Genencell COVID-19 Drug ES16001 Approved for Phase 2/3 Without Liver-Injury Endpoint Despite Phase 1 Enzyme Elevations
核心洞察
Genencell (搜索)'s COVID-19 (搜索) candidate ES16001 won phase 2/3 approval in 2021 with 11 secondary endpoints, none of which assessed drug-induced liver injury (搜索).
Phase 1 data showed a participant on the highest 1,440 mg dose reaching AST 108 and ALT 210, with enzyme rises also seen in animal studies.
Total exposure rose from 4,800 mg in phase 1 to 13,440 mg in phase 2/3, while the population shifted from healthy men to COVID-19 (搜索) patients.
South Korea's Ministry of Food and Drug Safety (搜索) (MFDS) approved phase 2/3 clinical trials of Genencell (搜索)'s COVID-19 (搜索) treatment candidate ES16001 in 2021 without any evaluation indicator for liver damage, even though the substance had repeatedly raised liver enzyme levels in earlier animal studies and phase 1 trials, according to documents reviewed by The Asia Business Daily.
The approval plan's list of 11 secondary endpoints — criteria set before a trial to determine a drug's effectiveness and safety — contains no indicator related to liver injury, the report said. Drug-induced liver injury (搜索) (DILI) is regarded as a major reason for discontinuation of new drug development, and the U.S. Food and Drug Administration (搜索) established its Drug-Induced Liver Injury Clinical Assessment guidance in 2009, recommending early detection of liver damage in new drug development.
Phase 1 Signal and Rising Exposure
In a phase 1 paper published in the European Journal of Medical Research in 2021, Genencell (搜索)'s research team stated that ES16001 exhibited good safety and tolerability but also noted that "further studies are needed regarding the rare possibility of drug-induced liver injury (搜索) (DILI)." At the time, ES16001 was under development as a treatment for shingles (搜索).
In the phase 1 trial of 48 healthy adult men, one participant who received the highest dose of 1,440 mg recorded aspartate aminotransferase (搜索) (AST) levels up to 108 and alanine aminotransferase (搜索) (ALT) levels up to 210. Increases in AST and ALT were also observed in a four-week animal study, according to the same paper.
The report said the issue of rising liver enzyme levels was likely exacerbated in phase 2/3 because drug exposure increased substantially. While the maximum daily dosage remained 960 mg, phase 1 dosing lasted five days, whereas the phase 2/3 regimen was twice daily for 14 days, raising total dosage from 4,800 mg to 13,440 mg. The trial population also shifted from healthy adult men to COVID-19 (搜索) patients, including women and older adults. Because COVID-19 infection itself can elevate liver enzymes and concomitant medications such as antipyretic analgesics and antibiotics can affect liver function, experts cited in the report said more thorough verification of DILI was required.
Expert and Regulatory Scrutiny
A professor of infectious diseases at a university hospital, described as having experience participating in COVID-19 (搜索) drug trials, said: "If the possibility of hepatotoxicity was raised in phase 1, it is logical to focus on related indicators in phase 2/3. I cannot understand why this was omitted at the next stage." The professor added that while the phase 1 values were not sufficient to completely halt further clinical development, "they are at a level where stopping the drug could be considered. This should have been an obvious part of the endpoints set at the planning stage."
A professor of clinical pharmacology at another university hospital said that if hepatotoxicity is considered a unique toxicity of a drug, the regulatory authority would specifically require its evaluation during the Investigational New Drug (IND) application process, and approval would not be granted if it were not reflected.
The National Institute of Food and Drug Safety Evaluation (搜索) (NIFDS), under the MFDS, requested revisions in 14 areas for the ES16001 phase 2/3 plan in 2021, including the absence of a Data Safety Monitoring Board (DSMB), according to the report. The company submitted supplementary documents 18 days later, and approval was granted eight days after that. The MFDS told The Asia Business Daily that it was difficult to comment on matters related to approval or review of specific items, adding that reviews were conducted in accordance with relevant regulations and standards.
Regulator Rejects Favoritism Claims
Speaking at a full session of the National Assembly's Health and Welfare Committee on the 11th, MFDS commissioner Oh Yu-kyoung said the ministry granted no preferential treatment in connection with lobbying allegations surrounding Justice Minister nominee Kim Seung-won, and rejected claims that the review period for Genencell (搜索)'s IND application was unusually short.
"The ministry has reviewed applications scientifically under the same regulations, review standards and procedures in the past, does so now, and will continue to do so," Oh said, adding that ministry officials had been under investigation over the case for a long time and that "prosecutors have already cleared the matter, finding that the ministry gave no preferential treatment."
Oh said the goal at the time was to complete reviews of COVID-19 (搜索) treatments within 15 days through an expedited review program. The ministry reviewed 45 COVID-19 treatments during that period, with an average review period of 10 days — one day shorter than the 11 days for Genencell (搜索). "The situation was extremely urgent overall at that time," she said.
Asked about the claim that review of Genencell (搜索)'s supplementary submissions was completed just eight days after the company was asked to address 14 items, Oh said the items "concerned revisions to the clinical trial protocol and did not involve additional experiments," adding that "the number of items does not scale directly with difficulty or the time required."
On safety concerns, Oh said that "when 48 healthy people were given the treatment in the Genencell (搜索) trial at the time, no serious or unexpected side effects were reported to us." Regarding claims that data showing hamster deaths during animal testing had been deleted, she said the ministry "typically requests additional data when adverse reactions occur in animals in non-clinical data," adding, "I believe the founder of Genencell was at fault, and that this was not something ministry officials were in a position to assess."