HLB Starts FDA’s New Drug Authorization Rechallenge

Earlier this year, HLB’s liver cancer drug “Rivoceranib,” which had failed to receive approval from the US Food and Drug Administration (FDA), has now embarked on a renewed attempt to enter the US market.

Although it missed out on the title of being the first Korean anti-cancer drug to receive FDA approval, the fact that it is a domestically developed drug advancing into the US market without export technology holds significant meaning. Many are watching to see if this renewed challenge will succeed.

According to industry sources, HLB submitted a re-examination document for new drug approval of Rivoceranib, a targeted anti-cancer drug, to the FDA on the 20th of this month (local time). This comes four months after receiving a Complete Response Letter (CRL) from the FDA in May, marking the official renewal of its challenge.

Rivoceranib is an oral TKI (tyrosine kinase inhibitor) that inhibits VEGFR-2 (vascular endothelial growth factor receptor-2), cutting off the oxygen and nutrients essential for cancer growth, leading to cancer cell death.

Rivoceranib was developed by Paul Chen, a former senior researcher at Amgen, in 2003, and HLB subsequently acquired the global patent rights for the substance. Since 2011, the drug has undergone multinational clinical trials for various cancers, including gastric cancer, hepatocellular carcinoma, colorectal cancer, and adenoid cystic carcinoma, with a research period spanning 20 years.

After confirming the potential for combination therapy with Rivoceranib, HLB, in May of last year, partnered with China’s Jiangsu Hengrui Medicine to submit a New Drug Application (NDA) to the FDA for the combination therapy of Rivoceranib and Camrelizumab as a first-line treatment for liver cancer.

The first attempt seemed promising. Last year, HLB presented clinical data at the European Society for Medical Oncology (ESMO 2023), announcing that the combination therapy achieved a median overall survival (mOS) of 22.1 months, which is the most favorable figure among existing first-line liver cancer treatments .

In July of the same year, the FDA began its full review of the new drug application and gave a “no issues” assessment in its interim review. The approval process seemed to face no significant obstacles, including the omission of an Advisory Committee Meeting where external experts usually provide input.

However, the FDA later found issues with the production facilities of Jiangsu Hengrui’s Camrelizumab and issued a CRL, leading to the failure of the first attempt. At the time, Jin Yang-gon, chairman of HLB, mentioned that Jiangsu Hengrui Medicine had failed to fully satisfy the FDA’s manufacturing process standards for Camrelizumab.

It was reported that during the FDA’s inspection of Jiangsu Hengrui’s facilities, issues were found with the chemistry, manufacturing, and controls (CMC) of Camrelizumab, leading to a request for corrective measures. While Jiangsu Hengrui has since expressed his commitment to addressing the identified issues, the problems were not resolved at the time.

On July 2, HLB’s US subsidiary Elevar and its Chinese partner Jiangsu Hengrui met with the FDA to discuss final corrective measures, marking the beginning of the renewed effort for approval.

In parallel, HLB continued to present efficacy data on Rivoceranib at several international cancer conferences. At this year’s American Society of Clinical Oncology (ASCO) meeting in Chicago, HLB reported that the combination therapy achieved more than 23.8 months in a global Phase 3 trial, surpassing the previous 22.1 months.

Additionally, in a Phase 2 trial for adrenocortical carcinoma (ACC), the combination therapy outperformed existing treatments and was selected as one of ASCO 2024’s top 10 research results in kidney and bladder cancer.

At the ESMO 2024 conference held this month, HLB also disclosed the results of a Phase 3 trial involving a combination of Rivoceranib and Fruzoparib, demonstrating the possibility of combining Rivoceranib with other anti-cancer agents beyond Camrelizumab.

Han Yong-hae, CTO of HLB Group, and Jung Se-ho, CEO of Elevar, who attended ESMO, commented, “All procedures, including the preparation of the liver cancer NDA submission, are proceeding smoothly,” adding that “in addition to the FDA approval process, we are in discussions with multiple companies regarding European rights and combination therapy expansion beyond liver cancer.”

However, there are concerns from some quarters that HLB’s partnership with China’s Jiangsu Hengrui might be affected by the impending enforcement of the Biosecure Act, a new US law aimed at preventing tax evasion and gene data leaks from bio companies in hostile nations.

The Biosecure Act primarily targets Chinese biotech companies, causing significant disruption to those seeking entry into the US market. However, HLB clarified, “Our US subsidiary, Elevar, has already acquired the global rights for the liver cancer division of Camrelizumab, resolving any issues related to China,” adding that “Jiangsu Hengrui is not included in the scope of the Biosecure Act, which restricts transactions with Chinese pharmaceutical and biotech companies.”

Given that the FDA has not raised any issues regarding the efficacy of the drug during the approval process, HLB believes it is likely to receive approval unless another unexpected issue arises.

The fact that many companies have obtained final approval after receiving a CRL is also seen as a positive sign for HLB. In fact, 92% of companies that received a CRL from the FDA eventually obtained final approval.

Merck’s blockbuster immuno-oncology drug “Keytruda” also received a CRL before eventually receiving approval. Similarly, Celltrion and Daewoong Pharmaceutical both received CRLs during the approval process for their biosimilar and botulinum toxin products in the US

An industry insider commented, “If another domestic anti-cancer drug successfully passes US regulatory hurdles after ‘Rexraza’ this year, it will have a significant impact on the domestic industry. The increasing number of Korean drugs challenging FDA approval is raising the status of Korea’s pharmaceutical and biotech industry.”

Louis KIM [email protected]