FROM THE LANCET
An anti-diabetes drug significantly improved motor function in patients with Parkinson’s disease who had off-medication symptoms despite dopaminergic therapy in a phase 2 trial.
Patients taking exenatide (Byetta), an agonist of the GLP-1 receptor, experienced a mean 2.5-point improvement in the part 3 motor score on the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) over 48 weeks, compared with a 1-point decline in patients taking placebo, Dilan Athauda, MBBS , and his colleagues reported ( Lancet. 2017 Aug 3. doi: 10.1016/S0140-673631585-4 ).
The benefit was largely sustained after a 12-week washout period, reported Dr. Athauda, a clinical research fellow at The National Hospital for Neurology and Neurosurgery, London, where the trial was conducted.
The mechanism of action is unclear, the investigators noted. Dopamine transporter scanning with [123I]FP-CIT single photon emission CT (DaTscan) revealed a tantalizing hint of neuroprotection, as the rate of decline in dopaminergic neurons seemed to be slightly reduced among those taking the medication. However, it’s also possible that exenatide somehow altered the pharmacokinetics of levodopa and other dopaminergic drugs, making them more effective, Dr. Athauda and his associates said.
Still, the double-blinded study’s positive results are encouraging, and they replicate those of the team’s 2013 open-label trial ( J Clin Invest. 2013 Jun 3;123:2730-6 ), they asserted.
“Whether this drug acts as a novel symptomatic agent, influences compensatory responses or behaviors, or has neuroprotective effects on underlying pathology is unclear, but there is a strong indication that GLP-1 receptor agonists may have a useful role in future treatment of Parkinson’s disease,” the investigators wrote.
The study randomized 62 patients who had Parkinson’s with off-medication motor symptoms to weekly injections of either placebo or 2 mg subcutaneous exenatide for 48 weeks. A 12-week washout period followed. Despite randomization, there were some important baseline differences between the groups. Those taking exenatide were older (62 vs. 58 years) and had a higher score on the part 3 motor score of the MDS-UPDRS, the study’s primary endpoint (32.8 vs. 27.1). Exenatide users were also taking a lower mean dopaminergic drug dose (mean 774 mg vs. 826 mg levodopa equivalent).
Patients were assessed in clinic every 12 weeks, not only for the primary endpoint of dyskinesia off-medication, but for cognition, quality of life, mood, and nonmotor symptoms. All assessments were done in the morning, after at least 8 hours off levodopa or 36 hours off long-acting dopaminergic drugs.
Exenatide’s benefit in off-medication dyskinesias was apparent after the first 12 weeks of treatment, Dr. Athauda and his coauthors noted. The MDS-UPDRS score had decreased from 32.8 to 30.2 in the active group, and increased from 27.1 to 27.6 in the placebo group. Those taking exenatide held steady at that improvement for the entire 48 weeks, ending at 30.3 (2.3 points below baseline). Those taking placebo continued to decline, ending at 28.8 (1.7 points above baseline). The adjusted between-group difference was 4.3 points, in favor of exenatide (P = .0026).
At 60 weeks, after the 12-week washout period, patients who took exenatide were still doing better, reaching an adjusted between-group difference of –3.5 (P-= .0318).
However, off-medication dyskinesia was the only improvement noted in the trial. Exenatide did not affect any secondary endpoints, including any sections of the on-medication MDS-UPDRS.
The investigators noted that, during the 60 weeks, mean levodopa equivalent dosage increased more in the active group than in the placebo group (132 vs. 112 mg). This brought the active group up much closer to the placebo group’s dose than had been observed at baseline (906 vs. 942 mg).
Exenatide was generally well tolerated, with the exception of a mean 2.6-kg weight loss among those taking it. This was likely related to an increased incidence of gastrointestinal side effects. Weight returned to normal during the washout period.
There were three drop-outs, two in the placebo arm because of worsening anxiety and worsening dyskinesia and one in the exenatide arm because of asymptomatic hyperamylasemia.
The investigators also measured dopamine transporter availability via DaTscan to assess exenatide’s potential impact on dopaminergic neurons. Although areas of decreased binding declined in both groups, the exenatide group showed a signal of reduced rate of decline in the right and left putamen.
“However,” the authors noted, “because this signal was detectable only at uncorrected height thresholds of P = .0034 or less, these data would benefit from larger confirmatory studies or studies of patients at an earlier disease stage when the rate of change of DaTscan uptake is greater, making group differences more readily detectable.”
It won’t be easy to discover how exenatide exerts its benefit, the authors said. They pointed to a robust compendium of preclinical data suggesting that the drug reduces inflammation, promotes mitochondrial biogenesis, exerts neurotrophic effects, stimulates neurogenesis, and restores neuronal insulin signaling.
“Whether some or all of these mechanisms contributed to the clinical effects in our study cannot be definitively established, but one or several of these mechanisms could have acted in synergy to promote cell survival, preserve compensatory responses, and prevent maladaptive responses.”
The Michael J. Fox Foundation for Parkinson’s Research funded the study. Dr. Athauda had no financial disclosures but several of his coauthors disclosed relationships with pharmaceutical companies.
On Twitter @alz_gal