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What's in the Parkinson's Pipeline?

By David G. Standaert, M.D., Ph.D.

If you are a person living with Parkinson’s disease (PD), you may be wondering if new and better medications will be available in the near future and how they may help you. 

It is difficult to predict which treatments in trials will be approved for the market, but we can assess the possibilities by looking at the “pipeline” — the process by which we find new treatments for Parkinson’s.  Currently, there are two categories of therapies, symptomatic and neuroprotective, which are making their way through the  PD pipeline. 

The first category, symptomatic drugs, treats both the motor and nonmotor effects of Parkinson’s.  There are already several treatments for Parkinson’s symptoms and these have made a tremendous difference in the lives of many who live with PD.  However, these medications have side effects and do not address certain symptoms — for example, none of them help with the common problems of fatigue, constipation or balance.  So, one goal is to find better symptomatic drugs. 

Second, there is excitement about the possibility of developing neuroprotective treatments, those that would slow or prevent the progression of Parkinson’s disease.  So far, no therapies have been proven to be neuroprotective and most of the candidates are in the early stages of the development process, years away from approval.

The Drug Development Process

Phases of the Pipeline

Scientists find new medications in one of two ways.  One way is to test the efficacy of compounds that have already been approved by the US Food and Drug Administration (FDA) for other diseases.  The other is to theorize a new pathway that may affect PD, and then to find a new compound to target it.  Under both approaches, the therapy must travel through a multi-step process before it can be approved for the market.

The first phase of this process is called preclinical research.  During this stage, a new compound is discovered and tested on model systems (meaning systems other than humans) that replicate some aspect of PD — from simple systems, using a Petri dish or test tube; to more complex models, like yeast and fruit flies; and eventually to very complex systems, such as mice and nonhuman primates. 

Once a potential new drug has been “validated” through animal testing, it may move to the phase where it needs to be tested on humans, called clinical trials.  Clinical trials typically proceed through four phases.  In a Phase I trial, a drug is tested for safety only, among a small group of 20 to 80 people.  A Phase II trial enrolls between 100 and 300 people and while continuing to assess the safety of a medication, now tries to get some idea of whether it is likely to be effective in treating Par­kinson’s.  A Phase III trial typically enrolls between 300 to 3,000 participants at multiple sites.  Phase III is the definitive study in which a potential drug is proven safe and effective — and therefore eligible for approval by the FDA — or it falls by the wayside.  After a drug is approved and is used by people with PD, a Phase IV “post market” trial may be conducted to find out more about how it works in large populations, how it interacts with other drugs, or if it has additional uses.

The Current Pipeline

The following is an assessment of the state of the current Parkinson’s pipeline.  It includes potential treatments, beginning at the end of the pipeline (Phase IV), and traveling back to the earliest studies (preclinical).  Most of the information is drawn from www.PDtrials.org.  Please note that each PD medication listed below may be referred to by one or more of its three names.  When a drug is in the early stages of development, it has only a chemical name, consisting of letters and numbers.  Later on, the medication will be given a generic name.  And once it is approved, it will acquire a brand name.  For example, a current Parkinson’s medication was first referred to by its chemical name, TVP-1012.  It then developed the generic name rasagiline, and is now known primarily by its brand name, Azilect®. 

Phase IV: Post Market Studies

Some drugs that have already been approved by the FDA, either for use in Parkinson’s or for another condition, are now being studied to see if they might work for additional Parkinson’s symptoms.  For example, the drug rasagiline was originally approved to treat Parkinson’s — both in the early stages (used alone) and in the later stages (as an adjunct to levodopa and other therapies).  Today, it is being studied for its effects when given in combination with dopamine agonists. 

Then there is naltrexone (brand names ReVia®, VivitrolTM and Depade®), which is currently used to treat addictions, but which scientists suspect may be useful for treating impulse-control disorders in PD, such as compulsive gambling or shopping.  Rivastigmine (Exelon®), a drug approved for the treatment of PD dementia, is being studied for treatment of additional cognitive symptoms.  Lubiprostone (Amitiza®), a gastrointestinal medication, is being evaluated for its efficacy in alleviating constipation.  Finally, donepezil (Aricept®), originally indicated for the treatment of Alzheimer’s, is under investigation for the treatment of dementia in Parkinson’s.

Phase III: “Pivotal” Studies

In Phase III trials, the “make-or-break” stage of the clinical research process, most of the candidate treatments are symptomatic.  Few of the neuroprotective therapies have made it this far.  The symptomatic therapies being studied include several reformulations of levodopa, which aim to address problems associated with current formulations, such as wearing-off — that is, when the time during which the drug is effective becomes shorter.  The newer medications are designed to provide more “on-time” for people with PD and simplify a person’s medication schedule by requiring less frequent dosages throughout the day.

One example is IPX066, which comes in pill formulation.  It is an extended-release medication — that is, it has a mechanism that releases the compound slowly in the bloodstream throughout the day rather than all at one time, thus requiring a person to take fewer pills.  Another therapy under study is intraduodenal levodopa (Duodopa®), which is a gel form of levodopa that is pumped directly into the intestines.  Its goal is to provide continuous amounts of levodopa to avoid wearing-off.  A third medication, safinamide, which is in the class of medications called MAO inhibitors, is also designed to increase “on-time” and decrease “off-time” associated with levodopa in the middle and late stages of PD.  This drug is being studied as an adjunct treatment, meaning it would be taken in addition to levodopa and other existing PD medications.  Also in Phase III is a medication called istradefylline (KW-6002), an adenosine (A2A) agonist.  Investigators hope that this drug will suppress dyskinesia, the involuntary movements caused by PD medications, as well as ease the motor symptoms of Parkinson’s itself. 

Finally, there are two symptomatic drugs under study in Phase III trials that address nonmotor PD issues: pimavanserin (ACP-103), which may suppress psychosis and hallucinations, and pitolisant (BF2.649) which addresses the excessive sleepiness that is experienced by many people with PD.

In the neuroprotective category, two medications have reached Phase III, both of them sponsored by the National Institutes of Health.  One is Coenzyme Q10 (CoQ10), and the other is creatine.  Both are substances that occur naturally in the body.  They are being given in much higher amounts than are normally present.

Phases II and I: Safety and Efficacy Studies

Earlier in the pipeline, we find four symptomatic therapies and four neuroprotective drugs under study.  Three of the symptomatic therapies — AFQ056, pardoprunox (SLV-308) and fipamezole (JP-1730) — target particular kinds of receptors in the brain with the hope of easing the movement symptoms of PD.  They are all taken as pills.  The fourth, Prosavin®, is a gene therapy that is administered surgically into the brain.  It consists of a genetically engineered virus that expresses enzymes in the brain that help levodopa to be converted into dopamine.  The hope is that boosting dopamine will alleviate the symptoms of PD.

Also in the neuroprotective category is a second gene therapy approach called CERE-120 (AAV neurturin), which uses a growth factor that makes the protein neurturin.  The hope is that neurturin will help regenerate the dopaminergic system and turn the clock back on PD.

Another interesting neuroprotective candidate being studied in Phase I and II clinical trials is isradipine  (DynaCirc® CR).  Isradipine is one in a class of medications called calcium channel blockers that is already used to treat high blood pressure.  An additional trial, called SURE-PD, is studying urate, a normal constituent in blood.  Several studies have shown that people with high natural levels of urate seem to be protected from PD.  Last among the neuroprotective agents in early phase trials is PYM50028 (Cogane®), which is derived from the extract of the sasparilla plant. 

Preclinical: Discovery and Validation

In earlier preclinical discovery phase, much of the excitement surrounds neuroprotective strategies, some of them using recent discoveries about the genetic causes of PD.  Drugs under investigation target the proteins produced by the genes known as alpha-synuclein and LRRK2.  Another approach in this phase is reducing inflammation in the brain.  A third approach is studying the use of growth factors and neuroregenerative approaches as an attempt to not only stop the progress of Parkinson's disease, but also to reverse it. 

Looking Forward

It is always difficult to predict which potential therapies will work and which will not.  At each step along this pipeline, research becomes much more expensive.  And for every potential therapy that enters the process, perhaps one in a thousand will end up being approved for use. 

That said, we can “forecast” that the drugs most likely to emerge soon from the pipeline are symptomatic treatments that have been studied the longest (in Phase II and Phase III trials).  These treatments include those that are finding new ways to use levodopa and dopamine agonists as well as those that aim to address fatigue, constipation and memory loss. 

Neuroprotective and restorative treatments are being studied at earlier phases in the pipeline.  Within about three years, the hope is that modestly effective neuroprotective therapies — perhaps CoQ10, creatine or isradipine — will be approved. 

While we can’t know exactly what’s next, we can be optimistic at the level and type of research ongoing for Parkinson’s, all of which aims to improve and perhaps more importantly, reverse the course of Parkinson’s for all of those living with the disease.

Dr. Standaert is John and Juanelle Strain Professor and Vice Chair of Neurology at the University of Alabama at Birmingham. 
In the last year, Dr. Standaert has served as a consultant to Solvay Pharmaceuticals, manufacturer of Duodopa®, and Teva Neuroscience, manufacturer of Azilect®.  He recently presented this topic at one of PDF’s PD ExpertBriefings. 

View his entire presentation