Adding Azilect (rasagiline) — a medication already approved to treat Parkinson’s disease — to Rilutek (riluzole) may be able to slow the advancement of fast-progressing amyotrophic lateral sclerosis (ALS), a Phase 2 trial suggests.
However, its positive safety results are being challenged by other physicians, who raise concerns that the design of randomized, controlled trials is not ideal for drawing conclusions about safety.
Trial results were published in the study, “Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial,” in the journal The Lancet Neurology.
Azilect is a monoamine oxidase-B (MAO-B) inhibitor approved for the treatment of Parkinson’s disease symptoms. It works by increasing the levels of dopamine — an important chemical messenger in the brain — which has been suggested to regulate motor nerve cell function.
Preclinical studies have shown that Azilect prolonged the survival of a mouse model of ALS in a dose-dependent way, alone or in combination with Rilutek (riluzole) — the first FDA-approved therapy for ALS. In addition, a small, open-label, single-arm, Phase 2 trial (NCT01232738) showed that Azilect positively changed exploratory ALS blood biomarkers.
Now, this study presents results for a randomized, double-blind, placebo-controlled, Phase 2 trial (NCT01879241) — sponsored by the University of Ulm in Germany — that evaluated the safety and effectiveness of Azilect combined with Rilutek for ALS patients.
The study enrolled 252 ALS patients, with a mean age of 60.2 years, at 15 study centers from the German network for motor neuron diseases (MND-NET). Eligible patients had ALS for between six months and three years, and the onset of progressive weakness within the three years prior to the study.
Patients were randomized to receive, on a daily basis, either 1mg of Azilect (127 patients) or a placebo (125 patients), in addition to 100mg of Rilutek, for 18 months.
The primary goal was survival time, defined as the time until death or until the study cutoff date, which was the last patient’s last visit, plus 14 days.
Secondary effectiveness goals included changes in patients’ overall function, assessed by the ALS Functional Rating Scale — Revised (ALSFRS-R); lung function, measured through slow vital capacity; and quality of life, using the Schedule for Evaluation of Individual Quality of Life (SEIQoL).
Results showed that the addition of Azilect to Rilutek treatment did not prolong the patients’ survival time, nor their overall function, lung function, or quality of life.
However, Azilect was found to significantly slow disease progression, both in terms of survival and overall function, in a subpopulation of participants who had fast-progressing ALS — defined as those with a decrease of more than 0.5 points per month in ALSFRS-R scores, between first symptoms and the beginning of the study.
These findings suggest that Azilect may not have a therapeutic effect in ALS in general, but ALS patients with fast-progressing disease may benefit from Azilect as an add-on therapy.
The researchers noted these results should be confirmed in a future clinical trial, and that disease-modifying therapies may have variable effects depending on the rate of disease progression.
“It appears mandatory that a careful analysis of disease progression rate should be done at trial inclusion to identify, and ideally stratify, patients with slow and fast progressing disease,” the team wrote.
In terms of safety, researchers found comparable frequencies of adverse and serious adverse events between the two groups, concluding that Azilect was well-tolerated and that most adverse events were associated with ALS disease progression.
However, a correspondence article in the same journal issue from a group of physicians in Lisbon, Portugal, challenged this conclusion. They argued that the comparable rates of adverse events between the two groups of patients may be caused by something called the nocebo effect, which seems to be stronger in ALS patients than in people with other neurological disorders.
Similar to the placebo effect, where health improves solely under the patient’s assumption of receiving the treatment, the nocebo effect works the opposite way, with patients experiencing side effects due to anticipating negative reactions to the treatment.
“We suggest these concerns should be considered on the critical appraisal of safety data from amyotrophic lateral sclerosis trials and for the design of future studies,” the physicians wrote.