Azilect®

Azilect® (rasagiline tablets) is Teva's second innovative drug, indicated for the treatment of Parkinson's disease (PD), both as initial monotherapy in the early stage of the disease and as an adjunct to levodopa in moderate to advanced stages of the disease. Its development was based on original research performed in the Rappaport Research Institute, Technion, Haifa, Israel by Profs. Moussa Youdim and John Finberg. Azilect® is a potent, second-generation, irreversible monoamine oxidase type B (MAO-B) inhibitor with neuroprotective activities demonstrated in various in vitro and in vivo studies. Its beneficial clinical effect, seen over the entire spectrum of the disease, combined with its once-daily dosing, lack of titration and high tolerability, allows Azilect® to address significant unmet needs in the treatment of PD. In addition, recent results of the ADAGIO trial suggest that Azilect® has benefits consistent with a possible disease-modifying effect and provide support for the possibility that early treatment with AZILECT® may slow the development of disability - the key unmet need for this disease...

Azilect® Product Profile

Azilect once daily is efficacious in the treatment of PD as monotherapy in early-disease, providing patients with symptomatic effects on motor symptoms, activities of daily living, and quality of life. Azilect® also has demonstrated efficacy as an adjunct therapy of PD: symptomatic control of PD and treatment of motor complications in moderate-to-advanced PD patients experiencing motor fluctuations. All adjunct effects were demonstrated on top of optimized anti-PD therapy. Azilect® has been proven to be safe and well tolerated in both monotherapy and adjunct therapy in PD patients of all ages, with low incidence of adverse events and low discontinuation rate. In contrast with most other treatments for PD, Azilect® has a simple dosing regimen of one tablet taken once daily, with or without food, and it does not require titration. This combination of simple regimen and very good tolerability contributes to patients' compliance with treatment, and therefore to the success of treatment.

Clinical Development of Azilect®

Azilect® has demonstrated efficacy and safety in three pivotal studies that included over 1,500 patients with Parkinson's disease at different stages of the disease.

TEMPO - performed in North America, demonstrated the clinical efficacy of Azilect® as monotherapy in early PD patients. Patients were then followed in a delayed-start design, which demonstrated less functional decline in patients that received Azilect® early. Patients were also followed through an open-label long-term extension phase of over 6 years, confirming the safety and efficacy of early treatment with Azilect in the long term.
LARGO - conducted in Europe, Israel and Argentina, and its results showed high efficacy of Azilect as an adjunct therapy, given on top of other anti PD medications, with entacapone as an active comparator.
PRESTO - performed in North America, results confirming the clinical efficacy of Azilect as adjunct therapy in moderate-to-advanced PD patients.

Based on the results of these trials, Azilect was granted marketing approvals in the US, Canada, the EU, Israel, and some additional countries.

The ADAGIO (Attenuation of Disease progression with Azilect® Once-daily) study

Until recently, no treatment had ever been proven to slow the progression of Parkinson's disease. The pharmacological strategy for the management of Parkinson's disease has involved the use of drugs to reduce the motor symptoms of the disease and to otherwise bring symptomatic relief to patients. Based on the findings of the 12-month TEMPO and its open extension results, as well as the broad pre-clinical evidence for the neuroprotective effects of rasagiline, Teva initiated the ADAGIO study with AZILECT in November 2005.

ADAGIO was a global study performed in 14 countries to explore the disease modifying effects of Azilect® using a novel delayed-start design in early na've PD patients. In June 2008, Teva announced the positive results of the ADAGIO study, which were then published in the New England Journal of Medicine in September 2009.

ADAGIO was one of the largest trials ever carried out in PD. The study recruited 1176 early PD patients in Europe, North America, Israel and Argentina. The novel delayed-start design employed a 9 month, double-blind, placebo-controlled phase, and a second 9-month active treatment phase comparing the early-start cohort with the delayed-start cohort. AZILECT® 1mg, the marketed dose worldwide, met all three endpoints of the primary analysis in a hierarchal manner.

Marketing and Distribution

Azilect® was first launched in Israel, in March 2005, and shortly thereafter, in the first EU countries, the UK and Germany. In the USA, Azilect® was launched in July 2006. Presently, Azilect® is available in 38 countries worldwide. Teva has a long-term agreement for the joint development and marketing of Azilect in Europe and some additional markets with H. Lundbeck A/S (www.lundbeck.com). In North America, Azilect® is marketed by Teva's wholly-owned subsidiary Teva Neuroscience (www.tevaneuro.com).

About Parkinson's Disease

Parkinson's disease (PD) is a degenerative disorder of the central nervous system that impairs the sufferer's motor skills and speech. PD is both a chronic and progressive illness, which results in a marked decrease in the health-related quality of life of patients and their caregivers and places a tremendous economic burden on society. An estimated four million patients are affected by this chronic disease worldwide, which typically occurs at a late age, affecting approximately 1% of the population over the age of 65. 1 in 20 people diagnosed with PD is younger than 40 years.

Selected Publications

TEMPO (6-months): Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol 2002; 59 (12):1937-1943.
TEMPO (12-months): Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61 (4):561-566.
TEMPO (up to 6.5 years): Hauser, RA et al. Long-term outcome of early versus delayed rasagiline treatment in early Parkinson's disease. Mov Disord. 2009;24 (4):564-73.
LARGO: Rascol O, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005; 365 (9463):947-954.
PRESTO: Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005; 62 (2):241-248.
ADAGIO: Olanow CW et al. A randomized, double-blind, placebo-controlled, delayed start study to assess rasagiline as a disease modifying therapy in Parkinson's disease (the ADAGIO study): rationale, design, and baseline characteristics.. Mov Disord 2008; 23 (15):2194 - 2201.
ADAGIO: Olanow, CW et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med. 2009;361 (13):1268-78.

For additional information about Azilect®, please see the product website: www.Azilect.com.

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