Why Did a GLP-1 Receptor Agonist Fail This Parkinson’s Trial?

Weekly injections of the GLP-1 receptor agonist exenatide (Byetta, Bydureon) did not slow Parkinson’s disease progression or improve symptoms, the phase III Exenatide-PD3 trial showed.

At 96 weeks, mean Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III scores when off dopaminergic medication worsened by 5.7 points in the exenatide group and 4.5 points in the placebo group (adjusted coefficient for the effect of exenatide 0.92, 95% CI -1.56 to 3.39, P=0.47), reported Tom Foltynie, MBBS, PhD, of University College London, and co-authors in The Lancet.

Secondary outcomes — including on-medication scores, non-motor scores, quality-of-life assessments, and changes in levodopa-equivalent daily doses — also did not improve with exenatide.

The results are a major disappointment for the Parkinson’s community, Foltynie said. “This trial was important, given the weight of expectation that exenatide would be the first proven disease-modifying drug for Parkinson’s disease,” he told MedPage Today.

“The laboratory data, epidemiology, and earlier trial data all indicated that this drug might be able to slow down disease progression in Parkinson’s disease,” Foltynie pointed out. “This trial was longer and larger than all the previous ones and, unfortunately, found no advantage in the use of exenatide on any of the measures collected.”

Why the phase III trial failed was unclear. In 2017, a phase II trial showed that Parkinson’s patients treated with exenatide for 48 weeks had a mean 3.5-point advantage compared with placebo in MDS-UPDRS part III off-medication scores. Another study exploring a pegylated analogue of exenatide (NLY01), however, found no overall benefit compared with placebo but suggested benefits in younger Parkinson’s patients.

Last year, a 1-year phase II trial of a similar GLP-1 receptor agonist, lixisenatide (Adlyxin), led to less progression of motor disability compared with placebo in early Parkinson’s disease.

Being unable to replicate the positive findings of a phase II study in a subsequent phase III trial is unfortunately the norm in Parkinson’s disease, noted Lorraine Kalia, MD, PhD, of the University of Toronto.

“This highlights the need to identify a biomarker outcome for phase II trials that can predict effects on clinical scores in phase III trials, similar to how disease-modifying therapy trials for multiple sclerosis use MRI brain lesions as predictable readouts of clinical relapses,” she wrote in an accompanying editorial.

Practical considerations often have higher priority in investigator-initiated trials than they do in industry-funded studies, Kalia noted. “These investigators opted to enroll participants already on dopaminergic medications, which facilitated recruitment and retention but resulted in using off-medication state scores for the primary outcome,” she said.

“Off-medication scores can be associated with a lot of noise due to variability in the time required for medications to wear off and a lack of objective methods to identify an individual’s maximal off-medication state,” she pointed out. “Furthermore, effects of chronic dopaminergic receptor activation might alter signaling within the nigrostriatal pathway unrelated to the neurodegenerative process.”

The GLP-1 receptor is present in the brain, and agonist activity is thought to be anti-inflammatory by reducing microglia activation. Observational research has demonstrated that Parkinson’s incidence is lower among people with diabetes treated with GLP-1 receptor agonists or DPP4 inhibitors compared with other diabetes drugs.

The phase III trial excluded people with type 2 diabetes, which may have resulted in a missed opportunity to establish whether people with both Parkinson’s and diabetes could benefit from GLP-1 receptor agonists, Kalia noted. There’s “emerging evidence to support an association between Parkinson’s disease and type 2 diabetes, suggesting shared underlying pathobiological processes that are not yet well defined but might involve peripheral or central insulin resistance,” she observed.

The Exenatide-PD3 trial randomly assigned 194 Parkinson’s patients who were on dopaminergic treatment to either 2 mg of extended-release exenatide by subcutaneous pen injection once weekly (97 people) or placebo (97 people). The mean age was 61, and most participants (71%) were men.

There were 10 serious adverse events in the exenatide group and 12 in the placebo group. Transient increases in serum amylase occurred in nine participants in the exenatide group but no one had clinically confirmed pancreatitis. Gastrointestinal symptoms were more frequent in those taking exenatide.

Despite the outcomes, the laboratory data supporting neuroprotective actions of this class of drugs remain very strong, Foltynie and colleagues said.

“We have previously established that exenatide can penetrate the human central nervous system, but only at very low concentrations compared with serum (approximately 2% of the serum level),” they wrote. Ongoing clinical trials of semaglutide (Ozempic, Wegovy) — including the GIPD trial in Parkinson’s disease and the EVOKE study in Alzheimer’s disease — may shed more light, they noted.

“It remains possible that there is a subgroup of people with Parkinson’s disease who may benefit from exenatide, although this is not yet clear,” Foltynie suggested.

“There is no obvious advantage in groups defined by age, sex, or weight,” he said. “It may be that some people with Parkinson’s have a tendency towards diabetes, which makes their Parkinson’s disease worse, and it is this mechanism that exenatide engages. We will be further exploring this possibility within the data collected in this trial.”

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