[E-Daily Reporter KIM SAE-MI ] HLB INC.(028300)’s new liver cancer drug, the combination therapy of “Riboceranib and Camrelizumab,” has received its third Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA). Since the manufacturing and quality control (CMC) issues—which were the cause of the previous two CRLs—have not been resolved this time either, a blow to HLB INC.’s confidence in securing approval, which the company has consistently emphasized, is inevitable. Given the intensifying competition in the market for first-line liver cancer treatments and concerns over high rates of adverse reactions, some observers point out that even if the drug is approved, its commercial success is far from guaranteed.

Third CRL Also Cites Manufacturing Facility Issues… FDA: “Re-inspection May Be Necessary”

According to the Financial Supervisory Service’s electronic disclosure system on the 10th, HLB INC.’s U.S. subsidiary, Elevate Therapeutics, received a CRL from the FDA on the 9th (local time) regarding the combination therapy of riboceranib and camrelizumab.

HLB INC. has been pursuing approval for the combination therapy—comprising the targeted anticancer drug riboceranib, developed by Elevate Therapeutics, and the immune checkpoint inhibitor camrelizumab from China’s Hengrui Pharmaceuticals—as a first-line treatment for liver cancer. The FDA conducted a combined review of the New Drug Application (NDA) for riboceranib and the Biologics License Application (BLA) for camrelizumab; the target decision date under the Prescription Drug User Fee Act (PDUFA) was the 23rd of this month.

In its Complete Response Letter (CRL), the FDA stated, “As a result of the Current Good Manufacturing Practice (cGMP) inspection, deficiencies were identified at the facility,” and added, “A re-inspection may be necessary to determine whether the facility has achieved cGMP compliance.”

The FDA also explained that the issues identified during the inspection may not be directly related to Eleva’s application. This means the problems may not be limited to the camrelizumab product itself, but could involve deficiencies found in the facility’s overall quality management system or other production processes. However, if the manufacturing facility listed on the application does not receive a cGMP compliance determination, the product cannot be approved.

HLB INC. also received CRLs in May 2024 and March 2025. The company has explained that on both occasions, the core issues were related to CMC and manufacturing facility inspections rather than clinical efficacy or safety. Although manufacturing facility compliance was identified as the final hurdle in the third review as well, the same type of issue has ultimately held the company back once again.

Until recently, HLB INC. had raised the possibility of substituting on-site inspections with document reviews, such as Reports in Lieu of Inspection (RLI). However, overseas regulatory experts viewed the likelihood of this actually being applied as low. One expert previously assessed, “While we cannot say there is absolutely no possibility of omitting an inspection or conducting a document review, it is highly unlikely that the FDA would substitute an on-site inspection with a document review.”

This disclosure did not reveal the exact names and locations of the facilities inspected by the FDA, the timing of the inspections, or the details of the deficiencies. On the 8th, an HLB INC. official told E-Daily in a phone interview regarding the inspection of Hangseo Pharmaceutical’s manufacturing facility, “The company has not received any additional information.” It remains to be confirmed whether the company was unaware of the inspection at the time or whether the facility in question is different from the Hangseo Pharmaceutical manufacturing facility that had previously drawn market attention.

Recently, issues with manufacturing facilities have repeatedly caused approval delays in other new drug reviews as well. On the 30th of last month, U.S.-based Unicycive Therapeutics received its second Complete Response Letter (CRL) for “oxylanthanum carbonate” (OLC), a treatment for hyperphosphatemia. Unicycive resubmitted its New Drug Application (NDA) after receiving its first CRL in June of last year, but the FDA determined that the deficiencies related to the third-party manufacturer—which had been pointed out in the previous CRL—had not been sufficiently resolved. Furthermore, the FDA did not conduct an on-site inspection of the facility during the resubmission review process.

Sweden’s Camurus also received a second CRL on the 10th of last month for “Oclaiz” (development code CAM2029), a long-acting injectable form of “octreotide” used to treat acromegaly. Previously, in September 2024, the FDA issued its first CRL in October of the same year, citing deficiencies related to the manufacturing facility based on the results of an inspection of the third-party manufacturer. Camurus subsequently resubmitted its NDA but received another CRL because the issues identified in the previous inspection had not been resolved.

HLB INC. stated, “We plan to promptly address the required corrections and proceed with a resubmission to the FDA.” However, it is expected to take a considerable amount of time to complete corrective and preventive actions at the facility, undergo FDA review, and, if necessary, prepare for a re-inspection before resubmission.

Approval Delays Cast Doubt on Commercial Viability… High Side Effects and Intensifying Competition Pose Burdens

Jin Yang-gon, Chairman of HLB INC., has recently demonstrated strong confidence in the approval of Riboceranib by personally visiting securities firm branches to conduct investor relations (IR) briefings. However, with the timing of approval once again becoming uncertain due to the third CRL, there is a growing view that even if approval is eventually granted, expanding actual prescriptions and achieving commercial success are separate issues.

With competition in the first-line liver cancer treatment market fiercer than ever, critics point out that the combination therapy of Riboceranib and Camrelizumab lacks a clear point of differentiation. A biotech industry insider stated, “Approval and sales are two different matters,” adding, “Given that side effects are said to be severe and other drugs are available, people are asking why they should use this particular drug.”

According to preliminary analysis of the CARES-310 trial, treatment-related adverse events occurred in 97% of patients in the riboceranib and camrelizumab group. Grade 3 or higher treatment-related adverse events reached 81%. Grade 3 or higher treatment-related adverse events occurred in 43% of patients receiving atezolizumab and bevacizumab, 41% of those receiving nivolumab and ipilimumab, and 25.8% of those receiving tremelimumab and durvalumab. Although direct comparisons are limited due to differences in patient demographics and evaluation criteria across clinical trials, the higher incidence of high-grade adverse events compared to major competing therapies is cited as a weakness.

HLB INC. countered that one should not conclude, based solely on adverse event incidence rates, that the safety of the riboceranib and camrelizumab combination therapy is inferior to that of competing therapies. HLB INC. explained, “The major high-grade adverse events—such as hypertension, elevated liver enzymes, proteinuria, thrombocytopenia, and hand-foot syndrome—are types already known to occur with anti-angiogenic TKI agents,” adding, “These can be managed to a significant extent through patient monitoring, temporary treatment interruption, and dose reduction of riboceranib.” The official also emphasized that in the CARES-310 trial, 4.4% of patients discontinued both drugs due to treatment-related adverse events, and the treatment-related mortality rate was 0.4%.

The distinction in terms of overall survival (OS) has also narrowed. The median overall survival (mOS) for the Opdivo/Yervoy combination therapy, which received FDA approval last April, was 23.7 months. The mOS from the final analysis of the CARES-310 trial for riboceranib and camrelizumab was 23.8 months. Although it is not possible to directly compare different clinical trials, as the absolute figures have become similar, it has become difficult for HLB INC. to differentiate its product from competing drugs based solely on the “longest OS ever” claim it has been promoting.

The company also appears to have set more conservative commercialization expectations than in the past. According to the securities registration statement amended by HLB PHARMACEUTICAL on the 2nd, domestic direct sales revenue for the riboceranib combination therapy is estimated at $741,000 (approximately 1.1 billion won) in 2029 and $16.75 million (approximately 25.3 billion won) in 2035. The domestic market share is assumed to start at 0.9% in 2029 and rise to 18% by 2035.

This shows a significant divergence from the forecast presented by HLB INC. in 2024, which projected global sales of 3.1 trillion won and a 50% global market share by 2029—the third year after launch. Direct comparisons are limited because the previous forecast focused on global sales, whereas this securities registration statement focuses on HLB PHARMACEUTICAL’s direct domestic sales. Nevertheless, it is worth noting that the projection assumes domestic market penetration will occur gradually following new drug approval and that it will be difficult to achieve large-scale sales in the short term.

Meanwhile, rumors have recently circulated in the market that Chairman Jin mentioned during an investor relations (IR) session that the approval decision could be delayed by three months. At the time, HLB INC. stated, “Nothing has been officially confirmed,” and did not issue a separate statement.