A clinical study led by Northwestern Medicine scientist Tanya Simuni, MD, has crossed a promising compound off the list of potential agents that may slow the progression of Parkinson’s disease.
Previous preclinical work showed that the compound, an FDA-approved drug called pioglitazone currently used to treat diabetes, has neuroprotective effects in animal models of Parkinson’s disease. But the phase two clinical study, published in Lancet Neurology, found that those disease-modifying effects do not translate to patients.
“It’s not enough to demonstrate that the drug is neuroprotective in animal models,” said Dr. Simuni, director of the Parkinson’s Disease and Movement Disorders Center. “You need to demonstrate that the effect can be achieved in humans at doses that are safe to be administered to patients.”
In the study, conducted by National Institute of Neurological Disorders and Stroke (NINDS) Neuroprotection Exploratory Trials of Parkinson’s Disease program, 210 patients recently diagnosed with Parkinson’s disease were randomly assigned to take one of two different doses of pioglitazone or a placebo for 44 weeks. Progression of their disease was measured using the most common Parkinson’s assessment, the Unified Parkinson Disease Rating Scale. Neither dose of pioglitazone slowed progression of disability compared to the placebo.
The study was designed not to definitively prove the effectiveness of the drug for Parkinson’s disease, but rather to determine whether additional trials should continue to test the compound.
“Asking this reverse question – is this molecule considered futile? – is more efficient than recruiting a large sample to answer the efficacy question in the phase two study,” Dr. Simuni said.
Indeed, the investigators do not recommend that scientists continue to pursue pioglitazone as a Parkinson’s disease treatment.
Why Preclinical Findings Didn’t Translate
Pioglitazone is not the first molecule to fail in a Parkinson’s disease clinical study despite rigorous tests showing promise in preclinical trials. Multiple reasons explain this, said Dr. Simuni. First, animal models are not ideal reflections of real Parkinson’s disease in human patients.
“Animal models are created to represent the clinical picture as best as we can,” she said. “We need better models.”
Second, patients may not have been exposed to a sufficient dose of the drug to experience its potential benefits.
“Within the safety parameters, we went as high as we could have gone,” Dr. Simuni said.
Third, the drug intervention may be coming too late in the disease process to help. By the time patients present symptoms and are diagnosed with Parkinson’s, they have already lost 70 percent of the brain cells that produce dopamine.
“The silver lining is that while the results are quite disappointing, this study is an example of an efficient phase two study that gave us a definitive answer about this molecule. We’re not left with a ‘maybe,’” Dr. Simuni said.
Though pioglitazone is off the list, there’s evidence that other molecules in the glitazone family of diabetes drugs may still help patients with Parkinson’s disease.
“The only way we will find efficacious molecules is to continue testing the drugs that have been best characterized in preclinical trials,” Dr. Simuni said. “The odds are against us statistically, but we as a scientific community are determined to win this battle.”
Dr. Simuni is the Arthur C. Nielsen, Jr. Research Professor in Parkinson’s Disease and Movement Disorders in the Ken and Ruth Davee Department of Neurology.
This study was funded by the NINDS.