Optimal Management of OFF Episodes in Parkinson's Disease - Episode 7

Continuous Subcutaneous Apomorphine Infusion in Development for OFF Episodes in Parkinson’s Disease

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Daniel E. Kremens, MD, JD: There’s a form of apomorphine that’s available in Europe, not used as an on-demand therapy, but as a continual treatment for Parkinson’s disease. It’s a subcutaneous infusion. Could you speak a minute on that, please?

Rajeev Kumar, MD: Sure. [Apomorphine] subcutaneous infusion has been available in Europe for more than 20 years. I briefly used it experimentally as a Fellow in movement disorders. In the last 4 years approximately, we’ve done long-term open-label studies in the United States. I’ve had several patients in clinical trials receiving [apomorphine] subcutaneous continuous infusion with a pump similar to an insulin infusion pump and much tinier than the pump used for Duopa [carbidopa/levodopa] therapy. 

The medication is administered via a very thin small needle that is applied underneath the skin of either the abdomen, upper thigh, or upper back. Most patients can manage this independently. Some patients would like to have a caregiver apply this. Usually they have a continuous infusion during the waking hours of the day. Most patients start it first thing in the morning and discontinue it at bedtime. In Europe, many patients have used it around-the-clock to also improve nocturnal akinesia. Due to being a continuously administered product, it is not designed for acute treatment of OFF episodes. Although, there is the option to administer a bolus dose on top of the continuous infusion to improve OFF episodes at that time without repoking yourself. That is a nice option when you already have the needle in place.

It can result in a clinically significant reduction in OFF time. If we were to look at the TOLEDO study, a European publication of a multicenter study in which there was double-blinded application of the pump, there was an OFF time reduction of more than 2 hours compared to placebo. That’s a very large and clinically important benefit. In many countries in Europe, this form of device-aided therapy is used in a widespread manner. It is pretty much mandatory in some countries, for example the United Kingdom, prior to considering either Duopa therapy or deep brain stimulation. It’s quite manageable for patients and caregivers, and it’s certainly easily reversible and less invasive.

It’s not that difficult to initiate. In Europe, they tend to initiate it very rapidly, typically in a hospital or an accelerated outpatient setting. In the clinical trials—and as it will probably be administered in the United States once hopefully approved next year—it will be administered through gradual titration, usually in visits every few days to a week, in which the pump rate is increased and oral drug dose is reduced. The goal is to continue a stable ON response. To do so, often the dose of the intermittent levodopa needs to be reduced to prevent overshooting. It does reduce dyskinesia, prevents undershooting, and reduces OFF time. Some patients, in my experience and in the European experience, could get rid of almost all or all the oral levodopa. If you’re able to do so, that produces a very smooth continuous ON response. You can achieve the sweet spot ON state without dyskinesia all day long. That’s the ideal patient. Not all patients can achieve that.

Daniel E. Kremens, MD, JD: In general, it does still have the typical [adverse] effects that we see with dopamine agonists. Additionally, there have been some reports of nodules at the site of the subcutaneous needle. However, there are also some data that suggest with proper skin hygiene you can help reduce that nodule problem. 

Rajeev Kumar, MD: The cutaneous problems are quite manageable, not only with hygiene but also by massaging the nodules. Usually the nodules are quite painless, which is good. It should be kept more in mind that with any dopaminergic medication, including intermittent Apokyn [apomorphine hydrochloride subcutaneous injection] and more importantly subcutaneous continuous infusion of apomorphine, impulse control disorder is a risk. Patients should be warned about this and monitored for the development of impulse control disorder with apomorphine subcutaneous but especially with continuous infusion.

Daniel E. Kremens, MD, JD: Well, that was a great discussion about apomorphine. It’s wonderful to have such an old drug resurging again. We’ve had Apokyn for a while. We’re now going to have Kynmobi [sublingual apomorphine hydrochloride]. Hopefully in the future, we’re going to have in the US the subcutaneous continuous infusion formulation, commercially known in Europe as APO-go.