These preclinical findings support an ongoing Phase 3 trial (NCT02168842), known as STEADY-PD III, that is evaluating Dynacirc’s potential to slow Parkinson’s progression in people with early-stage disease.
Findings from the animal study, “Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress,” were published in the Journal of Clinical Investigation.
“Obviously, humans are more complicated than mice, but we’re hopeful the trial will be positive,” D. James Surmeier, PhD, the study’s senior author and a professor at Northwestern University said in a university news article.
Dynacirc is approved to treat high blood pressure, reducing the risk of a heart attack or stroke. Patients taking this medication were seen to have a lower-than-average incidence of Parkinson’s disease, however, intriguing neurologists and neurologic researchers.
They hypothesized that Dynacirc could be exerting a neuroprotective effect on a group of nerve cells called dopaminergic neurons, the death of which is at the core of Parkinson’s motor symptoms.
Dopaminergic neurons are the main source of dopamine in the brain, and are responsible for activities that include mobilizing brain regions to make rapid movement possible.
As such, they have a high energy expenditure, holding their mitochondria — the cell’s power-plants — at full capacity.
“They tune up cellular respiration so that no matter what kind of demand or unexpected excitation comes their way, they can continue to do their job,” Surmeier said.
But 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.
In blocking calcium channels in a cell, Dynacirc slows cellular mitochondrial activity and thereby reduced 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 of neurons.
Researchers treated mice with Dynacirc (given intravenously) for seven to 10 days, successfully blocking calcium channels in dopaminergic neurons and reducing calcium levels inside these cells.
Upon treatment, the mitochondria of dopaminergic neurons showed less oxidant stress than that seen in untreated animals, implying an ability to protect these nerve cells from stress damage.
“We diminished the damage being done to mitochondria enough that dopaminergic neurons looked the same as neurons that are not lost in Parkinson’s disease,” Surmeier said.
No adverse side effects or impact on mice behavior were seen using Dynacirc, the study found, implying safety.
“These data provide additional strong pre-clinical rational for the ongoing Phase 3 study of israpidine [Dynacirc] in human patients,” said Tanya Simuni, MD, lead investigator of STEADY-PD III trial. “We are cautious as so many drugs have failed, but if successful, isradipine will be the first drug to demonstrate the ability to slow progression of Parkinson’s disease.”
The trial, which began in 2014 and is taking place at 54 centers in the United States and Canada, is assessing whether oral Dynacirc is effective in slowing Parkinson’s progression. About 336 patients with early disease were randomized to receive 5 mg of the treatment or a placebo twice a day for 36 months.
Efficacy will be measured by changes in Unified Parkinson Disease Rating Scale, an assessment of motor and non-motor symptoms, from baseline to study’s end, and changes between treated and placebo study arms. Results are expected in early to mid-2019.