The highest-profile symptoms of Parkinson’s disease (PD) are well known. But for many PD patients, there is a lesser-known but equally important symptom that affects their well-being: “freezing” or “off” episodes that are marked by acute immobility, occur between one and six times daily, and last from one to several hours. These episodes may be triggered when mainstream treatments such as levodopa or enzyme inhibitors are too slow in entering the bloodstream.
An acute rescue therapy exists to treat these “off” periods when they occur: apomorphine, the only drug approved (under the name APOKYN® in the U.S. and Japan and APO-go® in Europe and parts of Asia) to treat this symptom. Unfortunately, apomorphine is primarily available in an inconvenient and painful injectable form (as well as, in Europe, as an abdominal infusion pump)—problematic not only because it needs to be administered up to six times a day, but because the injection can produce painful reactions including irritation and nodules at the injection site on the body, since apomorphine is only stable in a highly acidic formulation.
Cynapsus Therapeutics, based in Toronto, is trying a novel approach to overcome the limitations of the injectable form. The company has developed APL-130277, a sublingual thin-film strip system similar to Listerine® Breath Strips. Placed under the tongue, the strip dissolves in about 1.5 minutes, delivering the drug to the bloodstream in a similar time interval—and a similar concentration—as an injectable dose. The strip utilizes the very same drug with its acidic ingredients an absorption enhancer that aids the push of the drug into the bloodstream and a buffer that serves to convert the acidity at point of contact from a pH of 2-3 to a pH of 5.5-6.5, potentially eliminating oral irritation.
Such a treatment would relieve many PD patients of the need for self-injections, along with the stress and injury this activity entails. For many of them, it would also relieve their caregivers of this responsibility, eliminating the trauma of administering a drug in a way that can cause pain or physical damage to their loved ones.
Over the years, many companies have tried to develop non-injectable forms of apomorphine. These have included tablets, rectal suppositories, syringes to squirt the drug under the tongue, nasal drops and inhalers. All these attempts have not succeeded or are just not commercially practical—they failed to deliver an adequate amount of the drug into the bloodstream quickly enough to help the patients, and failed to overcome the drug’s irritant effects.
Only a few prescription thin-film formulations are FDA-approved: Onsolis® (fentanyl, 2009), Suboxone® (buprenophine + naloxone; Reckitt Benckiser Pharmaceuticals, Inc.; 2010) and Zuplenz® (ondansetron, Vestiq Pharma, 2010). Given the positive results obtained from two healthy human volunteer pilot studies—one at the end of 2011 and one in mid-2012—the Cynapsus team is enthusiastic about having APL-130277 join this list. A Phase 1 trial comparing three doses of APL-130277 to three doses of APOKYN® injection is imminent; the results will inform the design of two subsequent, larger trials, the first intended to demonstrate PK bioequivalence of APL-130277 and APOKYN® injection, with approximately 110 healthy volunteers and the second intended to demonstrate tolerability in approximately 150 to 200 PD patients.
Cynapsus must submit a New Drug Application (NDA) to the FDA for approval of APL-130277. This is projected to be accomplished by mid-2015 following the completion of the two studies noted above. Cynapsus intends to partner the product for license or sale to a large pharmaceutical company soon afterward. It holds the potential to open a new chapter in PD treatment and to ensure that these “off” periods are quickly turned off, easily and conveniently. Given that the global PD population is forecast to double or triple in the next decade alone, due to the aging baby boomer generation, the unmet patient need for such a treatment could be considerable.
Anthony Giovinazzo is President and CEO of Cynapsus Therapeutics, Inc., which is developing the only non-injectable (sublingual) delivery of the only approved drug (apomorphine) to be used as a rescue therapy for “off” motor symptoms of Parkinson’s disease.