HLB's healthcare business division. [Provided by HLB Group]
HLB's healthcare business division. [Provided by HLB Group]

HLB's liver cancer drug rivoceranib has again failed to clear the US Food and Drug Administration, receiving a complete response letter for the third time. The latest setback was not triggered by flaws in clinical data but by recurring manufacturing inspection issues at Hengrui Pharmaceutical, the Chinese partner responsible for producing the combination therapy drug.

HLB said its US subsidiary Elevar Therapeutics received a CRL from the FDA on Thursday (local time) regarding the new drug application for rivoceranib. The CRL stemmed from observations identified during a routine current good manufacturing practice inspection of Hengrui's manufacturing facility listed in the rivoceranib NDA.

This is not the first time HLB has been blocked at the FDA's door. The company received its first CRL in May 2024 for the combination therapy of rivoceranib and camrelizumab, with the agency citing chemistry, manufacturing and controls issues at Hengrui's facility as well as incomplete bioresearch monitoring inspections at some clinical trial sites, a consequence of COVID-19 disruptions. A second CRL followed in March 2025, when HLB resubmitted with additional data but still failed to fully resolve outstanding CMC issues related to camrelizumab manufacturing and quality control.

HLB filed a fresh application earlier this year for its third attempt at approval, but the latest CRL makes further delays in entering the US market unavoidable.

The CRL cited the issuance of a Form 483 — a document notifying a facility of deficiencies found during an inspection — following the cGMP review of Hengrui's manufacturing site. The FDA said it will withhold approval of the rivoceranib NDA until the observations at the facility are resolved and compliance with cGMP standards is confirmed. The agency also attached an explicit condition that a pre-approval inspection of the facility may be conducted after the cGMP issues are addressed, and that satisfactory outcomes from both the cGMP inspection and the PAI are required before final drug approval can be granted.

The facility received the Form 483 after FDA inspectors identified observations during a cGMP inspection in April, and follow-up measures are ongoing. A final classification of the inspection outcome has not yet been determined. The inspection was the first at the site in about eight years since 2018; in five previous FDA routine inspections, the facility received four "no action indicated" ratings and one "voluntary action indicated" rating.

The company said that because the inspection underlying this CRL was a routine cGMP review rather than a pre-approval inspection, HLB and Elevar were not informed in advance of the inspection or the issuance of the Form 483. After receiving the CRL, Elevar confirmed that the inspection was ultimately connected to the drug approval review and formally requested from Hengrui the Form 483, response documents, and an estimated timeline for completing the required remediation.

HLB said it will closely analyze the FDA Form 483 and Hengrui's supporting materials before working with Hengrui to announce a concrete action plan for a swift resubmission.

"The CRL contains no observations regarding clinical efficacy or safety data, nor any request for additional clinical trials," said Kim Dong-geon, chief executive of Elevar Therapeutics. "Since the primary deficiency relates to the manufacturing facility's cGMP inspection, we will work closely with the FDA to confirm the necessary steps and pursue resubmission as quickly as possible."


silverpaper@heraldcorp.com