Statistically significant cognitive improvement observed in per-protocol set; experts call for balanced evaluation that accounts for observation period given the slow-progressing nature of the disease; oral treatment option with lower safety and cost burden draws renewed attention compared with high-priced injectables

[Getty Images Bank]
[Getty Images Bank]

A clinical re-evaluation of choline alfoscerate has found statistically significant improvements in the per-protocol set — participants who adhered to dosing requirements — as well as in secondary endpoints, drawing growing attention to the standards used to evaluate treatments for mild cognitive impairment.

Mild cognitive impairment is a pre-dementia condition in which some cognitive functions have declined but daily functioning remains largely intact. Because causes and progression patterns vary widely among patients and the disease advances slowly, differences between treatment and placebo groups may not emerge clearly in a 48-week clinical trial.

"It is not easy to assess whether cognitive function is maintained or improved over 48 weeks in patients with mild cognitive impairment whose cognition is still relatively well preserved," said Lee Jae-hong, a neurology professor at Asan Medical Center. "Even in the early stages of Alzheimer's dementia, a minimum follow-up of at least 18 months — 78 weeks — is the standard requirement for primary efficacy evaluation."

In the current trial, the pre-specified primary endpoint did not reach statistical significance. However, analysis of the per-protocol set and secondary endpoints showed statistically significant improvements. The degree of improvement also tended to grow as treatment duration and medication adherence increased.

Voices in the medical and pharmaceutical communities argue that detecting a meaningful improvement signal within just 48 weeks — in a condition characterized by small changes and slow progression — should be considered as grounds for re-evaluation.

The case of Leqembi, a new global antibody therapy, illustrates how complex it is to assess treatment effects in dementia and mild cognitive impairment trials. Leqembi received FDA approval based on 78-week trial results in patients with degenerative mild cognitive impairment, yet the difference in the primary endpoint score — the CDR-SB — was only about minus 0.45 points. Even so, the evaluation reflected the principle that in early-stage dementia, slowing disease progression itself carries therapeutic meaning, independent of the absolute score.

By that standard, the current re-evaluation carries clinical weight: even over the relatively short span of 48 weeks, statistically significant improvements were confirmed in the per-protocol set and in secondary endpoints.

Kwon Soon-uck, also a neurology professor at Asan Medical Center, said the results "suggest that if a longer-term clinical trial were conducted, the effect of choline alfoscerate on maintaining and improving cognitive function could become even more pronounced."

A dementia screening examination. File photo unrelated to this article. [Herald DB]
A dementia screening examination. File photo unrelated to this article. [Herald DB]

Leqembi is significant as a treatment with a novel mechanism of action, but questions have also been raised about its cost and patient accessibility, separate from its therapeutic effects. In South Korea, it is used without insurance reimbursement, with the annual drug cost alone reaching roughly 30 million won (about $19,800). When the costs of amyloid PET scans and regular MRI monitoring for side-effect management are added, the financial burden grows further. The need for elderly patients to make repeated hospital visits for intravenous infusions presents another practical barrier.

Against this backdrop, the practical value of choline alfoscerate is drawing renewed attention. As an oral medication, it offers convenience, and even after selective reimbursement was applied, its cost burden remains far lower than that of high-priced new drugs. With alternatives such as ginkgo biloba preparations and nicergoline in short supply, a long-term oral treatment option carries particular importance in managing patients at the pre-dementia stage.

Long-term data also support the clinical relevance of choline alfoscerate. A 2025 long-term follow-up cohort study of 510,000 people found that those taking choline had a 10.1 percent lower risk of progressing to Alzheimer's dementia and a 16.8 percent lower risk of progressing to vascular dementia compared with non-users.

"Dementia and mild cognitive impairment progress slowly, making it difficult to judge a drug's value based on a single clinical indicator," an industry official said. "The accessibility of existing oral treatments and long-term usage experience must also be factored in, and in a super-aged society, a balanced discussion is needed on how to sustain and evaluate realistic treatment options for patients at the pre-dementia stage."


silverpaper@heraldcorp.com