FDA approves anti-amyloid therapy for Alzheimer’s disease


Anti-amyloid therapy for Alzheimer’s disease has received renewed encouragement with the recent FDA approval of the second-generation monoclonal antibody lecanemab and the pending approval of donanemab.

Lecanemab (BAN2401) is a humanized MAb that binds to soluble amyloid-beta protofibrils. Approval was based on the results of a phase II proof-of-concept study in 854 patients with   early Alzheimer’s disease (AD), mild cognitive impairment (MCI) due to AD and mild AD dementia (Swanson et al. Alzheimer Res Ther 2021;13:80). The primary endpoint was a two-month clinical change on the Alzheimer’s Disease Composite Score (ADCOMS). While the study failed to meet its primary endpoint, a Bayesian analysis showed a 27% difference on ADCOMS, a 56% difference on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog14) and a 33% difference on the Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) in favour of lecanemab 10 mg/kg biweekly versus placebo.

More robust results were reported for the phase III CLARITY AD trial (van Dyck et al. N Engl J Med 2023;388:9-21). In that study, 1795 patients with mild cognitive impairment or mild dementia due to AD were randomized to lecanemab 10 mg/kg q2wk or placebo for 18 months; subjects were required to have evidence of amyloid on PET or in CSF. The primary outcome was the change from baseline on CDR-SB at 18 months. The mean change from baseline was significantly better with lecanemab vs. placebo (1.21 vs. 1.66). A treatment benefit was also seen in ADAS-cog14 score (-1.44), ADCOMS (-0.05), and the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL) (2.0). A PET substudy (n=698) reported a reduction in amyloid burden (-55.48 vs. +3.64 centiloids) at 18 months.

The estimated treatment benefit equates to a delay of 4-5 months in clinical progression over an 18-month period (Ramanan et al. Neurology 2023 Jul 26:10.1212/WNL.0000000000207757).

Serious adverse events occurred in 14.0% in the lecanemab group vs. 11.3% with placebo. The most common adverse effects with lecanemab were infusion reactions (26.4%); amyloid-related imaging abnormalities with microhemorrhages, cerebral macrohemorrhages or superficial siderosis (ARIA-H) (17.3%); and ARIA with edema or effusions (ARIA-E) (12.6%). A total of 2.8% of patients reported symptomatic ARIA-E. The incidence of ARIA was higher in ApoE ε4 homozygotes.

Donanemab is a MAb that targets the insoluble N-terminal truncated form of beta-amyloid in amyloid plaques. In the phase II TRAILBLAZER-ALZ trial (N=257), donanemab met its primary endpoint of change from baseline in Integrated Alzheimer’s Disease Rating Scale (iARDS) score (-6.86 vs. -10.06 with placebo) although it failed to meet all of its secondary endpoints (Mintun et al. N Engl J Med 2021;384:1691-1704).

In the phase III TRAILBLAZER-ALZ 2 trial, 1736 early AD patients with amyloid and tau pathology were randomized to donanemab 1400 mg q4wk (700 mg for the first three doses) or placebo for 72 weeks (Sims et al. JAMA 2023;330:512-527). The least square mean change from baseline in iADRS score was -10.19 with donanemab vs. -13.11 with placebo; this represented a slowing of disease progression of 22.3%. The treatment effect was somewhat better in the low/medium tau subgroup (iADRS -6.02 vs. -9.27; 35% slowing).

Brain amyloid decreased 87 centiloids with donanemab compared to a decrease 0.67 centiloids with placebo. About 76% of donanemab-treated patients achieved amyloid clearance at 76 weeks. The incidence of ARIA-E and ARIA-H with donanemab was 24.0% and 31.4%, respectively. There were three ARIA-associated deaths and three intracerebral hemorrhages >1 cm in the donanemab group.

Taken together, these studies demonstrate that amyloid clearance can improve cognitive outcomes, in contrast to earlier failed studies of first-generation MAbs (solanezumab, gantenerumab). However, several authors have raised concerns, noting that the treatment effect with lecanemab is smaller than estimates of the minimally important clinical difference (Burke et al. Neurology 2023 Jul 21:10.1212/WNL.0000000000207505). The safety of anti-amyloid MAbs in real-world practice – notably the rates of brain edema and intracranial bleeds – will also need to be determined.

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