New Formulation of Old Drug Shows Promise for “Off” Episodes

Administering an approved drug, apomorphine, by a new method — dissolving it under the tongue — can relieve “wearing off” episodes for people with Parkinson’s disease (PD), according to the results of a small, phase II clinical trial. The study appears in the July 19 online edition of Movement Disorders.

Levodopa, usually given as Sinemet®, is the gold-standard therapy for PD movement symptoms. But most people who take the drug for several years eventually experience fluctuations in its effectiveness, known as “off” periods, when movement symptoms return. While medication adjustments can help in the long term, the only approved therapy to rapidly address or “rescue” someone from such “off” periods is apomorphine, a drug that is injected under the skin. Although it is effective, injectable apomorphine is not widely used.

Seeking a more convenient way of giving the drug, Cynapsus Therapeutics, Inc., a company based in Toronto, Canada, developed APL-130277. It is a thin strip, about the width of a penny and very similar in appearance to a Listerine® breath strip, and is infused with apomorphine and a substance to prevent skin irritation. Holding the strip under the tongue quickly releases the drug.

Researchers led by Robert A. Hauser, M.D., at the University of South Florida, tested this way of administering apomorphine in 19 people with PD who experienced “off” episodes for more than two hours a day. Participants came to the clinic in the morning, before taking any levodopa or other PD medications. Researchers evaluated their movement symptoms (using a standard rating scale) before the strip was administered, and at 15, 30, 45, 60 and 90 minutes afterward.

Results: 

  • Of 19 study participants, 15 responded fully “on” after an apomorphine dose on average of about 20 mg.
  • Of the four who did not respond, two accidently swallowed the strip (at which point, it became inactivated by the stomach) and two had a limited response.
  • All 15 participants who responded were fully “on” within 30 minutes of taking the drug, and six of the 15 were “on” within 15 minutes.
  • Study participants maintained “on” time for 50 minutes on average, and nine of the 15 responders stayed fully “on” for 90 minutes or longer.
  • The drug was generally safe and well tolerated, although it had side effectsof dizziness, sleepiness and nausea for some participants.

What Does It Mean? 

For people with Parkinson’s disease, “off” periods can have a significant impact on quality of life. One way to cope with them is to work with the neurologist to adjust the dose and schedule of levodopa (Sinemet®), and/or to add other medications that extend levodopa’s effects. For many people, however, this is not enough, especially when “off” episodes become unpredictable. People with PD who develop unpredictable “off” periods may be reluctant to socialize or go outdoors for fear of developing an unexpected “off” period when away from home.

The results of this study, which assessed different doses of apomorphine given under the tongue in a small group of participants, demonstrate early evidence that the drug may have potential to help people with PD to cope with “off” times. Right now, in comparison to other drugs from the same class — ropinirole (Requip®), pramipexole (Mirapex®) and the rotigotine transdermal system “patch” (Neupro®) — apomorphine has a major advantage in that it takes effect very rapidly. However, it also has major drawbacks. For example, many who take the drug experience nausea and vomiting if they take the drug without also taking an anti-nausea drug. Plus, it also currently only available in the US as an injection. For those reasons, having an easy-to-use treatment during the “off” times would be a welcome addition to the roster of PD therapies.

While the results of this study are promising, additional research is needed. For example, the study group included no placebo group — all participants and medical personnel were aware that the drug was being given, so the placebo effect cannot be ruled out. To further assess the drug’s efficacy in Parkinson's, a “double-blind” phase III clinical trial, which includes comparison with a placebo in a larger group of study participants, is currently under way.

Reference

Hauser RA, Olanow CW, Dzyngel B, et al. (2016). Sublingual Apomorphine (APL-130277) for the Acute Conversion of OFF to ON in Parkinson’s Disease. Movement Disorders DOI: 10.1002/mds.26697

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