Azilect® (rasagiline) is a prescription drug indicated for the treatment of Parkinson’s disease as monotherapy for patients in the early stage, and as an adjunct to levodopa for patients in the moderate to advanced stage.
The drug was co-developed by Teva Pharmaceutical, a pharmaceutical company based in Israel, and the Technion – the Israel Institute of Technology. It is available as white-to-off-white, round, flat, bevelled tablets in 0.5mg and 1mg dosage strengths for oral administration.
Teva made an agreement with Lundbeck, a pharmaceutical company based in Denmark, to commercialise the drug in Europe and select Asian countries, including China, South Korea, Hong Kong, Malaysia, Thailand and the Philippines. In 2016, Lundbeck transferred the sales rights back to Teva for Europe upon the availability of the first generics.
Teva licensed the marketing rights for the drug in Japan to Takeda, a Japanese pharmaceutical company, in April 2014. The drug was approved in Japan in March 2018.
Regulatory approvals for Azilect
Azilect was approved for marketing in Israel in January 2005. It received approval from the European Medicines Agency (EMA) in February 2005, followed by approval from the US Food and Drug Administration (FDA) in May 2006.
The FDA expanded Azilect’s label as an adjunct to dopamine agonists (DAs) in June 2014.
Azilect is available in more than 50 countries globally, including the US, Canada, Israel, Mexico, selected Asian and all European Union countries.
Parkinson’s disease causes and symptoms
Estimated to affect more than ten million people worldwide, Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. It is a progressive neurological disorder characterised by tremors, stiffness in the limbs and slow movement as well as impaired balance and co-ordination. Primarily a disease of the elderly, its prevalence is projected to rise as the proportion of elderly people in the Western population continues to increase.
PD is a disease of the basal ganglia arising from the loss of dopamine-producing cells in the substantia nigra. The loss of dopamine, a major neurotransmitter, produces the characteristic motor symptoms of PD. Current treatments aim to address the deficiency in dopamine production.
Levodopa, a naturally occurring amino acid, has been the mainstay of treatment for PD for the last 30 years. Although it remains the gold standard, over time as many as three-quarters of patients on levodopa develop long-term side effects such as dyskinesias (involuntary movements), “on-off” motor syndromes and mental disturbances, such as hallucinations.
While the ultimate goal of treatment is to cure the disease, new drugs that can offer improved symptomatic relief are greatly needed. MAO-B inhibitors are an important new class of drugs for symptomatic relief of PD. As the name implies, they inhibit MAO-B, an enzyme responsible for the breakdown of dopamine. By preventing dopamine breakdown, MAO-B inhibitors may help reduce dopamine loss and delay the need for treatment with levodopa, thus increasing its clinical utility.
Selegiline was the first MAO-B inhibitor to be approved for the treatment of PD. Approval of rasagiline, a second-generation compound, has increased treatment options with this class of agents. Compared with selegiline, rasagiline exhibits more potent in vivo inhibition of MAO-B, and because its metabolism is different it appears devoid of the undesirable amphetamine-related effects seen with selegiline, such as an increase in blood pressure, sleep disturbances and euphoria.
Azilect’s mechanism of action
Dopamine insufficiency is the primary cause of the clinical signs of PD. Azilect is a selective irreversible inhibitor of MAO-B, which increases dopamine activity in the brain by preventing its breakdown to restore its levels to normal. It leads to the restoration of normal mobility, balance and co-ordination in patients.
Clinical trials on Azilect
The clinical efficacy and safety of rasagiline was evaluated in a series of phase III clinical trials. It was administered alone or in combination with standard levodopa therapy. In the 26-week TEMPO trial, in which rasagiline monotherapy was compared with placebo in 404 patients with early PD (who were not on levodopa), treatment with rasagiline was significantly more effective than placebo with respect to change in the Unified Parkinson’s Disease Rating Scale (UPDRS) score from baseline to endpoint.
When treatment was continued for a full 12 months, patients in the two active treatment arms (1mg and 2mg rasagiline) of the TEMPO trial showed a smaller decline in total UPDRS compared with those whose switch to active treatment was delayed by six months (placebo group). These findings suggest that early initiation of rasagiline may slow the progression of impairment associated with PD.
Efficacy was also demonstrated when rasagiline was given in conjunction with levodopa. In the 26-week placebo-controlled PRESTO trial involving 472 PD patients, rasagiline at a 1 mg per day or 0.5mg per day dose, given in conjunction with levodopa, significantly reduced “off-time” compared with placebo as well as improving motor function. “Off-time” is used to describe periods of poor overall function when the effects of levodopa wear off and symptoms return.
This is supported by data from the 697-patient LARGO trial, in which PD patients were randomised to 18 weeks of treatment with rasagiline, entacapone (a COMT inhibitor), and a placebo in addition to levodopa.
Consistent with the PRESTO trial, treatment with rasagiline reduced off-time, with the magnitude of response similar to that seen with entacapone. In this study, rasagiline was noted for its long duration of action.
The ADAGIO follow-up trial suggested that early treatment with rasagiline at a 1mg per day dose may exert a neuroprotective effect and slow the progression of PD in patients.