The US Food and Drug Administration (FDA) last week issued another complete response letter (CRL) to China-based Jiangsu Hengrui Pharmaceuticals Co., Ltd. (SHA: 600276) regarding its application for the combination of programmed death-1 (PD-1) monoclonal antibody (mAb) camrelizumab with small-molecule targeted cancer therapy apatinib as a first-line treatment for irresectable or metastatic hepatocellular carcinoma (HCC). The FDA’s decision focused not on clinical data but on unresolved issues at the manufacturing site, which require further response for inspection, with no specific reasons given in the letter.
Clinical Basis and Prior Approval
The filing was based on positive results from the global, multicenter Phase III CARES-310 study, which demonstrated significant survival benefits and tolerable safety for the combination in first-line advanced HCC, with a median overall survival (mOS) reaching 23.8 months. The combo was approved in China for first-line treatment of unresectable or metastatic HCC in 2023 based on these results. US-headquartered Elevar Therapeutics, a subsidiary of South Korea’s HLB Life Science, secured global exclusive development and commercialization rights (excluding Greater China and South Korea) to the combo via a licensing deal with Hengrui in October 2023.
Regulatory History and Next Steps
The FDA first issued a CRL to the filing in May of last year, followed by Hengrui’s resubmission in October. The rejection is attributed to unresolved manufacturing defects at Hengrui’s Suzhou plant, including inadequate control of microbial contamination, inconsistent visual inspection protocols, and incomplete automation systems at Suzhou Suncadia Biopharmaceuticals Co., Ltd., Hengrui’s wholly owned subsidiary, as outlined in the latest CRL. HLB emphasized that the combo’s efficacy was not a concern for the FDA, with its 23.8-month mOS still considered an advantage. A resubmission is expected as early as before May, with the former head of the FDA’s Chemical, Manufacturing, and Controls (CMC) Department hired to assist in the effort.-Fineline Info & Tech
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