Mirati’s Successful Targeting of the “Undruggable” Shapes Up Regulatory Showdown with Amgen
By Daniel Ojeda, Ph.D.
On October 25th, 2020, during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics (“ENA”), Mirati Therapeutics presented data of two of their compounds, MRTX849, and MRTX1133, which target different mutant versions of the KRAS protein.
KRAS Mutations and Cancer
The Kirsten rat sarcoma (KRAS) gene codes for a protein of the same name that plays an important role in cell proliferation. KRAS is one of the most commonly mutated genes in cancers. It is present in approximately 90% of pancreatic cancers, 30%-40% of colon cancers, and 15%-20% of lung cancers. The most common mutations in KRAS occurs at the 12, 13, or 61 amino acids. A mutation of the 12 amino acid, which is a glycine to any of the other amino acids, leads to the activation of KRAS and the possible development of cancer.
Additionally, KRAS has been considered “undruggable” due to two main reasons: the extremely high affinity of KRAS for its substrate and the lack of a common “pocket” for a small molecule to bind to the surface of the protein. However, new advances in drug discovery and structural insights have opened the door for new treatments to be developed. A drug targeting specific forms of KRAS could have a wide market due to the presence of different mutations in different types of cancers.
Successfully Targeting the Undruggable
The San Diego-based company showed updated results for Phase 1 and Phase 2 clinical trials for MRTX849 (Adagrasib) in patients with advanced Non-small cell lung cancer (NSCLC). MRTX849 is an orally available selective inhibitor of KRAS G12C, a mutation present in approximately 14% of NSCLC. Treatment with 600mg dose resulted in a 96% disease control rate and a 45% confirmed objective response rate.
As mentioned by the President and CEO of Mirati Therapeutics, Dr. Charles M. Baum, “The Adagrasib preliminary data presented today showed deep and durable anti-tumor activity in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and other solid tumors, providing renewed hope for patients that harbor a KRAS G12C” Dr. Baum added that enrollment for Phase 2 clinical trials for Adagrasib as a monotherapy treatment for patients in the 2nd / 3rd line NSCLC is completed.
Additionally, the company showed preclinical results for its first-in-class compound MRTX1133, which targets KRAS G12D. MRTX1133 is a selective, reversible inhibitor and over 1000 -fold more selective for the KRAS G12D than the normal (wild-type) KRAS. This is crucial to avoid negative side effects. The Executive Vice President and Chief Scientific Officer at Mirati said that they are pursuing both oral and parenteral routes of administration as they prepare for Phase 1 clinical trials.
The KRAS Race
The fact that Mirati was able to develop two selective inhibitors for different mutant versions of KRAS is promising; however, drugs against KRAS have a high failure rate. A recent example being Eli Lilly’s LY3499446, which was dropped from the pipeline after unexpected toxicity was observed in Phase 1 clinical trials. Several other companies are currently testing their own KRAS therapies. One of the candidates in the pipeline is Johnson & Johnson and Wellspring Biosciences treatment, JNJ-74699157, which is a direct KRAS G12C inhibitor and has recently concluded completed Phase 1 clinical trial, although no results are available yet. Additionally, Moderna is also collaborating with Merck to develop an mRNA vaccine against mutant KRAS. They are currently recruiting for a Phase 1 clinical trial after pre-clinical data showed immune cells responding to mutant forms of KRAS in animal models.
Currently, the biggest competitor for Mirati is Amgen. Amgen is testing their own KRAS G12C, Sotorasib, which has started recruitment for Phase 3 clinical trials. If successful, it will be a direct competitor for Adagrasib. Phase 3 clinical trials will reveal significant differences in effectivity between these two drugs and whether they have any side effects. This could ultimately decide which drug becomes the standard of care.
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