[Exclusive] Genencell Treatment With Elevated Liver Enzymes Approved for Clinical Trials Without Hepatotoxicity Indicators

Repeated Increases in Liver Enzymes Observed in Non-Clinical and Phase 1 Trials
Key Indicators Excluded in Phase 2/3 Despite Tripled Dosage

It has been found that, during the Ministry of Food and Drug Safety's (MFDS) approval process for phase 2/3 clinical trials of Genencell's COVID-19 treatment candidate in 2021, indicators to check whether the candidate could cause liver damage were not included among the clinical trial's endpoints.

This compound had previously shown elevated liver enzyme levels in prior animal studies and phase 1 clinical trials. Normally, it is necessary to include indicators for this issue among the endpoints for verification. This raises further concerns about whether the MFDS's procedures for review and verification in relation to the trial approval were conducted appropriately.

According to the phase 2/3 clinical trial approval plan for Genencell’s COVID-19 treatment candidate ‘ES16001’ confirmed by The Asia Business Daily on September 11, the list of secondary endpoints, which comprises a total of 11 items, did not include any indicator related to liver injury. Secondary endpoints are preset criteria for assessing a drug’s efficacy and safety before a clinical trial begins.

Liver injury caused by medications is cited as a leading cause of drug development discontinuation. The liver is the organ where most drugs passing through the body are metabolized and broken down, and substances generated during this process can damage liver cells or trigger immune responses. The United States Food and Drug Administration (FDA), in 2009, established guidelines for the ‘Clinical Assessment of Drug-Induced Liver Injury (DILI)’ and recommends early detection of liver injury during drug development.

Both preclinical animal studies and the phase 1 clinical trial of ES16001 previously confirmed elevated liver enzyme levels. In a phase 1 paper published in 2021 in the international journal European Journal of Medical Research, Genencell’s research team stated that, while ES16001 demonstrated good safety and tolerability, “further studies are needed regarding the rarely occurring possibility of drug-induced liver injury (DILI).”

At the time, ES16001 was being developed as a treatment for shingles. In this trial, which assessed safety in 48 healthy adult males, one subject who received the maximum dosage of 1440mg exhibited liver enzyme levels (aspartate aminotransferase, AST) as high as 108, and alanine aminotransferase (ALT) up to 210. According to the same paper, increased AST and ALT were also observed in animal studies conducted over four weeks.

The issue of elevated liver enzyme levels likely became more pronounced during phase 2/3, as drug exposure increased significantly compared to phase 1. Although the maximum daily dosage remained at 960mg, it was given for five days in phase 1, but in phase 2/3 it was administered twice daily for 14 days. The total dose increased from 4,800mg to 13,440mg.

The study population also shifted from healthy adult males to COVID-19 patients, including women and the elderly. Since COVID-19 infection itself can elevate liver enzyme levels, and concomitant medications such as antipyretics or antibiotics can also affect liver function, it was even more important to closely monitor whether liver injury was caused by the drug in this patient group.

Experts have also pointed out that it is important to pay attention to the lack of a hepatotoxicity assessment indicator in the phase 2/3 approval process. An infectious disease professor at a university hospital with experience participating in clinical trials for COVID-19 treatments stated, “If the possibility of hepatotoxicity was identified in phase 1, it would be reasonable to closely monitor related indicators in phase 2/3. I do not understand why they were omitted in the subsequent trial phase.” The professor added, “The values observed in phase 1 were not so severe as to halt further clinical trials, but discontinuation of the drug could be considered at that level. Inclusion of these indicators as endpoints should have been an obvious part of the planning stage.”

Another professor in clinical pharmacology at a university hospital explained, “If hepatotoxicity is judged to be a specific toxicity of the drug, a regulatory opinion would arise during the IND (investigational new drug) approval process calling for special assessment, and approval would not be granted if this is not reflected.” It is known that the Ministry of Food and Drug Safety’s National Institute of Food and Drug Safety Evaluation requested Genencell to address 14 points—including the lack of a safety monitoring board—regarding the phase 2/3 plan for ES16001 in 2021. The company submitted supplemental documents 18 days later, and approval was granted eight days after that.

The MFDS told The Asia Business Daily, “It is difficult to comment on approval or review matters related to specific products,” adding, “The review was conducted according to relevant regulations and standards.”

This content was produced with the assistance of AI translation services.