Monoclonal Antibody in Mild Alzheimer’s Disease

Published January 24, 2018

Is solanezumab effective in the treatment of mild Alzheimer’s disease?

Honig et al. conducted a randomized, double-blind, phase 3 trial (EXPEDITION 3), which enrolled only patients who had mild Alzheimer’s disease, defined as a Mini–Mental State Examination score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition), and had biomarker evidence of cerebral beta-amyloid deposition. Patients were randomly assigned to receive intravenous infusions of either solanezumab at a dose of 400 mg or placebo every 4 weeks for 76 weeks. This trial was intended to further investigate the secondary efficacy analyses from two earlier trials. Read the latest NEJM Original Article here.

Clinical Pearls

Q: What is the amyloid beta (Aβ) hypothesis regarding the pathogenesis of Alzheimer’s disease?

A: The neuropathological hallmarks of Alzheimer’s disease include extracellular plaques containing amyloid beta (Aβ) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein, along with synaptic and neuronal losses. The Aβ hypothesis of the mechanism of Alzheimer’s disease proposes that early pathogenesis of the disease results from the overproduction of or reduced clearance of Aβ, leading to the formation of oligomers, fibrils, and neuritic Aβ plaques. Treatments that slow the production of Aβ or that increase the clearance of Aβ may slow the progression of Alzheimer’s disease.

Q: What is solanezumab?

A: Solanezumab, a humanized immunoglobulin G1 monoclonal antibody that binds to the mid-domain of the Aβ peptide, was designed to increase clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses at a stage before the deposition of the fibrillary form of the protein.

Morning Report Questions

Q: Is solanezumab effective in the treatment of mild Alzheimer’s disease?

A: In the trial by Honig et al., the primary efficacy measure was the change from baseline to 80 weeks in the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). The trial showed no significant between-group difference at week 80 in the change in score from baseline (change, 6.65 in the solanezumab group and 7.44 in the placebo group; difference, −0.80; P=0.10).

Q: What are some possible explanations for the lack of benefit associated with solanezumab in the trial by Honig et al.?

A: According to the authors, the solanezumab dose that was administered in this trial was associated with a high level of peripheral target engagement, sufficient to reduce free plasma Aβ concentrations by more than 90%. However, this effect did not produce clinical efficacy. Thus, a reduction in peripheral free Aβ alone is unlikely to lead to clinically meaningful cognitive benefits. Second, the dose of solanezumab (400 mg, administered every 4 weeks) may have been insufficient to produce a meaningful effect. Third, the pathological changes in the mild stage of Alzheimer’s disease–related dementia may not be amenable to treatment with a drug targeting soluble Aβ. Fourth, solanezumab was designed to increase the clearance of soluble Aβ from the brain, predicated on the Aβ hypothesis of Alzheimer’s disease — that the disease results from the overproduction of or reduced clearance of Aβ (or both). Although the amyloid hypothesis is based on considerable genetic and biomarker data, if amyloid is not the cause of the disease, solanezumab would not be expected to slow disease progression.