Biogen has been buoyed by positive data from an early-stage trial of Alzheimer’s candidate aducanumab that also throws a lifeline to proponents of the beleaguered amyloid hypothesis.
Long-term data from Biogen’s phase Ib PRIME trial of aducanumab – reported at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting in San Diego – backed up earlier results showing an impact on amyloid plaques in the brain and a slowing in cognitive decline in patients in the early stages of the disease.
New data from patients treated for one year with a range of aducanumab doses revealed the drug outperformed placebo in reducing the number of plaques and on cognition, as measured by the Clinical Dementia Rating – Sum of Boxes (CDR-SB) and Mini-Mental State Examination (MMSE) scales.
In the case of the CDR-SB measurement there was evidence of a dose-dependent benefit, although this was less clear cut with the MMSE with quite a lot of variation between doses. Only the highest dose (10mg/kg) showed a significant benefit over placebo on the MMSE scale.
Meanwhile, some safety concerns were evident. The most common adverse event experienced by patients receiving aducanumab was amyloid-related imaging abnormalities (ARIA), which was particularly prevalent in individuals who were carrier of the ApoE4 gene.
ARIA has been linked to an elevated risk of brain swelling, and while these reactions are a worry for the project Biogen is encouraged by data suggesting that titrating the dose can reduce the risk and the effect is reversible.
The findings give a glimmer of hope that Biogen may succeed where countless other developers of amyloid-busting drugs have failed, and show that this approach can modify the underlying disease process in Alzheimer’s disease.
Most recently, Eli Lilly was forced to concede defeat and abandon efforts to develop its anti-amyloid antibody solanezumab for Alzheimer’s although it remains focused on pursuing other amyloid-targeting compounds.
Last week, it partnered with AstraZeneca (AZ) on MEDI1814, an antibody against amyloid-beta 42 (Aβ42) in phase I trials, and is also working with AZ on BACE inhibitor AZD3293, which is designed to stop amyloid from clumping together in the first place.
Biogen is being cautious on the findings while it waits for the results of two ongoing phase III studies – ENGAGE and EMERGE – that are due to generate results in 2019 and 2020. However, a closer look at the solanezumab data could be a confidence boost for Biogen and amyloid drug developers.
In the EXPEDITION 3 trial Lilly’s antibody achieved an 11% reduction in cognitive decline compared to placebo – not enough to support approval but some evidence of a benefit nonetheless.
Aducanumab acts differently than solanezumab, which was designed to mop up the peptide in the blood rather than break down already-formed amyloid plaques in the central nervous system directly, and is also being tested in earlier-stage patients.
SI Evercore analyst John Scotti said it appears aducanumab removes around ten times as much amyloid in the CNS as solanezumab, and the data with Lilly’s drug have “minimal to no negative read across to the amyloid hypothesis”.