Novartis and Mirati Enter Strategic Collaboration to Develop KRAS G12C Inhibitor MRTX849, Challenging Amgen's AMG 510

July 12, 2019/BioonBIOON/--Mirati Therapeutics is a clinical-stage targetedTumorMirati Therapeutics, Inc. Recently, the company announced that it has entered into a clinical collaboration with Novartis to evaluate the combination therapy of MRTX849 and TNO155 in patients with advanced solid tumors harboring KRAS G12C mutations. Of the two drugs, MRTX849 is a KRAS G12C inhibitor developed by Mirati, while TNO155 is an SHP2 inhibitor from Novartis. Under the terms of the non-exclusive collaboration, Mirati will sponsor the trial, and Novartis and Mirati will jointly oversee and share the costs of clinical development activities for the combination therapy.NovartisTNO155 will be provided free of charge.

SHP2 is an important mediator that transmits cellular signals through the RAS/MAP kinase pathway and is frequently overactive in various types of cancer. Preclinical data show that, based on complementary mechanisms of action, combining a KRAS G12C inhibitor with an SHP2 inhibitor has enhanced anti-TumorActivity.

Dr. James Christensen, Chief Scientific Officer and Executive Vice President of Mirati Therapeutics, stated, “In our nonclinical studies, the combination of MRTX849 with an SHP2 inhibitor had a significant impact on KRAS signaling compared to monotherapy, leading to anti-tumor effects in certain cancers.”Tumoractivity increased significantly. We believe this collaboration will strengthen and expand our KRAS program, potentially enhancing the efficacy of MRTX849 and providing another treatment option for patients with KRAS G12C mutations who have traditionally shown resistance to other therapies.”

MRTX849 is an investigational oral small molecule that potently and selectively inhibits KRAS with the G12C alternative mutation, a mutation present in approximately 14% of lung adenocarcinomas, 5% of colorectal cancers, and 1–3% of other solid tumors. To date, no drug targeting this mutation has been approved. Characterized by the KRAS G12C mutationTumorThese mutations are typically associated with poor prognosis and resistance to treatment, leaving affected patients with few therapeutic options. Currently, MRTX849 is being evaluated in a Phase I/II trial in patients with molecularly confirmed KRAS G12C-positive advanced solid tumors.

This June, in the United States clinicalTumorAt the American Society of Clinical Oncology (ASCO) Annual Meeting, Amgen announced the first human clinical data for the KRAS inhibitor AMG 510. In the Phase I study, among 10 patients with non-small cell lung cancer (NSCLC) treated with AMG 510 monotherapy, 5 achieved partial response and 4 had stable disease, resulting in an overall response rate (ORR) of 50% and a disease control rate (DCR) of 90%. Among 18 patients with colorectal cancer (CRC) treated with AMG 510 monotherapy, 13 had stable disease, yielding a DCR of 72%. No dose-limiting toxicities were observed at the tested doses in the study.

Notably, AMG 510 is the first KRAS G12C inhibitor to enter clinical development after 30 years of RAS research, having previously beenFDAOrphan Drug Designation Granted for the Treatment of KRAS G12C-Positive NSCLC and CRC.

AMG510 is also one of the most closely watched early-stage assets in the industry, potentially providing Amgen with an opportunity to conquer KRAS. KRAS was among the first oncogenes discovered, and its mutations are present in approximately one-quarter of human tumors, making it one of the most well-defined targets in oncology drug development. Unfortunately, despite its promising potential, KRAS has long been considered nearly undruggable due to its featureless, near-spherical structure lacking obvious binding sites, which makes it difficult to develop compounds that can specifically bind to and inhibit its activity. Currently, KRAS has becomeTumorSynonymous with “undruggable” targets in the field of drug development.

AMG510 is one of the first small-molecule inhibitors to successfully target KRAS and enter clinical development in humans, specifically inhibiting KRAS protein carrying the G12C mutation. AMG510 specifically and irreversibly inhibits its pro-proliferative activity by locking the G12C mutant KRAS protein in an inactive GDP-bound state. (Bioon.com)

Original Source:

1、Mirati Announces Clinical Collaboration to Evaluate MRTX849 in Combination with SHP2 Inhibitor TNO155

2、Amgen Announces First Clinical Data Evaluating Novel Investigational KRASG12C Inhibitor AMG 510 At ASCO 2019