The cornerstone of Parkinson’s disease treatment, levodopa, is an effective yet tainted drug - eventually causing side effects as debilitating as the disease it treats. Finding a replacement is a distant dream; in the meantime much work is going on to find therapies that alleviate its complications (see table).
Long term use of L-dopa causes dyskinesia, uncontrollable and jerky movements that increase over time. Several compounds with different mechanisms of action are looking promising at lessening these side effcts, although most are still in mid-stage trials. “An effective medication for dyskinesia would radically change the management of Parkinson’s disease,” says Todd Sherer, vice president of research programs for The Michael J Fox Foundation, a major investor in this space that has provided funding for a number of these candidates.
Parkinson’s disease (PD) is caused by the progressive loss of brain cells that produce dopamine, an essential neurotransmitter found in the portion of the brain that controls movement. The mainstay treatment is levodopa, or L-dopa, which the body can turn into dopamine.
L-dopa is incredibly effective at slowing the onset of PD and alleviating the stiffness, tremors and rigidity caused by dopamine deficiency. However its effectiveness wanes and patients experience more and longer “off” periods, when their paralyzing symptoms return.
At the same time, dyskinesia occurs more frequently during the “on” periods. Fear of this often harrowing L-dopa-induced dyskinesia (LID) means many patients wait as long as possible to begin using L-dopa. And as dyskinesia becomes more common, some start taking less L-dopa, reducing the efficacy of the drug in controlling “off” periods.
“There is a huge need to develop therapies that allow optimum treatment with L-dopa, but limit the side effects,” Dr Sherer says, saying work on LID is one of the most important areas of Parkinson’s research.
The Michael J Fox foundation has funded work in this area with companies including Addex Pharmaceuticals, Targacept and most recently with Adolor. All are working on agents with different modes of action that modify circuitry in an area of the brain called the basal ganglia, a promising strategy to alleviate dyskinesia.
Most recently, Adolor was handed a second round of funding for research into selective centrally-acting mu opioid receptor antagonists, called Camors. Increased opioid peptide transmission in the basal ganglia might underlie dyskinesia after chronic L-dopa treatment. As such, opioid antagonists might be useful as adjuncts to L-dopa therapy, the company believes. Only pre-clinical work has been done so far, and the new funds will be used to find a lead compound.
More advanced is Addex, which has a negative allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), ADX48621. A $900,000 grant from the foundation received earlier this year will help fund phase II studies of the compound, which should start before the end of the year.
Like dopamine, glutamate is a critical neurotransmitter and disruptions to both systems are believed to be an underlying cause of movement disorders like Parkinson’s disease. As such, inhibiting mGluR5 could help re-establish normal movement, but via a non-dopaminergic mechanism.
Vincent Mutel, chief executive of Addex, says ADX48621 is looking particularly promising because it is showing efficacy on the two aspects of dyskinesia – the irregular muscle contraction of chorea and the large twisting, jerking movements called dystonia.
“A lot of molecules work on chorea, but very few are working on dystonia; ours is active on both. Having efficacy on both chorea and dystonia is going to be the future of the therapy. A molecule that is not active on both symptoms I doubt will make it as an add-on therapy for LID,” he says.
The broader potential around the mechanism of mGluR5, which has shown to be effective in anxiety and pain and also on certain gastro-intestinal conditions, is also creating interest in these agents, he adds. Parkinson’s patients also suffer anxiety and depression and mood changes and these are also targets for research – for example Acadia Pharmaceuticals is developing pimavanserin for Parkinson’s disease psychosis.
However finding a therapy that enhances the effectiveness of L-dopa, by targeting dyskinesia, remains a big goal.
“I think the view in the future is to look at L-dopa-induced dyskinesia as an indication per se. It is very much seen as the key to improve L-dopa efficacy and Parkinson’s disease overall,” Mr Mutel says.
Despite this, no agent has been approved specifically for LID. To this end, the Michael J Fox Foundation is funding a $1m clinical study aiming to establish a framework for testing novel anti-dyskinesia treatments, by validating clinical scales used to measure changes in severity.
“We want to make sure the correct validated tools are in the hands of researchers,” Dr Sherer says. Results are due next year, which will come in handy as a number of these agents progress to later stage studies.
One LID agent close to entering phase III is Santhera Pharmaceuticals' JP-1730 (fipamezole), an antagonist of the adrenergic alpha-2 receptor. The company says the rationale behind the development is to increase noradrenergic release in certain areas of the brain, resulting in the rebalance of the distorted brain network.
Biovail handed back US rights to the agent in October, shortly after Santhera gained Ipsen as an ex-US partner the previous month. The Ipsen deal was worth €141m in total, including €13m upfront, encouraging news for Addex, which is also looking for a partner for its candidate.
Another closely watched drug that could enter pivotal stages soon is AFQ056, owned by Novartis, which also targets mGluR5. Encouraging phase II studies have made headway proving the mechanism of action in this setting, and the pharma giant recently said it hoped to get the product on the market for LID by 2013.
Still, the challenge of establishing efficacy in this setting was demonstrated earlier this month by Merck KGaA and Newron Pharmaceuticals, which are working on the dopamine re-uptake inhibitor safinamide. An 18-month follow up to a phase III study found that while the agent showed long term efficacy in improving “on” time, it failed to show any impact on improving dyskinesia. The companies point out that the study was not powered to show an impact on dyskinesia, and an ongoing phase II study specifically in the LID setting should report next year.
Agents like safinamide, and another big class called the adenosine A2A receptor agonists, are being trialed as L-dopa add-ons primarily seeking to augment its effect and improve the “on” time experienced by patients (Therapeutic focus - A2A antagonists lining up to enter final stage Parkinson's trials, April 22, 2010). Being able to also improve dyskinesia would be a big win for these agents.
With safinamide and a couple of A2As in late stage trials, it seems that new combination therapies, seeking to enhance the efficacy of L-dopa, are likely to start emerging in the not too distant future. But with L-dopa remaining the cornerstone therapy, its disabling dyskinesia side effects will remain an important target for improving the lives of PD patients.
“I think L-dopa is going to stay the gold therapy for PD, because so far there is no mechanism of action that we know has superior efficacy. It is not impossible a combination therapy will show the same or potentially superior therapy to L-dopa itself. But for sure, add-on therapy to treat dyskinesia will probably be the next step forward (for Parkinson’s disease)," Dr Mutel predicts.
|Selected agents in development for L-dopa-induced dykinesia in Parkinson's disease|
|Phase III||Safinamide||Merck KGaA / Newron Pharmaceuticals||Dopamine reuptake inhibitor|
|Phase II||NP002||Neuraltus Pharmaceuticals||Nicotinic agonist|
|JP-1730||Valeant Pharmaceuticals International / Santhera Pharmaceuticals / Ipsen||Alpha 2 adrenoreceptor antagonist|
|AFQ056||Novartis||Metabotropic glutamate receptor 5 (mGluR5) antagonist|
|Phase I||ADX48621||Addex Pharmaceuticals||Metabotropic glutamate receptor 5 (mGluR5) antagonist|
|Neu-120||Neurim Pharmaceuticals||MAOB inhibitor|
|MK-0657||Merck & Co||NMDA antagonist|