On 21 March, at the AD/PD 2026 International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders, during a symposium on “Targeting Tau: Mechanisms and Therapies”, Johnson & Johnson (J&J) presented data from its Phase IIb Autonomy trial (NCT04619420) for its anti-phosphorylated-tau (p-tau) monoclonal antibody (mAb) posdinemab for the treatment of early Alzheimer’s disease: mild cognitive impairment (MCI) and mild Alzheimer’s disease.
The Phase IIb results showed that there was no significant difference between either the low or high dose of posdinemab and placebo at week 104 for the primary endpoint of change from baseline in the integrated Alzheimer’s Disease Rating Scale for Mild Cognitive Impairment (iADRS-MCI) total score. The same non-significance was seen across the secondary endpoints of change from baseline in Clinical Dementia Rating – Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale – Cognitive, 13-item version (ADAS-Cog13) total score, and Alzheimer’s Disease Cooperative Study Activities of Daily Living for Mild Cognitive Impairment (ADCS-ADL-MCI) total score, highlighting that posdinemab was not able to improve either cognition or function. Given the negative trial results, J&J has discontinued development of posdinemab in Alzheimer’s disease.
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Intracellular neurofibrillary tangles (NFTs) of tau are one of the key pathological hallmarks of Alzheimer’s disease. It is thought that extracellular release of tau aggregates (known as tau seeds), being taken up by previously unaffected neurons drive the spread of tau and NFTs, thus contributing to disease progression. Posdinemab was designed to target extracellular tau, and J&J hypothesised that it would decrease the spread of tau, thereby slowing clinical decline. For the Phase IIb trial, tau positron emission tomography (PET) scans were used to map the tau naïve region of interest (ROI) at baseline. This could then be used to measure the spread of tau at the end of the trial. The tau PET results showed that while there was a significant slowing of NFT increase in areas already at a high tau-burden with the high dose of posdinemab compared with placebo, there was no difference in the rate at which tau naïve ROIs became tau-positive. Given the lack of clinical effect of posdinemab, the tau-PET results support the hypothesis that preventing the spread of tau accumulation is important for delaying disease progression, not just reducing accumulation of tau in areas of the brain where it is already present. Therefore, despite the negative efficacy results, the trial has demonstrated that tau-PET naïve ROI could be used as a biomarker in future clinical trials for drugs targeting tau.
J&J was keen to highlight that these trial results do not invalidate tau as a therapeutic target for Alzheimer’s disease; the trial helps further understanding of tau pathology. Many other developers are targeting tau, including with anti-tau mAbs. Notably, Eisai’s etalanetug is targeting a different part of the tau monomer to posdinemab and is in ongoing Phase III trials. Further, developers are also looking at alternative treatment modalities to target tau, such as TauRx’s hydromethylthionine mesylate, an oral small molecule targeting tau, and Annovis Bio’s oral small molecule buntanetap, which targets tau as well as amyloid beta precursor protein and alpha synuclein. Johnson & Johnson will now focus on its tau active immunotherapy, JNJ-2056, which it is developing in partnership with AC Immune. It is a novel, first-in-class vaccine targeting tau currently in Phase II development.
