The development of Alzheimer's disease treatments has suffered a series of setbacks in the past few days: Novo Nordisk attempted to explore the disease-modifying effects of semaglutide in early Alzheimer's disease by leveraging its potential role in metabolic and inflammatory regulation, but both large phase 3 trials failed to show a delay in cognitive or functional decline; at almost the same time, Johnson & Johnson's anti-tau antibody also failed to demonstrate any effect on disease progression in an interim study.

01 A Real-World Test of the GLP-1 Extension Path

Novo Nordisk's EVOKE and EVOKE+ results, announced on November 24, marked a temporary halt to the exploration of GLP-1 drugs in the field of Alzheimer's disease. These two trials enrolled 3,808 early-stage patients aged 55 to 85, aiming to evaluate whether the oral version of semaglutide could slow the rate of cognitive and functional decline over a two-year follow-up period. Novo Nordisk ultimately confirmed that the trials failed to meet their primary endpoint, and the observed disease progression showed no statistically significant improvement compared to the control group. This result reinforces previous uncertainties surrounding GLP-1 drugs in neurodegenerative diseases: even with well-proven efficacy in metabolic diseases, their cross-pathological applications have not been confirmed.

The EVOKE project was clearly exploratory from the outset. Novo Nordisk repeatedly emphasized that it was a "low-probability" attempt, aimed at verifying whether the few biomarker signals observed early on could translate into clinical benefits. However, the study was terminated early, with only two years of the planned three-year follow-up completed. It is widely believed that this was because the efficacy signals were insufficient to support continued progress. After the trial results were released, Novo Nordisk's stock price fell by more than 12%, reflecting the market's reaction to the shattered expectations of the company expanding into the field of neurological diseases.

From a strategic perspective, the failure of semaglutide means Novo Nordisk has lost a potentially huge new indication. There are over 55 million Alzheimer's patients, and currently only two drugs targeting the β-amyloid pathway to slow disease progression have been approved globally. If GLP-1 could successfully extend to neurodegenerative diseases, it would not only open up a completely new therapeutic area for this class of drugs but could also give Novo Nordisk a new competitive edge over Eli Lilly. However, the market now generally believes that the feasibility of this approach is far lower than previously expected; UBS even estimated the success rate at approximately 10% before the trial.

Novo Nordisk stated that it did observe changes in some biomarkers associated with Alzheimer's disease in the trial, but did not provide specific indicators or explain whether these changes had a consistent direction or statistical significance. In the absence of the primary endpoint, these biomarker changes were insufficient to alter the overall assessment. The Alzheimer's Association expressed disappointment but emphasized that GLP-1 inhibitors may still have research value under different mechanisms.

This failure has not only real-world implications for Novo Nordisk but also methodological significance for the entire field. GLP-1 is one of the most successful innovative pathways in the history of metabolic disease treatment, and its cross-system effects have therefore received considerable attention in recent years. However, the results of EVOKE and EVOKE+ suggest that in a highly structured pathological system like Alzheimer's disease, the indirect effects of metabolic or inflammatory improvements alone may not be sufficient to alter the disease trajectory. In contrast, the only validated strategy to date remains β-amyloid clearance, while tau protein-related therapies continue to face significant uncertainty.

02 Another major setback for Tau protein antibody therapy

Although the semaglutide trial in Alzheimer's disease was unsuccessful, this result itself has not diminished the industry's enthusiasm for exploring non-traditional pathological mechanisms. Compared to metabolic and inflammatory regulation strategies, research focusing on tau proteins has gained greater attention in recent years, and is seen as a key pathway that could potentially fill the gaps in amyloid therapy. For this reason, tau-targeted therapies have long been hoped to be the next class of methods that can truly alter the course of the disease. Against this backdrop, several recently published mid- and late-stage studies centered on tau have naturally become the focus of attention in the industry, making the results of these trials particularly noteworthy.

The reason for such high attention is that tau protein pathology is not limited to Alzheimer's disease itself. Alzheimer's disease belongs to a group of neurodegenerative diseases collectively known as taupathies, which share the common feature of abnormal structural and functional changes in tau protein within the brain. Under normal circumstances, tau maintains the stability of neuronal microtubules and supports intercellular signal transmission; when tau undergoes abnormal phosphorylation or aggregation, these basic functions gradually fail, leading to cognitive decline, memory impairment, and changes in mood and behavior. In addition to Alzheimer's disease, frontotemporal dementia, primary progressive aphasia, corticobasal degeneration, progressive supranuclear palsy, and chronic traumatic encephalopathy also share tau protein abnormalities as a core pathological mechanism, differing in the affected brain regions and clinical manifestations, but sharing similar neurotoxic processes.

This shared pathology across diseases has made tau one of the most promising targets in neurodegenerative disease research in recent years. Against this backdrop, several antibodies, vaccines, and gene regulation therapies targeting tau have entered clinical trials, and their success or failure will largely influence future assessments of this area.

Amidst escalating research into tau protein, Johnson & Johnson has announced the failure of one of its most important Alzheimer's disease programs. On November 24, 2025, the company confirmed that its anti-tau antibody, posdinemab, failed to slow the rate of cognitive and functional decline in patients with early-stage Alzheimer's disease during a Phase II clinical trial. An independent evaluation committee, in a routine data review, concluded that the treatment group showed no difference in changes on the iADRS (Integrated Awareness and Functional Scale) compared to the placebo group, and that continuing the study would not achieve the pre-set goals. Based on this assessment, Johnson & Johnson discontinued the study and stated that it would release more complete data later.

The Autonomy trial enrolled over 500 participants in the early stages of Alzheimer's disease. Patients were randomly assigned to receive either two different doses of posdinemab or a placebo. The primary endpoint was whether the decline in iADRS (individualized ADRS) showed a statistically significant slowdown at the end of the two-year follow-up period. This indicator, which encompasses both cognitive and daily functioning, is widely considered a key scale for assessing disease progression. In addition to the primary endpoint, the study also monitored multiple clinical measurements and imaging indicators to assess the drug's potential disease-modifying effects from multiple dimensions.

The significance of this study lies in its status as a crucial validation within the industry for determining whether tau antibodies can achieve real clinical improvement. Over the past decade, several companies, including UCB, Roche, and AC Immune, have designed antibody or vaccine-based therapies around tau, but none have met their primary clinical endpoints at different stages of research. UCB's bepranemab, after data release in 2024, also failed to show cognitive and functional improvements; while AC Immune's vaccine project faltered in earlier trials. Despite differences in target selection and antibody structure among companies, these consecutive negative results leave the question of whether tau antibodies can truly alter clinical progress unresolved.

Posdinemab targets the mid-region of the tau protein, similar to the site of action of UCB's bepranemab. Johnson & Johnson believed this strategy could scientifically address the shortcomings of previous N-terminal antibodies. In its earnings call, Johnson & Johnson stated that posdinemab targets a different epitope than previous failed projects, and preliminary experiments showed that this binding action could block the diffusion of tau between neurons. At the time, Johnson & Johnson believed that if the drug could achieve this effect, it would have the potential for approval around 2028 and peak sales of several billion dollars in mature markets.

With the release of clinical results, this idea has temporarily come to an end. Although Johnson & Johnson is still advancing another tau immunotherapy, JNJ-2056, and collaborating with AC Immune on related research, the failure of posdinemab once again highlights the limitations of the extracellular tau antibody strategy. Companies including Merck and Voyager Therapeutics are still developing antibody-based approaches, while Biogen is attempting to approach tau from the perspective of intracellular tau, with its antisense oligonucleotide project currently in phase II. Whether future data will provide different results remains to be seen.

Regardless of how subsequent data is interpreted, the failure of posdinemab has further deepened the controversy surrounding the tau target. With several antibody projects failing to demonstrate stable efficacy in clinical trials, the industry is becoming increasingly cautious about validating the tau pathway, making this once promising direction face a more complex evaluation environment.

03 The entire industry still relies on anti-β-amyloid antibodies

In the field of Alzheimer's disease, tau has long been a promising target due to its central role in the neurodegenerative process. The spread of pathological tau and neurofibrillary tangles are considered to be more directly related to cognitive decline and neuronal loss. Therefore, given the limited and highly variable clinical efficacy of anti-β-amyloid antibody therapy, the industry has generally placed its hopes on a series of strategies that are "closer to the core of the pathology," such as tau antibodies, tau vaccines, and gene regulation.

In stark contrast to the repeated setbacks of anti-tau protein antibodies, the β-amyloid pathway has gradually built up confirmatory evidence over the past few years. While Leqembi and Kisunla have limited efficacy and high barriers to entry, they have achieved the clearest clinical evidence standards in history for delaying cognitive and functional decline, and are currently the only disease-modifying treatments to receive regulatory approval. With the successive introduction of subcutaneous formulations and the ongoing progress of early intervention studies, the status of β-amyloid therapy in the industry has been strengthened again.

In this context, the repeated failures of the tau pathway are not only a setback for a single mechanism, but also a real shift in the focus of the entire research and development landscape: the industry was originally trying to find a second main route besides amyloid, and tau was considered the most likely to play this role; now, this hypothesis lacks clinical validation, making the amyloid pathway the only mechanism with a clear direction in the research and commercialization path.

This change does not signify the perfection of the β-amyloid pathway, but rather indicates that, within the current evidence framework, it is the only pathological pathway capable of generating stable signals in large-scale trials. With semaglutide failing to provide improved signals across pathological mechanisms, tau antibodies failing again, and other approaches yet to yield results that alter clinical pathways, amyloid has naturally become the benchmark for evaluating real-world progress in Alzheimer's disease treatment.

Because the tau pathway has failed to demonstrate clinical benefits in key studies, the entire R&D ecosystem currently exhibits a more singular structure: investment is concentrated on amyloid proteins, validation is focused on early intervention, and discussions about whether tau can achieve success at an earlier stage, through different methods, or with different biomarkers remain uncertain.

https://news.yaozh.com/archive/46372.html