GAITHERSBURG, MD. – The cholinesterase inhibitor rivastigmine is likely to be approved for a second indication: the treatment of mild to moderate dementia associated with Parkinson's disease, based on a study that found treatment was associated with significant benefits in cognition, behavior, and activities of daily living in such patients.
Only one study of rivastigmine–the EXPRESS trial–has been submitted to the Food and Drug Administration for approval of the new indication. However, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee unanimously agreed that the study was well designed for evaluating the efficacy and safety of the drug in treating mild to moderate dementia associated with Parkinson's, the indication proposed for approval by the manufacturer, Novartis Pharmaceuticals. Usually two studies are submitted to the FDA for consideration for approving a drug.
The panel was not asked to specifically vote on whether to recommend approval, but all eight panelists at the meeting agreed that the overall data indicated that rivastigmine, at a dose of 3–12 mg per day, was safe in this population. The panel voted 7 to 0 with one abstention that, based on its results, the study did not need to be replicated for the FDA to approve the new indication.
“What convinces me that one study is enough” is the amount of safety data available for its use in Alzheimer's disease and “robust finding[s] on all secondary end points” for Parkinson's dementia, which were congruous with findings on the primary end points, said panel member Dr. Ralph L. Sacco, professor of neurology and epidemiology at the Neurological Institute of New York at Columbia University.
Novartis markets rivastigmine as Exelon, which was approved in the United States in 2000 for mild to moderate dementia of the Alzheimer's type. It was approved for the Parkinson's indication in the European Union earlier this year, but there are no treatments currently approved for this indication in the United States. The FDA usually follows the recommendations of its advisory panels.
The EXPRESS study compared the impact of rivastigmine with that of placebo over 24 weeks in 541 patients with mild to moderate dementia (362 on treatment, 179 on placebo) with a mean age of 72 years. They had been diagnosed with Parkinson's a mean of about 9 years earlier, and a mean of about 7 years had elapsed between their diagnosis and the appearance of the first dementia symptoms.
At 24 weeks, changes from baseline in the primary efficacy outcome end points, two subscales of the Alzheimer Disease Assessment Scale (ADAS) that assessed cognition and overall dementia, significantly favored those treated with rivastigmine. The secondary outcome measures of activities of daily living, executive function, attention, and behavior at 24 weeks were also significantly improved among the treated patients.
Among those on rivastigmine, 27% discontinued treatment, compared with 18% of those in the placebo group; in both groups, most discontinued because of an adverse event. During the study and an extension study that followed patients for another 48 weeks, the most frequent side effects among treated patients were cholinergic, including nausea (29%), vomiting (17%), and worsening tremor (10%), which in most cases were mild to moderate and infrequently resulted in discontinuing treatment, according to Novartis.
Speaking on behalf of Novartis at the meeting, Dr. Clive Ballard, professor of age-related diseases at the Institute of Psychiatry, King's College, London, described Parkinson's dementia as a distinct dementia syndrome that can be “unambiguously diagnosed in routine clinical practice” by using three principles: The patient has an established diagnosis of idiopathic Parkinson's disease, develops dementia at least 1–2 years after the onset of PD, and has had other causes of dementia excluded.
Autopsy studies indicate that these criteria accurately diagnose 90% of cases, he said, adding that there is emerging evidence that a cholinergic deficit, shared by PD and Alzheimer's, is associated with many of the key cognitive deficits and neuropsychiatric symptoms.
In a unanimous vote, the panel agreed that there was a separate form of dementia associated with Parkinson's that is distinct from Alzheimer's disease, and that there are operational criteria that could be used for making the diagnosis clinically.
Dr. Russell Katz, director of the FDA's division of neurology products, explained that FDA reviewers had wanted to know whether the panel believed that the average practicing neurologist could reliably diagnose dementia in these patients and distinguish it from Alzheimer's dementia using the algorithm described by the company.
Panel member Dr. J. Eric Ahlskog, professor of neurology at the Mayo Clinic, Rochester, Minn., said that although clinicians in a busy clinic may not be good at sorting out specific changes such as changes in executive function, “we are pretty good as neurologists in saying yes, this person is demented.” He agreed that the type of dementia could be ascertained by the two-step process of determining whether a patient has Parkinson's and whether he or she has developed dementia after an interval of time.