New Drugs Hold Promise of Improved Quality of Life in PD

Megan Brooks

March 15, 2013

The results of 3 drug trials provide "promising news" for people with Parkinson's disease (PD), says Robert A. Hauser, MD, from University of South Florida, Tampa, and a fellow of the American Academy of Neurology, who participated in all 3 studies.

One trial provides new data on droxidopa (Northera, Chelsea Therapeutics) for neurogenic orthostatic hypotension (NOH), another reports on the safety and efficacy of tozadenant (SYN-115, Biotie Therapies) for wearing-off fluctuations in patients receiving levodopa, and the third tests rasagiline (Azilect, Teva Neuroscience) as add-on therapy to dopamine agonist monotherapy in early PD.

The trial results were released this week ahead of their presentation at the American Academy of Neurology (AAN) 65th Annual Meeting, which gets underway tomorrow, March 16, in San Diego, California, and runs through March 23.

Droxidopa for NOH

The droxidopa trial looked at the effect of the drug on orthostatic symptoms and standing systolic blood pressure in 225 patients with PD and symptomatic NOH.

The condition, which affects about 18% of patients with PD, stems from a failure of the autonomic nervous system to respond to changes in posture due to an inadequate release of norepinephrine. Droxidopa is an oral prodrug converted to norepinephrine.

Patients in the study were randomly allocated to placebo or droxidopa (titrated to 100 to 600 mg three times daily during a 2-week double-blind period, followed by 8 weeks of double-blind treatment at a stable dose).

The researchers say patients receiving droxidopa experienced significant improvement in dizziness/lightheadedness after 1 week compared with placebo (P = .008) and showed a trend toward improvement after 8 weeks (P = .077).

Standing systolic blood pressure improved significantly with droxidopa compared with placebo after 1 week (6.8 mm Hg; P = .014) and showed a numeric improvement after 8 weeks (2.2 mm Hg; P = .414).

Patients receiving droxidopa were also less apt to fall. During the entire 10-week study period, there were 0.38 fall per patient per week in the droxidopa group and 1.73 in the placebo group, a 78% reduction (P = not significant).

Droxidopa was well tolerated, the researchers say. The most common adverse events associated with droxidopa treatment ( > 5%) included headache, dizziness, hypertension, nausea, and fatigue.

The study was supported by Chelsea Therapeutics. As reported by Medscape Medical News, the company performed the study in response to a March 2012 request by the US Food and Drug Administration, which has raised concerns about whether the beneficial effect of the drug lasts.

Tozadenant Reduces Off-Time

The tozadenant trial was a 12-week, randomized, double-blind, phase 2 trial of patients with advanced PD taking stable-dose levodopa who were experiencing at least 2.5 hours of off-time per day. They were allocated to tozadenant, 60, 120, 180, or 240 mg twice daily, or matching placebo.

Tozadenant, an oral selective adenosine 2-α receptor antagonist, provided a "significant reduction in off-time combined with a significant improvement in on-time and improvement in PD motor scores and quality of life," C. Warren Olanow, MD, professor of neurology and neuroscience and director, Bendheim Parkinson Center, Mount Sinai School of Medicine, New York, who worked on the study, told Medscape Medical News.

"This class of drugs," he said, "is novel as they do not act directly on the dopamine system and thereby provide benefits that potentially avoid dopaminergic side effects." Further confirmatory studies are planned.

A total of 420 patients were randomly assigned, and 337 completed treatment. On average, they were 63 years of age and had had PD for more than 8 years. Their baseline off-time was roughly 6 hours.

The researchers say they observed significant reductions in mean placebo-corrected change from baseline in off-time with tozadenant, 120 mg twice daily (-1.1 hours; P = .0039) and 180 mg twice daily (-1.2 hours; P = .0039). On-time with troublesome dyskinesia was not significantly increased in any tozadenant group.

Tozadenant was also associated with improvements in Unified Parkinson Disease Rating Scale (UPDRS) I-III scores, as well as Clinical Global Impression-Improvement (CGI-I) and Patient Global Impression-Improvement scores.

The most common adverse events in the combined tozadenant groups were dyskinesia, nausea, dizziness, constipation, PD worsening, insomnia, and falls.

The study was supported by Biotie Therapies.

Add-On Rasagiline for Stubborn Symptoms

The rasagiline study was an 18-week phase 4 study involving 321 patients aged 30 years or older with early PD whose symptoms were not well controlled with stable doses of ropinirole (at least 6 mg/day) or pramipexole (at least 1.0 mg/day). Study patients were randomly allocated to add rasagiline, 1 mg, or placebo, while maintaining their stable dose of dopamine agonist.

Compared with adding placebo, adding rasagiline led to significant improvement in UPDRS total score (P = .012) and motor scores (P = .007), the researchers report in a meeting abstract. Groups did not significantly differ for UPDRS-ADL (activities of daily living, P = .301) or CGI-I scores.

Rasagiline was well tolerated, with no significant difference in percentage of patients with adverse events (64.2% vs. 61.0%) or serious adverse events (4.9% vs. 3.0%) compared with placebo, they say.

The study was supported by Teva Pharmaceuticals.

American Academy of Neurology (AAN) 65th Annual Meeting. Abstracts 010, 005, and 006. March 16-23, 2013.

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