First Results from Choline Alfoscerate Clinical Re-Evaluation... Debate Over Efficacy Assessment Emerges

Statistical Significance Not Achieved in Primary Endpoint
Improvement Observed in Some Analyses, Including High Adherence Group

With the partial release of clinical re-evaluation results for choline alfoscerate (hereafter referred to as choline preparations), a brain function improvement agent, attention is focusing on the future direction of a market worth several hundred billion won. While the primary endpoint for all patients did not achieve statistical significance, improvement signals were detected in certain analyses, raising the possibility of divergent interpretations regarding the drug’s efficacy.

Choline preparations are major products with prescriptions totaling 545.6 billion won last year alone. If the clinical re-evaluation ultimately fails and the related indications are removed, pharmaceutical companies will be required to return a portion of the prescription revenue generated thus far to the government. According to the terms of the reimbursement agreement signed in 2020 between the Ministry of Health and Welfare and companies holding choline preparations, 20% of the reimbursed prescription amount incurred from the date of clinical approval to the removal of indications is subject to clawback. This means that approximately 20% of revenue accrued over several years could be converted into costs all at once.

According to industry sources on July 2, Chong Kun Dang recently submitted the results of the clinical re-evaluation of choline preparations for vascular and degenerative mild cognitive impairment to the Ministry of Food and Drug Safety and shared the findings with participating pharmaceutical companies. The clinical results showed that the primary endpoint (rate of cognitive function maintenance or improvement) for all patients did not meet the pre-established statistical criteria.

However, in the per-protocol set (PPS) analysis—comprising participants who adhered to the clinical protocol and medication regimen—the rate of cognitive function maintenance or improvement in the choline group was 67.83%, 7.76 percentage points higher than the placebo group (60.07%). The probability (p-value) that this difference occurred by chance was about 4.8%, which meets the statistical significance threshold (less than 5%). Although the overall patient group did not exceed the target, improvements were observed in a subset of patients with good medication adherence, leading to differing interpretations among some observers.

Some experts argue that clinical trials evaluating cognitive function improvement differ from areas like blood pressure or glucose, where results can be determined by immediate post-medication changes in measurements. Since memory and cognitive function change slowly and incrementally, it is difficult to assess drug efficacy based on short-term evaluation alone. In particular, some interpret the widening gap between certain indices at the 48-week mark as evidence that long-term administration could yield effects.

Conversely, some remain cautious, arguing that since the primary endpoint—the core criterion for clinical trials—did not achieve statistical significance, it is difficult to acknowledge efficacy based solely on improvement signals seen in a subset of patients.

The inherent difficulty of evaluating drug efficacy for mild cognitive impairment adds fuel to this debate. Clinical studies on mild cognitive impairment are known to be an area where clear conclusions are hard to draw. The standard method—randomized, double-blind, placebo-controlled trials—has clear limitations for this disease. Slow progression requires long-term observation, but it is ethically problematic to give placebo to patients who may progress to dementia for extended periods. Furthermore, high dropout rates among elderly participants, comorbidities, and issues with medication adherence are additional challenges.

The assessment tools themselves have limitations. Cognitive tests such as the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Mini-Mental State Examination (MMSE) have difficulty detecting subtle changes in mild cognitive impairment, where daily function is still maintained, and repeated testing can introduce learning effects that affect results. For the same reasons, the recently approved antibody therapy lecanemab (brand name Leqembi) was evaluated over 78 weeks. The fact that the choline preparation trial did not show a clear difference at 48 weeks cannot be separated from these disease characteristics, according to supporters.

The choline preparation debate began in June 2020 when the Ministry of Food and Drug Safety requested submission of clinical data due to insufficient evidence of efficacy. Since then, multiple pharmaceutical companies have participated in the re-evaluation, with some of the original three indications selected for review. Chong Kun Dang (degenerative and vascular mild cognitive impairment) and Daewoong Bio (dementia) divided the clinical trials. The recently released results are from Chong Kun Dang’s two trials, while the Daewoong Bio trial is expected to conclude next year. Subsequently, the Ministry of Food and Drug Safety will decide whether to maintain the choline preparation’s indication for mild cognitive impairment through an expert committee review.

Pharmaceutical companies have already reflected potential clawback liabilities in their accounting. As of the first quarter of this year, Chong Kun Dang recognized a total of 107.1 billion won in refund liabilities, including 44.9 billion won as current liabilities and 62.2 billion won as non-current liabilities. Daewoong Bio also reclassified related liabilities as current liabilities in preparation for potential clawbacks related to choline preparations. If efficacy is recognized through clinical trials or if pharmaceutical companies win lawsuits, the liabilities may be reversed; thus, the final burden will depend on the results of the re-evaluation.

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