On January 10, pharmaceutical giant Eli Lilly announced positive results in a Phase 2 trial of donanemab, a monoclonal antibody targeting the amyloid-β peptide that accumulates into plaques associated with Alzheimer’s disease (AD).

The study, called TRAILBLAZER-ALZ, found that the drug reduced amyloid buildup in participants with early AD to levels seen in healthy volunteers. Cognitive decline, as measured by the Integrated Alzheimer’s Disease Rating Scale, was reduced by 32% in participants given the drug when compared to a placebo group.

According to the New York Times, the TRAILBLAZER-ALZ study marks the first positive result in a Phase 2 trial of an AD drug. Other drug candidates have produced negative results in Phase 2 trials or have bypassed Phase 2 altogether to begin Phase 3 trials earlier. None of these expedited Phase 3 trials have delivered promising results.

The goal of a Phase 2 trial is to collect the first data about a drug’s efficacy and to continue investigating side effects following the initial safety studies in Phase 1. The TRAILBLAZER-ALZ study confirmed a side effect found in the Phase 1 donanemab trial: amyloid-related imaging abnormalities (ARIA). ARIA are MRI-visible indicators of swelling (ARIA-E, for edema) or bleeding (ARIA-H, for hemosiderin) associated with amyloid-altering therapies. In the case of monoclonal antibody treatments, this is thought to be due to the immune response to amyloid induced by the drug. Twenty-seven percent of participants in the Phase 2 trial showed signs of ARIA-E. Once the efficacy and side effects of any drug are understood, it must next undergo a Phase 3 trial, often involving multiple years and thousands of participants, in order to be approved by the FDA.

The TRAILBLAZER-ALZ study has not yet been peer-reviewed and involved just 266 participants, small by clinical trial standards. TRAILBLAZER-ALZ-2, a larger Phase 2 trial of the drug with 500 participants, began in June 2020. The higher statistical power afforded by the larger sample size will allow researchers to include participants with higher levels of tau tangles.