held virtually and in-person in Atlanta, Georgia, December 11-14, 2021. The results will be presented on Saturday, December 11, 2021, at 1:15 p.m. ET, in an oral presentation titled "A Phase 1 Dose Escalation Study of IGM-2323, a Novel Anti-CD20 x Anti-CD3 IgM T Cell Engager (TCE) in Patients with Advanced B-Cell Malignancies." In the ASH (Free ASH Whitepaper) oral presentation, IGM plans to present additional safety and efficacy data collected subsequent to the April 30, 2021 data cut-off for the ASH (Free ASH Whitepaper) abstract, which was released online today in Blood, ASH (Free ASH Whitepaper)’s official journal.
As described in the abstract released today, as of April 30, 2021, 29 patients had been enrolled in the Phase 1 study of IGM-2323: 12 at 5 fixed dose levels (0.5, 2.5, 10, 20, 100 mg) and 17 at 5 dose titration levels (100, 200, 300, 600, and 1000 mg). All 29 patients received at least one dose and were evaluable for safety. There were no dose limiting toxicities (DLTs) and no neurotoxicity adverse events (AEs). No patients discontinued due to an AE. Of the 29 patients evaluable for safety, 6 patients had cytokine release syndrome (CRS), primarily Grade 1. As previously described, there were only two higher grade CRS events as of April 30, 2021, one Grade 2 and one Grade 3. As previously described, the Grade 3 patient had been treated with an experimental CAR-T and had high baseline circulating B-cells. Of the 11 evaluable patients treated in the titration dose cohorts, as of the April 30, 2021 data cut-off, there were 5 responses, 3 complete responses and 2 partial responses.

IGM-8444 (DR5)

Clinical development of IGM-8444 advances. IGM continues to advance the clinical development of IGM-8444, the Company’s IgM DR5 agonist, in an open-label, multicenter, Phase I study of IGM-8444 as a single agent and in combination in subjects with relapsed and/or refractory solid and hematologic cancers.
Every two-week monotherapy dose escalation cohort successfully completed. IGM announced that it has successfully cleared its highest single-agent dose escalation cohort (10 mg/kg Q2W) with no DLTs and no clinically significant liver toxicity observed to date.
Second FOLFIRI dose cohort successfully completed. IGM also announced that it has cleared the second of four planned FOLFIRI combination dose escalation cohorts (1.0 mg/kg Q2W) with no DLTs and no clinically significant liver toxicity observed to date. IGM is currently enrolling patients in the third of four planned FOLFIRI combination dose escalation cohorts (3.0 mg/kg Q2W).
No acute or chronic clinically significant liver toxicity or clinically significant anti-drug antibodies observed to date. IGM also announced today that there have been no DLTs and no clinically significant liver toxicities observed to date in the 32 patients treated with IGM-8444, of whom 11 remain on treatment. Importantly, 7 patients have been on treatment for 5 or more months without showing signs of any chronic toxicities to date. No patient has discontinued treatment for drug related safety reasons, and no clinically significant anti-drug antibodies have been observed to date.
First patient dosed in combination with birinapant. IGM announced that it has treated its first patient in a combination clinical study of IGM-8444 with birinapant, a SMAC mimetic which binds to and degrades inhibitors of apoptosis proteins (IAPs) leading to apoptotic cell death in tumors. The combination of these two apoptotic agents, IGM-8444 and birinapant, has shown strong synergy in preclinical testing, and IGM has acquired exclusive worldwide rights to manufacture, develop and commercialize birinapant. The first patient in this combination cohort was successfully treated with no clinically significant adverse events observed to date. IGM is currently enrolling additional patients in this first birinapant dose cohort. IGM is also preparing to enroll patients with chronic lymphocytic leukemia/small lymphocytic lymphoma in a venetoclax-IGM-8444 combination cohort.
Markers of on-target biological activity observed. Signs of biological activity consistent with the activation of DR5 by a DR5 agonist have been observed in some patients, both in circulating biomarkers and histological tumor samples.
"IGM-8444’s toxicity profile to date, which has not shown any clinically significant liver toxicity, differentiates it from some of the second generation DR5 agonists that have struggled to progress in the clinic due to liver toxicity," said Dr. Takimoto. "Importantly, we believe this safety profile will be critical to successful combinations with other drugs, which we believe represent by far the most exciting and promising uses of DR5 agonists for the treatment of multiple solid and hematologic cancers. For this reason, our clinical development focus continues to be on combinations of IGM-8444 with standard of care and novel agents, such as FOLFIRI, venetoclax and birinapant."

IGM-6268 (COVID-19)

IGM-6268 for the treatment and prevention of COVID-19 expected to advance into the clinic in the fourth quarter. IGM-6268 is an IgM version of an anti-SARS-CoV-2 IgG monoclonal antibody and is being developed as an intranasally administered agent for the treatment and prevention of COVID-19. It is expected to start clinical development by the end of 2021, initially in healthy volunteers.
IGM-7354 (IL-15 x PD-L1)

Phase 1 clinical testing expected to initiate in 2022. IGM plans to initiate a Phase 1 study of IGM-7354, the Company’s IL‑15 x PD‑L1 bispecific IgM antibody, in solid tumors in 2022.
IGM-2644 (CD38 x CD3)

Phase 1 clinical testing expected to initiate in 2022. IGM announced today that it plans to initiate a Phase 1 study of IGM-2644, the Company’s CD38 x CD3 bispecific IgM antibody, in multiple myeloma in 2022.
"We believe the safety and efficacy profile that we have observed to date in the clinical development of IGM-2323, our T cell engaging IgM antibody targeting CD20 on lymphoma cells, is very encouraging with respect to the future clinical development of IGM-2644, our T cell engaging IgM antibody targeting CD38 on multiple myeloma cells, as it has shown similar preclinical safety and efficacy features to those we observed with IGM-2323," said Bruce Keyt, Ph.D., Chief Scientific Officer of IGM Biosciences. "We hope to file an investigational new drug (IND) application with the FDA and begin the Phase 1 clinical development of IGM-2644 next year."

Corporate Updates

Announced leadership appointments and formation of IGM Infectious Diseases and IGM Autoimmunity and Inflammation business units. The new business units will utilize and build upon IGM’s platform technology to create and develop novel IgM and IgA antibodies to address infectious diseases, autoimmunity and inflammation. To lead the IGM Autoimmunity and Inflammation business unit, IGM announced the appointment of Mary Beth Harler, M.D., as President. To lead the IGM Infectious Diseases business unit, IGM announced the appointments of John Shiver, Ph.D. and Tong-Ming Fu, M.D., Ph.D., as Chief Strategy Officer and Chief Scientific Officer, respectively.
Third Quarter 2021 Financial Results

Cash and Investments: Cash and investments as of September 30, 2021 were $265.6 million, compared to $366.3 million as of December 31, 2020.
Research and Development (R&D) Expenses: For the third quarter of 2021, R&D expenses were $34.2 million, compared to $15.8 million for the same period in 2020.
General and Administrative (G&A) Expenses: For the third quarter of 2021, G&A expenses were $10.0 million, compared to $4.7 million for the same period in 2020.
Net Loss: For the third quarter of 2021, net loss was $44.2 million, or a loss of $1.32 per share, compared to a net loss of $20.3 million, or a loss of $0.66 per share, for the same period in 2020.
2021 Financial Guidance

IGM reiterates its previously issued financial guidance expecting full year GAAP operating expenses to be between $175 million and $185 million including estimated non-cash stock-based compensation expense of approximately $25 million. IGM expects to end 2021 with a balance of over $200 million in cash and investments.

On November 4, 2021 Targovax ASA (the "Company") reported that regarding the resolution by the Company’s board of directors to propose that the Company carries out a share capital increase, by way of a fully underwritten rights issue, to raise gross proceeds of NOK 175 million (the "Rights Issue") (Press release, Targovax, NOV 4, 2021, View Source [SID1234594410]).

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Date on which the terms and conditions of the preferential rights issue were announced: 4 November 2021

Last day including right: 25 November 2021

Ex-date: 26 November 2021

Record Date: 29 November 2021

Date of approval: 25 November 2021

Maximum number of new shares: 350,000,000

Subscription price: Minimum NOK 0.50 and maximum NOK 10.00

Ratio preferential rights: To be announced when final number of new shares is determined

Subscription ratio: To be announced when final number of new shares is determined

Managers: Carnegie AS and DNB Markets, a part of DNB Bank ASA

Will the rights be listed: The Company will apply for listing of the preferential rights on the Oslo Stock Exchange

ISIN for the preferential rights: To be announced when clarified

Other information: The subscription price for the new shares to be issued in the Rights Issue, and thus the final number of new shares and the exact amount of the share capital increase will be proposed by the board of directors, based on a recommendation from the Managers, the day prior to the extraordinary general meeting to be held on 25 November 2021 (the "EGM"). See the stock exchange announcement containing the notice to the EGM published earlier today, on 4 November 2021, for further information regarding the Rights Issue. The rights issue is subject to approval by the EGM.

This information is published in accordance with the requirements of the Continuing Obligations.