Johnson & Johnson's Posdinemab Fails Phase 2b Trial, Dealing Blow to Tau-Targeting Alzheimer's Therapies
核心洞察
Johnson & Johnson terminated its mid-stage AuTonomy study of posdinemab after the anti-tau (搜索) antibody failed to show statistically significant reduction in cognitive decline compared to placebo in over 500 early-stage Alzheimer's patients.
The failure adds to a string of setbacks for tau (搜索)-targeting treatments, following previous disappointments from Eli Lilly's LY3372689 and zagotenemab, and Roche's semorinemab programs.
Posdinemab's failure could cast doubt on the therapeutic potential of targeting tau (搜索) tangles, one of the hallmark features of Alzheimer's disease (搜索) alongside amyloid (搜索) plaques.
Johnson & Johnson has terminated its mid-stage study of posdinemab, an injectable anti-tau (搜索) antibody for Alzheimer's disease (搜索), after an early analysis showed the treatment would not prove more effective than placebo. The pharmaceutical giant announced Friday that it discontinued the AuTonomy study following recommendations from the data monitoring committee.
The phase 2b proof-of-concept trial was evaluating posdinemab (JNJ-63733657) administered by intravenous infusion compared to placebo in more than 500 subjects with early-stage Alzheimer's disease (搜索). The primary outcome measure was patient performance on the Integrated Alzheimer's Disease Rating Scale (iADRS), with the study originally planned to generate first results next year and continue following patients into the 2030s.
Tau-Targeting Strategy Faces Mounting Challenges
The posdinemab failure represents another significant setback for the tau (搜索)-targeting approach to Alzheimer's treatment. Tau tangles, formed by the accumulation of hyperphosphorylated, insoluble tau aggregates that clump together to form neurofibrillary tangles in the central nervous system, represent one of the hallmark features of Alzheimer's disease (搜索).
For years, researchers have hoped that interrupting tau (搜索) tangle formation could slow cognitive decline in a manner similar to the modest benefits seen with amyloid (搜索)-targeting drugs like Eisai/Biogen's Leqembi (lecanemab) and Eli Lilly's Kisunla (donanemab).
The failure adds to a growing list of tau (搜索) program disappointments. Just over a year ago, Eli Lilly's LY3372689, an O-GlcNAcase (搜索) (OGA) inhibitor, failed a phase 2 study in early symptomatic Alzheimer's. Lilly also abandoned its antibody-based tau inhibitor zagotenemab in 2021, while Roche handed back rights to its AC Immune-partnered candidate semorinemab last year, all following disappointing phase 2 data.
Broader Implications for Alzheimer's Drug Development
In a statement addressing the results, J&J acknowledged that the disappointing outcomes "underscore the deep complexity of the disease" and will help to "shape ongoing and future research as the understanding of Alzheimer's biology evolves." The company said it would present full data from the trial at a later date.
The posdinemab failure could cast a shadow over other companies developing similar tau (搜索)-targeting treatments. Biogen, UCB (搜索), and Voyager Therapeutics are among those developing comparable approaches in their Alzheimer's pipelines.
Remaining Tau Programs Continue
Despite the setbacks, several tau (搜索)-targeting programs remain in development. J&J continues to run mid-stage trials of a tau active immunotherapy codenamed JNJ-2056 for Alzheimer's disease (搜索). Other active tau programs include Eisai's antibody-based etalanetug (E-2814) in phase 2 and small-molecule approaches from Annovis Bio with buntanetap and TauRx Therapeutics (搜索) with HMTM.
TauRx's HMTM drug was filed for approval in the UK last year and remains under regulatory review after multiple requests from the UK medicines regulator, the MHRA, for additional data. Buntanetap is currently in a phase 3 trial for early Alzheimer's disease (搜索).
Tau (搜索) tangles are also implicated in other neurodegenerative diseases, including Parkinson's disease (搜索) and amyotrophic lateral sclerosis (搜索) (ALS), suggesting that successful tau-targeting approaches could have broader therapeutic applications beyond Alzheimer's disease (搜索).