Stuart Isaacson, MD: Raj, how soon after recognizing the OFFs do you think treatment to reduce the OFFs should be started? And of all the different classes of treatments that we have now, can you tell us a bit about how you see these classes individually or grouped into pre-synaptic and post-synaptic, or dopaminergic or non-dopaminergic, or GI [gastrointestinal] absorbed and non-GI absorbed? How do we understand all the different options we have? And tell us about the mechanics and how you plan to get them.
Rajesh Pahwa, MD: How many times have I, finally through education, taught my patients to recognize the OFF, they recognize the OFF and I tell them, maybe we should make some changes in your medicine so that we can eliminate the OFF. And the patient who says, “Well, I have an OFF but it doesn’t affect me, it doesn’t bother me. I am not ready to switch medications at this time. The good thing is. And we won the first battle by having the patient recognize the OFF. And I tell them, “Maybe before you come back for your next visit, it might become more obvious to you, maybe more serious to you. You need to call and come sooner rather than wait 6 months because I know it will get worse over time. This is another thing. Once a patient has an OFF time, for which they are already taking levodopa, one of the things that we often consider is whether we can increase the number of doses they are taking? If they take 3 doses per day, can we go to 4 doses per day? The challenge behind increasing doses is that compliance decreases once we start increasing the dosage. But at the same time, a lot of patients say, “No, I don’t want to add a new drug. I can take 1 extra pill during the day if it helps me get rid of my OFF. Which is perfectly fine if that’s what the patient does. This is a time when we need to have more and more conversations with our patients to discuss the different options available. Increasing dosing frequency is an option, but they should realize that failure to comply will not eliminate their OFF. We can replace them with time-release capsules, that’s definitely an option for them. And again, some patients may say, “It’s too expensive for me, are there other treatment options?” “We have dopamine agonists. Usually, if a patient is young, has a lot of dystonia, I may lean towards adding a dopamine agonist for them. In an elderly patient, maybe 70, 80, maybe with cognitive issues, maybe a little orthostatic, hypertensive, I can wait for a dopamine agonist and use another drug for him. We have COMT [catechol-o-methyl transferase] inhibitors, we have MAO-B [monoamine oxidase type B inhibitors] for some of these people. And I consider it a bit more potent agonists but also having more side effects compared to using MAO-B or COMT inhibitors. So now we also have an A2A antagonist, istradefylline [Nourianz]. And this is another option where you can use it to process OFF time. And we discussed earlier about a patient who has some degree of dyskinesia as well as OFF time using an NMDA [N-methyl-D-aspartate] antagonist, whether amantadine or amantadine ER [extended release], would definitely be another option to deal with. It’s important to remember that just because we’re using a drug from one class doesn’t mean we can’t add a drug from another class. We could very well have a patient taking levodopa, a dopamine agonist, your MAO-B inhibitor, or even an NMDA antagonist just to reduce their OFF time and dyskinesia, which can happen in some patients. The other option is to use on-demand therapies. I plan to use on-demand therapies once my patients start having an OFF time. Even in this patient whose example I gave you earlier who recognized the OFF time but does not want to add medication, I can say: “Here, if you want to have something on demand for your bad days , you can definitely have this with you. You don’t have to use it every day. You don’t even have to use it once a week. I discuss on-demand therapies, just like patients with headaches have migraines. This does not mean that they have to take their medication every day. But when they have a migraine, that’s when they use this on-demand therapy. And the same with our patients, when you have an OFF time, whether we add a complementary therapy or not, you have that on-demand therapy that you can always use to eliminate that particular OFF that you have. Complementary therapies reduce OFF time during the day. But with on-demand therapies, the patient can know that I am in an OFF state. I use my therapy on demand and once this drug works in 10, 15 minutes I won’t have the OFF after that. And that’s the advantage of on-demand therapy. If you look at the number of drugs that are available when we talk about COMT inhibitors, we have 2 drugs: entacapone [Comtan] is available with while you have to use with each dose of the drug or you can use Ongentys [opicapone] which you can use once a day. Same with MAO-B inhibitors. We have 3 MAO-B inhibitors that can be used. You have selegiline. You have rasagiline. In addition, you have safinamide. Again, when we talk about drug categories, these categories have several drugs available. And if a patient has side effects with 1 drug, we have the option of trying another drug. But when we talk about dealing with fluctuations more, we have to start thinking about using complementary therapies, using on-demand therapies. And when we can’t get by with medication, consider surgical therapies such as deep brain stimulation or carbidopa/levodopa enteral suspension.
Transcript edited for clarity