Current Series: Managing OFF Episodes in Parkinson Disease

Peter LeWitt, MD, M.Med.Sc: The message to our colleagues is, there’s been a slow revolution, rediscovery of old drugs, new ones, new pathways coming in that are non-dopaminergic and so on. There’s a lot of therapeutic nihilism out there. Patients with Parkinson disease are very unique compared to those with so many other neurodegenerative progressive disorders. This is a symptomatic therapy opportunity, and hopefully a curative therapy option for Parkinson disease. But take advantage of these. And that therapeutic nihilism that we’ll do 1 change every 6 months may not be the appropriate approach. The notion of keeping the number of medicines down to a bare minimum isn’t necessarily the way to go. The levodopa phobia is a myth. We know that patients should be encouraged to maximize control of their lives by choices of, “Let’s try this, let’s try that.” There isn’t any 1 algorithm that works anymore. These are new messages that a lot of general neurologists and even Parkinson specialists have to hear again and again, because these changes are happening month by month.

Stuart Isaacson, MD: And you brought up this idea, Dan, at the beginning, that this is a progressive degenerative disorder and people get worse over time. But in my experience, I’ve been struck by these infusion-based therapies restoring patients to years earlier, where patients who have an ON effect that may last 2 or 2.5 hours have dose failures throughout the day and never really know when the medicine is going to work and not work. Once they go on infusion-based therapy, the intestinal gel levodopa, carbidopa, or in the research programs that we’ve been part of, taking the subcutaneous apomorphine pump, the levodopa pumps, they’re always ON, and that’s remarkable.

Rajesh Pahwa, MD: Stu, you did studies with the subcutaneous apomorphine infusion. What types of patients are going to be candidates for it? How are they going to start the therapy? And what are the common adverse effects that neurologists should look for when this therapy is available?

Stuart Isaacson, MD: Well, I think resetting the bar, as Peter suggests, that probably the goal of treating Parkinson disease in the modern age is to be ON, a good ON, if not the best ON, continuously without adverse effects.

So patients who begin to have unexpected OFFs that can disrupt their days and nights really ought to be thinking about, “How can I be ON continuously and not have to have this disruption when an unexpected OFF occurs,” where they don’t know if they’re going to be able to turn back ON. And because they’re reversible—the subcutaneous infusions—they can try it.

Peter LeWitt, MD, M.Med.Sc: And because we don’t have head-on comparisons in our peer-reviewed literature or expert experience of which 1 works better, every patient is an N = 1 experiment. As you point out, you can try all of these therapies in relatively short periods, or hopefully with the economics not daunting this endeavor. It might be that for certain patients, subcutaneous levodopa, subcutaneous apomorphine, rescue therapy, or a better oral levodopa product might solve the problems in a population that you can’t anticipate. But we have the tools at hand to try, if not all of them, in many of them, in a structured way. I hope we’ll have some chance in the future to have studies that will take on head-on comparisons like the comparison of Duopa and apomorphine, so that question can be answered before we proceed too much further.

Stuart Isaacson, MD: You wonder if, in the future, that OFF may be a choice, not inevitable in Parkinson disease.

Daniel E. Kremens, MD, JD: This has been an extremely fascinating discussion, but before we close I’d like to get some final thoughts from our panelists. Maybe you’d each like to make a brief comment on the future of the treatment of OFF? Raj, do you want to start us off?

Rajesh Pahwa, MD: Yes. We talked a little bit about the future with apomorphine subcutaneous infusion. I think that is what we can look forward to in the next year or so. We talked about the apomorphine strip. That’s another exciting thing that would definitely be helpful for on-demand therapies. And a little bit further down the road for OFF, we are looking at subcutaneous levodopa preparations. For people who cannot tolerate some of the available preparations, subcutaneous levodopa might be something that would be helpful for these patients. So to me, this is what we are looking at in the next few years to try to eliminate the OFF periods that our patients suffer from.

Daniel E. Kremens, MD, JD: Peter, any additional thoughts?

Peter LeWitt, MD, M.Med.Sc: Well, over the last few years there have been a number of studies trying to see how the development of motor fluctuations of OFF time of dyskinesias can be achieved, and that has not borne fruit. So the best we can do is consider the continuity of therapies, dopaminergic and non-dopaminergic, as ways to manage these problems. Certainly, long-term symptomatic therapy continues to work. No one becomes immune to it. These options of improving motor fluctuations now, and in 5 and 10 years for your patients are there, and I just hope we will take advantage of them and look for the most cost-effective ways to make the best advantage for every patient.

Daniel E. Kremens, MD, JD: Jill?

Jill M. Giordano Farmer, DO, MPH: I think that with the landscape going forward, it has always been that you’re looking to improve the delivery mechanism. I think that will continue to be with the infusion therapies, but not just simply having it be infusion therapies but much more user friendly compact delivery systems that are able to achieve that goal.

Daniel E. Kremens, MD, JD: Stuart?

Stuart Isaacson, MD: Well, I think over the past decade we’ve seen the emergence of non-dopaminergic therapies to address some of the dopaminergic adverse effects, the non-oral therapies to address the GI [gastrointestinal] dysmotility and difficulty with absorption, and this era of continuous therapies, whether it’s long-acting orals or the subcutaneous infusions. So I think the symptoms are going to get much better controlled. I think we still have a lot of work to do on things that may slow the progression or interfere with the disease itself in trying to look at this from a protein aggregation problem with synuclein, a genetic problem with LRRK2 and GBA, and other mechanisms that are involved in inflammation and the proteasome degradation of proteins and such.

I think we still have a lot of work to do, and I think all of these emerging therapies still require patients to have access to them. One of the big problems that we may not have a good control over is our patients have to have access to these therapies. They have to be aware of them. They have to know when and how to use them. They have to have formularies that permit them to get them. They have to have step edits that allow them to get the therapies. And they have to be able to afford them. I think there’s a lot of work to be done regarding access.

Daniel E. Kremens, MD, JD: No doubt, there are challenges. And certainly, the whole topic of disease modification is for another day. But I would actually argue that the future is now. We have therapies available that are grossly underused, and these therapies are not difficult to use. These are therapies that general neurologists can be using—subcutaneous apomorphine, inhaled levodopa, non-dopaminergic therapies—and this is really about trying to raise awareness to help optimize the treatment for our patients. It doesn’t just have to be another dose of levodopa, which I think so often turns out to be the fallback course.

With that, thank you so much for joining us. On behalf of our panel, we hope you found this discussion to be useful and informative.