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Sunday, March 25, 2018

Tracking LRRK2-Parkinson’s Progression for Better Trial Design

March 23, 2018

Parkinson’s disease comes in many flavors, posing a challenge for researchers who design clinical trials in their search for treatments. Knowing how the disease progresses naturally may better their chance of success. A longitudinal study from the LRRK2 Ashkenazi Jewish Consortium provides just such data. Researchers led by Rachel Saunders-Pullman, Mount Sinai Beth Israel Medical Center in New York, compared how PD progressed in patients who carry the G2019S LRRK2 mutation and people with sporadic disease. Confirming previous studies, they found that motor symptoms advanced more slowly in mutation carriers. The results appear in the March 1 JAMA Neurology.

The study maps progression in people with and without the G2019S LRRK2 mutation.
Motor symptoms worsen more slowly in G2019S-PD.
The data may help clinicians better design clinical trials.

The size of the new data set and the length of follow-up supersede similar studies. “It is a substantive and important study, one of the biggest involving LRRK2 patients,” noted Mark Cookson at the National Institutes of Health, Bethesda, Maryland. Carole Ho of Denali Therapeutics in South San Francisco was encouraged by the quality of the study. “We are using the new data to design trials to test LRRK2 inhibitors,” she told Alzforum. “Knowing the natural course of disease is very important.”

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of familial PD, but their penetrance and prevalence varies greatly between populations. Also, while some LRRK2 variants slow down disease progression, others speed it up (Oosterveld et al., 2015). Because LRRK2-PD shares symptoms and pathology with the sporadic form, researchers believe that drugs targeting the kinase may help most PD patients. Moreover, because the kinase is overactive in disease, it is a tractable target for drug development. Pfizer, Merck, Glaxo-SmithKline, and Genentech have created an array of LRRK2 inhibitors. As they have begun testing them in clinical trials, the need to understand how PD progresses in LRRK2-PD patients has become urgent.

PD Trajectories. Motor symptoms develop more slowly in G2019S-LRRK2 (orange) than in idiopathic PD (blue). [Courtesy of Saunders-Pullman et al., JAMA Neurology, © (2018) American Medical Association. All rights reserved.]

Longitudinal studies of PD caused by G2019S, the most common LRRK2-activating mutation, are sparse, small, or cross-sectional (Healy et al., 2008; Alcalay et al., 2013; Yahalom et al., 2014). The Parkinson’s Progression Markers Initiative (Oct 2013 news) tracks data from LRRK2-PD patients, but until recently, was limited to a single follow-up visit at one year.

To chart progression specifically in G2019S LRRK2 PD, Saunders-Pullman analyzed data from 144 patients with the mutation and 401 with sporadic PD. The patients were recruited from the LRRK2 Ashkenazi Jewish Consortium. In this population, the G2019S mutation causes up to 15 percent of PD cases, compared to 1 to 2 percent worldwide, said Saunders-Pullman. Participants had undergone up to six extensive evaluations over six years. Using the Unified Parkinson’s Disease Rating Scale III, clinicians scored them on motor skills such as talking, finger tapping, walking, and standing up. The scale also measured tremor, rigidity, and slowness. Participants took the Montreal Cognitive Assessment, which tests memory, attention, concentration, language, and awareness of time and place. All examinations were done when patients were in the “on” state, meaning when they had maximum benefit from their PD medication.

After adjusting for sex, age, disease duration, and PD medication dosing at baseline, G2019S LRRK2 mutation carriers declined some 30 percent slower on the UPDRS than did those with sporadic PD (image above). The milder motor course is consistent with other studies.

Cognitive impairment followed a similar trend, though the difference was not statistically significant. “The cognitive phenotype is so variable that it’s not surprising it didn’t reach significance,” said Cookson. Nonetheless, Saunders-Pullman believes the trend reflects a real difference, and added that full neuropsychological assessments in a subgroup of patients should help resolve the issue.

Why the difference in progression? There is no easy answer, said Cookson, noting that PD pathology is very variable. “Sometimes you see different pathology even in the same family with the same mutation,” he said. Indeed, Lewy body pathology, a hallmark of idiopathic PD, surfaces in only some patients with the G2019S mutation (Kalia et al., 2015). It is still unclear whether the milder G2019S disease course is due to a subgroup of patients with more benign pathology bringing down the average, or if most mutation carriers have less aggressive pathology, noted the authors.

Matthew Farrer, University of British Columbia, Vancouver, Canada, welcomed the new findings, but said that future studies would benefit from longer follow-up. He noted that results for 62 of the patients were limited to a single time point, and only seven patients had five or more years of follow-up. Adding more patients with more data points should refine the progression model and help scientists address the question of how a person’s age of onset correlates with disease severity across different forms of PD (Trinh et al., 2014).

Will the new data improve the design of LRRK2 inhibitor trials? Ho said it is helping to calculate the number of patients needed for a Phase 1b study.

“I think it’s a very exciting time in the PD world,” said Saunders-Pullman. “The hope is that with more homogenous cohorts, we’ll find signals more easily.”—Marina Chicurel