We must do better (with rasagiline so far no better than levodopa as a disease-modifying therapy?)

These recent rasagiline data (Olanow et al., 2009) represent a laudable if not heroic effort on behalf of PD patients, but unfortunately they are inconclusive and  I believe they do not warrant a major change in clinical practice. The results are mixed and the benefit apparent at 1 mg (but not a 2 mg) per day, even if truly reflective of what we’re looking for (a treatment that slows down the disease), is relatively small.

Some perspective can be gained by comparing the ADAGIO results with those of another inconclusive disease-modification trial which were reported five years ago. The ELLDOPA (Fahn et al., 2004) trial endeavored to assess any disease modifying effect of levodopa the mainstay treatment of PD.   Although ELLDOPA used a less sophisticated study design to probe disease modification (with limitations that the delayed-start design of ADAGIO is intended to circumvent), the two studies share some parallel elements that allow for informative even if partial comparison. This is particularly the case for results from the phase I treatment period of the ADAGIO study and the only treatment period of ELLDOPA. During these periods UPDRS scores were serially measured in early PD subjects randomized to placebo versus increasing doses of a candidate disease-modifying agent with known symptomatic benefits (i.e., 2 doses of rasagiline in ADAGIO, and 3 doses of levodopa in ELLDOPA) for ~40 weeks. At that point the study designs diverge. The study drug was washed out in ELLDOPA for 2-4 weeks, whereas in ADAGIO the study drug was washed in to start phase II. (See Fig. 1 in Olanow et al., 2009, for conceptual orientation to the delayed-start design.)

Fig 1: ADAGIO -- Changes in Scores on the Unified Parkinson's Disease Rating Scale (UPDRS) in the Four Study Groups.The mean (±SE) change from baseline in the UPDRS score in the efficacy cohort for the second and third primary end points for patients receiving rasagiline at a dose of 1 mg per day (Panel A) and those receiving 2 mg per day (Panel B) are shown. The dashed lines indicate placebo, and the solid lines indicate rasagiline. (taken from Olanow et al., 2009)Note that in ELLDOPA levodopa not only markedly improved symptoms as expected compared to placebo but it did so with a dose-dependent decrease in the apparent rate of clinical decline over 40 weeks, seen as a decrease in the slope of the UPDRS change over time (Fig. 2).  This leveling off of the decline slope at its maxium with a moderate dose of daily levodopa (600 mg/day) appears greater than that seen with either dose of rasagine in ADAGIO (Fig. 1).  This change in slope is the 1^st of the 3 key end points deemed necessary to demonstrate disease modification in ADAGIO. (See Fig. 1 in Olanow et al., 2009)

In addition, after a washout period of 2-4 weeks in ELLDOPA those subjects who had been on levodopa showed persistently improved UPDRS score of 5 to 8 points for subjects who had been taking any levodopa dose compared to placebo (Fig. 2). Although a major limitation of ELLDOPA is uncertainty over how complete this washout was, these residual UPDRS changes greatly exceed the 1-2 or 0 points of persistent difference at the end of wash-in and phase II of ADAGIO for the 1 or the 2 mg dose compared to initial placebo, respectively. (See Fig. 1; this is the 2^nd of the 3 end points deemed necessary to demonstrate disease modification in ADAGIO.) 

Clearly there were caveats to the interpretation of the ELLDOPA study in terms of disease-modification (including also imaging results that did not correlate as expected with the clinical data). Similarly, the multiple caveats of interpretation of the ADAGIO study (and the preceding TEMPO study of rasagiline) as thoughtfully Fig 2: ELLDOPA -- Changes in Total Scores on the Unified Parkinson's Disease Rating Scale (UPDRS) from Baseline through Evaluation at Week 42.The changes in subjects treated with levodopa at different doses or with placebo were determined on the basis of the total scores on the UPDRS. The scores were obtained by blinded treating investigators who performed the evaluation before the morning dose of the daily dose of the study drug. The points on the curves indicate mean changes from baseline in the total scores at each visit. Improvement in parkinsonism is represented by lower scores, and worsening by higher scores. Negative scores on the curves indicate improvement from baseline. The bars indicate the standard error. (Taken from Fahn, et al., 2004)presented by the authors leave the disease-modifying potential of rasagiline unclear.  Thus at present I do not believe that a general recommendation to start levodopa or rasagiline in newly diagnosed PD patients is warranted. Given the inconclusiveness of ADAGIO and the mandate for clinicians to do no harm (such as that from even relatively mild side effects, financial burden or overstated hope), I respectfully disagree with the suggestion by some that rasagiline has now been shown to slow down this disease and that we should recommend its use to our patients who are newly diagnosed with PD without disabling symptoms.

So to respond to Dr. Fiske’s question, “…What now?”, I believe the answer is that we need to do better. It seems that further, perhaps more long-term study of the disease-modifying potential of rasagiline should be conducted in search of an indication that warrants a meaningful change in how we treat people with PD.  More importantly, we must press ahead with the development of other promising candidate disease-modifying therapeutics.