Parkinson's disease - sarizotan

Parkinson's disease is a degenerative disorder, and sufferers are afflicted by tremor and rigidity. These result from a deficiency of the neurotransmitter dopamine, which is caused by the degeneration of the substantia nigra that lead to the loss of cells that produce dopamine within the brain. Secondary symptoms include insomnia, depression and dementia.

It became treatable when it was realised that administering the dopamine prodrug levodopa restored the brain's dopamine levels, giving symptomatic relief. However, the drug commonly causes dyskinesias - involuntary movements - which adversely affect patients' quality of life and increase the overall healthcare cost burden of the disease.

The drug sarizotan was initially investigated by Merck KGaA as a treatment for schizophrenia, but it is now being developed as a potential treatment for this dyskinesia. It is an agonist at the 5-HT1A receptor and also exhibits antagonism/partial agonism at the dopamine D2 receptor, and the theory is that it would improve these motor side effects by reducing striatal serotonergic nerve impulse activity.

Several clinical trials have been carried out, including a double blind, placebo-controlled proof of concept study in 18 patients with moderate to severe Parkinson's disease, who had all been treated with levodopa for an average of six years and experienced peak dose dyskinesias.¹ After a one week run-in phase, they were given 2mg sarizotan twice a day for a week, and then 5mg twice a day for a further week. It had no effect on the severity of the Parkinson's, either alone or in combination with levodopa, but it reduced the levodopa dyskinesias by 40% compared with levodopa on its own.

In another trial, 64 patients with advanced Parkinson's disease and dyskinesias were escalated from 2mg twice a day through 5mg to a maximum of 10mg doses over the first three weeks.² They continued to receive this dose twice a day for nine weeks, followed by a two week withdrawal period. Subjects experienced a mean increase in time without dykinesia from 3.7 hours to 6 hours by the end of the maintenance phase, and there were also significant benefits in secondary efficacy parameters.

Subjects were then able to continue on the drug, open label, for up to two years, being titrated back to the optimal dose of 2, 5, 7 or 10mg of the drug as established in the previous study.³ A total of 46 patients continued therapy, and after one year the time without dyskinesias increased by a further 1.4 to 2.4 hours; dyskinesia was aggravated in 20% of patients. Phase III trials continue.