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    Home > Medical News > Latest Medical News > Can a number of pharmaceutical companies develop FGFR as a rising star in "unlimited cancer" therapy?

    Can a number of pharmaceutical companies develop FGFR as a rising star in "unlimited cancer" therapy?

    • Last Update: 2020-08-09
    • Source: Internet
    • Author: User
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    Genetic mutations are the key to normal cell carcinoma.
    the idea of developing targeted therapies based on specific genetic mutations is a common practice in the field of new drug research and development.
    study found that FGFR gene abnormalities are found in about 7% of all types of solid tumors, and are common in a variety of cancers, making it one of the most popular targets today.
    , large pharmaceutical companies such as Johnson and Johnson and Pfizer, as well as a number of innovative Chinese pharmaceutical companies such as Novartis Kinhua, Cinda Bio, Keystone Pharmaceuticals, Reding Pharmaceuticals, and Huang Pharmaceuticals, are developing FGFR targeted therapies.
    worldwide, two FGFR inhibitors have been approved, bringing bladder and bile duct cancer treatments into a new era of targeted treatment. At the same time,
    as one of the targets of "unlimited cancer", FGFR inhibitors have made good progress in the clinical research of lung cancer, liver cancer, breast cancer and other cancers.
    the future, how much potential does FGFR have?The abnormal frequency of FGFR in various solid tumors (Picture Source: References) FGFR mediates four key signaling pathways into fibroblast growth factor receptors (fibroblast growth factor receptor, FGFR) and are part of the tyrosine kinase family, including FGFR1, FGFR2, FGFR3, FGFR4 four receptor subtypes.
    when FGFR binds to ligands, it induces FGFR to form a dipolymer and catalyzes itself for phosphorylation, which activates four key downstream signaling pathways: RAS-RAF-MAPK, PI3K-AKT, signal transformers and transcription activators (STAts), and phosphase C-c.).
    the signalconducting pathways mediated by FGFR are necessary for normal cell growth and differentiation, and they are involved in physiological processes such as new angiogenesis, cell proliferation and migration, regulation of organ development, wound healing, etc.
    , the FGFR gene is also known as an important developmental gene.
    , however, when FGFR mutates or over-expression, it causes overactivation of the FGFR signaling pathway and further induces normal cell carcinoma.
    , the overactivation of RAS-RAF-MAPK stimulates cell proliferation and differentiation, PI3K-AKT overactivation inhibits apoptosis, SATA is closely related to promoting tumor invasion and metastasis, enhancing tumor immune escape, and the PLC gamma signaling pathway is an important way to regulate tumor cell metastasis.
    four key signaling pathways mediated by FGFR (Photo Source: References) According to a 2015 study published in Clinical Cancer Research, next-generation sequencing (NGS) of 4,853 solid tumors showed that about 7.1% of cancers found FGFR aberration (aberrations), most of which were genetic amplification (66%), followed by mutations (26%) and revolleyball (8%).
    almost all of the detected malignant tumors have FGFR distortion, the high incidence of cancer seropathic skin cancer, breast cancer, endometrial cancer, squamous epithelial cancer and so on.
    the development of inhibitors for FGFR is expected to be a new option for cancer treatment due to the prevalence of FGFR abnormalities in many cancers.
    of these candidates to block the FGFR-mediated signaling pathway by targeting the target area, thus achieving the goal of inhibiting tumor growth.
    at present, this target has become a hot research field in the industry, but also "unlimited cancer" therapy focus on one of the targets.
    two products approved around the world, ushering in a new era of bladder cancer, bile duct cancer targeted therapy, it is reported that there are a number of target FGFR candidates into the clinical research stage.
    these products can be broadly divided into two broad categories, one is "pan-FGFR inhibitors", which can inhibit a variety of subtypes of the FGFR family, and the other is FGFR4 inhibitors, which can selectively inhibit FGFR4.
    2019, Balversa, an oral pan-FGFR inhibitor developed by Janssen, was approved by the U.S. FDA for accelerated approval.
    the drug became the first targeted treatment for metastatic bladder cancer and the world's first approved FGFR-targeted drug.
    the drug is approved for indications in the United States as an adult patient with locally advanced or metastatic bladder cancer who carries a specific allergenic FGFR3 or FGFR2 gene mutation.
    in China, erdafitinib has been approved for three clinical trials, the indications of high-risk non-muscular dystrophy cancer that relapse after treatment with card-mediated seedlings and carries An FGFR mutation or fusion.
    April this year, the second FGFR inhibitor was approved for sale in the United States, developing the pan-FGFR inhibitor Pematinib for Incyte, which is the world's first targeted treatment for advanced bile duct cancer in adults carrying FGFR2 gene fusion or other re-type rearrangements.
    previously, the drug was fda-awarded breakthrough therapy, orphan drug eligibility and priority review.
    bile duct cancer is a rare cancer, with FGFR2 gene fusion found in tumors in approximately 9 to 14 percent of bile duct cancer patients.
    in China, Cinda Bio has the rights to the development and commercialization of this innovative therapy in Greater China.
    FGFR Gene Abnormality and Tumors (Photo Source: References) In addition to bladder cancer and bile duct cancer, currently currently in the global research FGFR targeted drugs in lung cancer (for FGFR1/2/3 small molecular inhibitors BGJ398 and AZD45 Good progress has been made in clinical trials of liver cancer (FGFR4 strong inhibitor BLU-554), breast cancer (non-selective FGFR inhibitor lucitanib), and urethra skin cancer (monoanti-vofatamab for FGFR3). In addition,
    , this kind of targeted therapy is also expected to treat other indications than tumors.
    2019, Pfizer acquired A recombinant human FGFR3 bait protein candidate TA-46 from Therachon, which is expected to be a potential "first-in-class" biologic for the treatment of cartilage insufficiency.
    previously, it has been granted the European Medicines Agency (EMA) and the U.S. FDA's status as an orphan drug.
    Nocheng Jianhua, Cinda Bio and other Chinese pharmaceutical companies have joined the current FGFR inhibitors have not been approved for listing in China.
    however, a number of Chinese companies are already involved in this field, including Nocheng Jianhua, Cinda Bio, Keystone Pharmaceuticals, Reding Pharmaceuticals, etc., the candidate drug as soon as clinical phase 3.
    most of these products in the study are oral small molecule-targeted drugs.
    , the products developed by Keystone Pharmaceuticals and Heyu Pharmaceuticals are selective FGFR4 inhibitors, and the candidate for FGFR2b overexpression is a monoclonal antibody drug.
    excerpts below are shared with you in the study of FGFR inhibitor information.
    : The company has developed a high-selective small molecule pan-FGFR inhibitor ICP-192 based on structural optimization design, which can be used to treat a variety of solid tumors, and is currently conducting a number of clinical studies in China and the United States.
    recently, the product has completed the first case of urinary path cancer and bile duct cancer in two phase 2 clinical cases.
    it is understood that Nocheng Jianhua is exploring the possibility of ICP-192 for different types of cancer to achieve "the same disease and treatment".
    in addition to single-drug treatments, the company will also collect additional data to evaluate the combination of ICP-192 and therapeutic drugs such as immunocheckpoint inhibitors as potential treatment options for patients with FGFR mutations.
    Cinda Bio: Pemigatinib was discovered and developed by Incyte and has been approved for sale in the United States as An FGFR inhibitor, Cinda Bio acquired the development and commercialization of the product's hematopathy and tumor indications in Greater China in 2018, and completed the first phase 2 critical registration study of patients with advanced bile duct cancer in China in March this year.
    in a Phase 2 clinical trial, pemigatinib single drug treatment in patients with previously treated local late or metastatic bile duct cancer with FGFR2 gene fusion or rearrangement, with the primary endpoint ORR reaching 36%, DCR 82%, median PFS at 6.9 months, and overall tolerance is good.
    Cornerstone Pharmaceuticals: Fisogatinib is a highly selective FGFR4 inhibitor developed by Blueprint Medicines.
    previously, Keystone Pharmaceuticals and the company have entered into an exclusive cooperation and licensing, obtained the candidate drug in Greater China exclusive development and commercialization authorization.
    January, the two companies have launched a Phase 1b/2 clinical trial of PD-L1 inhibitors and fisogatinib in combination with fisogatinib to treat patients with locally advanced and metastatic hepatocellular carcinoma (HCC).
    early clinical studies have shown efficacy and tolerance in the treatment of HCC patients with fisogatinib monodrug, in addition, the product in combination with PD-L1 has some therapeutic potential for FGFR4-driven patients with advanced HCC.
    the structure of FGFR and its ligands (Image Source: References) Reding Medicine: bemarituzumab is a best-in-class isogenic isomer selective monoclonal antibody, a targeted immunotherapy for FGFR2b overexpression of tumors, which directly kills tumor cells by enhancing the cell toxicaction (ADCC) of antibody-dependent cell mediated.
    Reding Pharmaceuticals, which obtains exclusive licenses from Five Prime in Greater China, is currently conducting a Phase 3 critical clinical study called FIGHT To explore the drug's role in treating gastric and gastroesophageal cancer synodic cancers.
    studies show that about 10% of stomach cancer patients have FGFR2b overexpression or FGFR2 gene amplification.
    According to re-Ding Pharma's first half 2019 annual report, the study progressed ahead of schedule as the positive rate of FGFR2b biomarkers remained stable at more than 30%.
    and Yu Pharma: The company has independently developed an innovative FGFR4 small molecule oral inhibitor ABSK01with with global intellectual property rights, and its excellent activity, selectivity and other physical and chemical properties indicate that the drug has global "best-in-class" potential.
    studies have found that the FGFR4 signaling pathway is often over-activated in liver cancer.
    currently, the product is conducting clinical research on liver cell carcinoma in Taiwan, China. In addition,
    , and AstraZeneca have entered into a global exclusive licensing agreement with AstraZeneca for the development and commercialization of the FGFR inhibitor AZD4547, which has been tested in the United States and Europe in a number of early stages.
    : The company is developing an oral pan-FGFR inhibitor derazantinib, a potential treatment for hepatic bile duct cancer (iCCA) and other cancerous tumors caused by The FGFR mutation.
    last April, the product was approved in China for a non-surgical excision or late-stage iCCA trial that treated FGFR2 gene fusion positive and failed in at least first-line system treatment.
    previously, the product in the ICCA patients with FGFR2 gene fusion in the clinical phase 1/2 study achieved good results, objective mitigation rate of up to 21%, nearly 3 times higher than standard chemotherapy.
    it is understood that Basilea, a partner of Theon Pharmaceuticals, is conducting a similar global registration study for patients with second-line iCCA in the United States and Europe with FGFR2 fusion genes.
    : 3D185 is an FGFR1/2/3 small molecule inhibitor, the early development and preclinical research of the project was jointly completed by Haihe Biology and the Shanghai Institute of Pharmaceutical Research of the Chinese Academy of Sciences, and in 2018, Indigo obtained its global development license for cancer and pulmonary fibrosis therapy.
    preclinical studies show that 3D185 has the advantages of strong anti-tumor activity, excellent PD-PK characteristics, low toxicity and high bioavailability, and has CSF1-R target ingress, suitable for the field of tumor treatment and pD-1/PD-L1 combination drug.
    currently conducting clinical research is a single-arm, multiple-dose, dose-increasing phase 1 clinical study.
    Beida Pharmaceuticals: BPI-17509 is a new chemical structure developed by Beida Pharmaceuticals, FGFR1/2/3 small molecule oral inhibitors, intended for the treatment of liver bile duct cancer, bladder cancer and lung scale cancer and other FGFR gene variants.
    In February last year, the product was approved for clinical use in China, and Beida Pharmaceuticals launched a Phase 1 clinical trial of the product for the treatment of advanced solid tumors in September last year.
    and Yellow Medicine: HMPL-453 is an FGFR1/2/3 inhibitor developed by HeHuang Pharmaceuticals, which has completed Phase 1 of the study in patients with advanced malignant mesothelioma in China and has initiated a phase 2 clinical study.
    in addition, there are many other clinically approved FGFR inhibitors in China, including E7090, developed by Eisai of Japan, which has been approved clinically in China and is suitable for patients with non-removable FGFR2 gene fusion or metastatic bile duct cancer.
    many potentials to be explored in the future It is worth mentioning that the two FGFR inhibitors that have been approved for sale are required to use FDA-approved accompanying test kits to detect whether patients carry applicable genetic mutations.
    this makes one wonder if the future of this field will produce the birth of targeted precision therapy across cancer species? It is reported that the company has taken FGFR as a focus on "unlimited cancer" therapy.
    , Jansen is conducting Phase 2 clinical trials in China and the United States, using a "basket" trial design to test erdafitini for patients with solid tumors that carry an FGFR-activated gene variant. <
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