Jiangsu Hengrui Pharma and Elevar Therapeutics have seen their hopes for a first-line liver cancer combination approval dashed by two separate FDA citations.
The FDA issued complete response letters targeting the combination of PD-1 inhibitor camrelizumab and VEGFR inhibitor rivoceranib, rejecting the application for previously untreated liver cancer patients.
Notably, the FDA’s objections did not centre on the clinical data the two companies had submitted in support of the combination regimen.
Instead, the FDA identified manufacturing deficiencies at a plant producing camrelizumab, along with unfinished clinical trial site inspections caused by travel restrictions in certain countries.
HLB Chairman Jin Yang-gon disclosed that trial sites located in Russia and Ukraine had not yet been inspected, complicating the regulatory review process further.
Jin expressed hope that the holdup could be resolved through alternative approaches, though no specific solution has been confirmed by regulators at this stage.
The manufacturing problems were particularly surprising given that the same plant has been producing camrelizumab for the Chinese market since 2019, where it is approved under the brand name AiRuiKa.
Hengrui submitted what Elevar CEO Saeho Chong described as a “very long, comprehensive” response to the FDA following the initial Form 483 citation flagging manufacturing shortfalls.
Chong noted that the FDA’s drug review team told both companies during a meeting that it was satisfied with Hengrui’s response, making the subsequent complete response letters unexpected.
Chong speculated that the FDA ultimately rejected the combination because the review team was uncertain whether a reinspection would be required before the PDUFA deadline could be met.
Hengrui must formally close the Form 483 with the FDA’s inspection team before the drug review team can greenlight the therapies for approval in the US market.
Whether an on-site reinspection is required will also determine the overall review timeline, which cannot be confirmed until the FDA formally accepts the companies’ resubmissions.
A class 1 resubmission would trigger a two-month review cycle, while a class 2 resubmission would result in a significantly longer six-month review period.
Both companies also planned to include an additional 14 months of follow-up data from the phase 3 CARES-310 trial as part of their resubmission packages.
At the final overall survival analysis from CARES-310, the camrelizumab and rivoceranib combination reduced the risk of death by 36% compared with Bayer’s established standard Nexavar in untreated liver cancer patients.
For both Hengrui and Elevar, a successful FDA approval for the combination would have represented their first commercially approved innovative products in the United States.