Blood Pressure Medicine Dynacirc Falls Short in Phase 3 Trial for Early Parkinson’s
These results contrast with what was previously observed in mice, in which the medication eased damage to dopaminergic neurons. An insufficient dose of Dynacirc and the absence of a direct measure of disease progression may have hampered similar observations in human patients, researchers suggest.
Findings were detailed in “Isradipine Versus Placebo in Early Parkinson Disease: A Randomized Trial,” a study published in Annals of Internal Medicine.
Dynacirc is a calcium channel blocker approved to treat high blood pressure, or hypertension. It works by preventing the influx of calcium into certain cells, such as those covering the arteries, helping blood vessels relax and ultimately lowering blood pressure.
Calcium channels are also present on a group of nerve cells called dopaminergic neurons, the death of which is at the core of Parkinson’s motor symptoms. These neurons have a high energy expenditure, holding their mitochondria — where cells get their energy — at full capacity.
However, a continuous high energy demand has consequences, including the production of toxic compounds that can damage and kill dopaminergic nerve cells, as is the case in Parkinson’s disease.
By blocking calcium channels in a cell, Dynacirc slows cellular mitochondrial activity and lessens the production of damaging byproducts. However, it is still unclear whether the compound can reach the brain and have a direct effect on the mitochondria in neurons.
Conducted in collaboration with the National Institute of Neurological Disorders and Stroke, the Michael J. Fox Foundation for Parkinson’s Research, and the Parkinson Study Group, the study included 336 patients — across 57 sites in the U.S. — who had been diagnosed within three years and were not on any dopaminergic medication.
Participants were randomly assigned to receive either 5 mg of Dynacirc twice daily or a placebo for three years.
During that time, they had to complete 12 in-person and four telephone visits, in which researchers evaluated changes in motor and cognitive function, as well as their ability to perform activities of daily living — measured with the Unified Parkinson’s Disease Rating Scale (UPDRS) in the “on” state — when antiparkinsonian medication is exerting its effects.
Results showed that patients on Dynacirc lost an average of 2.99 UPDRS points during the trial’s three-year period versus 3.26 points for control patients. This represented a small benefit for long-term Dynacirc — a slowing in disease decline by 0.27 UPDRS points — which did not reach statistical significance.
After adjusting for the use of antiparkinsonian medications, these differences remained non-significant.
Secondary assessments such as time to the start and use of antiparkinson medications, time to onset and severity of motor complications (motor fluctuations, dyskinesia), change in non-motor disability, and quality of life also were not significantly improved by Dynacirc treatment.
While the researchers in the study note that the “isradipine dose may have been insufficient to engage the target calcium channels associated with neuroprotective effects,” Washington University School of Medicine researchers Joel S. Perlmutter, MD, and Baijayanta Maiti, MD, PhD, suggest that the primary outcome measure might not be a direct reflection of neuronal damage and disease progression.
“One possibility is that the primary outcome measure — change in UPDRS ON score — was inadequate,” Perlmutter and Maiti wrote in an editorial accompanying the study. “Ideally, one would prefer a more direct, objective measure of disease progression, such as change in brain deposition of synuclein pathology.”
Studying if Dynacirc is indeed binding to its target calcium channels in dopaminergic neurons should also be assessed before any more studies of Dynacirc are considered, the two scientists also wrote.