Ceperognastat Fails to Slow Progression of Early Alzheimer’s Disease: JAMA
Researchers have discovered in a recent clinical study that ceperognastat, a novel oral small-molecule inhibitor of O-linked N-acetylglucosaminidase, did not slow disease progression in patients with early symptomatic Alzheimer's disease, indicating no significant clinical benefit in this setting. The study was published in JAMA by Adam S. and colleagues.
To conduct the rigorous investigation into the efficacy and safety of the novel oral drug, a highly rigorous framework of a study was created over 72 clinical sites in 5 countries. This clinical trial operated from September 2021 to August 2024, and included an extended post-trial observation phase during which patients' safety was assessed through May 2025, followed by data verification in early 2026.
The target group for the primary analysis was limited to patients with the presence of early symptoms of AD, together with verified biomarkers that proved the presence of tauopathy, with low or medium initial level of accumulation of the substance, while totally excluding the patients with high tauopathy as determined using advanced flortaucipir F18 positron emission tomography (PET) scans. In order to conduct the trial, patients were randomly assigned in 1:1:1 ratio to receive once daily treatment with ceperognastat 0.75 mg and 3 mg, or placebo.
The primary endpoint that was measured in this case was the long-term change in the Integrated AD Rating Scale (iADRS), using advanced Bayesian disease progression modeling approach, and 6 secondary endpoints including cognitive subscales, daily activity, total clinical dementia rating, tau PET tracer, and volumetric MRI.
Key findings:
- This randomized design recruited a baseline sample of 327 subjects, demonstrating an overall mean age of 73.4 years, with females representing 201 individuals (61.5%).
- There was a total number of 259 participants having proven low to medium levels of baseline tau who were separated for the main outcome analysis into groups that received ceperognastat 0.75 mg, ceperognastat 3 mg, and placebo in equal numbers of 87 each.
- The main iADRS endpoint measuring posterior mean change from baseline demonstrated reductions in scores of −8.39 in the 0.75 mg group, −13.27 in the 3 mg group, and −10.07 in the placebo group.
- Disease progression ratios versus placebo were calculated as 0.84 (95% credible interval [CrI], 0.66 to 1.04) for the 0.75 mg group and worsened to 1.32 (95% CrI, 1.10 to 1.58) for the 3 mg group, which means 16% slower and 32% faster disease progression, respectively.
- Volume MRI measurements at the end of treatment showed significantly lower whole-brain volume reduction in patients under therapy as compared with placebo, equaling 43.2% and 49.5%, respectively (both P < .001).
- Serious adverse events were heavily concentrated in the high-dose 3 mg group, tracking at 29 individuals (26.4%) compared to 13 individuals (12.0%) in the 0.75 mg arm and 17 individuals (15.7%) in the placebo group.
- Severe adverse events similarly spiked in the 3 mg group, presenting in 15 individuals (13.6%) compared to just 7 individuals (6.5%) in both the 0.75 mg and placebo arms.
Therefore, ceperognastat was ineffective in slowing down the progression of early-stage symptomatic AD. The highly surprising clinical figures from multiple centers demonstrate the invaluable empirical basis for modern behavioral neurology, which shows that structural changes seen on brain scans do not necessarily mean good cognitive function.
Reference:
Fleisher AS, Munsie L, Mancini M, et al. Ceperognastat in Early Symptomatic Alzheimer Disease: A Randomized Clinical Trial. JAMA. Published online July 13, 2026. doi:10.1001/jama.2026.12768
