[2025 Pharma-Biotech Review] Approval Hurdles for HLB, Nature Cell

Despite a year defined by the obesity drug boom, rapid progress in AI-driven drug development, and record technology exports, a series of regulatory setbacks heightened market anxiety. Delays in U.S. FDA approval for HLB’s liver cancer drug rivoceranib and the rejection of Nature Cell’s cell therapy Jointstem triggered strong reactions from investors and patients alike.

Coverage related to HLB appeared three times among the year’s top-10 most-read articles, reflecting sustained market attention. Nature Cell, meanwhile, recorded the highest number of reader comments, underscoring the intensity of public debate. As both companies encountered unexpected hurdles at the approval stage, they moved to secure alternative routes forward—ranging from overseas financing to a renewed focus on global markets.

In March, news that HLB’s liver cancer therapy rivoceranib—combined with Hengrui’s camrelizumab—had received a second Complete Response Letter (CRL) from the U.S. Food and Drug Administration sent shockwaves through the market. Expectations had been high after issues cited in the first CRL, related to Bioresearch Monitoring (BIMO) inspections at clinical sites, were resolved.

This time, however, the setback stemmed from chemistry, manufacturing, and controls (CMC) issues linked to partner company Hengrui. HLB Chairman Yang-gon Jin convened an emergency briefing to stress that the CRL was unrelated to rivoceranib’s efficacy, but rather procedural matters involving camrelizumab, including data consistency and sterilization processes.

Analysis of the Post Action Letter (PAL) indicated that the core challenge lay not in fundamental manufacturing flaws, but in the precision and completeness of supplemental data. While the resubmission timeline has been adjusted, HLB has emphasized “certainty over speed” for its third attempt. The company has stated that most required documents, including three months of safety data, are already secured, suggesting a refiling is imminent.

In parallel, HLB completed its merger with HLB Life Science in April, consolidating global rights to rivoceranib and strengthening its post-approval revenue structure. A $140 million investment secured in November from UK-based asset manager LMR Partners further helped stabilize market sentiment, signaling continued global confidence in the drug’s commercial potential.

The rejection of marketing approval for Nature Cell’s osteoarthritis cell therapy Jointstem sparked intense debate over the flexibility and scientific standards of Korea’s regulatory system.

In August, the Ministry of Food and Drug Safety (MFDS) denied approval for a second time following a similar decision in 2021, citing a “lack of clinical significance.” While statistical efficacy had been demonstrated, regulators argued that the degree of improvement perceived by patients fell short of expectations.

Controversy escalated after minutes from the Central Pharmaceutical Affairs Council were disclosed, shifting criticism toward regulatory fairness. It emerged that the Minimum Clinically Important Difference (MCID)—used to determine whether patients experience meaningful benefit—had not been pre-agreed upon or formally communicated to the company. Critics argued that the absence of clear guidelines allowed subjective judgment to play an outsized role, prompting Nature Cell to file an administrative lawsuit against the MFDS.

By contrast, the U.S. FDA designated Jointstem as both a Breakthrough Therapy (BTD) and a Regenerative Medicine Advanced Therapy (RMAT), and approved its use under an Expanded Access Program (EAP) prior to formal approval—highlighting a stark divergence in regulatory approaches.

Chairman Jung-chan Ra has since declared that the company will “make its case in the U.S.,” advancing plans to build the Biostar Stem Cell Campus in Maryland. Following completion of an End-of-Phase 2 (EOP2) meeting with the FDA, Nature Cell is now focused on accelerated approval and commercialization in the U.S. market.