Positive effects of RET-specific inhibitors in clinical trials April 18, 2018 Source: WuXi PharmaTech Recently, Blueprint Medicines announced at the 2018 annual meeting of the American Association for Cancer Research (AACR) that the company's specific RET receptor inhibitor BLU-667 has been actively tested in clinical trials for cancer patients with RET mutations. result. At the same time, preclinical and clinical data on the treatment of cancer by BLU-667 was published in Cancer Discovery. The RET receptor tyrosine kinase is an oncogene that occurs in various cancers including non-small cell lung cancer (NSCLS) and medullary thyroid carcinoma (MTC). There are currently no FDA-approved therapies for RET, and approved multi-protein kinase inhibitors (MKIs), although capable of inhibiting RET activity, may have toxic side effects due to off-target effects and have limited inhibition of RET activity. BLU-667 is a potent RET-specific inhibitor developed by Blueprint Medicines Inc., which specifically targets carcinogenic RET gene fusions and mutations to increase inhibition of RET mutants while reducing off-target effects. In vitro, BLU-667 is 10-10,000 times more potent against oncogenic RET variants and resistance mutations than already approved MKIs. Among them, RET-KIF5B fusion mutation is the most common RET mutation in NSCLC patients. For this mutation, BLU-667 is 20 times more potent than MKI named RXDX-105. In vitro experiments showed that BLU-667 is 88 times more specific for RET than VEGFR-2, and inhibition of VEGFR-2 is usually the main cause of toxic side effects. The researchers tested 371 other protein kinases and found that BLU-667 is 100 times more specific for RET than most other protein kinases (96%). In a mouse model of cancer induced by RET, BLU-667 is capable of potently inhibiting the growth of NSCLC, MTC, and colorectal cancer, including tumors that are resistant to MKIs. â–²Blueprint Medicines' clinical research and development pipeline (Source: Blueprint Medicines official website) In a clinical phase 1 trial called ARROW, 53 patients received dose escalation of BLU-667. These patients included 19 NSCLC patients, 29 MTC patients, and 5 other solid tumor patients. Of the 53 patients, 27 received MKIs and 18 received immunotherapy. The mid-term radiological test results of clinical trials showed that 84% of patients with RET-mutant solid tumors and whose lesions could be detected had a smaller tumor. The initial overall response rate (ORR) in patients with NSCLC is 50%, and patients with the most common RET-KIF5B and RET-CCDC6 fusion variants in NSCLC are able to respond to BLU-667. Moreover, BLU-667 is able to produce an anti-cancer effect on NSCLC metastases in the brain. The initial ORR in MTC patients was 40%, with one patient receiving confirmed complete remission. Patients with the most common RET-M918T mutation in MTC can respond to BLU-667 therapy. At the same time, BLU-667 showed good tolerance in the test, and the test results showed that the maximum tolerated dose (MTD) of BLU-667 was 400 mg once a day. At doses below the MTD, most of the side effects of BLU-667 in patients are grade 1 or grade 2. Pharmacokinetic data indicate that BLU-667 can be rapidly absorbed by patients with an average half-life of greater than 12 hours. This data supports the once-daily application method. "These data demonstrate the broad clinical potential of BLU-667, and it further demonstrates the power and repeatability of Blueprint Medicines' original drug discovery platform," said Dr. Andy Boral, Chief Medical Officer of Blueprint Medicines. "We think ARROW is clinical The safety, clinical efficacy, and pharmacodynamic results of the dose escalation portion of Phase 1 trials convincingly demonstrate the potential of BLU-667. We are particularly pleased to see that BLU-667 is capable of carrying different tumor types, different RET variants, And patients who have received other therapies show consistent efficacy. Based on these data, we will quickly expand the global expansion of clinical trials to further test and optimize the dose of BLU-667 in a wider patient population, striving for lasting results. Clinical efficacy." Reference materials: [1] Blueprint Medicines Publication in Cancer Discovery Highlights Preclinical and Clinical Proof-of-Concept Data for Highly Selective RET Inhibitor BLU-667 [2] Blueprint Medicines Announces Proof-of-Concept Data for Highly Selective RET Inhibitor BLU-667 from Phase 1 ARROW Clinical Trial in Patients with RET-Altered Solid Tumors [3] Precision Targeted Therapy With BLU-667 for RET-Driven Cancers Manual Massage Foot Spa Massager A manual massage Foot Spa Massager is a device designed to provide a relaxing and therapeutic foot massage. It is a manually operated handheld device, which means it does not require electricity or batteries to operate. The massager is made up of several parts, including the handle, rollers, and knobs. Manual Massage Foot Spa Massager,Portable Pedicure Tub,Bath Foot Massager,Foot Bath Machine Huaian Mimir Electric Appliance Co., LTD , https://www.mmfootbath.com
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Positive effects of RET-specific inhibitors in clinical trials