A novel agent with effects on glucose homeostasis may also be a key to modifying disease pathophysiology in Parkinson’s disease (PD). At least, that’s the hope with exenatide, a glucagon-like peptide-1 agonist, which showed improvement in off-time motor scores in patients with PD, according to a study published in The Lancet.1
Based on earlier preclinical research2-5 suggesting potential neuroprotective effects of exenatide, and following proof-of-concept studies demonstrating improvements in functional rating scores in 21 patients,6,7 the same group of multinational investigators from the United Kingdom and the United States conducted a clinical trial of exenatide to determine disease-modifying effects.
From June 2014 to March 2015, a group of 62 patients with moderate PD were assigned to either exenatide 2 mg once weekly by injection or placebo, as add-on therapy to their current regimen, for 48 weeks, followed by a 12-week washout period. At the end of 60 weeks, moderate increases of 1.0 points (95% CI, −2.6 to 0.7) in mean Movement Disorders Society Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 scores were demonstrated in the exenatide group (n=31), and a worsening of −2.1 points (−0.6 to 4.8) was seen in the placebo group (n=29). The washout period was designed to eliminate residual symptomatic effects to the treatment.
Several important features were noted in the study, the first of which was an exceptionally high compliance rate, in which 58 of 60 patients reported not missing a single dose. Second, significant therapeutic effects were recognized only on UPDRS Part 3 off-medication scores, with no significant changes to UPDRS Parts 1-4 on-medication scores. There were also no between-group differences in outcomes observed over a broad range of disease rating scores, including the Mattis Dementia Rating Scale, Montgomery-Asberg Depression Rating Scale, Unified Dyskinesia Rating Scale, Non-Motor Symptoms Severity Scale, Parkinson’s Disease Questionnaire summary index, EuroQol Five Dimensions Questionnaire, timed motor tests, and Hauser diaries. Adverse events were similar in both groups and considered to be unrelated to motor scores.
The effect of exenatide on UPDRS Part 3 scores was recorded early, at 12 weeks, and was greater at the end of 48 weeks of therapy than after the washout, all of which suggested a symptomatic effect. Although a potential for neuroprotection was reported in preclinical studies, neuroprotection was not observed in this clinical trial.24 However, the authors did not rule out the possibility of downstream effects from symptomatic improvements on disease pathophysiology. “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,” they wrote.
The positive results of this study were not enough to determine whether the effects of exenatide were mediated by pathophysiological changes in PD or simply produced long-lasting symptomatic relief, but in a disease where there have been few therapeutic developments since dopamine, the authors were confident exenatide offers a promising new channel of exploration.
- Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial [published online August 3, 2017]. Lancet. doi: 10.1016/S0140-6736(17)31585-4
- Harkavyi A, Abuirmeileh A, Lever R, Kingsbury AE, Biggs CS, Whitton PS. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson’s disease. J Neuroinflammation. 2008;5:19.
- Li Y, Perry T, Kindy MS, et al. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. PNAS. 2009;106:1285-1290.
- Bertilsson G, Patrone C, Zachrisson O, et al. Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J Neurosci Res. 2008;86:326-338.
- Kim S, Moon M, Park S. Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson’s disease. J Endocrinol. 2009;202:431-439.
- Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest. 2013;123:2730-2736.
- Aviles-Olmos I, Dickson J, Kefalopoulou Z. Motor and cognitive advantages persist 12 months after exenatide exposure in Parkinson’s disease. J Parkinsons Dis. 2014;4:337-344.