In 2017, Sanofi Genzyme launched a phase 2 clinical trial of a drug designed to target a specific genetic mutation in some patients with Parkinson’s disease (PD). Researchers hoped the drug would slow or even stop disease progression.
Like many before it, the trial yielded disappointing results and the company shut it down in 2021. It was the latest in a string of unsuccessful clinical trials testing disease-modifying PD drugs.
Although it failed, the Sanofi Genzyme study was different: It was the first to enroll PD patients with a specific genotype and marked the earliest days of precision medicine and gene-specific drug development for the disease.
Once thought to play only a small role in a small number of PD patients, a growing body of work has prompted researchers and drug developers to take a longer look at how genetics influence PD risk and progression.
“We’re about to enter this era of precision medicine for Parkinson’s disease, which makes genetic testing important,” James Beck, PhD, senior vice president and chief scientific officer for the Parkinson’s Foundation, told Medscape Medical News.
“A number of companies have clinical trials or are in preparation for clinical trials to test some specific therapies that would depend upon people having a specific genetic mutation,” he said.
Today, at least four clinical trials of drugs that target specific PD-related gene variants on LRRK2 and GBA are under way, and more are in the pipeline. Whether these drugs will be effective at modifying the course of the disease remains to be seen. First, the trials must enroll enough patients. And therein lies the challenge: Genetic testing isn’t part of routine PD care and isn’t covered by most insurance policies. Most patients don’t know their genotype.
It’s a significant roadblock to the future of a precision medicine approach that is based on a patient’s individual genotype, which some experts argue offers the best shot at slowing disease progression.
“To enroll in clinical trials for precision drugs people with PD have to be aware of their genetic status,” said Roy Alcalay, MD, chief of the Movement Disorders Division at The Neurological Institute of New York, Columbia-Presbyterian Medical Center. “How can a person with Parkinson’s and a LRRK2 mutation join a precision medicine trial for LRRK2 if she does not know she is a LRRK2 carrier?”
Free Genetic Testing
Previous studies have shown that some genetic variants increase the risk for PD after exposure to environmental factors such as pesticides. Research has also shown that a patient’s genotype can predict survival time and that certain medications may prove more effective at slowing disease progression in patients with specific genotypes. All of this points to a significant role for genetics in a disorder that is rapidly increasing.
This makes expanding patient access to genetic testing even more important, Alcalay said, noting that it’s equally important that patients are informed of their genotype, something that doesn’t usually happen in blinded clinical trials.
To that end, Alcalay hopes a national genetics study he is leading will address access and need-to-know issues. PD GENEration, a project launched in 2019 by the Parkinson’s Foundation, offers patients free genetic testing for seven clinically relevant PD-related genes.
Testing is done at home or in a nearby clinic and the results are shared with patients during a free genetic counseling session and with site investigators. Patient samples are stored in a genetic data bank that is open to researchers around the world.
“We surveyed clinical trialists in the PD field prior to initiation of PD GENEration and estimated that over 90% of people with PD prior to the effort were not aware of their genetic status,” said Alcalay, who also is director of the Laboratory of Biomarkers and Genomics of Neurodegeneration at Tel Aviv Sourasky Medical Center in Israel.
“I think precision medicine in PD will not happen without PD GENEration or similar efforts.”
“Overwhelming” Patient Interest
Participants in the study are screened for variants in seven genes known to be involved in PD risk: GBA, LRRK2, PRKN, PINK1, SNCA, PARK7, and VPS35.
In less than 3 years, the study has already produced what is thought to be the largest genetic data bank of sequenced sets of PD-risk genes made accessible to patients. Since the end of 2020, the first year of patient enrollment, the number of participants has increased from 676 to 10,515 and the number of participating clinical sites rose from 12 to 101.
The foundation has spent nearly $20 million on the project so far and plans to spend another $10 million to reach a goal of 15,000 patients. The study, which is funded by private donors, is so successful that the foundation has had to scale back enrollment.
“When we were at a peak, we had over 700 participants enrolling each month,” Beck said. Beginning in April, the program capped new sign-ups to 200 patients per month and created a waiting list for future enrollment. The waiting list is hundreds of patients long.
“The participants’ response to enroll in PD GENEration demonstrates there is an overwhelming interest by people with PD to learn more about their genetic risk factors for PD,” Alcalay said.
A Research Driver
Nearly 60% of participants enrolled so far are male and close to 80% are White. The average age is 69 years and 44% were diagnosed in the past 5 years. Close to 75% had never participated in a clinical trial.
Nearly 13% have tested positive for mutations on at least one of the seven target genes. Previous studies had suggested genetics were involved in only about 10% of cases.
The majority of those with positive results had early-onset PD, high-risk ancestry, or a first-degree relative with the disease. However, 9% of people who tested positive weren’t in any of those categories.
Genetic information collected by the project is shared with the Global Parkinson’s Genetics Program (GP2), a resource program of the Aligning Science Across Parkinson’s initiative that is focused on the disease’s genetic architecture. Researchers around the world have access to GP2 data to study known gene variants and identify new ones.
PD GENEration participants can choose to be notified if they are carriers of gene variants discovered in the future.
“All DNA samples shared by participants are undergoing research-grade testing,” Beck said. “Not only do we want to be able to inform people with Parkinson’s disease about their genetic status, but we also want to be able to use this precious resource to further drive research into the genetics of Parkinson’s.”
Early Success
Patient recruitment has long been one of the biggest challenges to any clinical trial’s success. Research suggests that 90% of all clinical trials fail to reach recruitment milestones in their allotted timeframe and two-thirds of multicenter trials fold because too few patients sign up. Data from the Parkinson’s Foundation show that only about 1% of all patients with PD participate in clinical trials.
Increasing those numbers is the primary goal of PD GENEration, Beck said. And there’s evidence it’s already paying off.
Earlier this year, one of the program’s participating clinical sites, Intermountain Health, in Salt Lake City, Utah, joined a phase 2 clinical trial of an experimental drug that targets a mutation on the GBA1 gene.
“One of the reasons we were able to participate was when we got the call about joining, we were able to say that we had patients with that specific gene mutation, and we could only say that because the patients had been genotyped through PD GENEration,” said Kathleen E. McKee, MD, director of movement disorders, associate medical director of neurosciences research, and PD GENEration principal investigator at Intermountain Health.
Since 2021, McKee has enrolled hundreds of patients in the foundation’s gene study and hopes to enroll even more. Few patients turn down the opportunity to participate, she adds. Knowing their genotype has proven empowering for her patients, most of whom could not afford genetic testing on their own.
“Previously I would tell patients this is not going to change your immediate management,” McKee said. “Now I tell my patients that these trials are out there, it may actually change how I treat you and what I recommend.”
Kelli Whitlock Burton is a reporter for Medscape Medical News covering neurology and psychiatry.
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