I recently watched a great local artist at work, focused on hanging his commissioned piece of art. As he was almost at the point of securing his artwork in the exact position, his hands began to shake uncontrollably and the frustration became evident in his face. He tried a number of times to secure the wire holding his artwork, but in the end he had to call upon his assistants to come and do what he could not for himself. While celebrities like Michael J Fox and Muhammad Ali have raised global awareness of Parkinson’s disease, this was the first time I had come face-to-face with the frustrations that an ‘average’ person with Parkinson’s has to deal with on a daily basis.
The progressive motor disorder is caused by the loss of dopamine-producing neurons in the brain (primarily in the substantia nigra). Parkinson’s is the second most common neurodegenerative disorder after Alzheimer’s disease, and it is estimated that 7 to 10 million people worldwide are living with Parkinson’s. Patients with Parkinson’s experience motor skill abnormalities including tremor, muscle stiffness, and unstable voluntary movements and posture. While the incidence of Parkinson’s increases with age, approximately 4 per cent of patients can be diagnosed with Parkinson’s before the age of 50. Furthermore, men are more likely to have Parkinson’s than their female counterparts.
While there are many drugs that are available for treatment of symptoms of Parkinson’s and to improve function, there is currently no drug that has been shown unequivocally to cure the disease or slow its progression.
Levodopa + carbidopa
Levodopa (a dopamine precursor; also called L-dopa) has been the mainstay of treatment for Parkinson’s since the 1960s, and its development represented one of the most important breakthroughs in the history of medicine. Unfortunately, levodopa is associated with long-term motor complications (eg motor fluctuations and dyskinesias), low blood pressure, arrhythmias, gastrointestinal problems, nausea, hair loss, sleep disorders, confusion, anxiety and hallucinations. Within four to six years of treatment with levodopa, the effects of the drug in many patients begin to last for shorter periods of time after a dose, called the ‘wearing off effect’. In response to this effect, patients may choose to increase their levodopa dosage and/or frequency, but in doing so they face an increased risk of dyskinesia. Therefore, alternative therapies to levodopa have required further investigation.
Levodopa is almost always administered with carbidopa, which prevents levodopa from being converted into dopamine in the bloodstream – allowing more levodopa to reach the brain and therefore ultimately requiring a lower initial dose. Levodopa/carbidopa is the gold standard therapy for symptomatic treatment of Parkinson’s; the most common product is called Sinemet (Merck Sharp & Dohme) and it is also available in a controlled-release formulation (Sinemet CR). Generic versions of this drug combination are also available, including Parcopa (Azur Pharma).
Osmotica Pharmaceutical is also developing a levodopa/carbidopa product utilising its proprietary Osmodex technology (OS 320). A phase II trial has been completed in Argentina, and a pivotal phase III study is underway, presumably in the US.
AbbVie (formerly Abbott Laboratories) is developing an intraduodenal gel formulation of levodopa/carbidopa (LGIC; Duodopa) for the treatment of late-stage Parkinson’s in patients who have failed conventional oral levodopa therapy. Marketing approval for this formulation has been granted in 28 European countries, and the US FDA has granted fast track status and orphan drug designation for the long-term treatment of motor fluctuations associated with advanced Parkinson’s. It appears that AbbVie will make its US submission during 2013, with subsequent launch during 2014.
An extended-release capsule formulation of levodopa/carbidopa (IPX 066; Rytary; IMPAX Laboratories) has also been developed, and is awaiting approval in the US for the treatment of idiopathic Parkinson’s. This formulation can either be swallowed whole or sprinkled on to soft food and will require less frequent dosing than traditional forms.
Dopamine agonists
Unlike levodopa, dopamine agonists do not change into dopamine, but rather mimic the effect of dopamine in the brain. Although dopamine agonists are not as effective as levodopa, they last longer in the brain and their effects do not wane over time. The side effects of dopamine agonists are similar to those of levodopa/carbidopa, but may also include hallucinations, swelling and sleepiness.
Dopamine agonists represent the most successful class of agents that make up approximately 70 per cent of the marketed therapies for Parkinson’s, either as single-agent compounds (eg pramipexole, ropinirole) or in multiple-agent drug combinations (eg entacapone/levodopa/carbidopa).
MAO B inhibitors
Monoamine oxidase B (MAO B) is an enzyme in our brain that breaks down dopamine. MAO B inhibitors block the breakdown of dopamine caused by the enzyme, slowing the loss of dopamine and several of the side effects associated with Parkinson’s. MAO B inhibitors are generally considered for initial treatment of early Parkinson’s. Currently available therapies of this class include selegiline and rasagiline.
Safinamide (Newron, Zambon and Meiji Seika Pharma) is a selective and reversible MAO B inhibitor in the absence of MAO-A inhibition. This oral alpha-aminoamide derivative has completed a phase III programme for use as an adjunctive treatment to dopamine agonists (in patients with early Parkinson’s) and levodopa (in patients with mid- to late-stage Parkinson’s), and global regulatory submissions are expected to be filed by the end of 2013.
There is very real hope that the genetic or environmental causes of Parkinson’s disease will be identified
Adenosine A2A receptor antagonists
Adenosine A2A receptor antagonists modulate the production of dopamine, glutamine and serotonin in specific regions of the brain. Therapeutics with this mechanism of action have been shown to significantly modulate the ‘off’ time without increasing dyskinesia in patients with Parkinson’s.
Istradefylline (KW 6002; Kyowa Hakko Kirin) is one such therapeutic in late-stage clinical trials in development as a once-daily oral therapy for Parkinson’s. A regulatory application has been filed in Japan for this indication. However, in the US, a non-approvable letter issued in February 2008 resulted in Kyowa Hakko Kirin suspending further development in North America and subsequently out-licensing the drug to Bioavail Corporation (now Valeant Pharmaceuticals) in June 2010 in North America. However, Valeant terminated its licence in this region in June 2011. Another therapeutic is preladenant (Merck & Co; originally discovered by Schering-Plough), which is in phase III trials for the treatment of Parkinson’s and other movement disorders.
COMT inhibitors
Catechol O-methyltransferase (COMT) converts levodopa in the periphery to 3-O-methyl-DOPA (3-OMD). This metabolite, which cannot be converted to dopamine, accumulates in plasma during levodopa therapy. Therefore, inhibition of COMT increases the bioavailability of levodopa, allowing a larger amount of levodopa to reach the brain and consequently raise dopamine levels. As COMT inhibitors alone do not have any effect on the symptoms of Parkinson’s, they are always taken in combination with levodopa.
Tolcapone (Roche, Valeant Pharmaceuticals) and entacapone (Orion, Novartis, Bristol-Myers Squibb) are two marketed Parkinson’s therapies in this class of agents. Opicapone (Bial) is a COMT inhibitor in phase III development in various European countries for the treatment of idiopathic Parkinson’s. Bial plans to develop opicapone to be administered in combination with levodopa/carbidopa or levodopa/benserazide preparations.
Can gene therapies deliver for Parkinson’s?
Neurologix in the US is developing a glutamic acid decarboxylase (GAD) gene therapy, NLX·P101, for the treatment of Parkinson’s using NLX, its proprietary gene transfer technology. NLX·P101 uses adeno-associated virus-mediated transfer to introduce the gene for GAD into the brain. GAD converts glutamate (ie main excitatory neurotransmitter) into gamma-aminobutyric acid (GABA; main inhibitory neurotransmitter). Patients with Parkinson’s have a decreased level of GABA in the subthalamic nucleus, leading to overstimulation of the area and symptoms such as tremors. The introduction of GAD may result in an increased level of GABA, thereby dampening the overstimulation of the subthalamic nucleus and subsequently reduce symptoms of Parkinson’s.
Other companies currently investigating gene therapies for Parkinson’s in clinical trials include: Ceregene (CERE 120; phase II in UK and US); Neurologix (NLX P101; phase II in US with fast track status); Oxford Biomedica (phase I/II in France and UK) and Genzyme (AV 201; phase I in US).
What lies beyond…
Research for Parkinson’s has made remarkable progress over the last decade. There is very real hope that the causes (genetic or environmental) will be identified and the precise effects of these causes on brain function will be understood. Although this article has focused primarily on therapies in mid- to late-stage clinical development, there are a number of less advanced therapies and research programmes that are exploring new facets of the disease (eg stem cell therapies) that should offer some hope to those who suffer the effects of this disease. While current therapies available to patients with Parkinson’s can substantially reduce their symptoms and allow them to live normal lives, researchers are still working hard to find better therapies – and an eventual cure.