Immunotherapies that have successfully targeted amyloid-β have failed to help Alzheimer's patients to any meaningful degree. This may be because amyloid-β is only relevant in the earliest stages of the condition, or because the most visible amyloid-β aggregation outside cells is a side-effect of neurodegeneration rather than a core disease process. The research community has in recent years turned increasing attention to immunotherapies that target tau aggregation, characteristic of the later stages of Alzheimer's disease. There appears to be a bidirectional relationship between neuroinflammation and the accumulation of toxic, altered forms of tau. As noted here, targeting tau in human trials is starting to produce data that is more suggestive of patient benefits. Still, this is a painfully incremental process, and the results are still only a marginal improvement. We can hope that targeting inflammatory processes, such as those connected to senescent supporting cells in the brain, may produce better outcomes.
In a first for the field, there is now a hint that a tau immunotherapy may have slightly benefited people with Alzheimer's disease (AD). Semorinemab, a monoclonal antibody specific for tau's N-terminus, stemmed cognitive decline by almost half among people with mild to moderate AD, according to topline results from the Phase 2 LAURIET trial. The findings are a welcome reprieve after most tau immunotherapies thus far, including semorinemab itself, have come up short in trials. In a previous Phase 2 study, called TAURIEL, semorinemab brought no cognitive or functional benefit to people with prodromal AD or mild cognitive impairment. Despite this negative result among people in earlier stages of the disease, the companies moved forward with LAURIET, which enrolled participants in the mild to moderate stages of AD.
LAURIET enrolled 272 participants whose Mini-Mental State Examination (MMSE) scores were between 16 and 21 and who had brain amyloid at baseline. After receiving three doses spaced two weeks apart, participants received monthly intravenous infusions of semorinemab, or placebo, for the remainder of the trial. The study enrolled two cohorts, which received treatment for either 48 or 60 weeks. For both enrolled cohorts, between baseline and 49 weeks, those in the semorinemab groups declined 43.6 percent less on the ADAS-Cog11 than did those in the placebo groups, satisfying one primary outcome. The same was not true for the other primary endpoint, the Alzheimer's Disease Cooperative Study-Activities of Daily Living. Both groups declined similarly on the ADCS-ADL, in which an appointed caregiver scores the participant on how they perform a variety of tasks.
Why a possible efficacy signal in LAURIET, but not a peep in TAURIEL? Researchers think that the difference could come down to which species of tau predominate in different stages of the disease. Perhaps specific hyperphosphorylated forms drive the earlier stages of disease, and semorinemab might not bind them.