Parkinson’s Researchers Debate the Clinical Relevance of MAO-B Inhibitors

March 19, 2016

The 10th World Congress on Controversies in Neurology (CONy), now taking place in Lisbon, Portugal, is hosting international experts in the field, and serving as a platform for the comparison of experimental clinical and basic data in a range of diseases. The congress also offers the opportunity for debate on unresolved scientific issues.

Research into Parkinson’s disease and movement disorders is among the main interests of the congress, which opened Friday, March 17, and ends Sunday, March 20.

The clinical relevance of improvements observed with inhibitors of monoamine oxidase (MAO)-B in patients with Parkinson’s disease (PD) was among the topics of Saturday’s Scientific Program, aired in a debate titled “Is the improvement of MAO-B-inhibitors clinically relevant?”

MAO-B is an isoform of the enzyme MAO that is able to degrade several neurotransmitters, including dopamine. MAO-B inhibitors can help block the degradation of dopamine in the brain, and they have shown modest benefits for motor symptoms in PD. These inhibitors can be either used as a monotherapy, usually early in the disease, or as an adjuvant treatment with other drugs, such as levodopa, a precursor for dopamine, increasing this drug’s effect.

The CONy debate, hosted by Dr. Heinz Reichmann, offered opposing views by Dr. László Vécsei, from University of Szeged, Hungary, and Dr. Spiros Konitsiotis, from University of Ioannina, Greece. The debate focused on contradicting clinical observations regarding MAO-B inhibitors.

On the one hand, while MAO-B inhibitors seem less potent than L-DOPA or dopamine agonists, improvements have been observed in patients with wearing-off complications (a levodopa “fading” effect), and in reducing off-episodes (periods in which PD symptoms re-emerge despite medication) and increasing on-episode time. Dyskinesias, the impairment of voluntary movement, is a possible side effect, but it can be reduced by adjusting L-DOPA dose.

Selegiline and rasagiline are both highly selective, irreversible MAO-B inhibitors, for which promising effects have been reported in some trials. Long-term trials with selegiline have shown improved motor outcome and reduced levodopa reliance; however, researchers could not conclusively attribute these findings to the disease-modifying effects of the drug, which remained to be proven.

On the other hand, rasagiline was reported to have potent anti-apoptotic effects independent of MAO inhibition in in vitro and in vivo experimental PD models. Furthermore, the drug was found to be well-tolerated and to have a “significantly higher compliance and higher persistence rates,” Dr. Vécsei said. However, it failed to show improvement on the PD Quality of Life summary score in a specific clinical trial.

Besides discussing study results for these two therapies, Dr. Vécsei, who argued in support of the clinical relevance of MAO-B inhibitors, presented the case of safinamide, a drug with a broad mechanism of action, including reversible MAO-B inhibition. In recent studies, safinamide was shown to improve motor control and function in PD patients with motor fluctuations as an add-on treatment to levodopa or a dopamine agonist. The researcher also noted that the drug was safe, with few side effects, and that its dual mechanism of action (reversible MAO-B inhibition and glutamate release inhibition) was responsible for the alleviation of motor symptoms in PD.

Dr. Vécsei concluded that MAO-B inhibitors may have “mild but significant clinical benefits,” as they can “reduce disability and decrease [motor] fluctuation.” The best compliance was found for rasagiline, and safinamide was reported to have powerful anti-dyskinetic properties. Importantly, these inhibitors are safe and have a “good side effect profile,” he said. Dr. Vécsei also mentioned that MAO-B inhibitors might be especially relevant for patients with severe dyskinesia, and for the elderly.

In contrast, Dr. Konitsiotis argued that the benefits offered by MAO-B inhibitors are not clinically relevant. “A clinical trial may identify a small but statistically significant change in an outcome measure that may have little or no relevance to whether a patient actually feels improved,” he said, referring to what is called minimal clinical importance difference (MCID) or “the minimal change in an outcome that can be recognized by patients and clinicians.”

Dr. Konitsiotis mentioned several studies evaluating the MAO-B inhibitor rasagiline, including the TEMPO study (assessing the inhibitor’s use in early PD), the PRESTO study (testing it as an add-on therapy to levodopa to improve off-time and motor fluctuations), the LARGO study (assessing it as an add-on therapy to levodopa in advanced PD patients), and the ADAGIO study (testing rasagiline’s potential disease-modifying effects in PD). He emphasized that none of the studies showed evidence of health improvements with rasagiline in comparison to a placebo. “All of these studies, no improvement compared to placebo, only less worsening.”

Based on the arguments provided, Dr. Konitsiotis concluded by asking, “Is the minimal clinical benefit what we demand from a treatment?” To the contrary, he said, substantial clinical differences should be the goal of therapeutic interventions.

For more information on topics discussed at CONy 2016 and for exclusive interviews, be sure to visit Parkinson’s News Today on Monday, March 21 for concluding coverage.

http://parkinsonsnewstoday.com/2016/03/19/cony-congress-debate-is-the-improvement-of-mao-b-inhibitors-clinically-relevant/