Question

• Discuss COMT and MAO-B inhibitors in the treatment of Parkinson’s disease

Answer 1

Ans) The COMT inhibitors are used in combination with levodopa/carbidopa; there is a triple-combination formulation with levodopa/carbidopa/entacapone.

- Two studies have looked at early initiation (at the time when levodopa is needed) with either levodopa/carbidopa or the triple combination. Unfortunately, they have different results.

- FIRST-STEP showed that the triple combination provided better symptomatic improvement than levodopa/carbidopa alone. On the other hand, in STRIDE-PD, the triple combination resulted in more dyskinesias. The results are not published yet, but were issued in the form of a letter. The hope was that we would not see an increase in dyskinesia.

- COMT inhibitors should still be used at the time of wearing off when the patients have been on levodopa and now require additional therapy because of motor fluctuations.

- These 3 classes of drugs, the MAO-B inhibitors, dopamine agonists, and COMT inhibitors, all have their place in the treatment of Parkinson's disease. It's not unusual for a patient with PD to be on polypharmacy. In fact it's the rule in more advanced disease. In early disease one could use an MAO-B inhibitor. It's easy to use once a day, and these drugs are virtually free of side effects. Rasagiline is approved as monotherapy to treat early PD, whereas selegiline and the sublingual selegiline are approved as adjunctive treatments.

- Dopamine agonists can be added to an MAO-B inhibitor as the symptoms progress, or they may be used as first-line therapy if the patient has more severe symptoms that you think will require a more potent drug.

- COMT inhibitors are approved only to treat patients with motor fluctuations, patients who are having wearing off, where each dose of levodopa doesn't last until the next dose, and either triple combination with the entacapone or tolcapone may be employed in this setting. Tolcapone is only used for more advanced patients, when other drugs have failed, because of concerns for liver toxicity, but it's still a good drug. Entacapone isn't associated with that problem. MAO-B inhibitors can also be used as adjunctive treatments in patients who have PD who are taking levodopa and are fluctuating. Dopamine agonists can also be used in that setting. Many of our patients are taking more than 1 drug, and appropriately so, because patients with PD often need a polypharmaceutical approach to treat their symptoms.

- Clearly the greatest unmet need in PD is disease slowing. We need to slow this disease. It's a complex neurodegenerative disease, and we have focused a lot on dopamine and dopamine systems. We've done well. Patients do well for many years, but eventually, as the Sydney multicenter study shows, many patients will suffer from cognitive impairment, falling, depression, autonomic problems, and dementia. Until and unless we find the underlying mechanism of the neurodegeneration and how we can slow it down, patients will continue to progress and become disabled. That's the greatest unmet need in Parkinson's.

- I think more drugs will be developed; hopefully, we'll have combinations of drugs that will slow down the disease. It may still progress and patients may die of natural causes. In many patients these days, we need surgical approaches. We need to consider deep brain stimulation once patients experience drug-resistant motor fluctuations and dyskinesias. Traditionally we've employed targets, such as the globus pallidus internus or the subthalamic nucleus, but in general those don't help improve gait imbalance, and we are exploring newer targets, like the peduncular pontine nucleus. We also look forward to future development of neural restorative therapies using gene therapy and possibly stem cells.

- So far the growth factors in a recently completed phase 2 gene therapy trial have been failures, however. In the future we hope to be able to use different techniques to slow down Parkinson's disease.