10 antibody drugs that will receive regulatory approval in the US and Europe by 2020 (II)
The following is a brief introduction to the remaining 10 antibody drugs in the report. Among them, the first 7 are for non-cancer indications, and the last 3 are for cancer indications.
Narsoplimab is a fully human IgG4 monoclonal antibody that targets mannose-binding lectin-associated serine protease 2 (MASP-2) and was developed to treat thrombotic microangiopathy (HSCT-TMA) related to hematopoietic stem cell transplantation. MASP-2 is an effector enzyme of the lectin pathway of the complement system. The lectin pathway is activated primarily by tissue damage or microbial infection. Importantly, unlike other complement-targeted drugs on the market or under development, the inhibitory effect of narsoplimab on MASP-2 does not interfere with the classical complement pathway, which is a key component of the immune response to acquired infections. The role of narsoplimab is to prevent complement-mediated inflammation and endothelial damage without affecting the function of other innate immune pathways.
Developed by Omeros, narsoplimab has been granted breakthrough drug status in the United States for the treatment of high-risk HSCT-TMA patients. Currently, narsoplimab is also in phase III clinical development and is being developed for the treatment of IgA nephropathy (IgAN) and atypical hemolytic uremic syndrome (aHUS). Previously, it was also granted orphan drugs and breakthrough drugs for IgAN in the United States, fast-track qualification for aHUS, and orphan drugs for IgAN in the European Union.
REGN-EB3 is a mixture of three fully human IgG1 mAbs, and is used for the treatment of Ebola virus infection. Ebola virus is the culprit causing Ebola hemorrhagic fever (EHF), an acute viral infectious disease with symptoms including fever, headache, joint and muscle pain, fatigue, diarrhea, vomiting, stomach pain, loss of appetite and abnormal bleeding. In the United States and the European Union, REGN-EB3 has been granted orphan drug status and has been awarded Breakthrough Drug Status (BTD) in the United States. In addition to REGN-EB3, a therapeutic mAb -mAb114- has also been awarded orphan drug status and BTD.
Isatuximab is an anti-CD38 IgG1 chimeric monoclonal antibody developed for the treatment of multiple myeloma (MM). The drug targets specific epitopes of CD38 receptors in plasma cells and can trigger a variety of unique mechanisms of action, including promoting programmed tumor cell death (apoptosis) and immunomodulatory activity. CD38 is expressed at high levels on MM cells and is a target for cell surface receptors for antibody therapy in MM and other malignancies.
Isatuximab was developed by Sanofi, and its applications for marketing for relapsed or refractory MM are under review by the US FDA and EU EMA. In the United States and the European Union, the drug is licensed as an orphan drug for relapsed or refractory MM. In a pivotal phase III ICARIA-MM study, isatuximab combined with pom-dex (pomalidomide + dexamethasone) significantly reduced the risk of disease progression or death by 40% and improved overall response compared to standard care. Currently, Sanofi is also evaluating the potential of isatuximab to treat other hematological malignancies and solid tumors.
Sacituzumab govitecan is a novel, first-in-class antibody drug conjugate (ADC) that combines the humanized IgG1 antibody targeting the TROP-2 antigen with SN-38, the metabolic activity of the chemotherapeutic drug irinotecan (a topoisomerase I inhibitor). It is currently being developed for the treatment of metastatic triple negative breast cancer (mTNBC). TNBC is a type of breast cancer with very limited treatment options. TROP-2 is a cell surface glycoprotein that is expressed in more than 90% of TNBC.
Developed by Immunomedics, Sacituzumab govitecan was submitted to the FDA in May 2018 for accelerated approval for mTNBC patients who have previously received at least 2 therapies for metastatic disease. However, it was rejected by the FDA in January 2019 because of manufacturing-related issues and no new clinical or preclinical data was required. At the beginning of December 2019, the company re-submitted BLA to the FDA. The last updated Phase II clinical data of the month showed that the total response rate of mTNBC treated by the drug was 34% and the median response duration was 9 months. Currently, the company is conducting a confirmatory phase III study. If approved, the drug will be the first ADC to treat mTNBC.
Tafasitamab is a novel humanized Fc domain-targeted CD19-optimized immune-enhancing IgG1 monoclonal antibody developed for the treatment of two types of B-cell malignancies: diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). CD19 is a clear biomarker for a variety of B-cell malignancies. The drug's Fc domain has been optimized to improve its affinity for activated FcγRIIIa on effector cells, significantly enhance antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP), thereby improving the key mechanism of tumor cell killing. In preclinical model studies, tafasitamab has been shown to induce direct apoptosis of cancer cells by binding to CD19.
The drug was developed by MorphoSys. At the end of last month, the company announced that it had completed its BLA submission and approved the application of tafasitamab in combination with lenalidomide in the treatment of patients with relapsed or refractory DLBCL. In the United States and the European Union, the drug has been granted orphan drug status for the treatment of DLBCL, and in the United States has also been granted fast-track status and breakthrough drug status for DLBCL. In a phase III clinical study, the total response rate of the drug combined with lenalidomide reached 60%, the complete response rate reached 43%, and the median progression-free survival was 12.1 months. Remissions are persistent with a median duration of 21.7 months. If approved, the drug will pose serious challenges to two CAR-T cell therapies on the market for relapsed or refractory DLBCL, including Novartis' Kymriah and Gilead's Yescarta.
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