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PRIORITY PRESS - 14th Congress of the European Federation of Neurological Societies

Geneva, Switzerland / September 25-28, 2010

Early diagnosis of Parkinson’s disease (PD) remains a key challenge to better treatment, according to Dr. Anthony Schapira, University College London, UK. Placebo-controlled clinical trials of candidate therapies underscore the importance of early diagnosis. Follow-up in the placebo arm of various trials have shown progression rates of 6.2 to 12.0 units/year in the Unified Parkinson’s Disease Rating Scale (UPDRS).

“We encounter 3 broad issues in the medical management of PD,” remarked Dr. Schapira. “Early diagnosis is the first issue; secondly, we must modify the rate of clinical progression; finally, we must establish and maintain symptomatic control.”

Several therapies have demonstrated the ability to provide symptomatic relief for patients with PD. Levodopa, dopamine agonists and inhibitors of monoamine oxidase-B (MAO-B) such as rasagiline have proven efficacy for symptomatic control, stated Dr. Schapira. Levodopa can cause troublesome motor complications and has the least favourable adverse-event profile among the effective therapies. Dopamine agonists and MAO-B inhibitors have a low risk of motor complications. With regard to the safety and efficacy of anticholinergics, b-blockers and amantadine, evidence is lacking, noted Dr. Schapira.

Benefits of Effective Therapy

Effective treatment of PD affords benefits that go beyond symptomatic control. A recent study examined the clinical course of 200 treatment-naive patients followed for 18 months (J Neurol Neurosurg Psychiatry 2007;78:465-96). All 8 domains of the PD questionnaire (PDQ-39) and the overall score worsened significantly (P<0.01). In contrast, self-reported health status tended to improve in a contemporary cohort of patients who initiated treatment at or soon after diagnosis of PD.

Effective therapy can lead to significant improvement in a relatively short period of time. In the TEMPO (TVP-1012 in Early Monotherapy for Parkinson’s Disease Outpatients) trial, for example, treatment of early-stage PD with either of 2 doses of rasagiline resulted in a 3- to 4-unit improvement in the UPDRS within 6 months compared with placebo (Arch Neurol 2002;59:1937-43). Moreover, treatment led to significant improvement in the individual components of the UPDRS.

Slowing Symptom Progression

Slowing symptomatic progression represents the greatest therapeutic challenge in the management of PD, according to Prof. Olivier Rascol, Université de Toulouse III - Paul Sabatier, France. Unfortunately, clinical trials involving a variety of therapies have failed to demonstrate disease modification. Explanations for these failures remain unclear.

Some encouragement emerged from the mixed results of the ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily) trial (N Engl J Med 2009;361:1268-78). The study design was to prospectively examine rasagiline as a disease-modifying therapy in PD and incorporated a delayed-start strategy whereby patients were randomized to immediate therapy with 1 of 2 doses of rasagiline continued for 72 weeks or to placebo for 36 weeks, followed by rasagiline therapy for an additional 36 weeks.

Immediate therapy with rasagiline 1 mg/day was associated with significant symptomatic improvement. However, the 2-mg dose was not significantly better than placebo. Investigators had no explanation for the disparate results which continue to be analyzed, Dr. Rascol told delegates.

The delayed-start design of ADAGIO reflects the belief that effects of early treatment slow symptomatic progression, whereas later activity slows clinical deterioration. The trial had 3 end points: efficacy of rasagiline vs. placebo with regard to the change in UPDRS score between weeks 12 and 36; superiority of immediate therapy to delayed therapy with respect to change in UPDRS score from baseline to 72 weeks; and non-inferiority of immediate vs. delayed-start therapy for change in UPDRS score between weeks 48 and 72. Rasagiline 1 mg/day met all 3 end points, but the 2-mg dose met none of them.

Further confounding results emerged from the 1-year data of the TEMPO trial which suggested that 2 mg/day did slow symptom deterioration, noted Prof. Rascol. Moreover, 1-year data from the TEMPO trial, which also had a delayed-start design (but was not specifically designed to measure disease-modifying effects), suggested that the higher dose did slow the deterioration of symptoms, adding to the uncertainty surrounding the results with the higher dose in the ADAGIO study, he told delegates.

Results of a negative trial of delayed-start therapy might have implications for other studies that employ the delayed-start design, Prof. Rascol continued. Investigators in the PROUD (Pramipexole on Underlying Disease) trial randomized patients to immediate or delayed treatment with the dopamine agonist pramipexole. Results of the study, reported only in abstract form thus far, showed no difference in outcomes after 15 months.

The PROUD trial differed from ADAGIO in several respects. The primary outcome of PROUD comprised a combination of clinical (change in UPDRS score) and imaging (changes in dopamine transporter) end points. Patients in PROUD received a lower pramipexole dose than the one that had demonstrated efficacy in earlier trials.

“Long-term follow-up is ongoing to assess the clinical meaning of the findings over time, measuring the effect of therapies on cumulative disability,” Prof. Rascol told delegates.

Mechanistic Explanation for Activity

Mechanistic differences among PD treatments may also explain disparate results from clinical trials that have a similar design but involve different agents that have demonstrated symptomatic benefits, according to Dr. Peter Jenner, King’s College, London, UK.

PD has a complex pathogenesis, but neuronal mitochondrial dysfunction is central to the disease process. Mitochondrial dysfunction triggers the cell-death cascade (apoptosis), which leads to dopaminergic cell loss in the substantia nigra, a characteristic pathologic finding. An intervention that disrupts the apoptotic process associated with mitochondrial dysfunction would have clear applicability to treatment of the condition.

“In studies involving isolated mitochondria, rasagiline significantly inhibited the [opening of the] mitochondrial transition pore, the decline in mitochondrial membrane potential and mitochondrial swelling, indicating direct targeting of mitochondria,” reported Dr. Jenner.

It also inhibits the release of cytochrome C and translocation of proapoptotic glyceraldehyde-3-phosphate dehydrogenase into the cell nucleus. Additionally, rasagiline induces pro-survival genes, such as Bcl-2 and Bcl-xl, and neurotrophic factors.

Aminoindan, the primary metabolite of rasagiline, has multiple characteristics consistent with symptom-altering activity, Dr. Jenner continued. Aminoindan prevents apoptosis; decreases cleavage of caspase 9 and caspase 3; upregulates genes associated with anti-apoptotic proteins; downregulates expression of pro-apoptotic genes; and increases levels of the pro-survival form of protein kinase-C.

“Emerging evidence from a variety of sources has suggested an interactive mechanism of action,” noted Dr. Jenner. “Symptomatic effects are enhanced by preservation of endogenous dopamine and a slowing of the breakdown of dopamine and an increase in compensatory changes.”?

Summary

The continued aging of the population suggests the physical, emotional and economic burdens of PD will continue to increase well into the future. This scenario has created a mandate for therapies that have the ability to alter progression of symptoms. Clinical studies with a variety of medications have generally yielded disappointing results with respect to that mandate. In the ADAGIO trial, the MAO inhibitor rasagiline 1 mg/day has demonstrated effects suggestive of potential slowing of clinical progression, consistent with earlier trials designed to assess the effects of early treatment. However, 2 mg/day failed to demonstrate effects that were distinguishable from placebo, a finding that has yet to be fully explained. Mechanistic studies suggest the MAO inhibitor has a highly focused activity that centres on neuronal mitochondria and inhibits mitochondrial dysfunction characteristic of PD. Further studies into potential disease modification are required in order to validate a therapy capable of reversing disease progression.