Positive Results for Amneal’s IPX-203 in Parkinson’s Disease

On 25 August, Amneal Pharmaceuticals announced that IPX-203 (carbidopa + levodopa) achieved its key primary and secondary endpoints in the pivotal Phase III RISE-PD clinical trial for patients with Parkinson’s disease (PD) who experience motor fluctuations. Although levodopa is a highly effective drug, the emergence of motor fluctuations with its prolonged use presents a major challenge for both physicians and patients.

IPX-203 is a combination of carbidopa and levodopa (CD/LD). Following the conversion of levodopa to dopamine, it mimics the effect of endogenous dopamine by targeting dopamine receptors, thereby compensating for the reduced dopamine levels in the basal ganglia of PD patients. Carbidopa inhibits the peripheral metabolism of levodopa and increases its bioavailability. Levodopa is often associated with complications such as wearing off (‘Off’ time) when motor symptoms of tremor and rigidity re-emerge, as well as levodopa-induced dyskinaesia (LID) and psychosis in patients with advanced-stage PD.

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An extended-release formulation of CD/LD is often preferred by physicians over the immediate release formulation for patients with motor fluctuations. IPX-203 is delivered orally in a gastric-retentive capsule that prolongs the absorption of levodopa and has a potentially superior profile when compared with long-acting preparations such as Amneal’s Rytary (carbidopa and levodopa).

The RISE-PD clinical trial was a multi-centre, randomised, double-blind, double-dummy, active-controlled, parallel-group, pivotal Phase III clinical trial conducted at 108 study locations across the US and Europe. The trial evaluated 506 PD patients with motor fluctuations. IPX-203 met the study’s primary endpoint by demonstrating a statistically significant improvement in efficacy for IPX-203 compared to immediate-release CD/LD, even when IPX-203 was dosed an average of three times a day and immediate-release CD/LD was dosed an average of five times a day.

IPX-203 treatment resulted in 0.53 more hours of ‘Good On’ time than immediate-release CD/LD (p=0.0194) when comparing change from baseline in both study arms. ‘Good On’ time is defined as the total time with either non-troublesome dyskinaesia symptoms or duration without dyskinaesia. The secondary endpoint for change from baseline in ‘Off’ time showed that IPX-203 resulted in significantly less ‘Off’ time compared with immediate-release CD/LD (-0.48 hr, p=0.0252). In addition, an analysis of the secondary endpoint for Patients’ Global Impression of Change (PGI-C) scores showed that 29.7% of patients treated with IPX-203 were ‘much improved’ or ‘very much improved’ compared with 18.8% of patients treated with immediate-release CD/LD (p=0.0015).

IPX-203’s change from baseline scores for Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III, or the sum of MDS-UPDRS Parts II and III, were comparable to those of immediate-release CD/LD. Amneal plans to submit a new drug application (NDA) for IPX-203 with the US Food and Drug Administration (FDA) next year. GlobalData forecasts that IPX-203 will generate global sales of $118m by 2029.

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IPX-203 is likely to compete with Intec’s Accordion Pill (CD/LD), which is also in Phase III development. The Accordion Pill packs small sheets of gastro-retentive biodegradable polymeric films inside the pill, which results in longer retention of levodopa inside the stomach, for up to 12 hours. Key opinion leaders (KOLs) interviewed by GlobalData, however, reported that IPX-203 and the Accordion Pill are expected to be a slight improvement on Rytary, an extended-release CD/LD treatment that was approved in 2015. As such, some KOLs believed that the pipeline oral reformulations would not have a big impact on their treatment algorithm if they were approved.

Furthermore, there are two novel levodopa delivery systems in Phase III development for PD that are expected to create more options for physicians to control various complications, namely AbbVie’s ABBV-951 (foslevodopa) and Mitsubishi/NeuroDerm’s ND-0612 (CD/LD). If approved, these therapies are expected to capture patient share from the oral levodopa versions. Both ABBV-951 and ND-0612 employ a subcutaneous bolus infusion to deliver the medication continuously via an external pump, resulting in a steady flow of levodopa throughout the day and night.

The pipeline candidates involving novel delivery systems and reformulations for levodopa hold great potential to decrease motor fluctuations and levodopa-induced complications. They show promise in lessening the pill burden of PD treatment and could offer an overall better quality of life in moderate to severe PD patients.