News in Context: Isradipine Deemed Safe For People With Parkinson's, But Will it Work as Disease-Modifying Drug?
At last month's Movement Disorder Society's Annual Congress, a clinical study of isradipine (brand name Dynacirc CR), a drug currently approved to treat high blood pressure, was awarded Blue Ribbon status for work investigating the drug's potential as a disease-modifying therapy for Parkinson's disease (PD). The study, called STEADY-PD (Safety, Tolerability, and Efficacy Assessment of Dynacirc CR for PD), was funded by The Michael J. Fox Foundation (MJFF), and led by principal investigator Tanya Simuni, MD, of Northwestern University.
STEADY-PD was designed to find out whether there were safety issues that would preclude further study of isradipine for people with PD (there were not, the study says), and to determine the optimal dose for use in future studies testing its ability to slow the progression of the disease (they've figured this out too). However, STEADY-PD was not designed to determine isradipine's disease-modifying effect. This work is still to come.
MJFF spoke with Dr. Simuni and MJFF staffer Jamie Eberling, PhD, to better understand what the newly announced results mean, and what work lies ahead.
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.
MJFF: Tell us about the drug isradipine, and why researchers think it has potential as a disease-modifying therapy for PD.
JE: Isradipine is a high blood pressure drug. Since it's already approved by the Food and Drug Administration to treat high blood pressure, if the drug was shown to be effective against Parkinson's, it's possible that the process to bring isradipine to market for PD could be accelerated. This idea is called repositioning.
To date, there are two main types of data that support the idea that it might be neuroprotective for people with PD. The first surrounds epidemiological data pulled from multiple clinical studies suggesting that those who take this type of drug have a lower incidence of PD. (Epidemiological data analyzes trends across populations, but is not verifiable within individual subjects). This general understanding of the distribution of the disease is buttressed by pre-clinical data from the lab of MJFF awardee D. James Surmeier, PhD, of Northwestern University.
MJFF: What has Dr. Surmeier learned?
JE: Here's the basic idea behind his research: Certain high-blood pressure medications such as isradipine work by blocking the activity of specific calcium channels (These drugs are appropriately called calcium channel blockers). Surmeier theorized that hyperactive calcium channels may stress dopamine neurons, leading them to shut down or die. His idea was that drugs like isradipine might reduce this stress, in turn slowing or even stopping the progression of PD. Pre-clinical studies funded by MJFF supported this premise.
MJFF: What was STEADY-PD looking to find out?
TS: STEADY-PD was designed to answer two questions: Is isradipine safe for people with Parkinson's and if so, what would be the best dose of the medication to use in further clinical studies testing to see if it might work as a disease-modifying drug?
MJFF: If isradipine is already approved by the FDA for high blood pressure, why might there be concerns surrounding safety for people with PD?
TS: Those with Parkinson's are predisposed to lower blood pressure as a result of the disease, so it was important to find out if a drug approved for high blood pressure would be safe, and not bring low blood pressure levels even lower. This was the first time that the drug was clinically tested in a reasonably large group of people with PD, and the good news is, STEADY-PD found that isradipine was safe.
MJFF: What did STEADY-PD learn about dosing?
TS: The study looked at different doses of the drug, in order to find out which dose would be the best for future clinical studies that would show whether or not the drug works to slow the progression of Parkinson's. Five, 10, 15 and 20 mg doses were tested, and the 10 mg dose was found to be the threshold for how much someone with PD could tolerate.
It's important to note: STEADY-PD was not designed to determine efficacy. And by and large, there was little to no efficacy signal shown, although we believe that there was a hint of difference between the active drug and placebo, and in a positive way.
MJFF: Is it problematic that the study didn't show any efficacy for the drug?
JE: Certainly, any time a study can show that a drug may be efficacious, it helps to gain support for an impending follow-up study. In this case, gaining support for the next phase along the pipeline, phase 3, is never an easy task, and showing real data that the drug might have an effect on slowing the disease would have made that task an easier one. Still, as Dr. Simuni explained, this study was not powered to assess efficacy -- there were simply not enough participants, or a long enough period of time, to make this determination.
Actually, it could be to isradipine's benefit down the road that no efficacy was shown. Here's why: Participant progress during the study was measured using the Unified Parkinson's Disease Rating Scale. If the volunteers had experienced any benefits from isradipine over a short run, the benefits could only have been symptomatic. Ruling out initial symptomatic benefit (which was another objective of the study) could make designing a potential phase 3 study to assess the disease-modifying potential of the drug a more straightforward task.
Still, it's complex work designing clinical studies, made the more so since we don't yet have a biomarker for Parkinson's that could measure how the disease progresses, and whether or not drugs being tested are actually slowing this progression. This is why the Foundation is so committed to finding such a biomarker through PPMI.
MJFF: What do these study results mean in terms of bringing isradipine to market for PD?
JE: It depends on whether Dr. Simuni's team can garner the necessary funding to move forward, which is no small task. But isradipine could certainly enter into a phase 3 study, which would be very intriguing: A pill that could slow the course of the disease is, of course, to date unprecedented.
MJFF: What are the next steps, then, in this process?
TS: Our plan is to move forward as quickly as possible with planning for a phase 3 placebo-controlled study of the optimal dose of isradipine, 10 mg. When and if we're able to secure necessary funding, we will need to recruit a sufficient number of patients for the study, probably more than 300. While the science behind the rationale for isradipine in PD inspires optimism, there is still a lot of work to do to validate the approach in a clinical setting.
MJFF: What would you tell people with PD about taking isradipine today?
TS: I would caution people against using isradipine as a drug to treat PD. We simply don't yet have enough information to know that it works.