Annovis Bio, Inc. announced the publication of new data from an earlier study supporting buntanetap as a translational inhibitor of amyloid precursor protein (APP) in patients with early Alzheimer?s Disease (AD). Buntanetap is an oral molecule that selectively binds to an iron-responsive element in the mRNA of APP and other neurotoxic proteins and inhibits their translation. Through this mechanism, buntanetap was shown to decrease the production of amyloid beta (Aß), a key hallmark in AD.

This study, which was finished in 2021, aimed to assess pharmacodynamic effects of buntanetap on the translation of APP mRNA by employing Stable Isotope Labeling Kinetics (SILK). SILK measures the translation, steady state, and degradation of a protein in the cerebrospinal fluid (CSF) and is able to detect subtle protein changes, which cannot be measured in normal CSF sampling. Here, SILK was used to measure the kinetics of APP in early AD patients and to quantify Aß40 in CSF.

In this randomized, double-blind, placebo-controlled study, participants received oral buntanetap (1x60, 2x60 and 3x60 mg per day or placebo) up to a 25-day period. At the end of the study, patients were catharized in the lumbar spine for 36 hours to accommodate the total time it takes for APP to be synthesized, processed into Aß, and degraded. A total of 15 patients completed the study.

Notably, the analysis of adverse events demonstrated no dose-dependent effect of buntanetap compared to placebo, affirming the drug?s safety and tolerability. Furthermore, multiparameter modeling of APP kinetics provided additional evidence for dose-dependent lowering of APP production by buntanetap. A model that included the pre-drug lumbar CSF concentration as a covariate showed statistical significance between the placebo and 120, 180 mg per day buntanetap groups, suggesting a drug effect on lowering APP production.

In general, buntanetap lowered the rate of translation, the maximum concentration (Cmax), lengthened the Tmax, and decreased the area under the curve (AUC). It is important to note that the results were not statistically significant (other than the difference between placebo and 120 and 180 mg mentioned above) due to a very small number of patients; however, the demonstrated trend fully mirrors the mechanism of action of buntanetap as a translational inhibitor of APP.