medwireNews: A modified version of the glucagon-like peptide (GLP)-1 receptor agonist exenatide, called NLY01, showed no motor or nonmotor benefits in patients with Parkinson’s disease (PD) in a phase 2 trial.
“Our findings contradict those from previous studies that suggest motor benefit with exenatide in Parkinson’s disease, and so it remains uncertain whether exenatide can have a beneficial effect on motor function in Parkinson’s disease,” write Andrew McGarry (Rowan University, Camden, New Jersey, USA) and colleagues in The Lancet Neurology.
NLY01 is a brain-penetrant, longer lasting analog of exenatide, say the researchers. It is designed to treat PD by reducing harmful inflammation caused by microglia in the brain, they add.
In the double-blind, placebo-controlled trial, 254 participants with early untreated Parkinson’s disease were randomly assigned to receive subcutaneous NLY01 at a weekly dose of either 2.5 mg (n=85) or 5.0 mg (n=85) or a placebo (n=84). The researchers then assessed the change in the sum of Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) parts II (motor aspects of experiences of daily living) and III (motor examination) at 36 weeks.
Baseline characteristics were similar across the treatment groups. The mean age of the patients ranged from 60.6 years in the NLY01 5.0 mg group to 62.1 years in the 2.5 mg group, 35% were women and 96% were White. The patients had an average time since diagnosis of 350 days and relatively mild motor symptoms, as shown by a baseline MDS-UPDRS part III score of 22.4 points.
At 36 weeks, the researchers found no effect of 2.5 mg nor 5.0 mg NLY01 on PD motor severity compared with placebo. From a baseline score of about 27.0 points for each of the three groups, the sum of scores on parts II and III of the MDS-UPDRS increased slightly less with 2.5 mg NLY01 than placebo, by 5.2 points versus 5.6 points, giving a nonsignificant least squares mean difference of 0.39 points. For those receiving the 5.0 mg dose, the increase from baseline was slightly more than with placebo, at 5.9 points and a nonsignificant least squares mean difference of 0.36 points.
There were also no significant effects of treatment on the trial’s secondary endpoints, including changes on the MDS-UPDRS part I (nonmotor aspects of experiences of daily living), the Schwab and England Activities of Daily Living Scale, the Parkinson’s Disease Questionnaire 39, and the Non-Motor Symptoms Scale.
However, in a prespecified subgroup analysis of patients younger than 60 years of age, both doses of NLY01 were associated with greater reductions in MDS-UPDRS parts II and III score from baseline than placebo. The least squares mean differences were a nominally significant 5.11 and 5.01 points for the 2.5 mg and 5.0 mg doses, respectively.
The same effect was not present in older patients and it is unclear whether the finding “represents a preferential treatment effect,” say McGarry et al, as PD deterioration among patients taking placebo was significantly greater in those under 60 than over 60 years.
“Whether or not microglial activation and astrocytic conversion are more relevant or robust a target in younger participants, or reduction thereof is more therapeutically efficient in that subgroup, is unknown but deserving of further exploration,” they add.
The investigators report that NLY01 was safe and tolerable, with similar rates of treatment-emergent adverse events, occurring in 84% of patients in the 2.5 mg group, 93% of those in the 5.0 mg group, and 87% of those given placebo. The most common adverse events were gastrointestinal disorders notably nausea, which was reported in 39% of patients in the 2.5 mg group, 58% in the 5.0 mg group, and 19% in the placebo group. There were no deaths during the study.
In a commentary related to the study, Claudia Trenkwalder and Brit Mollenhauer, both from University Medical Center Göttingen in Germany, say that trials such as the current one “are urgently needed, despite the long journey required before the drugs can be used in clinical practice.”
They suggest that “[o]ne strategy to move forward with GLP-1 agonists could be to better select the participants with Parkinson’s disease – eg, young people with high inflammatory activity who would benefit most from the targeted and metabolic mechanism of GLP-1 agonism.”
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