Article on Medscape on MAO-B Inhibitors (rasagiline, selegiline, and Zydis selegiline )

Challenges and Unmet Needs in Parkinson's Disease Treatment and the Role of MAO-B Inhibitors: An Expert Interview With Kapil D. Sethi, MD, FRCP

Medscape Neurology & Neurosurgery.  2007Posted 05/24/2007Editor's Note:
Marni Kelman, MSc, Medscape Neurology & Neurosurgery Editorial Director, discussed the challenges and unmet needs in the treatment of Parkinson's disease (PD), and the role of monoamine oxidase (MAO)-B inhibitors, with Kapil D. Sethi, MD, FRCP, Professor of Neurology and Director of the Movement Disorders Program at the Medical College of Georgia in Augusta.
Medscape: Can you please tell us what you think are the main challenges and unmet needs today in the treatment of PD?
Dr. Sethi: The most important need is to find treatments that will slow the disease process itself. Second, we need medications to treat symptoms that currently available therapies do not treat very well. These nonmotor symptoms include dementia and autonomic problems. Directly, all of those problems are linked to disease progression, so if you can find something to slow the disease, that would probably be the major advance in the treatment of PD.
Medscape: What about compliance? Do you find that compliance to therapy is an issue? Is there a benefit of having once-daily treatment?
Dr. Sethi: If there are 2 drugs that do the same thing and result in the same degree of symptomatic benefit, with the same cost and side-effect profile, if one is administered once a day and one is administered multiple times a day, obviously one would prefer a once-a-day formulation because of improved compliance. There are some studies on compliance that have been done in Glasgow, United Kingdom, and a nice study showed that PD patients are noncompliant mainly with the timing of the drug, and also with how much to take.[1]
So yes, compliance is an issue. Once a day is better if everything else is equal, but if one drug is clearly superior, then the once-a-day benefit would not disappear; it would be minimized.
Medscape: One of the things that we have learned is that many physicians are not confident in their ability to select treatments, and that they would like to get more information on guidelines and ways to optimize treatment. Do you have any insights into this or any suggestions about how this can be addressed?
Dr. Sethi: There are guidelines and algorithms available. The American Academy of Neurology issued some guidelines, and they looked at the evidence to support treatments. In the end, it's in the physician's hands. Every patient with PD is different, and the guidelines can only be a rough framework on which the physician has to base treatment.
The treatment of PD is becoming more and more complicated because the available choices are expanding. We used to have 1 MAO-B inhibitor; now we have 3. We used to have 1 L-dopa [levodopa] preparation; now we have 4 different preparations. It's a challenge for a physician who's a general neurologist or a general practitioner to keep up with all of these changes. Algorithms and guidelines can help a little bit, but in the end, you have to individualize treatments.
Medscape: What about considerations for treating early- vs late-stage disease?
Dr. Sethi: In PD the traditional view has been to postpone treatment until the symptoms interfere with the patient's day-to-day activities or work life. However, it's becoming increasingly clear that the earlier you start treatment, the better that the patients seem to do, at least in the first 2-3 years. One trial with L-dopa, a study called ELLDOPA,[2] and another with rasagiline, called the TEMPO trial with its extension,[3] showed that patients started on active drug earlier actually seemed to do better than if you withheld treatment.
So, we want to start treatment, some treatment, as early as possible. It may allow the cells that are overworking to compensate for the loss of other neurons; it may allow those cells to get some rest; and maybe it will result in slower disease progression. However, whatever the mechanism, it looks like earlier treatment is better. If you start someone with very early PD and with very minimal disability on treatment, the choice of drugs is very important because these patients are less willing to put up with side effects. They are functional and want to take a drug that's just a once-a-day preparation and forget about treatment for the rest of the day. That's where once-a-day formulations have a major advantage -- in very early disease.
When you have advanced disease, most patients are already on L-dopa and dopamine agonists. L-dopa has a very short half-life, so you have to take it multiple times during the day. However, when the patients start fluctuating, when their motor control waxes and wanes 1 hour to the other, then we have to consider adjunctive treatments. Again, once a day is better than a medication that you need to take multiple times, but patients will still have to take multiple dosages of their L-dopa. However, it's less complicated if they have another drug that's given once a day in addition to L-dopa.
Treatment for these advanced patients also has to be individualized. Let's say somebody is on carbidopa-levodopa alone and is fluctuating in advanced disease. If they are 70 years or older and have some cognitive issues, then you have to worry about dopamine agonists worsening their cognitive problems. So, then we need choices. We have found the MAO-B inhibitors rasagiline, selegiline, and Zydis selegiline useful in these patients.
Therefore, we have several choices in advanced disease. You have to look at the patients' profiles before deciding what to do once they start fluctuating.
Medscape: Now we would like to specifically discuss the MAO-B inhibitors. Can you please give us a brief overview of the different drugs, how they work, and their role in treatment?
Dr. Sethi: MAO-B inhibitors differ from the old, nonselective MAO inhibitors, in that they don't inhibit MAO-A. The propensity to cause the so-called "cheese effect" is minimal, if any, and therefore, these drugs are a lot safer. They have fewer contraindications and they are easy to use.
The first MAO-B inhibitor that was introduced was selegiline, and it was approved for advanced PD, but used off-label in early and advanced disease.
The mechanism by which MAO-B inhibitors work, at least for symptom control, appears to be due to their blockage of MAO-B in the brain and their ability to prolong the duration of the dopamine effect. They may have other mechanisms that have nothing to do with MAO-B inhibition in that they have antiapoptotic effects and may slow disease progression.
Selegiline, as I said earlier, was indicated for late disease, and the studies that resulted in its approval were done in another era. We didn't have a lot of objective measures or diaries at that point.
The next MAO-B inhibitor is rasagiline, and it is administered once a day, and indicated both for early and advanced disease. There are multiple well-conducted studies with rasagiline. Actually, the American Academy of Neurology guidelines state that rasagiline and entacapone have level A evidence, which means that that's the best available evidence for their use in PD as adjunctive therapy.
The third MAO-B inhibitor is Zydis selegiline. It is a buccal dissolving tablet that bypasses the liver and results in higher metabolism of the parent drug selegiline. Unlike selegiline, both rasagiline and Zydis selegiline do not produce any amphetamine metabolites, so they may have an edge because they have fewer side effects than conventional selegiline.
A patch formulation of selegiline was available to treat depression, but it is not approved for the treatment of PD.
If you stay within label, rasagiline is indicated for early and delayed treatment. We often think that the best patient for rasagiline would be an early, newly diagnosed PD patient who is not severely symptomatic, is not disabled, and wants to delay major dopaminergic therapies and wants to avoid the dopaminergic side effects.
By themselves, MAO-B inhibitors have a modest antiparkinsonian benefit, and sooner or later, patients have to be supplemented with something else. Nevertheless, we often start with rasagiline.
Medscape: What percentage of patients would you consider starting on rasagiline?
Dr. Sethi: I think we consider everyone a good candidate for an MAO-B inhibitor, depending on whether they can afford a drug like that because there are other, somewhat inexpensive options available in early disease. One of those is amantadine, which is a very old drug, which also can give you 6 months or sometimes up to a year of delaying dopaminergic therapy.
The treatment to start with needs to be individualized, but I would consider rasagiline in most patients if they come to you early enough and if their symptoms are not very severe. The symptomatic benefit of rasagiline is not as robust as the major drugs, such as dopamine agonists and especially L-dopa. L-dopa is still the gold standard. If patients have more severe symptoms, we often take out the big guns earlier. About a third of the patients who present to me are not yet severe enough to warrant dopamine agonists or L-dopa, and therefore, they should be candidates for rasagiline.
Medscape: I presume that the age of the patient is factored into this as well, in terms of how long somebody would be taking therapy for, correct?
Dr. Sethi: Yes. In general, if they're younger, we try to avoid L-dopa for a while. If they are older, let's say 70 years or older, there's really no reason to try multiple therapies. You just start them on low-dose L-dopa. However, under the age of 70, we always consider these other therapies to delay the use of L-dopa, but we also know that delaying L-dopa too long is not beneficial for the patient. We think that L-dopa remains the most effective symptomatic treatment, so we should give it when we think it's appropriate.
Having said that, rasagiline, and possibly Zydis selegiline, are very well tolerated by the elderly population, too. So that's where they have an advantage over, say, dopamine agonists. So both age groups are candidates for MAO-B inhibitors. One, perhaps, would take an MAO-B inhibitor as an adjunctive therapy, whereas the other would take it as monotherapy early in the disease. The younger the patient, the more likely that you're going to use non-L-dopa drugs to help their symptoms.
Medscape: Could you discuss the role that MAO-B inhibitors may have in modifying disease and providing neuroprotection?
Dr. Sethi: Well, clearly, that's the major unmet need, but unfortunately, we don't have any conclusive evidence that any available therapy slows PD. The inherent process goes on incessantly, and it's relentless and that's unfortunate. There are multiple drugs that have hinted that they can slow the disease, but nothing has conclusively proven to do so.
There were trials that suggested that early use of selegiline slows the progression of PD, but the other trials were negative.[4] The evidence with rasagiline is based on a delayed start trial, which showed that earlier treatment resulted in better outcomes at 1 year compared with delaying treatment. That may be due to disease modification, but it could also just mean that early treatment is better and that it just provides you with better symptomatic control, but that it has nothing to do with neuroprotection.
Overall, it is a very controversial area, and I don't believe that we know conclusively that MAO-B inhibitors slow the disease.
There is some evidence, but it's not conclusive. We need more studies. We need longer term studies than just 12 months. There is one study being done with rasagiline called ADAGIO. Patients are randomized to receive medication or placebo for up to 9 months, and then the placebo group gets the medication. The follow-up is longer than 1 year. Results from this trial might help substantiate whether rasagiline actually slows the disease process.
I believe that the future lies in combining drugs with different mechanisms, so-called "cocktail treatments," because I don't think that 1 drug is going to work for everyone because all patients with PD are different. We could combine MAO-B inhibitors with coenzyme Q10 or e something else, such as an anti-inflammatory drug, because inflammation seems to play a role in PD as well.
Medscape: Thank you for taking the time to speak to us today.
Dr. Sethi: Thank you.
Supported by an independent educational grant from Teva Neuroscience
ReferencesGrosset KA, Bone I, Reid JL, Grosset D. Measuring therapy adherence in Parkinson's disease: a comparison of methods. J Neurol Neurosurg Psychiatry. 2006;77:249-251. Abstract Fahn S, Oakes D, Shoulson I, et al; Parkinson Study Group. Levodopa and the progression of Parkinson's disease. N Engl J Med. 2004;351:2498-2508. Abstract Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol. 2004;61:561-566. Abstract Stocchi F, Olanow CW. Neuroprotection in Parkinson's disease: clinical trials. Ann Neurol. 2003;53(suppl3):S87-97; discussion S97-99.

Kapil D. Sethi, MD, Professor; Director, Movement Disorders Program, Medical College of Georgia, Augusta
Disclosure: Kapil D. Sethi, MD, has disclosed that he has received grants and honoraria from, and has served as a consultant to, Elan, Teva, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Solvay, and Allergan.

Disclosure: Marni Kelman, MSc, has disclosed no relevant financial relationships.
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