Ziihera fails to obtain orphan drug designation for gastric cancer

The Central Pharmacist Review Committee (CPAC) noted, "insufficient direct comparison data to prove superiority"

Lacking a direct comparison with existing stand of care (SoC) 'Keytruda + Herceptin'

Delays in approval and challenges with securing reimbursement erxpected

'Ziihera (active ingredient: zanidatamab, BeOne Medicines)', a next-generation HER2 bispecific antibody drawing attention, did not pass the hurdle for orphan drug designation as a first-line treatment for gastric cancer in South Korea.

The company sought various policy benefits, including a maximum 10-year exclusive data protection period. However, the BeOne Medicines' commercialization timeline and reimbursement strategy are expected to change.

According to the minutes of the Central Pharmacist Review Committee (CPAC) disclosed by the Ministry of Food and Drug Safety (MFDS) on the 22nd, the agenda on the 'validity of orphan drug designation of the ingredient under review for locally advanced or metastatic HER2-positive gastric, gastroesophageal junction, or esophageal adenocarcinoma' was ultimately rejected as 'not valid' in the written deliberation by the drug policy subcommittee held from August 3 to 5.

Most of the 10 participating committee members opposed the designation. Ziihera obtained the first domestic product approval as a second-line treatment for biliary tract cancer last March. Based on results from the global phase 3 clinical trial (HERIZON-GEA-01), the company applied for orphan drug designation by expanding the indication to first-line treatment for gastric cancer, but suffered a bitter defeat.

Lacking a 'head-to-head' comparison with 'Keytruda'

The key reason the committee members concluded the designation to be impossible is that this drug failed to meet the legal requirement for 'significant improvement in efficacy or safety compared to existing alternative drugs.'

Ziihera showed meaningful improvements in progression-free survival (PFS) and overall survival (OS) in a head-to-head clinical trial against trastuzumab (product name: Herceptin) + chemotherapy. However, it did not submit direct comparison data against the triple combination group of 'pembrolizumab (product name: Keytruda) + trastuzumab + chemotherapy', which has become the standard of care (SoC) in the clinical field.

One committee member pointed out, "There is no direct comparison data to prove superiority over existing alternative drugs, and it relies only on indirect comparison," adding, "Because indirect comparison makes it difficult to adjust for differences in patient group characteristics, follow-up periods, and subsequent treatments, the level of evidence is insufficient to recognize a significant improvement."

It also did not receive a positive safety evaluation. This is because the clinical trial results showed that the incidence frequencies of gastrointestinal toxicity, including grade 3 or higher diarrhea, decreased left ventricular function, and infusion-related reactions (IRR), were higher in the Ziihera-administered group compared to the control group.

The review committee members gathered their opinions, stating, "Safety improvement has not been proven as grade 3 or higher adverse events, such as diarrhea, were reported higher than in the existing treatment group," and, "It is inappropriate to apply an orphan drug designation in a state where significant improvement has not been established in both efficacy and safety."

In addition, criticisms were raised stating, "Gastric cancer is a market where effective alternative treatments and new drug developments are already actively taking place, and it is not a neglected disease lacking development incentives," and, "Giving rare disease benefits by fragmenting a common disease by detailed biomarkers or lines of treatment could undermine the original intent of the system and hinder equity with existing marketed drugs."

Did not obtain maximum 10-year exclusivity and economic evaluation exemption…difficulties in obtaining approval and drug pricing expected

With this decision, the pharmaceutical company has suffered a considerable blow. If designated as an orphan drug, it could have secured a clinical trial data protection period (market exclusivity) of a maximum of 10 years, which is longer than that for regular new drugs (6 years); however, as it now has to follow the standard track for adding an indication, the exclusivity period has been drastically reduced.

A red light has also turned on for the speed of commercialization and entry into the reimbursement list. Because it cannot use the expedited review (GIFT) track and must go through the standard change-approval review, the approval period is expected to increase. There is also a high possibility that strict demands for supplementary data regarding the limitations of indirect comparison and toxicity management will continue during the Ministry of Food and Drug Safety (MFDS)'s review process.

In particular, the biggest barrier is 'drug price negotiation.' Because it has become difficult to benefit from the 'economic evaluation exemption' under orphan drug status, Ziihera is expected to undergo price listing through the standard new drug track. Therefore, it must prove cost-effectiveness to the Cancer Disease Review Committee and the Pharmaceutical Reimbursement Evaluation Committee of the Health Insurance Review and Assessment Service (HIRA).

In particular, the committee noted that if it fails to prove a head-to-head comparative advantage over the existing standard therapy, it will be difficult to secure a high drug price, which could delay reimbursement listing.

The CPAC member concluded, "At present, it is more valid to strictly review the efficacy and safety through the standard new drug approval procedure rather than an orphan drug designation that provides regulatory exceptions."