Dr Stewart Factor on Implications, Treatment of OFF Periods in Parkinson Disease

There are a growing number of innovations within treatment of OFF periods in Parkinson disease that seek to address this unmet need in patient care, said Stewart Factor, DO, professor of Neurology and director of the Movement Disorders Program at the Emory University School of Medicine.

Transcript

AJMC^®: Hello, I'm Matthew Gavidia. Today on MJH Life Sciences News Network, The American Journal of Managed Care^® is pleased to welcome Dr Stewart Factor, professor of Neurology and director of the Movement Disorders Program at the Emory University School of Medicine. Can you just introduce yourself and tell us a little bit about your work?

Dr Factor: Sure. So, as you mentioned, I'm a neurologist who's trained in the specialty of movement disorders. Movement disorders include Parkinson disease (PD), and a variety of other disorders that are similar to PD. I've been at Emory for 15 years now as the director of the Movement Disorder Program. My clinical practice involves probably more than half of being PD, and then the other half being other movement disorders such as dystonia, Huntington's disease, tremors, and other things. I also am a investigator on several clinical trials, and I was an investigator on the Kynmobi phase 3 trial that was recently published. I do other work in relation to Parkinson phenomenology and cause of biomarkers and other things.

AJMC^®: Can you discuss what are OFF periods in patients with Parkinson disease and why these episodes occur in patients taking traditional treatments of oral levodopa and carbidopa?

Dr Factor: Sure. So, OFF periods are 1 of the unmet needs still in PD. For the last several decades, there have been many attempts to treat OFF periods by either preventing them or treating them as they come. So, what an OFF period refers to is a period of time when patients after they've started treatment, usually with the standard which is levodopa, they have periods when they feel as if the effect of the treatment disappears, at least partially or fully.

In those times, patients will get a return of their symptoms of PD—so their tremor, their slowness, their stiffness, their walking problems, and it probably doesn't occur very much in the first 4 years of treatment. For some reason the levodopa works really adequately at well spaced doses, but after a period of time, patients start to feel like the duration of the effect of the levodopa gets shorter and shorter. This sort of mirrors the half life of the drug which is very short. It's only an hour and a half to 2 hours.

So, the clinical response begins to mirror the pharmacology of the drug. The reason that happens is that as dopamine cells are lost because of progression of disease, the ability of the brain to take up the levodopa, convert to dopamine, and store it and use it as needed is lost. So, it becomes a direct reflection of the pharmacology. When OFF periods first occur, they are usually very predictable in nature. The patient will take their levodopa dose, it'll take 20 minutes or 30 minutes to kick in, and then it'll last anywhere from 2, 4, or 5 hours. Then they'll start to feel this waning of effect and they'll need to take the other dose.

Many patients can actually time their medicine based on how they're feeling without even looking at the watch to know it's time. So, it's very predictable at first, but with time, the occurrence of OFF periods actually becomes less and less predictable. So, what happens is some doses work very well and can last through the entire interval of the treatment, whereas other doses might not, and they can't really predict which doses will work. So, they may be OFF a few times a day, but not at predictable times.

Then later, sometimes they get delayed ON, where the medication just takes longer and longer to kick in after it's worn off. In some cases, patients get dose failures where they actually take their dose and nothing happens. Causes for that are variable, but food can sometimes play a big part because proteins interfere with the absorption of the drug. Then later on as the disease progresses, these OFF periods start to become very unpredictable and unrelated to the timing of medication. That used to be called, I guess we still call it, ON-OFF effect.

AJMC^®: What implications do OFF periods have for quality of life of patients with PD and their respective caregivers?

Dr Factor: So, when they have an inadequate response—an OFF period, it can certainly interfere with whatever they're doing and it can be pretty varied as far as the severity is concerned. So, in the earlier days, they'll get slower and stiffer. So, for instance, I recently had a patient who told me that when he's golfing, and the medicine starts to wear off, he can still walk and he can still play, but he can’t hit the ball as well. He's much slower, he has more difficulty, and so that certainly affects his quality of life to some extent, because he's not able to enjoy the game as much.

Later on, some patients become totally immobile. They can't walk or move, or sometimes their tremor just gets exceedingly severe and they can't function. So, it really varies from person to person, but it relates to just a decrease in their ability to function. You should know also that OFF periods don't just reflect a change in motor symptoms. Some patients have mood changes, anxiety, and depression, and can have other non-motor features that occur during the OFF periods that can be just as troublesome, just as disabling as the motor features can.

AJMC^®: The FDA’s recent approval of apomorphine hydrochloride sublingual film, sold as Kynmobi, marks the first sublingual treatment administered under the tongue for acute, intermittent OFF episodes in patients with PD. Can you discuss the phase 3 study results leading to its approval and what benefits are associated with its use?

Dr Factor: Sure. So, the main study that we were involved with that led to approval of the phase 3 trial was a trial where patients were admitted to the study, they had to have a certain amount of OFF time per day, and then they were tested in an open fashion, with doses ranging from 10 to 35 milligrams at five milligram increments as they went up to find which dose would provide them with their optimal treatment or their ON time that reflects a beneficial effect that the peak dose of levodopa would provide.

Once they found that, then patients were randomized to receive either placebo or the active drug, and then they were followed over 12 weeks to see how they would do with it over several months of treatment. The primary endpoint was—at the end of the 12 weeks, they would come in and be dosed in the office, and then we would evaluate them every 15 minutes to look for responsiveness of the drug. The primary endpoint was how much benefit they had at 30 minutes post-dose.

There was a substantial improvement in patients compared to the placebo group, and that was really the main finding that led to approval, I believe. Also, patients when they use the drug at home, they were asked to look at how often the drug would lead to a full ON, meaning an ON period that was their best functional time as it relates to levodopa. In the office we did that as well. So, we did that in 2 different ways, and a substantially higher number of patients receiving the active drug had an optimal improvement compared to the placebo group. I believe the home measure, it was almost 80% of the patients would reach an optimal response per dose whereas only 20 to 30% in the placebo group.

Then in the in-office, I actually have the data right here—in the in-office, it was 35% reached their optimal ON versus about 16% in the placebo group. Then for safety, the main side effects really were nausea, which is a known side effect of apomorphine. Apomorphine, so you know, is a drug that has been around for over 100 years. They didn't realize it was a dopamine type drug until the 60s–the 1960s, but it's been around and it's been available in the United States since I believe 2004 by injection to bring about reversal of OFF times. So, it's a well known drug, and the side effect profile of the sublingual form was similar to what we see with the injectable form.