Abbisko Therapeutics Co. Ltd. announced positive first-in-human data for its highly selective fibroblast growth factor receptor (FGFR) 4 inhibitor, irpagratinib (ABSK-011), for treating advanced hepatocellular carcinoma (HCC) with FGF19 overexpression, which is seen in roughly 30% of liver cancers.

Jing Ji, chief medical officer, Abbisko

The twice-daily (BID) cohorts demonstrated promising antitumor activity with an overall response rate (ORR) of 40.7% in FGF19-positive HCC patients with prior therapies, including one confirmed complete response and seven partial responses. The results are the first data to be reported for this target for a Chinese company, Abbisko Chief Medical Officer Jing Ji told BioWorld.

The ongoing phase I open-label study enrolled 78 patients as of Sept. 8, 2023, and 47 patients were evaluable, Ji said, noting that these are patients who have had two to three lines of prior therapy, and have limited treatment options. Current standard of care includes immunotherapy, Roche AG’s Avastin (bevacizumab ) and Eisai Co. Ltd.’s lenvatinib.

The overall response rate was better than expected, Ji said, and although ABSK-011 may not be first-in-class, it may be best-in-class, she said noting that there are safety concerns with current compounds and the overall response rate is quite low.

The most common adverse events for irpagratinib was diarrhea, and grade 3 events were liver enzyme related and are common and manageable in this population, Ji said.

There is currently no biomarker available for this patient population, and the FGF19/FGFR4 signaling axis could be a therapeutic target for HCC. ABSK-011 may have clinical benefit through biomarker selection of FGF19, and Abbisko is developing a companion diagnostic for FGF19 overexpression.

Liver cancer is the sixth leading cancer worldwide and is the third leading cause of death globally. Nearly 900,000 patients are diagnosed every year with liver cancer, 90% of whom die within the first year, Ji said. Roughly half of all liver cancer patients are in China where most cases are due to hepatitis A virus and hepatitis B virus; whereas in the U.S., liver cancer is mostly attributed to hepatitis C virus and nonalcoholic steatohepatitis (NASH).

There is no difference among Western and Asian populations for FGF19-positive expression that accounts for 30% of the global liver cancer population.

“In the Chinese market, we are the first locally developed FGFR19-positive compound and also the first company to report promising phase I data so far,” Ji said. In China, the compound will likely gain priority status under China’s National Medical Products Administration (NMPA) fast track due to the high unmet medical need in the country.

Abbisko recently received clearance from U.S. FDA to start clinical trials in the U.S. It expects to report full data in 2024 and move to a pivotal trial in China. Abbisko is also conducting a phase II trial of irpagratinib in combination with Roche’s PD-L1 antibody, atezolizumab, in HCC patients with FGF19 overexpression.

Oral small-molecule PD-L1 inhibitor has advantages

Although immunotherapies targeting the PD-1/PD-L1 pathway with therapeutic antibodies have shown strong antitumor effects, Abbisko’s oral small-molecule PD-L1 inhibitor (ABSK-043) offers lower immunogenic risk and convenience in administration.

The company reported preliminary results from the dose-escalation part of its first-in-human study of ABSK-043 in patients with advanced solid tumors, and the compound was well-tolerated up to 1,000 mg BID and has a safety profile consistent with monoclonal antibody checkpoint inhibitors.

Preliminary antitumor activity was observed, and further investigation will explore the efficacy in a larger number of patients.

Numerous PD-L1s are being developed in China, but they are monoclonal antibodies, Ji said, and Abbisko is the first Chinese company to report data for a PD-L1 inhibitor.

Abbisko will present data on both compounds at the 2023 European Society for Medical Oncology, held Oct. 20-24, 2023, in Spain.

China’s oncology drugs market is expected to reach $12.7 billion by 2026, growing at a compound annual growth rate of 8.7% from $6.5 billion in 2018, according to Allied Market Research. There are around 4 million new cancer cases in China each year.

Abbisko, of Shanghai, has 15 programs in its pipeline, two of which were in-licensed while the rest were internally discovered and developed. Seven programs are now in the clinic.

The company’s colony-stimulating factor 1 receptor (CSF-1R) inhibitor, pimicotinib (ABSK-021), advanced from phase I trials to pivotal phase III trials in patients with tenosynovial giant cell tumors (TGCT) in the U.S. and China following clearance from both regulators. Phase III trials are underway in China, the U.S., Canada and Europe, Ji said.

Pimicotinib is the first CSF-1R inhibitor developed in China entering global phase III trials. Registrational trials led by Chinese pharmaceutical companies and launched simultaneously worldwide are rare, Ji said.

In addition to TGCT, Abbisko is actively exploring the potential of pimicotinib in treating other indications, including solid tumors. It is also in a phase I/II trial in chronic graft-vs.-host disease.

Other compounds in the clinic include pan-FGFR inhibitor fexagratinib (ABSK-091) in phase I studies in patients with urothelial cancer harboring FGFR2 or FGFR3 alterations; ABSK-061, an EGFR inhibitor in phase I trials in achondroplasia in children; and next-generation pan FGFR inhibitor (ABSK-121), in phase I in advanced solid tumors.

By Tamra Sami

Link: https://www.bioworld.com/articles/701947-abbisko-reports-first-in-human-data-for-homegrown-fgfr4-inhibitor-and-pd-l1-inhibitor