Eli Lilly's Phase 2 PROSPECT-ALZ trial of ceperognastat, an inhibitor of O-linked-β-N-acetylglucosaminidase (O-GlcNAcase or OGA), has yielded mixed results in patients with early symptomatic Alzheimer's disease. While the drug demonstrated a slowing of brain atrophy and tau accumulation, it failed to improve clinical symptoms and, in fact, led to faster cognitive decline in the high-dose group compared to placebo.
The trial, which involved 327 participants stratified into low/medium and high baseline tau groups, evaluated the efficacy of 0.75 mg and 3 mg doses of ceperognastat against placebo over a 76-week period. Adam Fleisher of Eli Lilly presented the findings at the Clinical Trials on Alzheimer’s Disease (CTAD) conference, revealing that ceperognastat missed its secondary outcome of reducing clinical symptoms in either tau group. The 3 mg group experienced a significant decline on almost all cognitive measures relative to placebo. Furthermore, both dose groups exhibited a higher incidence of serious adverse events, including cardiac and nervous system disorders, as well as neoplasms.
Discordant Biomarker and Clinical Outcomes
Intriguingly, the primary outcomes presented a contrasting picture. Treatment with ceperognastat resulted in up to 45% less hippocampal volume loss compared to placebo. The 3 mg group also showed a statistically significant reduction in tau accumulation in the temporal lobe, as measured by flortaucipir PET. Additionally, ceperognastat improved plasma biomarkers, lowering phosphorylated tau217 levels and inflammation signals in the low/medium tau population.
Lilly acknowledged the discordant clinical and biomarker results in a statement to Alzforum, noting that the company is continuing to monitor data from an extended safety study concluding in February 2025. "Although the primary endpoint was not met, this study provided learnings with regards to the possibility of discordant outcomes of clinical and biomarker endpoints," the company stated, suggesting that future studies might be considered, while emphasizing their continued exploration of treatments targeting tau pathology.
Concerns over Off-Target Effects
Experts in the field have expressed concerns about the potential for off-target effects with small molecules targeting post-translational tau modifications. Adam Boxer from the University of California, San Francisco, noted that OGA drugs have been in development for a while, and these results provide definitive data. Rakez Kayed at the University of Texas Medical Branch, Galveston, was not surprised by the negative trial outcome, suggesting that targeting an enzyme affecting thousands of proteins throughout the body is inherently risky due to potential off-target effects.
Boxer also raised the question of whether the observed adverse events and worse clinical outcomes were attributable to off-target effects, stating, "These are pretty dirty drugs, and you can't interpret the tau PET without the context of everything else going on... Such a large attenuation of atrophy may mean it’s affecting many things in the brain."
The Broader Landscape of OGA Inhibitors
Ceperognastat is one of three OGA inhibitors currently in clinical trials for Alzheimer's disease and the first to reach Phase 2. Biogen's BIIB113 completed its Phase 1 trial last year, but the company has not yet disclosed its future plans for the molecule. Asceneuron is currently conducting a Phase 2 safety and biomarker trial of its OGA inhibitor, ASN51, with results expected in 2026. Ferrer is also conducting a Phase 1 trial of a different OGA inhibitor for progressive supranuclear palsy.
