Reports

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17th World Congress on Parkinson’s Disease and Related Disorders

Amsterdam, The Netherlands / December 9-13, 2007

In the body, dopamine is constantly produced by hydroxylation of L-tyrosine to levodopa by tyrosine hydroxylase followed by decarboxylation of levodopa. In patients with Parkinson’s disease (PD), there is loss of dopamine in the presynaptic compartment through the action of monoamine oxidase type B (MAO-B). Dopamine continues to be formed, but the concentration is not sufficient to ensure correct neurotransmission. Therefore, blocking the action of MAO-B—in the case of the MAO-B inhibitor rasagiline, by irreversibly binding to the enzyme—increases the dopamine concentration. “The irreversibility of this binding means that the action of rasagiline is very long-lasting,” explained Prof. Fabrizio Stocchi, Department of Neurology, IRCCS San Raffaele Pisana, Rome, Italy.

Treatment in Early PD: The TEMPO Study

He cited the TEMPO (Rasagiline Mesylate [TVP-1012] in Early Monotherapy for PD Outpatients) study, where 404 untreated patients with early PD were randomized to rasagiline 1 mg or 2 mg or placebo (Parkinson Study Group. Arch Neurol 2002;59(12):1937-43). The primary efficacy outcome measure was change in total Unified Parkinson’s Disease Rating Scale (UPDRS) between baseline and week 26.

The mean total UPDRS score was almost unchanged for both treatment groups but deteriorated by approximately 4 points in the placebo group (P<0.001 for comparison of both treatment arms with placebo). Active treatment was also beneficial for both motor and non-motor components of the UPDRS and as Prof. Stocchi noted, “Single symptoms such as tremor also improved in patients on rasagiline treatment.” No safety concerns were identified.

Potential Benefit of Early Treatment

At the end of the 26-week placebo-controlled period of the TEMPO study, all patients received active treatment and were followed for a further 26 weeks. Patients then received therapy that was considered best by their treating physician, although they continued to be followed. In this long-term follow-up, almost half the patients were still receiving rasagiline monotherapy after two years of treatment, providing further evidence of both its efficacy at controlling the disease and its good tolerability.

What researchers also found interesting is that the benefit in terms of total UPDRS score in patients initially on rasagiline was carried over into the long-term follow-up. After six years, there was a significant 16% difference in mean change from baseline between the two groups, indicating a possible disease-modifying effect of rasagiline.

The ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily) study, currently ongoing in over 1000 patients, was designed to confirm this hypothesis; results are expected in 2008. The mechanism for a possible disease-modifying effect can only be speculative at present, although presentations by Dr. Wilfried Dimpfel, Justus-Liebeg University, Hessen, Germany, and Jonathan M. Brotchie, PhD, Senior Scientist, Division of Brain Imaging and Behaviour Systems/Neuroscience, Toronto Western Hospital, Ontario, showed results from animal models suggesting that both rasagiline and its metabolite 1-aminoindan may have anti-parkinsonian effects in addition to MAO-B inhibition.

Dopaminergic Therapy

Most patients with PD will eventually progress and require levodopa. Despite coadministration of a D-carboxylase inhibitor to block peripheral conversion to dopamine, motor fluctuations affect 80% of levodopa-treated patients and can represent a major cause of disability. Currently, non-motor symptoms, such as anxiety, restlessness and irritability, are also receiving attention.

Two large pivotal studies have been performed with rasagiline as an adjunct to levodopa. The PRESTO study compared 1 mg or 0.5 mg/day doses with placebo (Parkinson Study Group. Arch Neurol 2005;62(2):241-8) and the LARGO study compared rasagiline with entacapone or placebo (Rascol et al. Lancet 2005;365(9463):947-54). In both studies, active treatment significantly reduced “off” (poor motor function) time and lengthened “on” time compared to placebo. “What was even more interesting,” Prof. Stocchi observed, “was that rasagiline was as effective as a well-established drug such as entacapone in increasing ‘on’ time.” Moreover, in additional analysis of the severity of “off” time in the morning before the first dose, patients receiving rasagiline fared better than those receiving entacapone or placebo, an observation that Prof. Stocchi related to the irreversible binding to MAO-B. In a pooled analysis of these two studies, the frequency of adverse events was similar for placebo and rasagiline, even for patients >70 years of age, suggesting that treatment is safe in older patients.

Everyday Clinical Practice

In view of the encouraging findings from the TEMPO study, the MDS and EFNS guidelines both indicate that rasagiline monotherapy is effective for control of symptoms and the NICE guidelines recommend MAO-B inhibitors as first-choice therapy in early PD. Findings from PRESTO and LARGO prompted the NICE guidelines to recommend MAO-B inhibitors as first-choice therapy in late PD and both the AAN and EFNS guidelines indicate that rasagiline can reduce “off” time in patients with motor complications.

An important point with rasagiline is its simple dosing regimen. According to Prof. Heinz Reichmann, Department of Neurology, University of Dresden, Germany, “Adherence is poor in PD, perhaps because of the rigid and difficult regimens, but the simple once-daily regimen of rasagiline should improve adherence.” Prof. Reichmann also presented the results of a post-marketing study in an everyday clinical setting. In total, 754 patients recruited from neurological practices were evaluated at baseline, four weeks and four months. In the analysis of patients receiving adjunct therapy, the total and classical motor subscores on the Columbia University Rating Scale had improved by the final evaluation. Prof. Reichmann reported, “Non-motor subscore improved as well, patients reported less sialorrhea, getting up improved and even posture improved.” Given that some patients in the study showed improvement only after four weeks, Prof. Reichmann commented, “I normally advocate that the improvement should come in the first four weeks and afterwards I would not expect any more improvement, but maybe that is not true and we should give rasagiline longer before making a final decision.”

Its use in the clinic was further illustrated in a series of case reports presented by Prof. Murat Emre, Department of Neurology, Istanbul Faculty of Medicine, Turkey. For example, a 55-year-old woman with no relevant medical history had been suffering from pain in her left shoulder for one year. This had been diagnosed as tendonitis but anti-inflammatory treatment and physiotherapy had not alleviated pain. She reported a slight loss of dexterity when sewing and her daughter had also noticed a slight intermittent rest tremor in her left hand. On examination, finger tapping was minimally slowed but no rigidity was apparent. Minimal rest tremor was apparent when performing mental activity. Walking was normal except for a slight reduction in left arm swing. Prof. Emre had diagnosed early pre-motor PD and prescribed rasagiline. After three months, the patient’s tremor and shoulder pain had improved. “I recently saw her after six months and she is doing fine,” he added. In this case, diagnosis of early PD seemed clear after a detailed examination and rasagiline effectively reduced her symptoms.

Summary

The efficacy expected from the mechanism of action of rasagiline was confirmed in three pivotal clinical trials. The promising findings of these trials have since been confirmed by post-marketing studies and general clinical experience, with very few safety problems identified.