Ceperognastat no boon in early AD

O-linked N-acetylglucosaminidase inhibition with ceperognastat falls short of slowing disease progression in patients with early Alzheimer’s disease (AD), according to a phase II study.

A total of 327 patients (mean age 73.4 years, 61.5 percent females) were randomly assigned to receive ceperognastat at 0.75 mg (n=110) or 3 mg (n=108) or placebo (n=108) for up to 124 weeks.

The primary outcome was change in Integrated AD Rating Scale (iADRS) score, with treatment success defined as a ≥60-percent probability of achieving ≥25-percent slower progression with ceperognastat vs placebo. Secondary outcomes included AD Assessment Scale–Cognitive Subscale, AD Cooperative Study–Activities of Daily Living scale, Clinical Dementia Rating–Sum of Boxes, Mini-Mental State Examination, tau PET, and volumetric MRI.

Of the patients, 87 receiving ceperognastat 0.75 mg, 86 receiving ceperognastat 3 mg, and 86 receiving placebo were included in the primary outcome population (mean age 74.3 years, 62.2 percent female). Compared with placebo, ceperognastat exerted no clinically meaningful effect on the primary endpoint at 100 weeks. Mean changes in iADRS scores from baseline were −8.39 with ceperognastat 0.75 mg and −13.27 with the 3-mg dose vs −10.07 with placebo.

Ceperognastat at 0.75 and 3 mg were associated with 16-percent less progression (disease progression ratio, 0.84, 95 percent credible interval [CrI], 0.66–1.04) and 32-percent greater progression (disease progression ratio, 1.32, 95 percent CrI, 1.10–1.58), respectively, relative to placebo.

Similarly, ceperognastat showed no significant effect on most secondary endpoints.

From baseline to 76 weeks, ceperognastat 3 mg was associated with a significantly smaller regional increase in tau PET standardized uptake value ratio in the lateral temporal lobes compared with placebo (p=0.04). This was not observed with ceperognastat 0.75 mg.

Volumetric MRI imaging data showed less whole brain volume loss in participants who received ceperognastat vs placebo (difference, 43.2 percent with 0.75 mg and 49.5 percent with 3 mg vs placebo; p<0.001 for both).

Serious treatment-emergent adverse events (TEAEs) occurred more frequently among patients who received ceperognastat 3 mg (12 percent with 0.75 mg, 26.4 percent with 3 mg, 15.7 percent with placebo), as did severe TEAEs (6.5 percent, 13.6 percent, and 6.5 percent, respectively).