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A Drug that Melts in Your Mouth

For fifty years, L-dopa has been the gold standard for treating the symptoms of Parkinson’s disease. Much less has been written about another drug, apomorphine, a powerful dopamine agonist, which produces an L-dopa like response.  

The drug has a fascinating history, which British neuroscientist Andrew Lees deftly discusses in his new book, Mentored by a Madman: The William S. Burroughs Experiment. In the 50s, the maverick physician John Dent used apomorphine to treat beat generation writer William Burroughs’ opiate addiction. Andrew Lees later discovered that the drug could also be used to manage advanced Parkinson’s disease, rescuing patients whose L-dopa had worn off, and converting those individuals from an “off” to an “on” state.

Apomorphine, which has traditionally been either injected or infused through a needle under the skin, works by tricking the brain’s receptors into thinking they are receiving dopamine. In certain situations, says Henry Ford Hospital Professor Peter LeWitt, it’s fast and reliable. “Let’s say someone is in restaurant and they have had a meal and they experience a freezing episode. The Parkinson’s patient can’t count on his G.I. tract getting a new levodopa pill to be absorbed for between 30 and 45 minutes. In this situation an apomorphine injection offers a significant benefit unfreezing the individual in 5 to 8 minutes.”

Unfortunately, apomorphine comes with some unpleasant side effects, such as nausea and vomiting. Additionally, because the drug needs to be preserved in an acidic form, the injection and infusion sites typically become irritated, yielding unpleasant nodules.

Now a Canadian company may have solved a difficult puzzle in medicinal chemistry and come up with a much simpler way of delivering apomorphine to Parkinson’s disease patients. As CEO and President of Toronto-based Cynapsus Anthony Giovinazzo puts it, the company’s new product, APL-130277, embeds apomorphine “into a multilayer thin film strip – rather like a Listerine strip – that dissolves under the tongue.” The drug and the acidity are placed on one layer. Fabricated together in a second layer are a buffer (to mop up the acidity) and a permeation enhancer (to disperse the drug effectively and minimize nausea and vomiting). The trick, says Giovinazzo, is to allow both layers to dissolve in unison. So, once under the tongue, the drug and the acidity separate and the buffer in the second layer promptly mops up the acid, while the active drug is dispersed. The strip, which has a menthol flavor, dissolves quickly (in 1-3 minutes) effectively changing apomorphine “from a highly irritant product to one that is almost completely neutral and easy to use.” 

APL-130277 is currently undergoing Phase 3 trials. If all goes well, Cynapsus expects the product to be available by early 2018 in the USA and 2019 in Europe.

But while Cynapsus’ new product comes with fewer side effects, it may not be fast acting enough to succeed commercially as a rescue therapy. The apomorphine in the strip passes through the oral mucosa into the blood stream and enters the brain. This takes significantly longer than when apomorphine is directly injected under the skin. Cynapsus’ website reports that the strip took considerably longer than 5-8 minutes to unfreeze the patient. Specifically, the product converted PD patients “from the morning OFF state to the full ON state with 100% of responders turning fully ON within 30 minutes and 40% within 15 minutes.” According to LeWitt, that may be just too long. 30 minutes is a long wait, because remember that a levodopa tablet goes to work about 30 minutes as well.”

Commercial success, therefore, will likely depend on whether or not PD patients find the apomorphine strip faster and more reliable than oral levodopa tablets. “That’s the practical question, says LeWitt. “Will they think it is better than taking another Sinemet tablet and waiting it out.”