Apokyn®
Current Parkinson’s Disease Therapies
Summary
Apokyn® (apomorphine hydrochloride injection) is the only therapy available in the US for the treatment of “off” episodes (re-emergence of Parkinson’s disease symptoms) associated with advanced Parkinson’s disease. It is used as an adjunct to other Parkinson’s disease medications and is administered, as needed, by means of an injector pen to treat periods of poor mobility in people with advanced disease.
In April 2004, Apokyn® received FDA approval with Orphan Drug designation to treat advanced Parkinson's disease patients in the U.S. who experience the severe "on/off" motor fluctuations that are unresponsive to other oral Parkinson’s disease therapies. Approximately 112,000 patients with Parkinson’s disease experience such “off” episodes despite optimal oral Parkinson’s disease therapy.
Apokyn® was launched in the U.S. in July 2004 and Vernalis acquired the North American commercial rights from Mylan in November 2005. Mylan originally licensed the product from Britannia Pharmaceuticals Limited in 1999.
Mylan stopped promoting Apokyn® in July 2005 and Vernalis' speciality neurology sales force re-launched this promotion-sensitive product in February 2006. Apokyn® is sensitive to promotion due to the need to clarify appropriate patient candidates and to assist physicians and their staff with the Apokyn® initiation and titration process. Proper initiation and titration is important to ensure that each patient is individually titrated to their optimal dose and to help minimise the risk of first dose side effects.
During H2 2006, Vernalis established several marketing initiatives to make physicians and patients aware of the benefits of Apokyn® at optimal dosing levels and help reduce the barriers that prevent patients from starting to use the product. These efforts include a comprehensive support programme (The APOKYN® Circle of CareTM) which includes a nurse call centre, home healthcare visits and a pilot clinical liaison programme where nurses assist both physicians and patients through the whole treatment cycle. These initiatives are expected to become fully effective about 6-months after their introduction and hence improve prescription levels during 2007.
Apokyn® should not be used by patients who are being treated with certain drugs to treat nausea and vomiting or irritable bowel syndrome. These medications (including, for example, ondansetron, granisetron, dolasetron, palonesetron, and alosetron) are called 5HT 3 antagonists or blockers. In addition, Apokyn® should not be used by patients who have an allergic reaction to the drug or its ingredients (notably sodium metabisulfite). Apokyn® should be injected under the skin only, and not into a vein. Because Apokyn® can cause severe nausea and vomiting, it is taken with an oral medicine that helps to prevent these effects. Apokyn® may lower blood pressure (orthostatic hypotension), cause fainting, and increase the risk of falling. At recommended doses minimal increases in QTC were observed. Caution should be used when prescribing apomorphine with drugs that prolong the QT/QTC interval. Some patients treated with Apokyn® may get sleepy during the day or fall asleep without warning while doing everyday activities. The most common side effects of Apokyn® are yawning, dyskinesias, nausea and/or vomiting, sleepiness, dizziness, runny nose, hallucinations, fluid retention, chest pain, increased sweating, flushing, and an unusually pale complexion.
Background
It is estimated that approximately 1.5 million people in the U.S. have Parkinson's disease, a condition that results from selective degeneration of an area of the brain called the substantia nigra, which is located towards the base of the brain in the basal ganglia. Normally these nerve cells release dopamine - a chemical that transmits signals between nerve cells (called a neurotransmitter). This central signalling pathway is essential for the fine control of movement and posture, and breakdown results in the symptoms of Parkinson’s disease namely tremor, rigidity, slow movements and postural instability. Muscle rigidity can become so severe as to result in “freezing” also referred to as “off” episodes, when patients are rendered immobile. Patients also suffer from problems relating to impaired control of blood pressure (postural hypotension) and gut motility, which can impair the absorption of food and drugs.
The disease is progressive and the signs and symptoms generally worsen over time. However, while Parkinson's disease may eventually be disabling, the disease often progresses gradually and with appropriate treatment many patients have a number of years of productive life after initial diagnosis.
Current Parkinson’s Disease Therapies
Unlike some other neurologic diseases, Parkinson's disease is amenable to symptomatic treatment and there are a number of therapies currently on the market including:
Levodopa - For a number of years levodopa, commonly known as L-dopa, has been the cornerstone of Parkinson's disease treatment. This drug is a precursor to dopamine and is converted into dopamine in brain cells. However, L-dopa does have side effects, and it is thought it can become less effective as the disease worsens. After a number of years of treatment patients often develop unwanted movements (dyskinesias) as a side-effect of L-dopa therapy. As a result, newer drugs have been introduced to improve symptom control, either alone or in combination with L-dopa. L-dopa is usually administered with another drug, carbidopa, which helps reduce side effects. The most widely used versions of these L-dopa combination drugs are Simemet® and Madapar®.
Dopamine agonists: Unlike L-dopa these drugs are not changed into dopamine. Dopamine agonists are drugs that stimulate dopamine receptors in the brain that would normally respond to dopamine itself. In effect, these drugs reproduce the effects that the missing dopamine would have produced had it been present in normal quantities. Dopamine agonists are used both as adjuncts to L-dopa therapy and also in early Parkinson's disease, especially in younger adults. Examples of dopamine agonists include Mirapex®, Requip®, Cogentin® and Parlodel®.
Clinical Studies
The effectiveness of Apokyn® for the acute, intermittent treatment of "off" episodes associated with advanced Parkinson's disease was established in three randomised controlled clinical trials. On average, patients participating in these trials had Parkinson's disease for 11.3 years and were being treated with L-dopa and at least one other agent, usually an oral dopamine agonist. One of the three studies was conducted in patients who did not have prior exposure to apomorphine and two were conducted in patients with at least 3 months of Apokyn® use immediately prior to study enrollment. Almost all patients without prior exposure to apomorphine began taking an antiemetic (trimethobenzamide) three days prior to starting apomorphine. After exposure to apomorphine, 50% of patients were able to discontinue use of a concomitant antiemetic, on average 2 months after initiating apomorphine.
In clinical studies, Apokyn® was shown to be effective in the acute, intermittent treatment of “off” episodes demonstrating a highly significant improvement in Unified Parkinson 60 Disease Rating Scale (UPDRS) Part III motor scores at 20 minutes, with statistical improvements in some measures noted as early as 10 minutes. The UPDRS is used by researchers and clinicians around the world to measure disease severity in patients.
Regulatory Status
Apokyn® was approved through the FDA's Orphan Drug route in April 2004 and was launched in the US in July 2004. It was marketed by Mylan Pharmaceuticals until November 2005 when it was acquired by Vernalis. For full prescribing information, please visit: www.apokyn.com .
In November 2005, Vernalis entered into a collaboration with Britannia Pharmaceuticals Limited to explore the development of new formulations of apomorphine for the U.S. market. Vernalis has rights to Britannia's technology to develop a continuous sub-cutaneous infusion of apomorphine and rights to negotiate terms for a nasal powder formulation of apomorphine, which is currently in clinical development in Europe.