Easing Dyskinesia: PDF-funded Research from 2007 Leads to Testing of Experimental Drug

Earlier this week, PsychoGenics Inc., announced that an experimental drug for Parkinson’s, eltoprazine, seemed to reduce dyskinesia in people with Parkinson’s in early studies.  Dyskinesias are the twisting and writhing movements that occur as PD progresses – a common side effect of the medication levodopa (Sinemet®).   

Back in 2007, it was PDF-funded researcher Manolo Carta Ph.D., along with Anders Björklund, M.D., who performed the pre-clinical research that led to the identification of this drug.  At the time, while many researchers were looking at dopamine neurons as the culprit behind dyskinesias (through their interaction with levodopa), Dr. Carta’s proposal suggested something different – serotonin neurons.  His proposal led to a one-year research fellowship funded by PDF.

After completing his year of research with PDF funding during which he laid the foundation for this approach, he and his colleagues were able to investigate an experimental compounds that might help with dyskinesias.  With the support of other funders, they have now been able to study the effects of eltoprazine in people in this early stage trial – to see whether it is a viable drug treatment.

The study results announced earlier this week indicate positive news about eltoprazine’s potential to ease dyskinesia and possibly some non-motor symptoms of PD.

However, the drug will have to undergo rigorous testing – in additional people with Parkinson’s in phase II and phase III clinical trials – before we know if it’s safe and effective.  While we don’t yet know the fate of this drug, the results help us learn more about dyskinesias so we can find a solution in the future.

PDF believes it’s important to fund ideas like this so that scientists can have both the freedom to explore novel ideas for Parkinson’s and the time they need to gather data that can prove the promise of their ideas.  In Dr. Carta’s work, this proved to be the case. 

We believe this philosophy – funding creativity early on – will help researchers prove their case to other funders that can help them to further develop their ideas ... ultimately into new treatments and a cure for Parkinson’s. 

What are your thoughts? Do you or a loved one need a drug for dyskinesia?

Please share your thoughts below, and as always, call our HelpLine at (800) 457-6676 with any questions you or a loved one may have about Parkinson's.

Understanding the FDA Committee’s Decision to Recommend Approval for Neurogenic Orthostatic Hypotension Drug

From James Beck, Ph.D., Director of Research Programs

You may have read the recent news about the small pharmaceutical company,Chelsea Therapeutics, and their drug Northera™ (droxidopa). Chelsea recently received the recommendation of a FDA advisory committee to approve droxidopa as a treatment for neurogenic orthostatic hypotension or NOH for short. This recommendation was a big surprise since FDA documents released ahead of the committee meeting showed that agency staff members were clearly against approval; nevertheless, this approval recommendation will strongly influence the final decision expected to be made later this month.


What is NOH?
Normally, blood pressure increases as you move from a lying down to a standing position. This increase is necessary in order to maintain adequate blood flow to the brain. Not enough blood (or the oxygen it carries) results in a host of unpleasant issues including light headedness, dizziness, fainting and falls. Your nervous system automatically senses when you stand and then causes this pressure change. For some, the neural response fails to work and they develop precipitously low blood pressure when they stand, hence the name neurogenic (neural origin) orthostatic (standing) hypotension (low blood pressure). There are reports that about 40 percent of people living with Parkinson’s disease have some degree of orthostatic hypotension that is almost always neurogenic in origin.


How might droxidopa treat NOH?
Just like levodopa is the precursor of dopamine for Parkinson’s disease, droxidopa is the precursor of the norepinephrine neurotransmitter for NOH. Norepinephrine is used by the peripheral nervous system to help regulate blood pressure, generally more norepinephrine leads to a higher blood pressure. These levels fluctuate as you move about your day. Therefore, the concept behind droxidopa is that the peripheral nerve cells that regulate blood pressure are able to convert droxidopa into norepinephrine and provide an increased blood pressure. Several studies done in people with multiple system atrophy and peripheral autonomic failure (two diseases that can lead to NOH) have shown promising results. Currently, Chelsea Therapeutics is also conducting a fairly large (200 participants) study of droxidopa in PD. Preliminary results from that have been encouraging as well.

The problem of current therapies
There is currently only one FDA approved drug, midodrine, that is used to treat orthostatic hypotension. Because of the rare nature of NOH, midodrine was approved as an orphan drug before large, key studies showing efficacy were performed. (Because orphan drugs are therapies that target rare diseases, they get special treatment from FDA.) However, for midodrine, those studies were not done as required. Now the FDA is pressuring the manufacturer of midodrine to do the studies or pull the drug off the market.


Why would the FDA be against droxidopa?
Even though droxidopa has shown evidence of helping with NOH, the clinical studies to demonstrate the efficacy of this drug are far from clear-cut. The issues are outlined in the FDA Advisory Committee materials. For instance, in one study, the droxidopa demonstrated a strong, initial increase in blood pressure, but the effect slowly declined over a period of weeks. The therapeutic effect only returned after people were told they were on the drug and advised to stay on it during an open label part of the trial. Despite the variable effect of droxidopa on blood pressure, participants in the study kept diaries that consistently indicated a benefit of the drug. Besides issues of efficacy, there are concerns that long-term use may cause problems because of drug toxicity and that contaminants in the manufacturing process may also be dangerous.



So why did the committee recommend droxidopa?
Others who observed the hearings have suggested that, ultimately, NOH is a serious unmet medical need worthy of its orphan drug status. Moreover, several people who are affected by NOH made compelling remarks that provided a human face and story to the effects of this condition. Even though those people were reimbursed by Chelsea for their travel, I think it helps demonstrate the importance of people living with a disease being able to speak up for their needs. And all the more reason that PDF is behind its Parkinson's Advocates in Research program to help empower people to do just that.

Droxidopa is still far from being approved, but I think the recent vote demonstrates the importance of having people living with a disease, whether it be NOH or Parkinson's, involved in all stages of the clinical research process to insure that their voice is heard.