FDA asking for more safety data on extended-release IPX203

Carbidopa-levodopa form aiming for longer symptom control up for approval

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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The U.S. Food and Drug Administration (FDA) is asking for more information concerning the safety of  IPX203, an extended-release oral formulation of carbidopa and levodopa, before a final approval decision in treating Parkinson’s disease symptoms can be made.

In a complete response letter to Amneal Pharmaceuticals, the therapy’s developer, the FDA stated that sufficient scientific evidence supported the safety of levodopa in this combination, based on studies of how it is processed in the body (pharmacokinetic studies). But the same level of evidence was not established for carbidopa, its other ingredient.

The FDA did not mention any concerns regarding the effectiveness or production of IPX203, Amneal stated in a company press release.

Amneal intends to work closely with the FDA to address its issues and plans to meet with the agency to discuss best ways of moving forward.

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IPX-203 aims to extend ‘good’ on time for Parkinson’s patients

The response letter comes nearly eight months after the agency accepted the therapy’s application for review, and about 10 months after Amneal filed its approval request.

“We are committed to advancing IPX203 for Parkinson’s disease, which has been developed to provide a longer duration of therapeutic benefit than existing formulations with fewer doses,” said Chirag and Chintu Patel, the company’s co-chief executive officers. “We plan to work closely with the FDA to address the agency’s feedback and we remain confident in bringing this new treatment to Parkinson’s patients as soon as possible.”

Levodopa is a precursor of dopamine, a major brain signaling molecule that is produced by the specialized nerve cells progressively lost in the disease. Considered a mainstay Parkinson’s treatment, it is often given in combination with carbidopa, which helps to prevent levodopa-to-dopamine conversion outside the brain, allowing more of levodopa to reach target tissue and increase dopamine levels.

An extended-release formulation of carbidopa and levodopa (CD/LD), oral IPX203 aims for longer and better control of the signs and symptoms of Parkinson’s than current immediate-release CD/LD tablets, such as Sinemet, as well as Amneal’s older extended-release CD/LD formulation, sold as Rytary.

It consists of immediate-release granules of carbidopa and levodopa in a 1-to-4 ratio — similar to marketed combinations — in addition to coated extended-release beads of levodopa alone. This new formulation is meant to improve the medicine’s absorption and release into the bloodstream in a way that maintains clinically relevant levels for longer times.

IPX203 also is expected to help reduce off episodes, enabling longer “good” on periods, when symptoms are adequately controlled without dyskinesia. Typically characterized as uncontrolled, involuntary movements, dyskinesia is a common side effect of long-term levodopa-based treatment.

RISE-PD trial supported IPX203 as more effective than immediate-release tablets

Amneal’s application mainly was supported by data from the international Phase 3 RISE-PD trial (NCT03670953), which finished in 2021. That study enrolled 506 adults with advanced Parkinson’s, who were experiencing off episodes despite stable CD/LD treatment.

Participants were assigned randomly to IPX203 or immediate-release CD/LD oral tablets for about three months (13 weeks), following two consecutive dose-adjustment periods. The immediate-release tablets were a Sinemet generic.

Top-line results showed that IPX203 was associated with significantly more daily good on time (by 0.53 hours) and 0.48 fewer hours of daily off time compared with the immediate-release therapy.

The therapy resulted in 1.55 more good on hours per day relative to standard immediate-release tablets, according to a post hoc analysis conducted after trial data had been collected.

A significantly greater proportion of patients given IPX203 also reported being “much improved” or “very much improved” with their assigned treatment, compared with those in the immediate-release group (29.7% vs. 18.8%).

Importantly, the greater and longer benefits seen with IPX203 came with less frequent dosing relative to the immediate-release CD/LD oral tablets — with an average dosing of three versus five times a day.

IPX203, however, was associated with greater rates of adverse events (42.2% vs. 31.6%) and serious adverse events (3.1% vs. 1.6%) than the standard immediate-release tablets. Those most frequently reported included nausea, dry mouth, urinary tract infection, and falls.

The RISE-PD study was followed by an open-label extension trial (NCT03877510), in which 419 main trial patients chose to be treated with IPX203 for nine months. Preliminary findings from this study, which concluded in April 2022, supported the therapy’s safety profile and efficacy being generally sustained with longer treatment.

Common side effects, which usually were mild or moderate, included falls (5%), dyskinesia (5%), and urinary tract infections (5%), with only dyskinesia considered related to treatment.