On-Demand Non-Oral Therapies for OFF Episodes in PD

Daniel E. Kremens, MD, JD: Despite the fact that we’re talking about all these therapies to treat ON time, in all of the studies and in our patients’ real lives, they continue to have OFF episodes. So we need these on-demand therapies. I think we should discuss those a little bit. Stu, what’s your approach with the on-demand therapies?

Stuart Isaacson, MD: Well, I think there are 2 approaches. These on-demand therapies can be very helpful, but sometimes even before we think about that in some patients, depending on how many OFF episodes they have, we think about keeping them ON all the time. And while we can’t always do that, even with the once-a-day non-dopaminergics, and once-a-day COMTs [catechol-o-methyl transferase inhibitors] coming, and once-a-day MAO [monoamine oxidase] inhibitors, and the once-a-day oral and transdermal agonists, these infusion therapies…. Apomorphine is a different type of dopamine agonist than we discussed before. We focused a lot on the D2, D3 receptor affinities that might underlie some of the compulsivity, problems, hallucinations. Dopamine agonists that may have some affinity for D1 receptors might be useful, and apomorphine infused subcutaneously, in the recent European study, kept patients ON pretty continuously throughout the day and didn’t seem to have some of these adverse effects that plagued the oral agonists.

Rajesh Pahwa, MD: We still have apomorphine subcutaneous injections available for on-demand therapy. And to me, we have not used on-demand therapies as much as we should be using them. Part of it could be lack of awareness, and part of it not knowing what on-demand therapies are. Because we have not talked much about on-demand therapies. But to me, the advantage of on-demand therapies, just like with migraine headaches—patients take medications for migraine all the time. And then, when they have a headache on top of it, they take an on-demand therapy to help with that headache.

So to me, the same thing should be done. Patients are on multiple medications for OFF time, and then when they have an OFF episode or an OFF period, they take the on-demand therapy, such as subcutaneous apomorphine, and get back ON. And that gives them the power of knowing when they can use the therapy, knowing that it is much more likely to work, and knowing it’s going to work fast. So to me, that makes it a very much patient-controlled therapy as far as on-demand therapies….

Peter LeWitt, MD, M.Med.Sc: Yes, and it is even an adjustable therapy. The dose that a patient gives can also be tempered to their experience in using it. Just carrying it in their pocket can give a level of confidence that they can go to a shopping center, a social event. Some patients might even use it in advance of a situation where they fear they might turn OFF. And it’s safe in that fashion as well. It is a drug that in Europe has been in use since the 1980s, so it’s not new in the scene. It’s been used in the United States since 2006 as an approved drug.

Stuart Isaacson, MD: And we may get a new formulation with the strip under the tongue that’s in phase 3 development.

Rajesh Pahwa, MD: Because that’s one of the challenges. Patients are afraid of the needles and injections, and physicians are afraid of the injections or giving a patient injections. So I think something like a strip could help with the needle phobia, so to speak.

Stuart Isaacson, MD: It’s interesting that apomorphine has the same robust efficacy as levodopa becoming dopamine, and yet it’s not as widely used, perhaps, as it should be. Because patients who have OFF episodes probably should have some on-demand therapy, whether it’s the apomorphine subcutaneous injection, or waiting for the apomorphine strip, or the recently available inhaled levodopa.

Peter LeWitt, MD, M.Med.Sc: You might consider oral levodopa as an on-demand therapy when it works well. It’s worth pointing out that from pharmacokinetic studies, the fastest that it gets to that threshold to turn you ON is 15 to 20 minutes when things are working well. So the window of opportunity of being faster than 20 minutes is something that has been met by the inhaled levodopa powder, apomorphine injection. We’ll have to see, with the sublingual delivery of apomorphine, if that reliability and the speed of action is met. But that is often a window of concern to patients who, at work, in social settings, cannot tolerate waiting 15 or 20 minutes with that old-fashioned generic drug—levodopa in oral form.