Recently Approved Oral Therapies for OFF Episodes in Parkinson’s Disease


Kremens and Kumar review istradefylline and opicapone oral capsules—both recently approved for treatment of OFF episodes in Parkinson’s disease.

Daniel E. Kremens, MD, JD: We’ve focused a lot of our time today on OFF episodes—treating them acutely. However, there have been a couple of medications approved recently in the United States. Although, indicated for OFF episodes, they’re more for treating OFF periods in general in my mind. One of them has a novel mechanism. It’s an A2a antagonist called istradefylline [Nourianz], and it became available in the United States earlier this year. It’s been available in Japan since 2013. Do you want to say anything about A2a antagonism?

Rajeev Kumar, MD: Yeah. This is an interesting mechanism of action. This is the first of 3 different A2a antagonists that I’ve been involved with in terms of clinical trials. I was involved in all the phase 2 and subsequent phase 3 trials. It is a useful medication. A2a receptor antagonism is not the first thing that comes to mind when we think about Parkinson’s disease treatment because it’s acting downstream of the dopaminergic system. 

When dopamine is released in the striatum, it binds to D1 and D2 receptors on medium spiny GABAergic neurons. When it binds to D2 receptors mediating the indirect pathway, we reduce the overactive indirect pathway. On those same neurons that are D2 bearing, we have A2a receptors. If we antagonize the A2a receptor overactivity, we can reduce the activity of the indirect pathway. If we take our foot off the brake—which is what the indirect pathway does, to keep it very simple, then we can improve the severity of the OFF period.

It’s quite interesting that in the earlier animal model data there was suggestion that istradefylline would be effective in monotherapy. Unfortunately, that did not pan out in the early human clinical trials in monotherapy. However, it has been shown to be effective as an adjuvant to levodopa to improve OFF time. 

It is a little disappointing that in the phase 3 clinical trials there was not as much reduction in OFF time as I had hoped. In the phase 2 clinical trials, we had almost 2 hours of OFF time reduction compared with the placebo-treated arm. In the subsequent phase 3 trials—there have been several, and this is why it took so long to get approved in the United States, there was reduction in OFF time by about 45 minutes to an hour compared with the placebo-treated arm. Good improvement, but perhaps not at the same level of magnitude as some of the other therapies.

What’s nice about this therapy is it’s extremely easy to use. It’s used once a day. The majority of patients do well with 20 mg, but you can also use 40 mg a day. It’s a very long half-life drug—about 80 hours—and it has relatively few drug interactions. CYP3A4 is the main one. Interestingly, smokers require a higher dose and go straight to the 40-mg dose. Typically, one doses it for about a month at the lower dose—20 mg. If the patient tolerates it well and does not have adequate efficacy, it’s reasonable to give them a trial at the higher dose of 40 mg per day.

It’s not a really dopaminergic medication, and doesn’t suffer from a lot of the adverse effects that we get with typical dopaminergic therapy. Hallucinations are very uncommon. Orthostasis and nausea are uncommon. Since it’s acting downstream to improve motor function, the main adverse effect one should be aware of is increased dyskinesia—seen in maybe 10% to 15% of individuals. There are various ways of handling it. Of course, you can stop the medication, but that’s not really what you want to do. What you want to do is keep that patient ON. In my experience, if patients have dyskinesia, then—in the majority of patients—that also means that their OFF time has been significantly improved. My usual strategy is first try to reduce the amount of levodopa to see if I can keep them ON—keep that benefit—but reduce the dyskinesia to a level that is not troublesome or hardly noticeable.

This is an interesting new drug to our armamentarium. I use it not up front as an add-on to first-line drug, because we have less experience with it and perhaps the potency may be a little less. However, it can be used in patients who have commonly tried or are currently taking multiple medications or 1 other medication as an add-on and are still struggling.

I especially find it helpful in patients who have had trouble with dopaminergic adverse effects. For somebody who has had nausea or hallucinations with other drugs, this might be a good drug to try. For somebody who has had orthostasis with the other drugs, this is a good medication. For somebody whose options are now limited because they’ve had troublesome impulse-control disorder, this may be a good drug. It’s rarely been reported with this medication.

It’s a unique medication and a nice addition to our armamentarium.

Daniel E. Kremens, MD, JD: Yeah, I agree. The only thing I would add is although the effect we saw in the phase 3 trials wasn’t necessarily as robust as in the phase 2 trials, I still think it’s important that people understand that these were patients getting an additional 45 minutes or hour on top of already being on lots of other medications. They could be on lots of other medications in the study and weren’t just on levodopa. They were on levodopa, dopamine agonists, or MAOB inhibitors and achieved an additional 45 minutes to an hour. That’s important.

Another medication that was recently approved in the United States, and has been available in Europe since 2016, is opicapone [Ongentys]—a COMT inhibitor, right? We haven’t heard about COMT inhibition in Parkinson’s disease in a while. What thoughts do you have on opicapone?

Rajeev Kumar, MD: From the trial data, it looks very nice, interesting, and easy to use. All the studies with opicapone to date have been done in Europe. So, I don’t have personal experience. However, when I look at the data—including some additional PK [pharmacokinetic] data, it seems to last a really long time. It’s a once-a-day COMT inhibitor. It acts peripherally, so it’s like entacapone, but seems to be more potent. It achieves almost complete COMT inhibition within 1 to 2 doses. When you stop it, the effect continues for 2 or 3 days. That is quite nice, especially if the patient is a little off schedule with their dose. You know, “I forgot to take it this morning. Can I take it this afternoon?” Yeah, you can take it in the afternoon.

Daniel E. Kremens, MD, JD: Ongentys is dosed at bedtime, and that’s critical. Dose at bedtime without food because food can affect the absorption of Ongentys. That’s going to be 1 of the critical teaching points when we start patients on it. However, it is once a day. As for the safety profile, there’s none of the chromaturia that we get with entacapone. There were no signals of any liver issues whatsoever like we got with tolcapone—a good medicine, but it had a lot of safety issues. We have new options for our patients, including a once-a-day COMT inhibitor that’s been used in Europe for 3 years. I’m excited to give that a try as well.

Rajeev Kumar, MD: Yeah. What also is interesting is they’ve done some head-to-heads against entacapone and data suggest opicapone is more effective. When given the choice—if we’re given the choice from an insurance perspective, of course—I would rather go right to opicapone.

I expect because of financial issues, for many patients we may have to try entacapone and show that they’re not doing adequately, then get an approval for opicapone. However, this is mysterious right now until we actually see it marketed in the United States.

Daniel E. Kremens, MD, JD: We’re going to have to see.

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