Pioglitazone not effective in PD


Pioglitazone is a PPAR (peroxisome proliferator-activated receptor)-gamma agonist of the thiazolidinedione class that is used to treat insulin resistance in patients with Type 2 diabetes. Prior studies in the MPTP mouse model reported that the drug prevented dopaminergic cell loss in the substantia nigra (Breidert et al. J Neurochem 2002;82:615-624). The implication was that the drug might be usefully employed as a neuroprotective agent in Parkinson’s disease.

Accordingly, the NINDS Exploratory Trials in Parkinson Disease (NET-PD) group launched a phase II trial to evaluate the potential benefits of pioglitazone (NET-PD FS-ZONE Investigators. Lancet Neurol 2015;14:795-803). A total of 210 subjects with early PD and on a stable drug regimen (rasagiline 1 mg/day or selegiline 10 mg/day) were randomized to one of two doses of pioglitazone (15 or 45 mg/day) or placebo. The primary outcome was the change from baseline in the total UPDRS score at week 44. The null hypothesis was a mean UPDRS change three points less with active treatment versus placebo.

The mean total UPDRS change at week 44 was 4.42 with pioglitazone 15 mg, 5.13 with pioglitazone 45 mg, and 6.25 with placebo. The mean difference from placebo with the two doses was -1.83 and -1.12, respectively.

The group concluded that study doses of pioglitazone were unlikely to modify progression in early PD, adding that larger trials in PD patients were not recommended.

Dr. Susan Fox:
The study finding is disappointing as it reports yet another agent that showed robust neuroprotective effects in animal models of PD but failed in clinical studies. Many issues remain with the translational process of potential novel neuroprotective agents for PD, not least the validity of the preclinical testing, where animal models do not replicate the progressive or pathological changes underlying the neurodegenerative process in PD. The acute MPTP toxin models used previously clearly do not predict the clinical usefulness of potential neuroprotective agents. This is where newer models (e.g. with alpha synuclein pathology) will hopefully be more useful. In addition, testing interventions at an earlier stage of the disease is also likely a key factor. Thus, earlier diagnosis and evaluating PD patients in the ‘pre-motor’ phase may yield better outcomes. The crude outcome measure of the total UPDRS used in clinical trials is also biasing the results and is probably not the way to detect potential benefit at this very early stage of PD. The hunt for reliable biomarkers continues.

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