Disappointing results of two human trials of monoclonal antibodies in Parkinson’s disease

Like Alzheimer’s disease, Parkinson’s disease is a progressive, neurodegenerative disorder that involves deposits of an abnormal protein in the brain.  In Alzheimer’s disease, these abnormal proteins are extracellular beta-amyloid and intraneuronal hyperphosphorylated tau. In Parkinson’s disease, the neuropathological findings are protein deposits of aggregated alpha-synuclein within neurons in  the substantia nigra but also in other locations in the brain. These clumps of alpha-synuclein are called Lewy bodies. Although Parkinson’s disease can certainly cause dementia, the first symptoms usually involve problems with movement. For many, the first problem is an intermittent resting tremor, usually on one side.  The tremor goes away when the arm is used and may get worse while walking. Handwriting may get very tiny. Balance is usually affected, and a shuffling gait may be the first sign of the disease. Interestingly, as in Alzheimer’s disease, most people with Parkinson’s disease have loss of smell before any other symptoms occur, and Lewy bodies can be found in the olfactory bulb very early in the disease. For those wanting more details about the putative role of alpha-synuclein and Lewy bodies in Parkinson’s disease, I recommend this excellent and comprehensive open-access review paper.

In animal models of both Alzheimer’s disease and Parkinson’s disease, therapies directed at removing these abnormal protein deposits have shown success in halting progression of the disease. However, at least in Alzheimer’s disease, human trials conducted for medications designed to remove beta-amyloid or tau from the brain have all failed to show meaningful slowing of cognitive decline despite being effective at removing the targeted protein.  Some of these drugs have actually worsened the cognitive decline in Alzheimer’s disease.

In a recent issue of the New England Journal of Medicine, we now have reports of two phase 2 human trials of monoclonal antibodies directed at alpha-synuclein in subjects with early-stage Parkinson’s disease, prasinezumab and cinpanemab. The subjects were treated for at least 52 weeks with either active drug or placebo.  Mild side effects were common in both studies, mostly at the time of the monthly infusions, but no serious side effects were encountered. Disappointingly, no significant benefits were seen with either drug for primary and secondary endpoints compared to subjects receiving placebo.

What is the take home message here?  I think nearly everyone in the field is frustrated.  Multiple animal studies have shown beneficial effects of targeting these abnormal proteins in the brain, beta-amyloid and tau in Alzheimer’s disease and now alpha-synuclein in Parkinson’s disease, but none of the monoclonal antibodies or other drugs targeting these proteins have shown any significant, clinical benefit in humans. Several of the anti-amyloid monoclonal antibodies including the FDA-approved aducanumab are very effective in removing amyloid plaques from the brain, but so far they have not been shown to be effective at slowing cognitive decline. Some researchers feel that we have been barking up the wrong tree and that we need to change course.  Others are proposing that these drugs may still be helpful if started earlier in the disease, perhaps even before any symptoms have occurred. Hopefully, we will learn from these failures and discover new paths leading towards successful treatments of Alzheimer’s, Parkinson’s, and the other neurodegenerative disorders, but there is still a lot of work to do.