Could donanemab be the breakthrough we have been waiting for?

Yesterday Eli Lilly issued a press release summarizing positive results of the TRAILBLAZER-ALZ 2 Phase 3 study showing that donanemab significantly slows cognitive and functional decline in people with early symptomatic Alzheimer’s disease. Donanemab is unique among anti-amyloid monoclonal antibodies as it specifically targets N-terminally truncated pyroglutamate-modified amyloid-β (Aβ_pE), a form of amyloid-β apparently found only in amyloid plaques.

According to the press release, the primary analysis population consisted of participants with an intermediate amount of tau as assessed by PET scans and also had cognitive impairment consistent with mild Alzheimer’s disease. In this population, the primary endpoint (integrated Alzheimer’s Disease Rating Scale, or iADRS) showed 35% slowing of decline compared to placebo and a secondary endpoint (Clinical Dementia Rating-Sum of Boxes, or CDR-SB) showed 36% slowing of decline over 18 months. In addition, nearly half (47%) of the participants on donanemab, compared to 29% on placebo, showed no clinical progression at 1 year as defined by absence of decline in the CDR-SB score. 

As in all preceding clinical trials of this class of drug, amyloid related imaging abnormalities (ARIA) were common, ARIA-E (swelling of the brain) occurred in 24.0% and ARIA-H (microhemorrhages in the brain) occurred in 31.4%.  Most of the ARIA were described as mild to moderate, but 1.6% were severe, and unfortunately, three subjects died either during or following a severe ARIA episode. This is the highest death rate yet reported in a trial of an anti-amyloid monoclonal antibody.

An important potential advantage of donanemab compared to other anti-amyloid monoclonal antibodies is that it is so effective at removing amyloid-β from the brain that treatment may not have to be given longer than 12 – 18 months. Over half of all participants in this study completed their course of treatment by 12 months. We do not know yet whether the amyloid-β will reaccumulate in the brain with time.

I need to caution that this press release is just that, a press release. It has not been peer-reviewed. Scientists from Eli Lilly will be presenting the data in July at the Alzheimer’s Association International Conference in Amsterdam, and a peer-reviewed paper will be forthcoming. Despite my concerns about the three deaths related to severe ARIA, I think this study supports the amyloid cascade hypothesis and widens the path forward to effective treatment of Alzheimer’s disease.