Commentary
Video
Phase 3 RISE-PD Trial and Supportive Evidence for IPX203
Dr. Hauser and Dr. Fernandez provided insight on the body of supportive evidence for IPX203, the notable takeaways from RISE-PD, and the long-term benefits observed from treated patients.
Earlier this month, the FDA approved Amneal Pharmaceuticals’ investigational agent IPX203, an oral formulation of carbidopa/levodopa (CD/LD) extended-release capsules, as a treatment for patients with Parkinson disease (PD). Marketed as Crexont, the therapy is an oral formulation CD/LD which includes immediate-release granules as well as extended-release pellets. In its announcement, Amneal noted it expects the oral treatment to be available to patients in the United States in September 2024.
Amneal’s CD/LD ER capsule product was approved based on data from the phase 3 RISE-PD clinical trial (NCT0300788), a double-blind study published in JAMA Neurology in August 2023. In the study, those treated with IPX203 at least 3 times per day (n = 256) showed a statistically significant improvement of 0.53 hours (95% CI, 0.09-0.97; P = .02) in daily good ON time relative to those on IR CD/LD (n = 250), who were dosed 5 times per day.
Following the approval, NeurologyLive® assembled a panel of movement disorder experts to discuss the downstream impacts of IPX203 as a new treatment for patients with PD. The panelists include Robert Hauser, MD, a professor of neurology at the University of South Florida and director of the Parkinson’s Disease and Movement Disorder Center, and Hubert Fernandez, MD, a neurologist and director of the Center for Neurological Restoration at the Cleveland Clinic.
In this episode, the duo described the efficacy and safety data that supported IPX203’s approval, including the pivotal phase 3 RISE-PD trial. Hauser and Fernandez discussed the unique aspects of the trial, including the benefits observed when patients switched to IPX203. Additionally, they touched upon the gain in good ON time, the duration of benefit per dose, and the consistent treatment effect seen throughout the study.
Transcript below edited for clarity.
Robert Hauser, MD: That brings us to the RISE-PD trial, which was the phase three trial comparing IPX203 to immediate-release carbidopa-levodopa. Like many fluctuator trials, it enrolled patients on immediate-release carbidopa-levodopa who had motor fluctuations, with an average of about six hours of off time per day. Patients were optimized on IR carbidopa-levodopa, then converted to IPX203, and then they were baselined. All of that was open label. Once they were baselined, they were randomized in a double-blind fashion to treatment on either their optimized IR carbidopa-levodopa regimen or their IPX203 regimen and maintained for 13 weeks. The primary outcome of the trial was good on time, comparing the end of the study to baseline, comparing IPX203 to IR treatment. What was seen was that patients who received IPX203 had significantly better ON time compared to those on IR carbidopa-levodopa, even though IPX203 was administered an average of three times per day compared to IR, which was administered five times per day. So that's the main outcome of the trial. Hubert, would you like to comment on that?
Hubert Fernandez, MD: I mean, certainly. I like the design of the RISE-PD trial. I think my two take-home messages for this trial, especially for those in our group or academic neurologists in our society and sub-specialty, are: if you look at the improvement in good on time, it seems rather small—about 30 minutes. The corresponding improvement in off time is about the same, around 30 minutes. So someone might think, "Is this worth it for just a half-hour improvement?" The nuance to remember here is that the comparison was against optimized immediate-release levodopa, which is as good as it gets in the outpatient setting for IR levodopa. A medication that can improve further on that is significant, especially considering that most clinical trials compare a medication to a patient's baseline or regular levodopa regimen, not an optimized one. So the fact that IPX203 could still provide a benefit on top of optimized IR levodopa is a win. The second point is that you achieve this gain with less frequent dosing. So, the practicality of having a gain on an optimized levodopa regimen with a three-times-a-day dosing is a significant victory for our patients.
Robert Hauser, MD: Yeah, that's right. You have to remember how many doses were given. I've talked about a critical parameter of a levodopa formulation being the benefit per dose. We did some analyses of the RISE-PD study, and what we saw was that the duration of benefit with IR was about 2.2 hours, which isn’t long. And it’s even worse because sometimes it's shorter, sometimes longer—there’s a lot of unpredictability. In contrast, for IPX203, the duration of benefit was 3.8 hours, which is 1.6 hours longer. So, when you think about building out a day, using IR means building it out with 2.2-hour intervals, requiring many doses and bringing variability with when it kicks in, wears off, and is affected by factors like protein. So getting this increase in duration per dose with IPX203 is really important—it gives clinicians and patients a better way to structure dosing throughout the day, with more benefit per dose and more good on time.
Hubert Fernandez, MD: I agree with you. I think the sub-analysis looking at the on time duration per dose really drives home the message for our patients.
Robert Hauser, MD: Yeah, I also think that when clinicians and patients consider converting over, keeping that 1.6 hours of more benefit per dose in mind is a good thing, and it may help with the transition.
