Novel Anti-Amyloid Slows Alzheimer's Disease Progression, Finds Phase 2 Study

Donanemab is a humanized immunoglobulin G1 antibody specific for an N-terminal pyroglutamate amyloid-β epitope that is present only in mature brain amyloid plaques. In Phase 1, donanemab significantly reduced amyloid plaque, even with a single dose, in participants with amyloid-positive AD. For further evaluation, Dr Mark A. Mintun, M.D. and colleagues conducted a phase 2 study to assess the safety, tolerability and efficacy of donanemab.

TRAILBLAZER-ALZ was a multicentric, randomized, double-blinded, placebo-control study of 257 patients with early symptomatic Alzheimer's disease who had tau and amyloid deposition on positron-emission tomography (PET). Researchers randomly assigned them to receive either donanemab (700 mg for the first three doses and 1400 mg thereafter) (n=131) or placebo (n=126) intravenously every 4weeks for up to 72 weeks. The major outcome assessed was the change from baseline in the score on the Integrated Alzheimer's Disease Rating Scale (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks. Researchers also assessed the change in scores on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog13), the Alzheimer's Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET.

Key findings of the study were:

• The baseline iADRS score was 106 in both groups.

• Researchers found a change from baseline in the iADRS score at 76 weeks which was −6.86 with donanemab and −10.06 with placebo (difference, 3.20).

• However, the results for most secondary outcomes showed no substantial difference.

• At 76 weeks, they noted reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo.

• They also noted amyloid-related cerebral edema or effusions (mostly asymptomatic) with donanemab.

The authors concluded, "In patients with early Alzheimer's disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed. Longer and larger trials are necessary to study the efficacy and safety of donanemab in Alzheimer's disease."

For further information:

https://www.nejm.org/doi/full/10.1056/NEJMoa2100708