New Treatment Options for Parkinson's Disease Show Promise

Kathleen Louden

July 01, 2008

July 1, 2008 (Chicago, Illinois) — Phase 2 results with a new nonergot compound called pardoprunox (SLV308, Solvay Pharmaceuticals) may be effective in treating Parkinson's disease (PD), although adverse effects may be an issue with this new agent.

In a separate pilot study, novel transdermal delivery of a levodopa prodrug in a small number of patients resulted in increased blood levels of levodopa, raising hopes for the development of a levodopa patch.

Both studies were presented as posters here at the 12th International Congress of Parkinson's Disease and Movement Disorders, sponsored by the Movement Disorder Society.

Pardoprunox Better Than Placebo

The first study — an international, phase 2, proof-of-principle trial — compared the short-term efficacy and tolerability of pardoprunox vs placebo in 139 patients with early-stage PD. Pardoprunox, which combines a partial dopamine-receptor agonist and a full serotonin-receptor agonist, has shown benefit in animal models of PD, the authors reported.

The literature offers no consensus on the efficacy of partial dopamine agonists in the treatment of PD, said lead author Juliana Bronzova, MD, DSc, from Solvay Pharmaceuticals. "But pardoprunox has a complex mechanism of action," she said in an interview.

Serotonin has been used in the treatment of dyskinesia, Dr. Bronzova added.

In their study, the investigators randomly assigned 69 PD patients to receive the active drug and 70 to receive placebo. Patients were older than 30 years, and none had secondary parkinsonism, Parkinson-plus syndrome, or a current primary psychiatric disorder.

Those who received pardoprunox had a fixed-flexible dose titration over 2 to 6 weeks from 9 to 45 mg/day, with the rate of titration being determined by tolerability, the authors' results showed. Only patients who could tolerate a 30-mg dose and in whom further efficacy was expected received a higher dose, up to 45 mg/day. For all patients receiving pardoprunox, a 3-week maintenance dose was followed by tapering off and discontinuation of the medication during the 1-week follow-up.

The primary efficacy outcome measure was change from baseline to end of treatment in the Unified Parkinson s Disease Rating Scale (UPDRS) motor score. The 2 groups had similar mean motor scores at baseline.

At the study's 10-week end point, there were significantly more responders in the pardoprunox group vs the placebo group (50.7% vs 15.7%; P < .0001, 2-sided), the authors found. The UPDRS motor score decreased from baseline by a mean of 7.3 points in the pardoprunox group and only 3 points in the placebo group (P < .0001), the abstract notes.

Adverse Effects a Problem

At least 1 adverse event occurred in 59 patients (86.8%) in the pardoprunox group and in 38 (54.3%) of the patients receiving placebo, they note. Adverse events reported most frequently in the pardoprunox group were nausea (47.1%), dizziness (26.5%), and somnolence (25%). As an antiemetic, patients received domperidone, which is not approved in the United States.

Before the end of the study, 22 patients discontinued pardoprunox treatment: 15 because of adverse events and 7 reportedly for other reasons ("withdrew consent"). Seven patients receiving placebo did not complete treatment, 6 of whom stopped because of adverse events. They note that 5 of the 47 patients who completed treatment with pardoprunox did not reach a dosage of 9 mg/day.

The authors called the tolerability of pardoprunox "acceptable." However, a neurologist not affiliated with the study disagreed.

"Side effects are numerous for such a short-term study," said Kathleen Shannon, MD, a neurologist from Rush University Medical Center, in Chicago, Illinois, and cochair of the congress local organizing committee. "Some patients may have stayed in the study despite side effects because they knew it was for a short time."

Asked for comment on the adverse-effects profile by Medscape Neurology & Neurosurgery, Dr. Bronzova acknowledged that "there is a need for optimization of titration and dose selection in future studies. We had a frequency of nausea that we want to improve on."

Patch Delivers Levodopa to Bloodstream

The second trial, a pilot study conducted in 6 healthy volunteers in Israel, tested a patch containing a levodopa prodrug.

The patch was applied on the back and left on for 24 hours. Carbidopa (50 mg) was administered orally at 8-hour intervals. Blood samples were obtained at various time points, and plasma concentrations of the levodopa ester, levodopa, 3-O-methyl-DOPA, and carbidopa were determined by liquid chromatography-mass spectrophotometry.

The authors found that the transdermal drug maintained therapeutic blood levels of levodopa (500 to 1000 ng/mL) until the patch was removed. Levodopa plasma levels declined slowly after removal of the patch, suggesting the establishment of a levodopa depot during transdermal delivery of the prodrug, the abstract noted. No blood concentrations of levodopa ester were detected at any time point within 24 hours, suggesting a rapid hydrolysis of the ester after penetrating the skin.

"This is the first human study in which near-constant therapeutic levodopa blood concentrations were shown during transdermal delivery," wrote lead author Moshe Kushnir, MD, head of neurology at Kaplan Medical Center, in Rehovat, Israel. "This novel method of drug delivery may provide a practical therapeutic option for PD patients experiencing motor complications."

Rush University's Dr. Shannon cautioned that the results were preliminary but said she found it interesting that the transdermal levodopa ester turned into levodopa in the body.

"Our patients all want a levodopa patch," she said.

This latter study was supported by a grant from the Michael J. Fox Foundation for Parkinson's Disease Research. Dr. Kushnir is employed by NeuroDerm, which makes the levodopa prodrug patch. Dr. Bronzova is an employee of Solvay Pharmaceuticals, which makes pardoprunox. Dr. Sullivan reported no relevant financial disclosures.

12th International Congress of Parkinson's Disease and Movement Disorders: Abstracts 588 and 592. Presented June 24, 2008.


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