With the transaction exceeding 300 million US dollars reached, how is the exploration of Chinese inhibitor KRAS G12C?

On September 2, Innovent announced that it had reached a global exclusive licensing agreement with Genfleet. Innovent, as an exclusive partner of Genfleet, will obtain the right to develop and commercialize GFH925 (KRAS G12C inhibitor), a candidate drug targeting KRAS G12C that is commonly found in lung cancer and other solid tumors, in China (including Chinese Mainland, Hong Kong, S.A.R., China, Macau, S.A.R., China and Taiwan, China). At the same time, Innovent will also have the option of global development and commercialization rights.

According to the agreement, Innovent will pay Genfleet a down payment of USD22 million and a cumulative amount of less than USD50 million to support the global development. If Innovent exercises the option of global rights and interests, Genfleet will be eligible for milestone payment of no more than USD240 million from Innovent and gradient royalties based on the annual net sales of GFH925 in China and worldwide. This cooperation of authorization involves an amount of more than USD300 million.

GFH925 is an efficient oral new molecular entity compound independently developed by Genfleet with complete intellectual property rights. By covalently and irreversibly modifying the cysteine residue of KRAS G12C protein mutant, it effectively inhibits GTP/GDP exchange mediated by this protein, thus down-regulating the activation level of KRAS protein. Preclinical selective test for cysteine also shows high selective inhibitory effect of GFH925 on this mutation site. In addition, GFH925 can inhibit the downstream signal transduction pathway after inhibiting KRAS protein and effectively induce apoptosis and cell cycle arrest of tumor cells, thus achieving anti-tumor effect.

According to the preclinical experimental data, GFH925 has the potential best-in-class activity. It can effectively inhibit the growth of various tumor cell lines carrying KRAS G12C mutation, which will accelerate the clinical validation. Other preclinical trials also show the potential of combination with other therapies.

The Marketing of Amgen AMG510 breaks the "curse" that it's impossible to create effective medicine for KRAS G12C.

As one of the three major types of RAS genes, KRAS is the most common oncogene, accounting for 85% of RAS mutations. According to the basic research, KRAS has mutations in various cancers, among which the mutation rate of pancreatic cancer is as high as 90%, and this mutation also occurs in colon cancer and lung cancer (mostly NSCLC), as well as cholangiocarcinoma, carcinoma of small intestine, skin cancer, bladder cancer and breast cancer. Unfortunately, because KRAS is a featureless and nearly spherical structure and has no obvious binding site, it is difficult to synthesize a compound that can target binding and inhibit its activity. Therefore, it is almost impossible to be overcome for a long time, and was once considered as a non-pharmaceutical target.

In May this year, Lumakras (AMG510), an inhibitor of KRAS G12C developed by Amgen, was approved for marketing by FDA and became the world's first anticancer drug targeting specific KRAS gene mutation. The listing of Lumakras (AMG510) seemed as an official announcement dispelling the saying that it's impossible to create effective medicine for KRAS oncogene and caused a sensation in academia and industry. More and more healthcare supply companies at home and abroad were attracted to join this subdivision track.

At present, no drugs with the same target have been approved in China. Besides GFH925, there are drugs under research such as D-1553 of Inventisbio, JAB-21822 of Jacobio, BPI-421286 of Betta.

D-1553 of Inventisbio

D-1553 is an oral inhibitor of KRAS G12C mutation independently developed by Inventisbio, which is aimed at advanced solid tumors such as non-small cell lung cancer and colorectal cancer with KRAS G12C mutation. D-1553 has shown excellent selectivity and tumor inhibition effect in preclinical studies.

D-1553 was approved for Phase I/II clinical trials by the Center for Drug Evaluation, NMPA (National Medical Products Administration) in January 2021. Prior to this, Inventisbio started Phase I clinical trial of D-1553 in America, Australia, Taiwan, China, Korea and other countries and regions in October last year, and it is progressing well.

JAB-21822 of Jacobio

JAB-21822 is a small molecule anti-tumor drug independently developed by Jacobio, which will be used to treat patients with advanced solid tumor of KRAS G12C mutation. JAB-21822 is a potential "best-in-class" project among KRAS G12C inhibitors. Compared with its peers, JAB-21822 has better oral bioavailability, systemic drug exposure, and better pharmacokinetic characteristics and tolerance in the internal head-to-head study.

BPI-421286 of Betta Pharmaceuticals

BPI-421286 is a new molecular entity compound owned by Betta Pharmaceuticals with completely independent intellectual property rights. It is a novel, potent and highly selective covalent irreversible oral small molecule inhibitor of KRASG12C, which is intended to be used for the treatment of unresectable, locally advanced or metastatic solid tumor patients with KRAS G12C mutation.

According to preclinical data, BPI-421286 has the same biological activity in vivo and in vitro. It can effectively inhibit the proliferation of tumor cells carrying KRAS G12C mutation, and has shown good anti-tumor effect on various transplanted tumor models carrying KRASG12C mutation. BPI-421286 is expected to provide a new molecular targeted therapy for cancer patients with KRAS G12C mutation.

In January 2021, the company submitted the application for clinical trial of BPI-421286 to NMPA and was accepted.

It should be noted that KRAS G12C is only one kind of KRAS gene mutation. KRAS G12C gene mutation accounts for a small proportion in the whole KRAS patients. Although the research on KRAS G12C is in full swing in China, the attentions of fast-follow mode are paid on the target of KRAS G12C, with relatively concentrated indications, and the track is characterized by homogenization. However, regarding the targeted therapy for KRAS mutants other than KRAS G12C mutants, such as G12D, G12V, G13, G61, etc., these different kinds of KRAS mutations together account for 20%-30% of all tumors, and there is no targeted therapy for other KRAS mutants in the clinical trial across the world.

Reference:

1.Timothy F Burns, Hossein Borghaei, Suresh S Ramalingam. Targeting KRAS-Mutant Non-Small-Cell Lung Cancer: One Mutation at a Time, With a Focus on KRAS G12C Mutations.  2020 Oct 26; JCO2000744. doi: 10.1200/JCO.20.00744.

2.Yang A, Li M and Fang MZ. The Research Progress of Direct KRAS G12C Mutation Inhibitors. Pathol Oncol Res. 2021 Apr 23;27:631095.doi: 10.3389/pore.2021.631095.

3.NMPA。

3. Official website of NMPA.