NEW ORLEANS—The results of trials of some of the newer approaches to not only treating but preventing Parkinson’s disease were much in evidence at the Ninth International Congress of Parkinson’s Disease and Movement Disorders. The pharmaceutical approaches reported included not only the familiar dopamine agonists for treatment and selegeline as a neuroprotective agent but also new monoamine oxidase B inhibitors, a new A_2A adenosine receptor antagonist, using triple therapy in the form of levodopa and carbidopa plus entacapone, and treatment with a non-ergot dopamine antagonist. Also discussed were new ways to deliver antiparkinsonian medications, including a transdermal patch, a subcutaneous pump for the continuous infusion of drugs such as apomorphine, and a duodenal delivery system for levodopa in advanced cases of the disease.

A. Jon Stoessel, MD, a Professor of Neurology at the University of British Columbia in Vancouver, who delivered a plenary lecture on the subject, also noted that some drug trials are targeting nondopaminergic mechanisms such as glutamate receptors in the motor complications of the disease, with at least one “powerful receptor antagonist” under study. Another nondopaminergic receptor system under investigation, he said, is the serotonin system, which is a partial agonist of the D₂ receptor.

Dr. Stoessel also noted that “there is some evidence that giving dopa continuously, either by giving dopa infusions or subcutaneous infusions of apomorphine, you have the potential to reduce the risk of dyskinesias.” He added that “if you take levodopa four times daily, there is a reduction in the risk of dyskinesias. Also, if you take the combination of levodopa, carbidopa, and entacapone it will delay the time to onset of dyskinesias, versus levodopa/ carbidopa alone.”

Brief summaries of some of the drug studies are reported below.

RASAGILINE REDUCES MOTOR COMPLICATIONS

This particular drug, which is a selective, irreversible MAO-B inhibitor, generated some excitement with a report by Mark F. Lew, MD, of the Department of Neurology at the University of Southern California, Los Angeles, and others. The multicenter US and Canadian TEMPO (TVP-1012 Early Monotherapy for Parkinson’s disease Outpatients) Extension study group showed that this agent was not only effective as an adjunctive therapy, but also had to be administered only once daily.

The TEMPO study indicated that after the initial double-blind phase—which showed a significant improvement in symptoms in patients on rasagiline over those on placebo and less functional decline as well at 12 months—85% of the original patient group elected to receive, or continue to receive, the drug.

The open-label extension study is continuing, with patients now having received the drug for a mean of 3.5 years, with some patients on rasagiline for up to 6.5 years. The study also showed that after two years, about half of the patients who were maintained on rasagiline did not need additional dopaminergic treatment.

Also, the patients on this drug had better Unified Parkinson’s Disease Rating Scale (UPDRS) scores compared with historical controls. The drug was well tolerated, with only 11.3% of 398 patients discontinuing treatment because of adverse events. The most common adverse events were infection, accidental injury, nausea, and arthralgia, the investigators said.

• Another study of rasagiline was reported by Lawrence Elmer, MD, PhD, Director of the Center for Neurological Disorders at the Medical College of Ohio in Toledo for the Parkinson Study Group. Investigators found that in a cohort of 472 patients, rasagiline 1 mg/day offered benefit in the form of a reduction in motor complications even in patients judged already to be optimally treated with levodopa and catechol-O-methyltransferase inhibitors.

NONDOPAMINERGIC DRUG TARGET REDUCES OFF TIME

Two studies reported at the meeting indicated that blocking adenosine A_2A receptors, which are expressed abundantly in striatal output neurons, can have a positive effect in patients with advanced Parkinson’s disease.

Margery H. Mark, MD, of the Department of Neurology at the University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School in New Brunswick, and colleagues reported on the long-term efficacy of istradefylline, which is a selective adenosine A_2A receptor antagonist.

In this 52-week, multicenter, open-label study patients were started on 40 mg/day, which could be titrated to 60 mg/day or to 20 mg/day, and were permitted to continue on other antiparkinsonian medications. They also had a minimum one-year history of response to levodopa and had been on a stable regimen of this drug for at least four weeks before the start of the study.

Within two weeks, patients taking istradefylline reported more than a 12% reduction in off time, and researchers concluded that the drug was safe and well tolerated. The most frequent adverse events were dizziness, nausea, and dyskinesias, but the dyskinesias may have been related to the levodopa/carbidopa and other antiparkinsonian medications the patients were also taking, the researchers noted.

• A second study, reported by Mark Stacy, MD, of the Movement Disorders Center at Duke University, Durham, North Carolina, and colleagues, evaluated the use of istradefylline in 591 patients in two study protocols in which patients were randomized to the drug or to placebo. The investigators found that 88% of the patients in each trial completed the 12-week treatment period. In both groups, they said, adverse events were the chief reason for discontinuation; these were similar in both groups except for dyskinesias, which were modestly increased in istradefylline-treated patients. However, these were primarily nontroublesome dyskinesias, they added. “Istradefylline may be used safely in maximally treated subjects with advanced Parkinson’s disease and motor complications,” they concluded.

DOPAMINE AGONIST RESULTS REPORTED

Piribedil is a non-ergot D₂/D₃ receptor agonist which was studied by a group led by Olivier Rascol, MD, PhD, of Institut National de la Santé et de la Recherche Médicale in Toulouse, France, in an international, randomized, double-blind, placebo-controlled two-year study of 225 patients with early disease. The researchers found a continued improvement in motor complications over that time period in patients on piribedil, with 88% of patients randomized to the drug continuing with it as monotherapy during the entire time period. They asserted that piribedil has the advantage of sparing the need for these patients to start on levodopa. Adverse events were seen in a small number of patients taking piribedil, but they were similar to those seen in patients on placebo.

• Pramipexole, a dopamine agonist currently approved for the treatment of Parkinson’s disease, demonstrated rapid effectiveness and was well tolerated in the treatment of restless legs syndrome, according to the results of a large safety and efficacy trial by Boehringer Ingelheim. A total of 345 patients with restless legs syndrome participated. The investigators found that a once-daily dose of pramipexole improved restless legs syndrome symptoms for a 24-hour period; the drug also had a rapid onset of action and produced significant improvements in patients’ sleep.

COMBINING DRUG THERAPIES IMPROVES QUALITY OF LIFE

Two studies reported advantages in using a combination of levodopa, carbidopa, and entacapone. Leslie J. Findley, MD, consultant neurologist at the Essex Neurosciences Unit, Oldchurch Hospital, Essex, United Kingdom, and colleagues reported that the new oral combination drug significantly improved quality of life for Parkinson’s patients with wearing- off symptoms as measured by the UPDRS, while being cost-effective.

• Mikko Kuoppämaki, MD, of the Neurodegenerative Diseases Research Center, King’s College, London, and colleagues pooled data from four published phase III trials involving more than 800 patients to show that “optimizing traditional levodopa therapy with entacapone significantly increased daily on time, decreased daily off time, and decreased UPDRS part III subscores compared to placebo in patients with or without adjunct dopamine agonists.”

DRUG DELIVERY

Rotigotine is a D₃/D₂/D₁ dopamine agonist developed for transdermal delivery that has previously been shown to significantly reduce UPDRS II and III scores in three double-blind, placebo-controlled trials. In a new analysis, Ray L.Watts, MD, Professor and Chairman of the Department of Neurology at the University of Alabama, Birmingham, and colleagues aimed to investigate the efficacy of the patch in subgroups of patients with Parkinson’s disease, based on gender, age, disease severity, and duration of disease.

In this multicenter, randomized, placebo-controlled trial, participants were started at 4.5 mg/day and were titrated up to an optimal dose of 13.5 mg/day, where they were maintained for six months. The main efficacy measure was the change from baseline to the end of treatment in UPDRS parts II and III.

According to Dr. Watts, the study showed that 13 mg/day rotigotine was both effective and well tolerated, independent of age, gender, disease severity, or duration.

• Subcutaneous apomorphine is a non-ergoline dopamine agonist which has previously been shown to be effective in the acute treatment of off episodes in advanced Parkinson’s disease, but concerns have been raised about cardiac arrhythmias caused by high doses, based on animal studies.

In a study in 62 patients who had been using subcutaneous apomorphine for off events for three months or more, James H. Sherry, MD, PhD, of Mylan Bertek Pharmaceuticals Inc in Morgantown, West Virginia, and colleagues reported that patients did not show significant changes in PR or QRS intervals, adding that “apomorphine does decrease heart rate and thus increases uncorrected QT intervals,” but they said there is no evidence that it raises QTc. Nevertheless, they added, “More studies are needed to further evaluate the effects of apomorphine, especially at higher doses, on QT intervals.”

• In another report, a Belgian group reported on a long-term follow-up (three years or longer) of the tolerability and safety of the continuous infusion of apomorphine by pump, 24 hours a day, in patients who had been on this therapy for at least three years. Jean-Emile Vanderheyden of the Parkinson Unit-B, Montigny Le Tilleul, Belgium, and colleagues found that the therapy was safe and effective in patients in the advanced stages of idiopathic Parkinson’s disease who are resistant to the usual antiparkinsonian medications.

They also found that it is efficacious on both motor and nonmotor fluctuations, dyskinesia, dystonia, and sleep, while reducing the need for levodopa. Adverse effects consisted mainly of subcutaneous nodules.

• In another model of continuous drug delivery, Ivar Sonbo Kristiansen, MD, Associate Professor at the University of Odense, Denmark, and colleagues investigated the cost-effectiveness of delivering Duodopa (levodopa 20 mg/mL, carbidopa 5mg/mL) by continuous duodenal delivery in severe cases of Parkinson’s disease compared to apomorphine and oral drugs. They concluded that if Duodopa improves disease severity by one Hoehn and Yahr stage, this method of delivery would be cost-saving.

TREATING NONMOTOR COMPLICATIONS

While the main thrust of the drug-study reports at the conference were aimed at the prevention of dyskinesias or other motor complications, there were also drug studies which were aimed at preventing some of the nonmotor complications of Parkinson’s disease, such as dementia and depression.

In one study reported by Werner Poewe, MD, Chairman of the Department of Neurology at Innsbruck Medical University, Austria, the benefits of rivastigmine (3 to 12 mg/day) were investigated in 211 patients with dementia due to Parkinson’s disease compared to 123 such patients randomized to placebo over a period of 24 weeks in an open extension trial following an original 24-week trial of the drug.

All patients entering the extension trial were started on the same 1.5-mg, twice-daily dosage. During the next 16 weeks, patients were titrated to their highest well-tolerated dose. Altogether, 273 patients completed both trials. The investigators concluded that the drug appeared to provide sustained benefits, with no safety concerns, for up to 48 weeks. “Continued treatment with rivastigmine may maintain cognitive and functional performance, and prevent the worsening of neuropsychiatric symptoms, for at least one year,” they said.

NR

—Jean McCann

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