Jiangsu Hengrui Pharmaceuticals and its partner Elevar Therapeutics will have to wait even longer before their PD-1 inhibitor camrelizumab can enter the U.S. market.

The FDA has once again issued a complete response letter to Hengrui and Elevar’s applications for camrelizumab and the VEGFR inhibitor rivoceranib as a combination for the first-line treatment of liver cancer, Hengrui said in securities filing (PDF, Chinese) to Shanghai Stock Exchange.

The FDA first snubbed the combo in May 2024 due to deficiencies it identified during an inspection of a Hengrui manufacturing facility in China. The agency also cited an incomplete clinical trial site inspection as another reason for the prior rejection.

This time around, in the new CRL, the FDA again raised manufacturing issues that require responses from Hengrui, although the agency didn’t spell out specific reasons, Hengrui said in the filing.

“The company will keep close communication with the FDA and will take measure as soon as possible upon confirming the specific reasons and resubmit the application, in hopes of obtaining an approval,” Hengrui said.

During the first review cycle for the combo, U.S. regulators issued a 10-page, 10-observation Form 483 to Hengrui’s subsidiary, Suzhou Suncadia Biopharmaceuticals. At the firm’s Suzhou facility, which produces camrelizumab, FDA inspectors in 2023 found myriad problems regarding protection of data integrity, prevention against microbiological contamination, potential mix-ups between raw materials meant for the Chinese and U.S. markets, and other issues.

Following that first CRL, Hengrui and Elevar quickly refiled their applications, which the FDA accepted in October 2024. The pair also updated their data package to include the final analysis from the phase 3 Cares-310 trial, which showed that the camrelizumab-rivoceranib combo reduced patients' risk of death by 36% versus Bayer’s Nexavar in those with first-line unresectable hepatocellular carcinoma. Patients who received the combo lived a median 23.8 months, compared with 15.2 months for the control group.

The FDA conducted a reinspection of the Hengrui plant in January 2025 and confirmed that all shortfalls spotted in the previous CRL were resolved, Hengrui said, according to multiple Chinese media reports. But this time, the U.S. agency raised three new issues for improvement, and Hengrui has already responded to the agency's concerns stemming from that inspection, the company said.

Because rivoceranib, which carries a brand name Tulvegio, is used as part of a combination with camrelizumab, the FDA cannot approve the VEGFR inhibitor alone, Elevar’s parent company, HLB, said in a filing to the Korea Exchange.

“We were not anticipating the FDA’s decision based on recent final label negotiations and positive interactions with the FDA,” Elevar CEO Saeho Chong, Ph.D., said in a statement to Fierce Pharma. 

Chong stressed that the FDA didn’t raise any issues about clinical data or rivoceranib and that the rejection was “solely to unresolved site remediation at the camrelizumab facility.”

Roche’s combination of the PD-L1 inhibitor Tecentriq, used together with bevacizumab, is a standard combination for first-line liver cancer in the U.S. AstraZeneca’s immunotherapy duo of Imfinzi and Imjudo is also an option. 

Bristol Myers Squibb is awaiting an FDA decision for its PD-1/CTLA-4 cocktail of Opdivo and Yervoy in the same condition, with a target decision date set for April 21.

Outside the U.S., Elevar plans to submit an application for camrelizumab and rivoceranib in first-line liver cancer to the European Medicines Agency in September 2025, according to the company. The combo was first cleared in that indication in China in January 2023.

Editor's Note: The story was updated with additional comments from Elevar.