Parkinson’s Gene Mutations Determine Treatment Response to Rasagiline

Gene mutations are often associated with something negative, but analyzing data from ADAGIO — the largest Phase 3 clinical trial to date exploring the drug rasagiline (Azilect) in patients with early stage Parkinson’s disease — researchers identified two gene variants that determine a particularly good treatment response.

Published in the journal Brain, the study, “Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson’s disease: a pharmacogenetic study,” impacts not only doctors’ possibilities to tailor the treatment to individual patients, but could also help researchers design better future clinical studies.

Rasagiline is a drug blocking the dopamine-degrading enzyme monooxygenase B, and has been FDA-approved as a treatment for Parkinson’s disease since 2006.

Varying responses to drug treatment are the inevitable result of human biology, with each person having a somewhat different set of bodily tools processing a drug once it is inside the body. Knowing which factors impact the response would allow doctors to better adjust treatment to individual patients, but such data is often not available.

The research team analyzed point mutations, known as single nucleotide polymorphisms or SNPs, in genes linked to the processing of the drug in the body, also looking at genes known to impose an increased risk of developing the disease. They had plenty of material to work with, as the trial had DNA samples of 692 patients.

Senior author Dr. Joanne Knight from the Data Science Institute and Faculty of Health and Medicine at Lancaster University in England brought her expertise in handling large genetic datasets to the study, allowing the research team to spot the two genes impacting response.

“It was exciting to be able to examine data from a clinical trial. Genetic studies of drug response are often based only on memory of the response rather than systematically recorded data,” she said in a news release.

“These findings need to be interpreted with caution, as in all studies replication is needed. However, we hope that such studies will encourage other companies to make data from clinical trials available to researchers,” she said.

The two mutations linked to a better response were both present in the dopamine D2 receptor gene (DRD2), but at the moment, researchers cannot say what features of the receptor the mutations impact to boost the response to rasagiline.

The study was featured in a research highlight of Nature Reviews Neurology, where Ian Fyfe, associate editor of the journal, emphasized that the findings might allow doctors to better predict whether rasagiline will benefit specific patients.