Evoke and Evoke+: Oral Semaglutide in Early Alzheimer's Disease

The phase 3 evoke and evoke+ trials evaluated oral semaglutide versus placebo in amyloid-confirmed early symptomatic Alzheimer’s disease, and the authors report no statistically significant difference on the prespecified primary clinical outcome at week 104.

evoke and evoke+ were multicenter, randomized, placebo-controlled phase 3 trials enrolling adults aged 55–85 years with early symptomatic disease (mild cognitive impairment or mild dementia), with amyloid confirmation required for inclusion. Oral semaglutide was administered once daily with flexible dosing up to 14 mg, and the program was conducted across 566 sites in 40 countries. evoke+ permitted participation of individuals with significant small vessel pathology, distinguishing it from evoke. The prespecified primary endpoint was change in Clinical Dementia Rating—Sum of Boxes (CDR-SB) score from baseline to week 104.

For the primary endpoint at week 104, the authors report that in evoke, the mean CDR-SB change from baseline was 2.3 (SE 0.1) with semaglutide and 2.3 (0.1) with placebo, with an estimated between-group difference of −0.08 (95% CI −0.35 to 0.20; p=0.57). In evoke+, the mean CDR-SB change was 2.2 (0.1) with semaglutide and 2.1 (0.1) with placebo, with an estimated difference of 0.10 (−0.17 to 0.38; p=0.46).

The investigators report treatment-emergent adverse events in 1729 (91.2%) of 1896 participants receiving semaglutide and 1613 (84.8%) of 1902 receiving placebo.