Alzheimer’s disease (AD) is a complex and poorly understood disorder that ultimately leads to neurodegeneration in patients afflicted with the disease.
The pathophysiology of AD is still unknown, but the disease is characterised by the formation of protein deposits known as plaques (made of amyloid-beta [Aβ] protein) and neurofibrillary tangles (made of tau protein) in patients’ brains as well as the involvement of the blood-brain barrier (BBB) in the pathogenesis of the disease.
The BBB is a protective element that restricts the movement of molecules between the bloodstream and central nervous system and prevents immune cells and large molecules from invading the brain tissue. This barrier has been a major challenge to the development of therapies for AD, in particular, large molecules, such as antibodies, due to the limited ability with which they can penetrate through the BBB.
The long list of failures in the amyloid hypothesis also cast doubts on the theory that the neurodegeneration in AD may be caused by deposits of Aβ in plaques in brain tissue. However, experts in the field think that the Aβ theory is very important to understand and to develop new treatments for AD, and getting drugs across the BBB could be the key to develop more successful therapies to treat this disorder.
Roche’s ‘brain shuttle’ Phase I trial
With the goal to restore the Aβ theory’s reputation despite the repeated failures, Roche started to test its “brain shuttle” technology in a Phase I trial of its pipeline product gantenerumab, a fully humanised anti-Aβ monoclonal antibody (mAb) designed to bind to a conformational epitope on fibrillary Aβ and cross the BBB.
Roche has created a bispecific antibody that targets the transferrin receptor, to transport the antibody into the brain, and the protein β-secretase 1, an AD target involved in the production of amyloid peptides in the brain. As only a small fraction of the drug may reach the brain with systemic medicine, Roche is aiming to deliver more efficiently the drug in the brain.
In preclinical studies, this brain shuttle technology was just tested in mice and it showed that the target engagement of investigational antibodies in the brain was increased by over 50-fold compared to the parent antibody. After these positive results, the company decided to start the trials in humans in November 2019.
Several AD clinical trials have been discontinued due to failure to reverse or even slow the cognitive decline associated with the disease, leading some researchers to question whether they are pursuing the right target. However, Roche’s continued work with gantenerumab and recently also Biogen’s, surprisingly revaluate aducanumab, after the data published last spring showed no statistical efficacy, demonstrate that this is not a universal conclusion. While the long list of Phase III clinical trial failures has raised doubts about the approach and not all scientists are convinced that Aβ is the primary cause of AD, the Aβ hypothesis remains central in the development of anti-AD drugs.
GlobalData (2018) Alzheimer’s Disease: Dynamic Market Forecast to 2026, October 2018, GDHC006FS
GlobalData (2017) PharmaPoint: Alzheimer’s Disease – Global Drug Forecast and Market Analysis to 2026, August 2017, GDHC149PIDR