Orion: Primary objective of STRIDE-PD study was not achieved
The result of the primary endpoint measured in STRIDE-PD, a clinical study with Orion's proprietary drug Stalevo® (levodopa, carbidopa and entacapone) in 747 patients with early Parkinson's disease (PD) requiring levodopa treatment, demonstrates that Stalevo does not delay the onset of involuntary movements, dyskinesia. The study was aimed to provide support for extending the current EU indication to early Parkinson's disease.
Stalevo is currently indicated for the treatment of adult patients with Parkinson's disease and end-of-dose motor fluctuations not stabilised on levodopa/dopa decarboxylase inhibitor (DDCI) treatment. Applications for extending the indication of Stalevo to patients requiring initiation of levodopa therapy are already under review by the European Medicines Agency (EMEA) and the U.S. Food and Drug Administration (FDA), based on the favourable results from FIRST-STEP, a study conducted in North America and Europe by Novartis, Orion's marketing partner for the product. Procedures have been initiated with the health authorities to evaluate the implications of the results received from STRIDE-PD on the ongoing review processes.
The aim of the STRIDE-PD study (STalevo Reduction In Dyskinesia Evaluation) was to evaluate, whether Stalevo (combination formulation of levodopa/carbidopa/entacapone in one tablet), when used as initial levodopa therapy for Parkinson's disease, would be able to delay the time to the onset of involuntary movements (dyskinesia), when compared with a standard formulation of levodopa/carbidopa. The primary endpoint was the time to onset of dyskinesia.
STRIDE-PD was a multicenter, double-blind, randomized, flexible-dose (200 to 1000 mg of levodopa) study with a variable treatment duration of 134 to 208 weeks. The target daily dose was 400 mg levodopa given as carbidopa/levodopa or Stalevo divided in four doses per day given at 3.5-hour intervals. The study was performed from 2004 to 2008 in collaboration with Novartis, Orion's marketing partner. A total of 747 patients were randomized at 77 centers (57 for Novartis, 20 for Orion) in 14 countries in Europe and North America. The study population consisted of early-stage Parkinson's disease patients who required initiation of levodopa therapy. Other permitted concomitant anti-parkinsonian medication included dopamine agonists, monoamine oxidase type B inhibitors, and anticholinergics.
Primary and secondary efficacy endpoints
The objective of the STRIDE-PD study was to demonstrate, that Stalevo given four times daily at 3.5 hours intervals delays the time to development of dyskinesia in comparison to a standard formulation of carbidopa/levodopa in Parkinson's disease (PD) patients warranting initiation of levodopa treatment. The results of the study showed, however, that the time to dyskinesia was statistically significantly shorter in Stalevo-treated patients compared to carbidopa/levodopa-treated patients.
The incidence of dyskinesia during the study period was higher in Stalevo-treated patients in comparison to the carbidopa/levodopa group. Wearing-off was reported more frequently in carbidopa/levodopa-treated patients vs. Stalevo-treated patients. Patients treated with Stalevo had slightly better PD symptom control in comparison to carbidopa/levodopa-treated patients during the whole study period.
Safety and tolerability
The known gastrointestinal disorders of nausea and diarrhea were more frequently reported with Stalevo. Preliminary results indicate that, although the frequency of ischemic heart disease events in STRIDE-PD was similar compared with previous entacapone studies as well as the incidence noted in a similarly-aged general population, less events of myocardial infarction were observed in the carbidopa/levodopa group. Overall, the occurrence of neoplasm was similar in both treatment groups, but there were less cases of prostate cancer and more cases of skin cancer in the carbidopa/levodopa group. These imbalances are being investigated, and discussion with the regulatory authorities is ongoing.
Timo Lappalainen Olli Huotari
President and CEO Senior Vice President, Corporate Functions
Dr. Reijo Salonen, SVP, Pharmaceutical R&D, phone +358 10 426 3647
Useful additional information
Stalevo is a proprietary treatment for Parkinson's disease originated and manufactured by Orion Corporation. It was approved in the US and EU in 2003 for the treatment of adult patients with Parkinson's disease and end-of-dose motor fluctuations not stabilized on levodopa/dopa decarboxylase (DDC) inhibitor treatment. Stalevo contains both a DDC inhibitor (carbidopa) and a COMT inhibitor (entacapone) that prevent the breakdown of levodopa and so provide a more continuous supply of levodopa to the brain. Stalevo tablets are available in six different strengths, each with a 1:4 ratio of carbidopa to levodopa and combined with 200 mg of entacapone in a standard-release formulation. The product is now available in about 80 countries worldwide including all EU countries and the USA. Since the launch, the cumulative exposure to Stalevo is more than 715,000 patient years.
The most common side effects of Stalevo are unwanted or uncontrollable movements (known as dyskinesia), nausea, diarrhea, excessive muscle movements (known as hyperkinesia), harmless discoloration of urine, sweat and/or saliva; diminished or slow movements (known as hypokinesia), abdominal pain, dizziness, constipation, fatigue, pain, and hallucinations.
About Parkinson's disease
Parkinson's disease is a progressive disorder of the central nervous system that affects over six million people worldwide including 1.5 million in the US alone. While their cause is unknown, the symptoms of Parkinson's disease may include tremor, slowness of movement, stiffness and rigidity of limbs and balance problems. The symptoms are primarily the result of a degeneration of dopaminergic cells, or neurons, in the substantia nigra, a part of the brain that controls and modulates movement. As the disease progresses, these symptoms usually increase and impact a person's ability to function. More information about PD is available on, e.g., the homepage of the European Parkinson's Disease Association, EPDA, http://www.epda.eu.com/.
Dyskinesia in PD are involuntary movements associated with dopaminergic drug therapies
Involuntary movements, also known as dyskinesia, are associated with prolonged use dopaminergic therapies. The mechanisms behind dyskinesia are not fully understood, but their emergence is believed to be caused by changes in the neuronal network in the basal ganglia area in the brain related to the implications of both Parkinson's disease and its medicinal treatment.
Orion is a European pharmaceuticals and diagnostics company dedicated to treating and preventing disease by discovering and developing innovative medicinal treatments and diagnostic tests for global markets. Orion is engaged in human and veterinary drugs, active pharmaceutical ingredients and diagnostic tests. In 2008, Orion's net sales were € 710.7 million. Operating profit was € 184 million, and the company invested € 99 million in pharmaceutical research and development. The number of employees is about 3,100. Orion corporate headquarters are in Espoo, Finland. Orion is listed on NASDAQ OMX Helsinki. For more information, please visit: http://www.orion.fi/english/.
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