As a pioneer in China's Innovative Drugs sector, Jiangsu Hengrui Pharmaceuticals has attracted attention in recent years for its expansion into international markets. Its independently developed "Dual A" product—carnitizumab (PD-1 inhibitor) combined with apatinib (VEGFR inhibitor)—aims to provide a first-line treatment option for patients with unresectable or metastatic hepatocellular carcinoma (HCC).

However, the product's path to the USA market has been full of twists and turns. After receiving the complete response letter (CRL) from the U.S. Food and Drug Administration (FDA) for the first time in May 2024, Jiangsu Hengrui Pharmaceuticals received another CRL this year. Today, HLB, Hengrui's partner, announced on the South Korea Exchange that the product has been rejected for approval by the FDA again.

This has sparked widespread concern in the market regarding the prospect of Hengrui's Dual A product being launched in the USA. The two rejections undoubtedly cast a shadow over the launch of this highly anticipated domestic Innovative Drug in the USA.

"Dual A" USA Launch Progress: The Twisted Path of Two CRLs.

"Dual A" combination, which is carnitizumab combined with apatinib, is an Innovative Therapy developed by Jiangsu Hengrui Pharmaceuticals for advanced liver cancer. The product enhances the immune response via the PD-1 inhibitor while using the VEGFR inhibitor to block tumor angiogenesis, demonstrating a synergistic anti-cancer effect.

Based on the excellent data from the international multicenter Phase III clinical study (CARES-310 study), "Dual A" was approved by the National Medical Products Administration (NMPA) of China in 2023, becoming the first domestic PD-1 combination therapy approved for first-line treatment of unresectable or metastatic liver cancer.

The journey of Jiangsu Hengrui Pharmaceuticals' "Dual A" product into the USA market began in 2023 and has encountered numerous setbacks since.

1. August 2023: First submission of BLA.

• Jiangsu Hengrui Pharmaceuticals submitted a Biological Product License Application (BLA) to the FDA, officially starting the approval process for 'Double Ai' in the USA, targeting first-line treatment for unresectable or metastatic liver cancer.

• The FDA issued the first CRL, indicating deficiencies found during the on-site inspection, and due to travel restrictions in some countries, the Biological Research Monitoring Program (BIMO) clinical inspection could not be completed, leading to delays in approval.
• Hengrui quickly rectified the issues and resubmitted the BLA application in October 2024, demonstrating a positive response attitude.

• In 2025, the FDA issued a second CRL, requesting further responses regarding the inspection of the production site but did not specify the specific deficiencies. According to Hengrui's announcement, the FDA re-inspected the production site in January 2025, confirming that the issues pointed out in the 2024 CRL had been rectified, with only three new improvement suggestions raised. The company has responded promptly and maintained close communication with the FDA, planning to resubmit the application after confirming the specific reasons.

The two CRLs indicate that, although Hengrui has made progress in compliance improvements, the FDA's high standards for its production and data validation have still not been fully met.

Analysis of the core issues raised by the FDA.

The two CRLs from the FDA reveal multiple challenges faced by the launch of "Dual Ai".

1. Compliance of production facilities.

• The FDA has very strict requirements for pharmaceutical production facilities, covering multiple dimensions such as process flow, quality control, and equipment maintenance. The first CRL in 2024 clearly pointed out production defects. Although Jiangsu Hengrui Pharmaceuticals passed the inspection in 2025 after making corrections, the FDA still proposed new improvement requirements, indicating a very high level of attention to detail.
• Potential shortcomings include production consistency verification or record integrity, which need further optimization to meet the standards.

• BIMO inspections aim to verify the authenticity and reliability of clinical trial data. Due to travel restrictions caused by the pandemic, the FDA was unable to complete all on-site verifications, becoming one of the bottlenecks for the 2024 CRL.
• As global travel gradually resumes, this issue is no longer a major obstacle, but it is still necessary to ensure that all data can withstand scrutiny.

• The specific reasons for the CRL in 2025 were not clearly defined, indicating a communication gap between the FDA and Jiangsu Hengrui Pharmaceuticals in problem delineation. Jiangsu Hengrui Pharmaceuticals needs to better understand the FDA's expectations to expedite the approval process.

Jiangsu Hengrui Pharmaceuticals' Response Strategy and Future Path

1. Strengthen Collaboration with the FDA

• Jiangsu Hengrui Pharmaceuticals stated that it will continue communication with the FDA to clarify the specific requirements of the CRL as soon as possible and submit improvement plans. The company has actively responded to the three new suggestions presented, demonstrating efficient execution.

• Through repeated rectifications, Jiangsu Hengrui Pharmaceuticals is gradually improving its production system. This not only paves the way for the "Double A" products but also lays the foundation for the internationalization of its subsequent products.

"Double A" products face a challenging path to market in the USA, but opportunities are also significant. In response to the new CRL received, Jiangsu Hengrui Pharmaceuticals expressed a positive attitude to Wall Street Journal, stating that they will take measures quickly after confirming the specific reasons and resubmit the application with the hope of obtaining approval. Meanwhile, the excellent data from the CARES-310 study provides a solid scientific basis for the product, and the likelihood of obtaining approval based on the data remains high. However, Jiangsu Hengrui Pharmaceuticals currently needs to focus on production optimization and communication with the FDA to ensure the next BLA submission is flawless.

Conclusion

The dual antibodies from Jiangsu Hengrui Pharmaceuticals faced another setback in the USA, highlighting the FDA's stringent requirements for pharmaceutical production quality and compliance. Although this therapy has shown tremendous potential in clinical efficacy, any lapse in the production process could become an obstacle to entering the US market.

For Jiangsu Hengrui Pharmaceuticals, learning from this experience and continuously enhancing production quality management, as well as strengthening communication with the FDA, is key to ultimately obtaining approval.

This incident also serves as a warning for other Chinese pharmaceutical companies looking to enter the international market: while the development of innovative drugs is important, establishing a production quality management system that meets international standards is equally crucial. Only by achieving world-class standards in both research and production can Chinese pharmaceutical companies gain greater influence in the global pharmaceutical market.