by Elena Moro
For October 2016 we have selected: Sevigny J, Chiao P, Bussiere T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016;537:50-56.
Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder. It is also extremely disabling with severe impact of the quality of life of patients and caregivers. The main pathological process is related to the toxic deposition of amyloid-β plaques and neurofibrillary tangles. No effective treatment is currently available to slow down the disease progression. Several preclinical studies have recently focused on drugs able to interfere with the amyloid-β deposition but their further clinical applications have been rather disappointing.
Aducanumab is a human monoclonal antibody able to selectively bind Aβ aggregates, including soluble oligomers and insoluble fibrils. It can cross the blood-brain barrier and, in transgenic mouse brains, it has shown the ability to reduce amyloid-β plaques. In this paper the authors present the interim results of a phase 1b, randomized, double-blind, placebo-controlled, multicenter trial (PRIME study) to investigate safety, tolerability, pharmacokinetics, and pharmacodynamics of monthly IV infusion of aducanumab in patients with prodromal of mild AD.
At 33 study centers in the USA, 165 AD patients between 50-90 years of age were randomized to receive IV monthly perfusion of placebo (30 patients) or aducanumab at doses of 1 (21 patients), 3 (26 patients), 6 (23 patients) or 10 (21 patients) mg/kg for one year. AD patients were selected on the basis of clinical diagnosis of prodromal or mild AD and brain amyloid-β pathology confirmed by molecular positron emission tomography (florbetapir PET) imaging. Primary outcome was to evaluate safety and tolerability of multiple doses of aducanumab, whereas secondary outcomes were the drug effects on cerebral amyloid-β plaques with florbetapir PET (at 26 and 54 weeks), drug serum concentration and immunogenicity. Moreover, the effects of aducanumab on clinical measures of disease progression, including CDR-SB, NTB and FCSRT, ApoE ε4 carrier status, and volumetric brain MRI were also assessed. The primary analysis was based on ANCOVA, adjusting for baseline and ApoE ε4 status. Serum pharmacokinetics were determined by nonlinear mixed effects model (NONMEM) approach.
At one-year follow-up, 125 patients had completed the study. 40 patients discontinued the treatment, 20 of them due to adverse events (AEs). The most common AEs were amyloid-related imaging abnormalities (ARIA), headache, urinary infection, and upper respiratory infections. ARIA-vasogenic oedema abnormalities arose in 27 patients receiving aducanumab, mostly with 6 and 10 mg/kg dose patients. This AE occurred early during the treatment and resolved within 4-12 weeks, allowing 56% of these patients continuing the treatment.
At the end-point, forbetapir PET showed that treatment with aducanumab was able to reduce brain amyloid-β plaques in a dose- and time-dependent fashion. After 54 weeks of therapy the mean PET standard uptake value ratio (SUVR) composite score decreased significantly (P<0.001) compared to baseline in the 3, 6, and 10 mg/kg dose groups. The 10 mg/kg dose group showed the most relevant reduction. Regional analysis of SUVR changes showed significant dose-dependent reduction in all brain regions. Reduction in amyloid PET SUVR score was similar in patients with mild and prodromal AD and in both ApoE ε4 carriers and non-carriers. Antibody-response were transient, with minimal titers. Aducanumab did not affect plasma or brain amyloid-β concentration, since it does not bind to soluble amyloid-β monomers. The study was not powered to detect clinical changes. However, a significant dose-dependent slowing of clinical progression comparing at baseline and one-year the Clinical Dementia Rating-Sum of Boxes and the MMSE scores was identified.
This study shows that one-year treatment with aducanumab can decrease amyloid-β pathology in AD patients. The treatment was generally well tolerated and safe. The effects seemed to be time- and dose-dependent, with 10 mg/kg dose being the most effective. Moreover, the slower progression of cognitive decline in the aducanumab patients suggests that the drug has some clinical benefit. These clinical results will be soon confirmed or not by the ongoing phase 3 clinical trials.
Please continue reading and visit the round-table discussion of the EAN Scientific Panel on Dementia and cognitive disorders here.