Addex Adds It Up for Parkinson's Patients
On Wednesday, March 21, biotech company Addex Therapeutics announced positive results from a Phase IIa clinical study of their drug candidate dipraglurant to treat dyskinesia in people with Parkinson's disease (PD).
Dipraglurant complements levodopa (long the gold standard for treating PD) by targeting the brain's glutamate system. The drug would allow patients taking levodopa to experience better "on" times without dyskinesia that so often affect those on a levodopa regimen.
MJFF spoke with Bill Langston, MD, scientific director and chief executive officer of The Parkinson's Institute in Sunnyvale, California, and MJFF staff scientists Jamie Eberling, PhD, and Audrey Dufour, PhD, to gauge what the Addex results might mean for the search for a dyskinesia drug, one of the most significant unmet needs for those living with PD today.
MJFF: Let's start with today's findings. What is Addex really reporting here?
Jamie Eberling: Addex has shown that their drug dipraglurant is safe and tolerable, an important step in bringing any drug closer to market. Throughout the course of this study, serious events that could impact both the long-term safety of the patient, and also, unpleasant side effects like nausea, were limited. The drug also had no negative effects on the motor symptoms of people with PD, as measured by a clinical scale. In other words, the drug didn't make parkinsonian symptoms worse.
But more than that, the study also showed intriguing evidence that the drug could be effective in limiting the often disabling dyskinesia associated with PD.
Many patients who take levodopa experience "off" periods, when the medication's effects wear off before they are ready to take their next dose. This can leave them in a state where symptoms such as rigidity or slowness of movement may return. But even in an "on" period, they may experience dyskinesia, which can be equally limiting.
The Addex study demonstrated positive implications for this cyclical response to taking levodopa. Results showed up to twice as much daily "on" time without dyskinesia for those who took dipraglurant compared to those who had taken a placebo. Patients taking the active drug also reported a reduction in the amount of "off" time they experienced throughout the day.
MJFF: Tell us more about how dipraglurant works.
There are complicated networks of neurons throughout the brain. Scientists have found that the loss of dopamine in PD leads to excessive stimulation of glutamate in a particular pathway in the brain, which may be a contributor to dyskinetic movement. By inhibiting a specific glutamate receptor called mGluR5, dipraglurant could limit this overstimulation, potentially providing a new way to limit dyskinesia as well.
MJFF: If dipraglurant became a drug, how would it be used by patients?
Audrey Dufour: The idea is that it could serve as a complementary treatment to levodopa. We anticipate that patients would continue to take levodopa to increase the dopamine produced by remaining neurons in the brain, and the Addex drug to maintain the balance of glutamate in this particular part of the brain. Dyskinesia would potentially be reduced while symptoms of the disease were still being treated.
MJFF: What would a successful dyskinesia treatment mean for patients?
Bill Langston: Over the past few years, some in the field have put forth that dyskinesia seems to be less prevalent in people with PD than they had in the past. While this is generally true, I think this has come at a cost. Many of us, as physicians, are at least to a modest degree, under-treating our patients to avoid these side effects. The longer a patient takes the drug, the more likely they are to need larger doses to control symptoms. This means that they need to up their dose in order to achieve the same symptomatic benefits of the drug. But the more levodopa they take, the more likely they will be to develop dyskinesia as a side effect. Dyskinesia can eventually become disabling and dose-limiting to the people that experience it. But, as noted above, waiting to take, or limiting the use of levodopa is problematic too: Patients don't receive the maximum benefit of the drug.
Dyskinesia is therefore a real roadblock to maximizing the long term treatment of PD. Finding a successful treatment to limit this side effect would, I believe, do more overnight for the PD community than any other type of drug.
We have been searching for a real target for such a treatment for a very long time. In my opinion, the mGluR5 receptor shows great potential. There are at least two drugs that are targeting the glutamate receptor for dyskinesia that are currently in clinical testing (including the Addex drug, and one from Novartis). In addition, my team at the Parkinson's Institute is currently testing an mGluR5 targeted drug called fenobam in pre-clinical models. Early pre-clinical work studying fenobam has shown remarkable reduction in dyskinesia.
MJFF: What are the next steps?
Jamie Eberling: The Addex trial, while encouraging, needs to be replicated with a larger group of patients to truly understand how well the drug is working. This trial involved 76 people with PD; a phase 3 would likely engage several hundred. So their next step will likely be to seek support for the trial, and then begin recruiting participants. Once they are ready to recruit, the trial will be listed on Fox Trial Finder (www.foxtrialfinder.org) to make it easy for patients and their loved ones to find out if it's a good match and volunteer for the trial if so.
The Addex drug would be only the second dyskinesia-targeted drug to make it into the third phase of clinical testing, essentially the last round before a drug would look to be approved by the FDA. No dyskinesia treatment has been approved by the FDA yet. It is good news that both Addex and Novartis could have compounds targeting mGluR5 in this third phase of testing. The more shots on goal, so to speak, the better the chances of finding a drug that works.
NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson's disease and any other medical condition be made in consultation with a physician or other qualified medical professional.