FDA Rejects China-Made PD-1 Elevar, Hengrui's Liver Cancer Combo

Unresolved manufacturing issues and unfinished inspections in Russia and Ukraine have led the FDA to issue a complete response letter concerning Jiangsu Hengrui Pharma and Elevar Therapeutics' liver cancer drug applications. The applications involved the PD-1 inhibitor camrelizumab and the VEGFR inhibitor rivoceranib, which the companies hoped to get approved for first-line liver cancer treatment.

The rejection marks yet another instance where FDA scrutiny has hampered the progress of China-made PD-1 inhibitors. This setback was first reported by HLB, Elevar's South Korean parent company, through the Korea Biomedical Review. Jiangsu Hengrui also shared its complete response letter with the Shanghai Stock Exchange.

The FDA's decision benefits Roche, whose anti-PD-L1/VEGF combination of Tecentriq and Avastin remains the only FDA-approved immunotherapy for first-line liver cancer. Despite having no qualms with the clinical data presented by Hengrui and Elevar, the FDA flagged issues related to manufacturing and clinical trial site inspections.

Hengrui has yet to address manufacturing deficiencies noted during an earlier FDA inspection for camrelizumab, which is already approved in China under the brand name AiRuiKa for various conditions. The FDA stated that a complete evaluation would follow once Hengrui addresses these shortfalls. Additionally, the FDA has been unable to complete clinical trial site inspections due to travel restrictions in countries like Russia and Ukraine.

HLB Chairman Jin Yang-gon revealed through a YouTube announcement that the sites in Russia and Ukraine have yet to be inspected. He expressed optimism that the regulatory hold-up might be resolved through alternative methods. Hengrui indicated that it plans to maintain close communication with the FDA to potentially refile the application soon.

Elevar expressed surprise at the FDA's complete response letter, especially as label discussions had been ongoing as recently as the past week. CEO Saeho Chong confirmed that the clinical data was not in question. Manufacturing and site inspections have also caused delays for other China-made PD-1 medications. Coherus BioSciences' Loqtorzi received a similar response letter in 2022, delaying its approval until October. BeiGene faced a 20-month delay for its PD-1 drug Tevimbra due to COVID-related travel restrictions affecting preapproval inspections.

Had the FDA approved camrelizumab, it would have become the third China-made anti-PD-1 antibody available in the U.S. The camrelizumab-rivoceranib combination was approved in China for first-line liver cancer early in 2023. Camrelizumab, branded as AiRuiKa in China, is also approved as a monotherapy for second-line liver cancer. Rivoceranib, known as Aitan in China, has approval as a second-line treatment as well.

The drugs showed significant clinical efficacy in the global phase 3 CARES-310 study, reducing disease progression or death risk by 48% compared to Bayer’s Nexavar. An interim analysis also showed a 38% reduction in death risk, with a median overall survival of 22.1 months—the longest observed in a global phase 3 trial for this setting. Comparatively, Roche’s Tecentriq and Avastin achieved a 42% reduction in death risk and had a median overall survival of 19.2 months in the IMbrave150 trial.

The results of these studies, however, are not directly comparable due to differences in patient demographics. Importantly, CARES-301 included sites in the U.S., unlike Innovent Biologics’ PD-1 inhibitor Tyvyt, which the FDA rejected in 2022 because its pivotal data came solely from China.

If approved, the Elevar-Hengrui combination would compete with AstraZeneca’s Imfinzi and Imjudo, which showed a 22% reduction in death risk over Nexavar, and Bristol Myers Squibb’s Opdivo and Yervoy, which also demonstrated superiority over Nexavar and Lenvima.

Rivoceranib was initially developed by Advenchen Laboratories in Southern California, licensed to Hengrui in China in 2005, and to Elevar in 2008 for the rest of the world. Hengrui licensed camrelizumab’s rights outside China and Korea to Elevar in 2019, the same year HLB acquired Elevar through a triangular merger.