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Medications for Parkinson's Disease: What's on the Horizon?

By David B. Sommer, M.D., M.P.H., and Mark A. Stacy, M.D.

In the three decades since carbidopa/levodopa (Sinemet®) revolutionized the treatment of Parkinson’s disease (PD), 15 new PD drugs have been brought to market in the United States.  With the exception of amantadine, all 15 medications treat Parkinson’s in a similar way — adjusting for loss of dopamine in the brain either by increasing available dopamine in the brain or directly stimulating dopamine receptors in the brain.
 
While these medications have improved PD care by extending available options — options that allow physicians to tailor medications that maximize benefit and minimize adverse reactions for each person with PD — they do not stop the progression of PD, nor do they address all of its symptoms sufficiently. 

Scientists continue to study new ways to treat PD — both dopaminergic and non- dopaminergic — that may better address motor fluctuations and nonmotor symptoms.  Several potential medications are now in development, but are not yet on the market — or, if they are, have not yet been approved specifically to treat PD. 

Such potential treatments generally represent an evolution of current treatment strategies — meaning that even though the medication may not work in a drastically different way than current medications, it may be better tolerated, its delivery may be different to maximize benefit, or its use in Parkinson’s may be novel.

Below, we discuss these potential treatments and tell you where they are in the development ‘pipeline.’  By pipeline, we mean the phases of research that bring medications to your pharmacy.  To better understand how these phases of research work, see the graph below.


Dopaminergic Therapy

Levodopa

Levodopa (the compound that is converted into dopamine in the brain) is still the gold standard therapy for PD.  In advanced PD, after years of using the medication, a person may experience fluctuations in his or her PD motor symptoms and fluctuations in blood levels of levodopa.  Low levels of levodopa, or “off” periods, can lead to slowness, stiffness, and tremor, while excessively high levels of levodopa, or “on” periods, often cause dyskinesias (involuntary movements).

Scientists are studying ways to eliminate “on” and “off” periods by changing the way in which levodopa is delivered, with the goal of providing a more steady and continuous level of the compound than is currently provided by pills.  In theory, a skin patch could do this.  One pharmaceutical company is currently developing a patch, but no clinical data are yet available.  Another is developing a modified form of levodopa that is “actively transported” from the gut to the blood stream (i.e. the medication is picked up by proteins in the gut that usually transport nutrients).  While this would not guarantee constant drug levels, the sponsors hope that active transport would eliminate the variability in drug absorption that causes “on” and “off” periods.  This medication is still in pre-clinical development.

A more invasive, but well-proven way to achieve constant blood levels of levodopa is to deliver it continuously into the gut.  Duodopa®, a gel form of carbidopa/levodopa that is continuously pumped into a person’s small intestine via a small tube that goes through the skin into the stomach, is available in Canada and all European Union countries.  It is now under review by the US Food and Drug Administration (FDA).

Dopamine Agonists

Dopamine agonists (chemicals that mimic the role of dopamine in the brain) are commonly used alone to treat early PD or along with levodopa to treat advanced PD.  When used in early PD, dopamine agonists have been found to be less likely to cause dyskinesias than levodopa, but they also provide slightly less benefit and perhaps a higher incidence of hallucinations and daytime drowsiness. 

Several new dopamine agonists are being studied to potentially join ropinirole (Requip®) and pramipexole (Mirapex®), which are already on the market.  One of these, pardoprunox, has progressed to Phase III trials.  Another, aplindore, is being studied in a Phase II trial and a third, lisuride, which is in the form of a skin patch and is already marketed in Europe, has progressed to a Phase II trial.
 
Another dopamine agonist, apomorphine, is currently marketed in the US as an injection for the treatment of acute “off” periods.  An orally-inhaled form of apomorphine, which may be easier for a person with PD to administer than the current version, is in the early stages of development. 

As for the first three — pardoprunox, aplindore, and transdermal lisuride — it remains to be seen whether any of them will be substantially different from the dopamine agonists now available.  Each aims to improve upon their predecessors in one of two ways — that is, better tolerability and/or better effectiveness in relieving symptoms.  We do not know whether they will accomplish either of these goals.  We do know that individuals have different reactions to medications, so a certain dopamine agonist may work better for one person than for another.

COMT Inhibitors and MAO-B Inhibitors

 
COMT inhibitors and MAO-B inhibitors are compounds that impair the breakdown of dopamine and thus increase the amount of dopamine that is available to neurons.  COMT inhibitors currently available in the US include entacapone (Comtan®) and tolcapone (Tasmar®).  MAO-B inhibitors now available include selegiline (Eldepryl®, Zelapar®) and rasagiline (Azilect®).  A novel COMT inhibitor, nebicapone, has shown promising results in preliminary trials.  A novel MAO-B inhibitor, safinamide, is being studied in a Phase III trial.
 
As with the new dopamine agonists, whether these new medications will have substantially improved effectiveness or tolerability over those currently available, remains to be seen. 

Non-Dopaminergic Targets

Neurotransmitters

Ever since it was discovered that replacement of the neurotransmitter dopamine (a chemical used by cells in the brain to communicate with each other), could improve PD symptoms, medications that correct for the loss of dopamine in the brain have formed the mainstay of PD therapy.  Only one non-dopaminergic therapy, amantadine, is widely used to treat Parkinson’s, but there is a great deal of interest in finding others.  Scientists are looking to certain other neurotransmitters such as adenosine and glutamate, to treat the symptoms of PD.  They are investigating ways to either modify the production of these neurotransmitters or to modulate their respective receptors (proteins on the surface of neurons that sense the presence of a released neurotransmitter and send a signal to the receiving cell).  These efforts could lead to a significant breakthrough in therapy, but no therapies have yet been discovered that are significantly more effective than dopamine replacement.

Perhaps the most studied non-dopaminergic target is the adenosine A2A receptor.  These receptors are concentrated in the motor control part of the brain that is most affected in PD.  One adenosine A2A antagonist, Istradefylline®, was taken to Phase III trials, but it failed to prove effective.  Four other potential adenosine receptor antagonists — fipamezole (JP-1730), SCH-420814, BIIA-014 and Lu AA4707 — are in earlier phases of development.

Several types of glutamate receptors in the brain — AMPA, NMDA and metabotropic glutamate — have been targeted as potential therapies for PD.   Amantadine, mentioned earlier, was recently discovered to be an NMDA receptor antagonist.  Perampanel (E-2007), an AMPA receptor antagonist, was developed through Phase III trials, but recent results have been disappointing.  A metabotropic glutamate (mGlu5) receptor antagonist has completed a Phase I trial.  And FP0011, a compound that reduces central glutamate levels, is now being studied in a Phase II trial.

Other Non-Dopaminergic Targets 

Researchers in Japan have published results from a large randomized trial in which zonisamide — an antiepileptic drug widely used in the US — improved the motor symptoms of PD.  The mechanism by which zonisamide may improve PD remains unexplained.  A second trial will be needed to independently confirm or refute its efficacy as a PD therapy.

Treatment of Nonmotor Symptoms

Nonmotor symptoms of PD include dementia, fatigue, depression, psychosis, and orthostatic hypotension (low blood pressure).  Most of these problems are addressed through the off-label use of medications that were originally developed for other diseases, but are not yet approved for use in PD.  Several are now being investigated for use in PD.
   
Dementia and psychosis (e.g., hallucinations or paranoia) often complicate late-stage PD.  Memantine and galantamine, medications on the market for Alzheimer’s, are being tested in clinical trials for the treatment of dementia in Parkinson’s.   Atomoxetine (currently marketed as Strattera® for the treatment of Attention Deficit Hyperactivity Disorder [ADHD]), is being investigated as a treatment for dementia in PD.  Pimavanserin, now in Phase III trials, is a novel drug that blocks subtypes of dopamine and serotonin receptors.  Its goal is to treat the psychotic symptoms that sometimes emerge in advanced PD, without worsening a person’s motor symptoms.

No new drugs are being developed specifically to treat depression in PD.  But three drugs commonly used for the treatment of depression generally — venlafaxine, paroxetine, and duloxetine — are currently being tested in people with PD.
 
Impulse control disorders (ICD) such as pathological gambling, binge eating, hypersexuality, and punding (compulsive performance of repetitive tasks) are associated with the use of dopaminergic medication, particularly with dopamine agonists.  Acamprosate, which is approved for the treatment of alcohol dependence, is now being investigated for its potential to treat ICD in Parkinson’s. 

Orthostatic hypotension, which can be a troublesome symptom for people with advanced PD, is now treated with midodrine and fludrocortisone.  But these medications have limited effectiveness and often cannot be used because they can increase blood pressure excessively while a person with PD is lying down.  Droxidopa® has been shown to be effective in treating orthostatic hypotension without causing excessive increases in blood pressure.  It is being studied in a Phase III trial for the treatment of orthostatic hypotension in various neurologic conditions, including PD.

Conclusion

Of the agents mentioned above, those that come to market will most likely represent no more than minor refinements in proven therapeutic strategies, rather than major therapeutic breakthroughs.  The quest for a major breakthrough — that is, a treatment that will halt or reverse the progression of PD (approaches known respectively as neuroprotective and neurorestorative) — continues to be the focus of much scientific inquiry.  Nonetheless, the next generation of treatments on the horizon will likely enhance the ability of clinicians to control the motor and nonmotor symptoms of PD and offer at least a modest improvement in quality of life for the people who live with PD.

David Sommer, M.D. M.P.H., is a clinical and research fellow at the Movement Disorders Center at Duke University Medical Center.  Mark Stacy, M.D., is an Associate Professor in the Division of Neurology and Director of the Movement Disorders Center at Duke University Medical Center.
 
Portions of the content of this article are abstracted from Sommer DB, Stacy MA, What’s in the pipeline for the treatment of Parkinson’s Disease? Expert Rev Neurother 2008 [in press].

This article is a companion piece to another that appeared in the Spring 2008 issue of PDF News & Review, in which Marina Emborg, M.D., provided an update on other investigational therapies, including gene therapy, stem cells and other cell-based therapy.  Read, A New Generation of Anti-Parkinson Treatments: What's in the Pipeline, online, or obtain a copy by calling PDF at (800) 457-6676.