On November 24, Novo Nordisk announced that semaglutide failed in two Phase III clinical trials (EVOKE and EVOKE+) for Alzheimer's disease, failing to meet the primary efficacy endpoint.

EVOKE and EVOKE+ are international, multicenter, randomized, double-blind, placebo-controlled phase III clinical trials that enrolled a total of 3,808 patients aged 55-85 with early symptomatic Alzheimer's disease (1,855 for EVOKE and 1,953 for EVOKE+), including those in the mild cognitive impairment (MCI) and mild dementia stages.

The trial used an oral semaglutide 14 mg once daily dosing regimen, with the target dose achieved through 8-week dose escalation (3 mg → 7 mg → 14 mg), for a total treatment duration of 156 weeks (104 weeks of primary treatment + 52 weeks of extension treatment).

The primary endpoint of the trial was the change in the Clinical Dementia Rating Scale-Sum (CDR-SB) score relative to baseline at week 104. The CDR-SB scale assesses six dimensions: memory, orientation, judgment and problem-solving, community affairs, family and hobbies, and personal care, with a total score of 0-18. Higher scores indicate poorer cognitive function.

The final results showed that although the semaglutide treatment group showed improvement on multiple Alzheimer's disease-related biomarkers, this change failed to translate into a significant delay in disease progression.

Specifically, during the 104-week primary treatment period, the trial failed to demonstrate that semaglutide was superior to placebo in terms of CDR-SB score, meaning there was no statistically significant difference between the two groups in terms of cognitive and functional decline. Based on these results, Novo Nordisk has announced the termination of the one-year extension study.

This failure has significantly impacted Novo Nordisk's strategic plans. The company had hoped to develop semaglutide as its third growth driver, alongside obesity and diabetes, to counter fierce competition from rivals like Eli Lilly. Following the trial failure, the company has clearly stated that it will terminate further development of this indication.
Coincidentally, Johnson & Johnson also recently terminated its Phase 2b study of posdinemab for Alzheimer's disease. This study evaluated the efficacy of posdinemab in early-stage Alzheimer's disease, but failed to reach statistical significance in slowing clinical decline. Just two years ago, Johnson & Johnson predicted that the drug could reach peak sales of $5 billion.
In conclusion, the failure of semaglutide in the treatment of Alzheimer's disease once again underscores the extreme complexity of treating neurodegenerative diseases. Although the two-year trial failed to demonstrate clinical benefit, positive signals from biomarkers and preventative evidence from real-world studies still offer a glimmer of hope for the application of GLP-1 inhibitors in neuroprotection.

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