On May 2, 2021 Jacobio Pharmaceuticals (1167.HK) reported the U.S. Food and Drug Administration (FDA) has approved company’s Investigational New Drug (IND) application to develop a KRAS G12C inhibitor (Press release, Jacobio Pharmaceuticals, MAY 2, 2021, View Source [SID1234579033]). IND application to the National Medical Products Administration (NMPA) in China was accepted on March 17. It will be used to treat advanced solid tumors with the KRAS G12C mutation, including but not limited to non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and other advanced solid tumors. Patient enrollment for clinical trials in the U.S. and China will begin in the second half of 2021.
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JAB-21822 is Jacobio’s innovative in-house small molecule anti-cancer drug, which is designed to target the KRAS G12C mutation. The global incidence of the KRAS G12C mutation in patients with NSCLC, ovarian cancer, CRC and pancreatic cancer reached approximately 295,000 in 2019. To date, there has been no approved and marketed KRAS G12C inhibitor globally.
JAB-21822 has best-in-class potential among KRAS G12C inhibitors. Internal pre-clinical head-to-head animal studies comparisons have shown JAB-21822 to have a superior pharmacokinetic (PK) profile and favorable tolerability as well as potential for a superior dosing profile in comparison with its competitors.
KRAS is the most frequently mutated oncogene in human cancers. KRAS mutations promote a variety of fatal tumors in humans and are present in more than 90% of pancreatic cancers. There are very limited effective treatment options for patients with pancreatic cancer, evidenced by the fact that only 7.2% of patients with pancreatic cancer have a 5-year overall survival rate in China. KRAS mutations are also found in CRC (40%), NSCLC (25%), thyroid cancer, ovarian cancer, and bladder cancer.
Although KRAS and its role as an oncogene was discovered as early as 30 years ago, no therapeutic agent directly targeting KRAS has been clinically approved despite decades of research. KRAS has long been considered "undruggable" for several reasons. Firstly, it is a very small-sized molecule that has a relatively smooth surface with few deep pockets for drug-binding. Secondly, because of the high picomolar affinity of KRAS towards nucleotide GTP, drugs are generally unable to reach a certain concentration to compete with GTP in binding the nucleotide binding domain to the protein.
Dr. Wayne Long, Jacobio’s Vice President of Chemistry said, "The strategy of the use of allosteric inhibitors is a breakthrough of this previously "undruggable" target. Jacobio has developed the highly selective KRAS G12C inhibitor JAB-21822 based on our own allosteric inhibitor platform and an "iterative chemotype evolution" approach."
Based on the in-depth understanding of KRAS G12C, Jacobio has further discovered two inhibitors targeting KRAS G12D and KRAS G12V. The KRAS G12D inhibitor has obtained highly active and selective lead drug molecules, while KRAS G12V has also obtained multiple hits. These two inhibitors are expected to be submitted as INDs in 2022-2023 and 2023-2024, respectively. To date, there is no IND application for these two targets globally.
"KRAS G12D and KRAS G12V are two exciting programs that cement our position in the top tier of global biotech companies," said Dr. Steve Zhou, Chief Biologist and Senior Vice President of Jacobio. "The R&D of KRAS G12D inhibitors draws on our experience and expertise of the KRAS G12C inhibitor. The combination of various advantages including development experience, coupled with our in-house chemical library and focused library design, as well as small molecule drug development capabilities based on the allosteric inhibitor platform, puts us in a favorable position in the global R&D landscape of KRAS inhibitors."
Jacobio has six programs targeting the RAS pathway, including SHP2 inhibitors (upstream from the RAS pathway). Clinical studies have shown that SHP2 inhibitors may potentially be the best combination therapy partners for KRAS inhibitors. Jacobio is one of the few biotech companies in the world that has both SHP2 inhibitors and KRAS inhibitors, which brings much convenience and flexibility to the clinical trials of in-house combination therapy.