麻豆传媒

PHILADELPHIA -- An anti-hypertensive drug failed to outperform placebo in slowing Parkinson's disease progression, results from the highly-anticipated trial indicated.

No significant difference was seen after 36 months in average Unified Parkinson Disease Rating Scale (UPDRS) Part I-III scores measured in the ON state for patients receiving isradipine (DynaCirc) at 10 mg daily versus placebo (treatment effect 0.27 points, 95% CL -2.5 to 3.0, P=0.85), reported Tanya Simuni, MD, of the Northwestern University Feinberg School of Medicine, and colleagues.

Secondary outcomes, including change in non-motor disability and time to initiation/utilization of dopaminergic therapy and onset of motor complications, did not improve either, according to an abstract to be presented next week at the .

"The study was based on solid mechanistic rationale, partly on animal data, and epidemiological data supporting that this mechanism is relevant to this human disease," Simuni told 麻豆传媒. "Negative results of the study are very disappointing, but that's what's called science."

Isradipine is a calcium-channel antagonist that had appeared neuroprotective in animal models. In 2007, findings from a study published in led by James Surmeier, PhD, at Northwestern, linked the death of dopaminergic neurons -- the hypothesized the cause of Parkinson's disease -- with the excitement of calcium channels in these cells. A suggested a different calcium channel blocker, felodipine, might also be effective against Parkinson's disease and other neurodegenerative conditions.

If the "pace-making" properties of these cells could be slowed by reducing the stress of calcium-channel activity, it could make neurons more resistant to Parkinson's disease pathology, Simuni said.

The initial studies were followed by a 2013 phase II trial conducted by the Parkinson's Study group, which established 10 mg of controlled-release isradipine as the maximum tolerable dosage for patients with early Parkinson's disease; with fewer than 30 patients in each study arm, it was not powered to demonstrate efficacy. Notably, the phase III trial used an immediate-release formation, raising the question of whether that factored into the drug's failure.

It remains unclear why STEADY-PD III produced negative results, said David Standaert, MD, PhD, of the University of Alabama at Birmingham, who was not involved with this study. He suggested that intervening with this calcium channel is simply insufficient to slow the disease in humans, despite the short-term success the treatment demonstrated in rodent models, he said.

"One of the frustrating things about this outcome and this kind of study is, we really don't know exactly why it didn't work," Standaert told 麻豆传媒. "You can't really distinguish between 'it failed because the drug was not effective' or 'it failed because the mechanism was just not going to work.'"

Simuni said this is because it's impossible to determine whether isradipine actually affected the target calcium channels in live patients.

"Specifically for this drug, we don't have a way to measure how much the drug has reached those channels and whether we've blocked enough of the channels to demonstrate the efficacy of the drug," she said.

Another possibility is that the intervention was administered too late in the progression of disease, Simuni said. Even when patients have "newly" diagnosed Parkinson's disease, 50%-60% of the dopamine-producing cells have already been destroyed, and therefore the dopamine-protective qualities of this intervention would be ineffective, she said.

Simuni emphasized that she doesn't believe these findings negate the underlying mechanistic hypothesis.

"What this study demonstrates is that this particular drug at this particular dose does not have the benefit of slowing progression of early Parkinson's disease," she said.

For the trial, Simuni and her team enrolled patients with newly-diagnosed (<3 years) Parkinson's disease ≥30 years at the time of diagnosis, who did not require dopaminergic or symptomatic therapy, from 54 sites across the U.S. and Canada from 2014 through 2015. Overall, the study retention rate was high at 95% and recruitment was achieved 6 months ahead of schedule, Simuni said.

In total, 336 patients, mean age 66, were included, 68% of whom were male and 10% of whom were nonwhite. Characteristics were similar between active and placebo groups, with an overall mean 0.9 years since Parkinson's disease diagnosis and average UPDRS I-III score of 23.1. Edema was reported by some patients on isradipine.

After 3 years, patients given isradipine had adjusted mean UPDRS I-III ON changes of 2.99 points compared to 3.26 in placebo.

Details of the study's secondary findings will be presented at the AAN conference on Tuesday May 7. Simuni said her team is currently investigating whether certain subsets of patients might have benefited from the drug.

"I want to clearly communicate that the results reflect a lack of biological effect in a very well designed, very well executed study," she said. "The data generated from this study will be essential in the design of future trials."

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