Video
Recent Approval of Sublingual Apomorphine for Off-Episodes in Parkinson Disease
Author(s):
Daniel E. Kremens, MD, JD: I’m somebody who believes that a rising tide raises all ships. We spent a lot of time talking about Apokyn [apomorphine hydrochloride subcutaneous injection], but I’d like to shift the conversation to a new apomorphine hydrochloride product that’s been approved by the FDA in the United States. It’s a sublingual form of apomorphine hydrochloride commercially known as Kynmobi. I know you’ve had some involvement with that. Could you tell us about Kynmobi [apomorphine hydrochloride sublingual]? Talk about its dosing and efficacy and your experience with it.
Rajeev Kumar, MD: I was involved with the phase 2 trials using the initial strips, which are interesting. They’re fairly small, about an inch by an inch. They’re rectangular and look a bit like Listerine strips. It’s placed under the tongue. The patient is instructed to keep their mouth closed and to not swallow because the medication is absorbed sublingually.
Just as with subcutaneous apomorphine, the patient should be premedicated with Tigan [trimethobenzamide] for about 3 days and will need titration. Typically, one begins at 5 mg of sublingual apomorphine or 10 mg, and then titrate up in 5-mg increments—with the highest dose being 35 mg. This can be used just as you might use subcutaneous apomorphine. It can be used for early morning akinesia and unpredictable off-episodes. It can be used for any off-episode legitimately.
It’s different in that you are now giving it sublingually rather than injecting it. The absorption kinetics are expected to be different, and as a result, the time to on and duration of action are expected to be different. If one looks at the recent Lancet Neurology publication, one can see that the time to an on-state is slower than subcutaneous apomorphine; however, the patient doesn’t need to inject themselves. For patients who have significant squeamishness or concerns about injecting themselves, this may be a reasonable option.
The duration of action is different from subcutaneous apomorphine. It’s longer. One can expect a duration of action of at least 90 minutes and up to 2 hours. Therefore, we need not be in as much of a rush to dose the patient with oral levodopa, but we do need to recognize that the duration is typically shorter than oral levodopa. This product will get you on while allowing time to get and stay on with oral levodopa.
If one looks at the trial data in terms of magnitude of on-state response, one would expect to obtain a full on-state response. This is apomorphine, and that’s what we saw in the phase 2A trials. However, if you look at the phase 3 trials, most patients can get fully on, but the magnitude of the on-state response, based on the graphs from the Lancet Neurology paper, was a little less than what was seen with subcutaneous apomorphine. We see an on-state motor response of about 15 points, which is less than the 20 to 25 points we discussed earlier with the old-fashioned Unified Parkinson’s Disease Rating Scale with Apokyn [apomorphine hydrochloride subcutaneous injection]. Perhaps a little less potent—we’re going to need more experience to know. The patient numbers in the phase 3 trial were relatively small, less than 100 patients per group. We need a lot more experience with this drug.
Daniel E. Kremens, MD, JD: In terms of reliability, it works quite well. Roughly 83% of patients got to a full on state vs 95% with the injection. Again, it’s a strip, not an injection, and for a lot of people it may be a more acceptable option. I’d love to offer patients options.
What were some of the adverse effects that you saw? Were there any that were different because of the sublingual delivery system that wasn’t seen with subcutaneous?
Rajeev Kumar, MD: That’s the key issue. The advantage of Kynmobi [apomorphine hydrochloride sublingual] is you don’t need to inject it. The disadvantage is you get all the usual adverse effects of subcutaneous apomorphine—eg, sleepiness and nausea—in addition to oral problems. Up to 30% of patients may get oral ulceration or other oral mucosal problems. It’s important to warn patients of that. It’s also important to periodically inspect the mouth for problems when you see patients. We don’t want patients to get an infection or more serious adverse effects as a result of unrecognized or untreated oral problems.
Patients’ oral problems are relatively mild. It didn’t result in serious adverse events—eg, patient getting hospitalized or osteomyelitis of the jaw. However, it is a concern, and patients should be aware of that. There was a small yet definite number of patients who discontinued therapy because of oral problems. It’s something one should be aware of. I agree, it’s nice to have additional options when thinking about apomorphine injection. If the patient is unwilling or scared of injecting, it’s reasonable to consider this option for the patient. The patient should be aware of the adverse-effect profile and should be aware of the need to titrate and customize the therapy.
Daniel E. Kremens, MD, JD: It’s different from a needle. This comes in a package, sort of like rabbit ears that a patient is able to tear apart. Most of the patients were able to do this, even in an off-state, and apply the sublingual strip. A potential challenge could be for Parkinson disease patients with bad drooling. Also, many Parkinson disease patients keep their mouths open. We have to instruct that it’s important to keep your mouth closed and don’t swallow. There were some challenges in the early studies with patients who would occasionally swallow them.
Rajeev Kumar, MD: That’s very true. It is not easy for patients to keep something in their mouth and not talk or swallow. Several of the patients at my site, in the phase 2A trials that have been published, tended to swallow the drug. That affected the efficacy of therapy. If the patient swallows the medicine, it’s not going to work well. That’s very clear. You’ve got to keep this gummy mixture of saliva plus the strip in the mouth for about 5 minutes and not talk.
Daniel E. Kremens, MD, JD: Right. Again, with appropriate instruction. It’s great to have options to offer patients having off-episodes because they’re so troublesome. I’m looking forward to when this is going to be commercially available in the United States. It’s approved, and I’m sure I have patients who will be very interested in trying this.
