Results were presented on Monday for TRAILBLAZER-ALZ-2, a registration trial of the monoclonal antibody donanemab, which was previously announced as positive. The data were highly convincing that donanemab has a significant effect of slowing disease progression in Alzheimer’s disease and almost certainly points to a full clinical approval for the drug by the FDA in the future. The primary analytic group under study in this TRAILBLAZER study (there are several different clinical trials of donanemab sponsored by Eil Lilly under the moniker of “TRAILBLAZER”) was patients with “low-to-medium tau burden,” assessed with a tau PET scan. Unlike the previous trial of donanemab, TRAILBLAZER-ALZ-2 also included patients with medium-to-high tau burden, but these were included only in secondary analyses. Patients also had to demonstrate elevated amyloid and other clinical criteria to qualify. The other highly novel aspect of the donanemab treatment program is that the drug is delivered until amyloid burden has been reduced to “normal” levels, at which time patients are switched to placebo in the trials and would go off drug in an eventual clinical practice.
As in previous trials, donanemab seemed to be effective in lowering amyloid. More than 70% of participants had been lowered to “normal” amyloid levels by one year and more than 80% by 76 weeks (the end of the trial). And this lowering of amyloid was effective in slowing disease progression. Donanemab slowed disease progression on the primary outcome and all key secondary outcomes, offering convincing support that the effects are real. Similarly, the replication of key findings from TRAILBLAZER-ALZ-1 in TRAILBLAZER-ALZ-2, should reflect the robustness of the result.
As with all anti-amyloid drugs, there were some safety concerns. Thirty-seven percent of patients treated with donanemab (compared to 15% of patients treated with placebo) experienced ARIA; including 24% who experienced ARIA-E (swelling, compared to 2% of patients treated with placebo) and 31% who experience ARIA-H (microhemorrhages, compared to 14% of patients treated with placebo). Three patients died due to complications from ARIA. Most ARIA cases, however, occurred within the first three infusions and resolved without sequelae.
The major limitation of the trial is that it included mostly non-Hispanic White participants with low representation of Asian and Hispanic patients (~6%) and very low representation of Black or African American participants (~2%). These very low sample sizes essentially render any secondary analyses of drug safety and efficacy uninformative. In those analyses, donanemab trended the wrong direction for the primary outcome for Black patients and the wrong direction for a key secondary outcome for Hispanic patients. However, it must be noted this is with extremely high levels of uncertainty.
All told, these results are very exciting for the field and signal that anti-amyloid therapies are indeed effective, provided that they lower amyloid fast enough and far enough. Patients will soon have more options for slowing their disease with these aggressive therapies, which, at least for now, require fairly burdensome routine administration via infusion and monitoring for safety through MRIs. This, we hope, is a step toward the ultimate goal of treatments that arrest disease progression entirely and—when started early enough—allow a person to live out their days without cognitive impairment or dementia.