China's First NDA for a KRAS G12C Inhibitor: NMPA Accepts New Drug Application for GFH925 and Grants GFH925 with Priority Review Designation

SHANGHAI, Nov. 24, 2023 /PRNewswire/ -- GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, today announced the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) of China has accepted the New Drug Application (NDA) for GFH925 (IBI351) and granted GFH925 with Priority Review designation, for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring KRAS G12C mutation who have received at least one systemic therapy. It's the first China-developed KRAS G12C inhibitor that has its NDA submission accepted and granted with Priority Review Designation by NMPA. GFH925 also received Breakthrough Therapy Designations this year for treating advanced KRAS G12C-mutant NSCLC that have received at least one systemic therapy and colorectal carcinoma (CRC) patients who have received at least two systemic therapies.

The Priority Review designation is based on the results from a single-arm registrational Phase II study of GFH925 monotherapy treating advanced KRAS G12C-mutant NSCLC patients who failed or was intolerant of standard-of-care treatment in China (NCT05005234). The results will be presented at the upcoming European Society for Medical Oncology (ESMO) Asia Congress 2023.

The results of GFH925 from a Phase I trial was updated in an oral presentation at the 2023 AACR Annual Meeting. As of data cutoff date (February 10, 2023), of the 67 evaluable NSCLC patients, 41 achieved partial response (PR), with investigator assessed ORR 61.2% and DCR 92.5%. Of 30 patients with NSCLC treated at 600mg BID (the recommended phase 2 dose), better efficacy signal was observed, with investigator assessed ORR 66.7% (confirmed ORR 53.3%) and DCR 96.7%.

In combating NSCLC, the multi-center trial of GFH925 and ERBITUX® (cetuximab, EGFR inhibitor) has progressed into phase II study in Europe with favorable safety and encouraging efficacy and numerous patients were observed with partial response. The trial is led by led by Professor Rafael Rosell, a world-renowned expert in particular in the field of lung cancer, and partial responses were observed among advanced KRAS G12C-mutant patients. In China, Innovent is also exploring the potential of IBI351(GFH925) in combination therapies for previously untreated advanced NSCLC patients with KRAS G12C mutation; two Phase Ib studies of IBI351（GFH925）in combination with cetuximab and sintilimab (TYVYT®, PD-1 inhibitor) respectively are currently ongoing.

"GFH925 is GenFleet's first NDA-stage product and becomes China's first KRAS G12C inhibitor that receives NDA acceptance and Priority Review Designation. That demonstrates GFH925's encouraging safety and efficacy in treating advanced NSCLC, and its potential in commercialization in the future. Meanwhile, GenFleet's combination study of GFH925 and cetuximab treating NSCLC in 1st line also progressed smoothly in Europe with preliminary results of good safety and efficacy. GenFleet will promote the advancement of more multiple-regional studies in monotherapy and combination therapies and we look forward to positive progress of this study and other studies of GFH925 conducted by Innovent." stated Yu Wang, M.D.,Ph.D., Chief Medical Officer of GenFleet.

KRAS mutation as the 'undruggable' target for decades has become one of the most popular directions for clinical development recently. IBI351 is a novel, irreversible covalent inhibitor of KRAS G12C mutation. IBI351 monotherapy demonstrated favorable safety and promising activity in KRAS G12C mutated advanced NSCLC. We look forward to the NDA approval of this novel drug to benefit more NSCLC patients with KRAS G12C mutation soon." stated Professor Yi-Long Wu from Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital.

GFH925 is also the first domestic KRAS G12C inhibitor that received CDE Breakthrough Therapy Designation as monotherapy for previously treated KRAS G12C mutant CRC patients. According to the preliminary data of GFH925 monotherapy treating CRC at the 2023 ASCO Annual Meeting, favorable safety/tolerability and promising antitumor activity of GFH925 monotherapy were observed among patients. As of data cutoff date (Feb 16, 2023), a total of 54 metastatic colorectal cancer patients were included for analysis; of 42 evaluable subjects at 600mg BID, ORR was 42.9% (18/42), confirmed ORR was 31.0% (13/42), DCR was 88.1% (37/42).

About KRAS G12C Mutated Non-small Cell Lung Cancer

Lung cancer is one of the malignancies with the highest incidence and mortality worldwide, among which non-small cell lung cancer (NSCLC) is the most common pathological type, accounting for about 85% of all lung cancers. KRAS mutations are common driver gene mutations in NSCLC, most of which occur in lung adenocarcinoma. KRAS mutations rarely co-exist with driver mutations such as EGFR and ALK, and patients with advanced NSCLC with KRAS G12C mutations are often unable to benefit from the multiple drugs already on the market that target these mutations or rearrangements. After the progress of first-line standard treatment in this population, there are limited second-line treatment options with low effective rate and poor prognosis.

About GFH925（IBI351）

RAS protein family can be divided into KRAS, HRAS and NRAS categories. KRAS mutation are detected in nearly 90% of pancreatic cancer, 30-40% of colon cancer, and 15-20% lung cancer patients. The occurrence of KRAS G12C mutation subset is more frequently observed than those with ALK, ROS1, RET and TRK 1/2/3 mutations combined.

Discovered by GenFleet Therapeutics, GFH925 (Innovent R&D code: IBI351) is a novel, orally active, potent KRAS G12C inhibitor designed to effectively target the GTP/GDP exchange, an essential step in pathway activation, by modifying the cysteine residue of KRAS G12C protein covalently and irreversibly. Preclinical cysteine selectivity studies demonstrated high selectivity of GFH925 towards G12C. Subsequently, GFH925 effectively inhibits the downstream signal pathway to induce tumor cells' apoptosis and cell cycle arrest. 

In September 2021, Innovent and GenFleet Therapeutics entered into an exclusive license agreement for the development and commercialization of GFH925 in China (including mainland China, Hong Kong, Macau and Taiwan) with additional option-in rights for global development and commercialization.

About GenFleet Therapeutics

GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies, is dedicated to serving significant global unmet medical needs in oncology and immunology. Based on the deep understanding of disease biology and translational medicine, GenFleet's proprietary and fully integrated R&D platform highlights multiple cutting-edge products with novel mechanisms and global IP.

Since its inception in 2017, GenFleet has built up industry-leading capabilities and expertise in developing novel drug candidates - both small molecules and biologics. Its pipeline includes over 10 programs, many of which have entered multi-regional clinical trials across China (including Taiwan), the United States, Europe and Australia. To date, GenFleet has over 5 clinical studies encompassing IND stage to phase II studies and completed co-development partnerships with numerous publicly listed companies worldwide.

GenFleet is expected to progress additional programs into the clinic, as well as transition from a clinical stage biotech company into a commercial stage biopharmaceutical company in the next 3-5 years.

SOURCE GenFleet Therapeutics