J&J's Investigational Anti-Tau Alzheimer Drug Posdinemab Fails to Meet Primary Endpoint in Phase 2b Trial

Johnson & Johnson announced Friday that its investigational anti-tau antibody posdinemab has failed to demonstrate statistically significant efficacy in slowing clinical decline in patients with early Alzheimer disease (AD), leading to the immediate termination of the phase 2b AuTonomy trial.¹

The AuTonomy Trial

The multicenter study, which began enrollment in January 2021 according to its ClinicalTrials.gov listing,² enrolled more than 500 adults with early AD who were randomly assigned to recieve either a high or low dose of posdinemab or placebo. The primary endpoint was change in integrated Alzheimer's Disease Rating Scale (iADRS) at week 104, a composite measure assessing both cognitive function and activities of daily living. The trial's expected completion date was set for February 2026.²

At a scheduled interim data review, posdinemab failed to achieve statistical significance on the primary endpoint. Secondary clinical and imaging endpoints were also evaluated, though detailed results have not yet been disclosed. In its announcement, J&J characterized the findings as underscoring "the deep complexity of the disease" and stated it will provide a comprehensive data analysis to the scientific community in "due course."¹ Despite the dissappointmment of terminating the study, the company was optimistic that it "will offer valuable insights that will shape ongoing and future research as the understanding of Alzheimer’s biology evolves."¹

The FDA had granted posdinemab Fast Track desgnation in January this year.³

Precision Medicine Approach

J&J had employed what it termed a "first-of-its-kind precision approach" to patient selection for the AuTonomy study. Fiona Elwood, J&J's vice president and disease area stronghold leader for neurodegeneration, explained to First Word Pharma that the trial aimed to enroll "Goldilocks patients who have enough tau in their brains that they will have significant clinical progression that we can then measure and modify, but not so much that we can no longer block the spread of tau."⁴

To implement this strategy, J&J developed a proprietary phosphorylated tau-217 (p-tau217) blood-based biomarker as a prescreening tool for patient selection in AuTonomy, according to Elwood.⁴

Mechanism of Action

Posdinemab represents a mid-domain targeting approach to tau pathology, distinguishing it from earlier anti-tau antibodies that engaged the N-terminus of the protein. Both posdinemab and J&J's other tau candidate target epitopes adjacent to the microtubule binding domain of tau—the region of the protein thought to drive aggregationm according to the company.³ This targeting strategy was selected based on preclinical evidence suggesting it could effectively prevent the spread of pathological tau aggregates between neurons—a key mechanism in AD progression.³

Implications for Anti-Tau Therapeutics

This failure marks another setback for the anti-tau monoclonal antibody approach to treatment for AD. The results follow similar disappointment with UCB's bepranemab, another mid-domain targeting anti-tau antibody that failed to improve cognition and function in early AD in a phase 2 trial reported last November—approximately one month after partner Roche abandoned the collaboration.⁵

The timing is particularly notable as the announcement comes just ahead of the Clinical Trials on Alzheimer's Disease (CTAD) conference in San Diego, December 1-4, where Eisai is scheduled to present data on its anti-tau antibody etalanetug.⁶

The repeated failures of extracellular tau-targeting antibodies have prompted some researchers to question whether this therapeutic strategy can effectively modify disease progression. Alternative approaches targeting intracellular tau, including antisense oligonucleotides currently in development, may offer different mechanisms for engaging this critical pathological protein.

Ongoing Research

Despite this setback, J&J stated it "remain[s] committed to transforming the future of Alzheimer's care and confident in our pioneering pipeline of therapies."¹ The company continues to pursue tau-directed therapies through its collaboration with AC Immune on JNJ-2056, a tau-targeted active immunotherapy that recently entered phase 2 testing. JNJ-2056 is being evaluated to delay or prevent cognitive decline in pre-symptomatic patients with Alzheimer's disease and, like posdinemab, targets epitopes adjacent to the microtubule binding domain of tau.⁴

The broader pharmaceutical industry remains committed to tau as a therapeutic target, with multiple companies including Merck, Voyager Therapeutics, and Biogen pursuing various approaches to modulating tau pathology in AD.

Posdinemab's failure follows closely on another high-profile AD setback: Novo Nordisk reported a GLP-1 receptor agonist failure in Alzheimer's disease just 3 days prior,⁷ underscoring what has been "a rough few days for the Alzheimer's space."

References

1. Johnson & Johnson statement on the AuTonomy study. News release. Johnson & Jonhson. November 21, 2025. Accessed November 24, 2025. https://www.jnj.com/media-center/press-releases/johnson-johnson-statement-on-the-au%CF%84onomy-study
2. A study of JNJ-63733657 in participants wtih early Alzheimer's disease (Autonomy). ClinicalTrials.gov ID NCT04619420. Updated November 11, 2025. Accessed November 24, 2025. https://clinicaltrials.gov/study/NCT04619420#study-plan
3. Halsey G. FDA grants fast track designation to posdinemab for early Alzheimer disease. Patient Care Online. January 8, 2025. Access November 4, 2025. https://www.patientcareonline.com/view/fda-grants-fast-track-designation-to-posdinemab-for-early-alzheimer-s-disease
4. Eaton ES. J&J discontinues Alzheimer's study of tau-targeting antibody. FirstWord Pharma. November 23, 2025. Accessed November 24, 2025. https://firstwordpharma.com/story/6685352
5. McKenzie H. J&J's anti-tau bet falls flat in major mid-state Alzheimer's trial. BioSpace. November 24, 2025. Accessed November 24, 2025. https://www.biospace.com/drug-development/j-js-anti-tau-bet-falls-flat-in-mid-stage-alzheimers-trial
6. Halsey G. Two Alzheimer disease therapies to watch at CTAD 2025: Lecanemab and Sabirnetug updates. Patient Care Online. November 19, 2025. Accessed November 24, 2025. https://www.patientcareonline.com/view/two-alzheimer-disease-therapies-to-watch-at-ctad-2025-lecanemab-and-sabirnetug-updates
7. Halsey G. Semaglutide fails to slow progression of Alzheimer diseae compared to placebo: Novo Nordisk phase 3 trial update. Patient Care Online. November 24, 2025. Accessed November 24, 2025. https://www.patientcareonline.com/view/semaglutide-fails-to-slow-progression-of-alzheimer-disease-compared-to-placebo-novo-nordisk-phase-3-trial-update