Ceperognastat in Early Symptomatic Alzheimer Disease

Importance Inhibiting O -linked N -acetylglucosaminidase (OGA) is hypothesized to slow accumulation of aggregated, hyperphosphorylated tau and neurofibrillary tangle formation. Objective To evaluate the efficacy and safety of the potent oral OGA inhibitor ceperognastat in early symptomatic Alzheimer disease (AD). Design, Setting, and Participants This double-blind, randomized, placebo-controlled phase 2 study was conducted at 72 sites in 5 countries from September 2021 to August 2024, with a posttreatment observational extension period through May 2025. The primary outcome population comprised participants with early symptomatic AD and biomarker evidence of tau pathology, including low to medium baseline tau levels (excluding individuals with high levels), as measured by positron emission tomography (PET) with flortaucipir F18. Intervention Participants were randomized 1:1:1 to receive once-daily, oral ceperognastat at doses of 0.75 mg (n = 110) or 3 mg (n = 108) or placebo (n = 108). Main Outcomes and Measures The primary outcome was change in Integrated AD Rating Scale (iADRS) score. The success criterion was a 60% or greater probability of achieving greater than or equal to 25% slower progression vs placebo using a bayesian probabilistic disease progression model. The 6 secondary outcomes were Alzheimer's Disease Assessment Scale–Cognitive Subscale, 13-item version; Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale; Clinical Dementia Rating–Sum of Boxes; Mini-Mental State Examination; tau PET; and volumetric magnetic resonance imaging. Results Of the 327 randomized participants (mean age, 73.4 years; 201 61.5% females), 259 (87 receiving ceperognastat 0.75 mg, 86 receiving ceperognastat 3 mg, and 86 receiving placebo) with low to medium baseline tau levels were included in the primary outcome population (mean age, 74.3 years; 161 62.2% females). In this population, no clinically meaningful benefit vs placebo was observed for the primary end point (iADRS score) at 100 weeks: posterior mean change from baseline was −8.39 with ceperognastat 0.75 mg, −13.27 with ceperognastat 3 mg, and −10.07 with placebo. The disease progression ratio relative to placebo was 0.84 (95% credible interval CrI, 0.66-1.04) for the ceperognastat 0.75 mg group and 1.32 (CrI, 1.10-1.58) for the ceperognastat 3 mg group, corresponding to 16% less and 32% greater progression, respectively. No benefits were demonstrated for secondary clinical end points. From baseline to 76 weeks, least-squares mean change in standardized uptake value ratio on PET showed a statistically significantly smaller increase ( P = .04) vs placebo only for the ceperognastat 3 mg group in the lateral temporal lobe. Volumetric magnetic resonance imaging showed less whole brain volume loss in participants treated with ceperognastat vs placebo (43.2% ceperognastat 0.75 mg and 49.5% ceperognastat 3 mg less vs placebo; both P lt; .001). The ceperognastat 3 mg group had more serious (ceperognastat 0.75 mg: n = 13 12.0%; ceperognastat 3 mg: n = 29 26.4%; placebo: n = 17 15.7%) and severe (ceperognastat 0.75 mg: n = 7 6.5%; ceperognastat 3 mg: n = 15 13.6%; placebo: n = 7 6.5%) treatment-emergent adverse events. Conclusions and Relevance Ceperognastat did not slow disease progression of early symptomatic AD. Trial Registration ClinicalTrials.gov Identifier: NCT05063539