J&J has discontinued a phase 2 study assessing its Alzheimer’s disease candidate posdinemab after an interim evaluation showed the treatment did not significantly slow clinical decline. The company had been pursuing the antibody as a major commercial opportunity, but the planned data review resulted in the termination of the Autonomy trial.
The study involved more than 500 individuals with early Alzheimer’s disease. Participants were randomly assigned to receive one of two doses of posdinemab or a placebo. The trial used change on the iADRS scale at Week 104 as its primary endpoint, with several clinical and imaging-based assessments forming part of the secondary endpoints.
J&J disclosed the findings in a brief announcement stating that posdinemab did not achieve statistical significance in slowing decline at the scheduled review point. Following the outcome, the company halted the trial and stated it would release a full analysis of the data at a later time.
The failure adds to other setbacks in efforts to develop monoclonal antibodies targeting tau for Alzheimer’s disease. One year earlier, UCB reported that its anti-tau antibody bepranemab did not improve cognition or function in people with early Alzheimer’s. Roche ended its involvement with the program around that period, while UCB continued to examine secondary outcomes to support the candidate’s future prospects.
Posdinemab and bepranemab both bind to the mid-domain of tau, distinguishing them from antibodies that act on the N-terminus. J&J and UCB had each identified the mid-domain as central to their scientific approach. Before the trial results were announced, John Reed, M.D., Ph.D., J&J’s executive vice president for innovative medicine, R&D, said on an earnings call that “we have designed our antibody to attack a specific epitope in tau that’s differentiated from what some others have exploited and feel confident in the ability to prevent the spread of tau based on the preclinical data.” He also previously indicated that J&J has additional tau programs that are close to entering human testing.
J&J had projected a significant market opportunity for posdinemab. Two years ago, Bill Martin, Ph.D., the company’s global therapeutic area head for neuroscience, said the treatment might be available as early as 2028 and anticipated peak sales could exceed $5 billion.
The company is also advancing other tau-directed work alongside its effort with posdinemab. Through a collaboration with AC Immune, J&J has moved the active immunotherapy JNJ-2056 into phase 2 development. The therapy is designed to prompt patients’ immune systems to generate antibodies that target tau.
The tau-focused pipeline at J&J is part of a broader industry effort to pursue treatments aimed at this protein. Companies such as Merck & Co. and Voyager Therapeutics are developing anti-tau antibodies. Other approaches are also under investigation.
Biogen, for example, is evaluating an antisense oligonucleotide targeting tau in a phase 2 trial. On an October earnings call, Priya Singhal, M.D., Biogen’s head of development, suggested that the difficulties encountered with antibody programs may relate to their emphasis on extracellular forms of tau and noted that the company has identified intracellular engagement as another potential route.
Despite the setback, J&J stressed that the discontinuation of posdinemab does not mark the end of its commitment to exploring tau-targeted therapies. The company pointed out that the data gathered from the now-terminated AuTonomy study — though disappointing — will inform future research design, patient selection, and timing of intervention in Alzheimer’s disease.
Executives noted that deeper analysis of the study’s biomarker and imaging data could shed light on whether certain subgroups responded differently or whether earlier intervention might yield a different outcome.
At the same time, the failure of posdinemab adds to growing concern within the Alzheimer’s research community over the viability of extracellular anti-tau antibodies as a therapeutic strategy. Several competing programs — including bepranemab, which also targeted tau’s mid-domain — have now failed to demonstrate clinical benefit in early-stage Alzheimer’s, casting doubt on whether interrupting tau spread outside neurons is sufficient to alter disease progression.
