Two recent setbacks in Alzheimer’s disease clinical trials – one from Novo Nordisk and another from Johnson & Johnson – have underscored the challenges of developing effective treatments for neurodegenerative diseases, prompting calls for a re-evaluation of how and when potential therapies are tested.
Novo Nordisk announced Monday, November 24, 2025, that its phase 3 trials of an oral version of semaglutide, the active ingredient in Ozempic and Wegovy, failed to slow the progression of Alzheimer’s disease in over 3,800 participants with early-stage symptoms. The trials, known as Evoke and Evoke+, did not meet their primary endpoints, according to a company statement. The results were released within hours of Johnson & Johnson’s announcement that it was halting its phase 2 trial of posdinemab, a therapy targeting the tau protein, after a data review showed no slowing of cognitive decline compared to a placebo.
These failures follow a string of disappointing results in 2025 for Alzheimer’s therapies targeting various pathways, including TREM2 and neuroinflammation, according to experts. While acknowledging the inherent complexity of neurodegenerative diseases, some researchers argue that the current approach to clinical trials may be flawed, pushing for interventions to be tested on a larger scale before a complete understanding of the underlying disease mechanisms is achieved.
“While We see disappointing that the trials did not meet their primary endpoints, they show a fundamental shift in how we approach the development of new Alzheimer’s treatments, expanding beyond amyloid to target the complete pathobiology of the disease,” said Howard Fillit, MD, Co-Founder and Chief Science Officer of the Alzheimer’s Drug Discovery Foundation (ADDF), in a statement following the Novo Nordisk announcement. Novo Nordisk did note improvements in Alzheimer’s-related biomarkers in both trials, raising the possibility of exploring semaglutide as part of a combination therapy.
The failures highlight a growing tension between the accelerating pace of clinical testing, enabled by innovative trial designs and regulatory flexibility, and the need for a more robust mechanistic understanding of neurodegenerative diseases. Decades-long disease progression, the presence of compensatory mechanisms, and the difficulty of accessing diseased tissues all contribute to the challenge of determining when a therapeutic target is truly viable, researchers say.
Experts suggest a greater emphasis on “mechanistic sufficiency” before initiating clinical trials. This includes demonstrating that a target sits upstream of irreversible damage and that modulating it has a therapeutic effect at the appropriate time. Advances in genomics, single-cell profiling, fluid biomarkers, and neuroimaging are providing new tools to investigate these mechanisms directly in living patients, offering a path toward more informed trial designs.
“GLP-1 [drugs] have given us so many wonderful results, but tackling these very challenging brain disorders has been disappointing,” said endocrinologist Daniel Drucker, who has consulted for Novo Nordisk in the past. “No one expected that it was going to shut down the progression of Alzheimer’s disease, but there was a hope that we would see some benefit, and we didn’t.”
The consequences of clinical trial failures extend beyond financial investment and scientific setbacks. They can discourage patient participation in future studies and create ambiguity about whether a therapeutic hypothesis has been disproven, or simply tested at the wrong time or in the wrong population. Novo Nordisk has confirmed it is ending its semaglutide trials on Alzheimer’s, including tests involving the injectable version of the drug.
Researchers emphasize the value of definitive, even negative, trial results, arguing that they can be more informative than ambiguous positive outcomes. A shared commitment to a minimum mechanistic threshold before clinical testing, coupled with alignment between mechanism, biomarker, and clinical endpoint, is seen as crucial for future progress. The Alzheimer’s Drug Discovery Foundation plans to discuss the implications of these trial results at the upcoming Clinical Trials on Alzheimer’s Disease (CTAD) conference.
