Extended-release IPX-203 Reduces ‘Off’ Time in Advanced Parkinson’s
Top-line data from a Phase 3 clinical trial testing IPX-203 showed Amneal Pharmaceuticals’ carbidopa-levodopa (CD/LD) extended-release capsules work better than immediate-release tablets at reducing “off” time in people with advanced Parkinson’s disease and motor fluctuations.
These benefits were observed even when IPX-203 was taken two times less per day, on average, than immediate-release CD/LD tablets, taken five times a day.
Based on these positive results, along with other supportive findings, Amneal announced its plans to file a regulatory application with the U.S. Food and Drug Administration (FDA) in mid-2022 requesting IPX-203’s approval for Parkinson’s.
“Despite the introduction of several new medications for Parkinson’s disease in recent years, new treatment options are needed that provide longer-lasting duration of benefit with each dose and simplify medication regimens for patients affected by this devastating disease,” said Alberto Espay, MD, professor of neurology at the University of Cincinnati and director of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at UC.
The trial’s findings highlight that IPX-203 “has the potential to offer patients superior ‘Good On’ time with reduced dosing frequency, compared to immediate-release CD/LD,” said Robert A. Hauser, MD, professor of neurology at the University of South Florida (USF) and the director of USF’s Parkinson’s Disease and Movement Disorders Center.
“We look forward to submitting [a regulatory application] with the FDA and potentially making this treatment available to the PD [Parkinson’s disease] community,” said Chirag and Chintu Patel, co-CEOs of Amneal, previously known as Impax Laboratories.
Oral levodopa is one of the mainstays of Parkinson’s treatment. It increases the brain levels of dopamine, the signaling molecule progressively lost in Parkinson’s, by delivering its precursor to cells.
The therapy can be used alone, or in combination with carbidopa, an agent that helps prevent levodopa breakdown, so more of it is available to make dopamine. This reduces the amount of levodopa that needs to be administered, reducing side effects.
CD/LD therapies are available in many forms, such as controlled or extended-release tablets — two FDA-approved ones are Rytary and Sinemet — and as an approved intestinal gel, marketed in the U.S. as Duopa.
Notably, however, levodopa-based medications often become less effective over time, leading to the development of “off” periods, or times when the treatment effects wear off and symptoms are not controlled effectively.
IPX-203 is a new version of extended-release CD/LD capsules expected to reduce “off” periods in Parkinson’s patients. While its CD:LD ratio is 1-to-4, similar to marketed formulations, IPX-203 is made of immediate-release and extended-release granules, combined with special beads meant to provide the desired levels of levodopa in the blood.
This new formulation is designed to cause a quick rise in levodopa levels, followed by steady concentrations that extend beyond currently available products.
A previous Phase 2 trial (NCT03007888) involving 28 adults with advanced Parkinson’s and motor fluctuations showed that IPX-203 was superior to immediate-release CD/LD tablets at maintaining steady levodopa levels in the blood, reducing “off” time, and easing motor symptoms.
This led to the launch of the Phase 3 RISE-PD trial (NCT03670953), which evaluated the safety and effectiveness of IPX-203 against immediate-release tablets in 506 adults, ages 40 and older, with advanced Parkinson’s and experiencing motor fluctuations.
Participants, recruited at 108 clinical sites across the U.S. and Europe, underwent a three-week period of immediate-release CD/LD dose adjustment, followed by a four-week period in which they were switched to IPX-203.
After those seven weeks, patients were randomly assigned to receive either IPX-203 (with matching immediate-release CD/LD placebo tablets) or immediate-release CD/LD tablets (with matching IPX-203 placebo capsules) for 13 weeks or a little more than three months. The dosage and frequency were patient-specific.
RISE-PD’s main goal was to assess changes between weeks seven and 20 in “Good On” hours per day, defined as the sum of “on” time without uncontrollable involuntary movements (dyskinesia) and “on” time with non-troublesome dyskinesia.
Secondary goals included changes in daily “off” time and the proportion of patients who were either “much improved” or “very much improved” in Patient Global Impression of Change (PGI-C) — which reflects a patient’s beliefs about a treatment’s efficacy.
Changes in Parkinson’s motor symptoms and overall symptoms also were assessed using the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale.
The results showed that IPX-203 was associated with significantly greater efficacy, compared with immediate-release tablets, meeting the trial’s main goal and most secondary endpoints.
Particularly, 13 weeks of treatment with IPX-203 led to 0.53 more hours of “Good On” time relative to immediate-release CD/LD — or 1.55 more hours, as assessed with a different method in which results are adjusted for means of other factors.
This translated into 0.48 hours less of feeling “off” with IPX-203 and in a significantly greater proportion of IPX-203-treated patients reporting to be “much improved” or “very much improved” as compared with those in the immediate-release tablets group (29.7% vs. 18.8%)
No significant group differences were observed in terms of changes in Parkinson’s motor and overall symptoms.
Notably, IPX-203’s superiority was seen even when it was dosed less frequently than immediate-release CD/LD tablets — specifically with a mean of three versus five times per day.
A greater proportion of IPX-203-treated patients reported adverse events (42.2% vs. 31.6%) and serious adverse events (3.1% vs. 1.6%) relative to those given immediate-release tablets. The most common adverse events included nausea, dry mouth, urinary tract infection, and falls.
A nine-month safety extension study is ongoing.