Last updated July 5, 2023, by Marta Figueiredo, PhD
Fact-checked by Ana de Barros, PhD
What is IPX203 for Parkinson’s disease?
The therapy was developed by Impax Laboratories, which is now part of Amneal Pharmaceuticals. Amneal applied to the U.S. Food and Drug Administration (FDA) for IPX203’s approval in August 2022. In July 2023, the FDA issued a complete response letter, raising concerns about the safety of carbidopa in the treatment and requesting additional information before a final decision.
How does IPX203 work in Parkinson’s disease?
Parkinson’s is caused by the progressive death of nerve cells that produce dopamine, a major brain signaling molecule involved in controlling voluntary movement. As dopamine can’t be directly administered to patients, therapies based on levodopa, its precursor, are a mainstay of treatment.
While this type of therapy aims to increase dopamine levels in Parkinson’s patients, a variable dosage may reach the brain with traditional levodopa tablets, due to varying amounts of it being absorbed in the digestive system.
Levodopa is usually given in combination with carbidopa, which prevents it from being converted into dopamine before it reaches the brain. This way, more levodopa is available to make dopamine, reducing the amount needed to be administered and its side effects.
Immediate-release carbidopa/levodopa oral tablets also typically require frequent doses, with their concentrations often fluctuating over time while patients are receiving treatment.
As a result, dopamine receptors in the brain are stimulated intermittently. Researchers believe this explains why patients using levodopa for prolonged periods often have motor complications, such as dyskinesia or uncontrolled, involuntary movements.
IPX203 is an extended-release oral formulation of carbidopa/levodopa designed to maintain steady levels of the molecules in the body and improve absorption efficacy. It contains both immediate-release granules of carbidopa and levodopa in a 1-to-4 ratio — similar to marketed combinations — and extended-release beads of levodopa alone.
Previous data indicated carbidopa’s availability in the body would be greater if all its content was in an immediate-release formulation. The levodopa beads are coated with specific molecules that allow its slow release, prevent its early disintegration in the stomach, and boost its absorption in the intestinal area where it’s effectively absorbed.
IPX203’s innovative formulation is designed to provide immediate delivery of 25% of the levodopa dose, causing a quick rise in levodopa levels, followed by a steady release of the remaining 75% for a longer period relative to currently available products, including Amneal’s other carbidopa/levodopa extended-release capsule called Rytary. IPX203 is expected to be better absorbed and have longer lasting effects with fewer daily doses.
How will IPX203 be administered in Parkinson’s disease?
In clinical trials, participants underwent a dose-adjustment period before receiving IPX203 oral capsules, which were typically taken three times a day, with dosing intervals ranging from six to 12 hours and dose strengths ranging from 45 to 270 mg of levodopa.
IPX203 in Parkinson’s disease clinical trials
Amneal’s application to the FDA is mainly based on results from Phase 2 and Phase 3 clinical trials comparing IPX203 with other formulations of carbidopa and levodopa in people with advanced Parkinson’s and having off periods.
A Phase 2 trial, dubbed IPX203-B14-02 (NCT02271503), investigated the single-dose pharmacological properties of IPX203 against Sinemet — immediate-release carbidopa/levodopa tablets — and Rytary extended-release capsules.
The study included 26 Parkinson’s patients with two or more hours of daily off time while on stable levodopa-based treatment. All received a single dose of each of the treatments separated by about one week. The order of the treatments was randomly assigned for each patient.
Blood levodopa levels increased rapidly and similarly across all three treatments, results showed. However, levodopa was maintained at more than half its highest concentration for longer with IPX203 (4.7 hours) than with Sinemet (1.9 hours) or Rytary (3.9 hours).
Longer effects were also observed with the experimental therapy for motor improvements, as assessed with part three of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).
Also, IPX203 resulted in a significant reduction in daily off time relative to immediate-release tablets (by 2.7 hours) and Rytary (by 0.9 hours), based on investigator assessments. This off time was generally converted into hours of good on time, when symptoms are adequately controlled without troublesome dyskinesia.
The U.S-based, Phase 2 IPX203-B16-01 trial (NCT03007888) tested multiple doses of IPX203 versus Sinemet in 28 adults with advanced Parkinson’s. Despite being on a stable carbidopa/levodopa regimen, all were waking up in an off state most mornings, were having at least two hours a day of off time during waking hours, and had motor complications such as dyskinesia.
Participants were randomly assigned to receive either a two-week daily treatment with Sinemet followed by a two-week daily treatment with IPX203, or vice-versa. Treatment periods were separated by a one-week “washout” period, where they only took their pre-study Parkinson’s medication regimen.
Data showed comparable initial increases in levodopa concentrations, but longer effects with IPX203, even though the experimental therapy was taken less frequently (2 vs. 3.1 times a day).
According to patient diaries, IPX203 resulted in a significantly lower percentage of off time during waking hours compared with Sinemet (19.3% vs. 33.5%), meeting the trial’s main goal. This translated into a 2.3-hour greater reduction in daily off time and a 1.9-hour increase in daily good on time with IPX203.
Motor improvements, as assessed with part three of the MDS-UPDRS, were significantly greater and lasted significantly longer with IPX203 than Sinemet.
The Phase 3 RISE-PD trial (NCT03670953) enrolled 506 adults with Parkinson’s with off periods at sites in the U.S. and Europe.
Participants underwent a dose-adjustment period with a generic of Sinemet for the first three weeks followed by four weeks wherein they switched to IPX203. Patients were then randomly assigned to either IPX203 (with matching Sinemet generic placebo tablets) or a Sinemet generic (with matching IPX203 placebo capsules) for 13 weeks (about three months). The dosage and frequency were tailored to each patient.
RISE-PD’s main goal was to assess changes in daily good on hours between weeks seven and 20.
Results showed IPX203-treated patients had 0.53 more hours of good on time a day and 0.48 fewer hours of daily off periods than those on immediate-release tablets. A posterior analysis that adjusted results for means of other factors indicated IPX203 was associated with 1.5 more good on hours per day.
Also, a significantly greater proportion of IPX203-treated patients reported that their condition “much” or “very much” improved relative to those in the Sinemet generic group (29.7% vs. 18.8%).
IPX203’s superiority over immediate-release tablets was seen despite its less frequent dosing (mean, three vs. five times a day).
No significant group differences were observed with changes in Parkinson’s motor and overall symptoms, as assessed with the MDS-UPDRS.
After completing the RISE-PD study, 419 participants chose to enroll in an open-label extension trial (NCT03877510) where all received IPX203 for nine months. Preliminary results indicated the therapy was generally safe and well tolerated and its effectiveness was sustained over nine months.
Common side effects of IPX203
The most common side effects reported with IPX203 in clinical trials include:
- urinary tract infections
- dry mouth
- back pain
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