FDA Accepts NDA for Parkinson Disease Treatment IPX203

Meglio,Marco;

IPX203, an oral formulation of carbidopa/levodopa, the standard treatment for Parkinson disease, demonstrated statistically significant results in improving ON time relative to immediate release CD/LD.

Gustavo Pesquin

According to an announcement by Amneal Pharmaceuticals, the FDA has accepted its new drug application (NDA) for IPX203, a novel, oral formulation of carbidopa/levodopa (CD/LD) extended-release capsules intended to treat patients with Parkinson disease (PD). The FDA has scheduled a PDUFA date of June 30, 2023, to complete its evaluation of the NDA.¹

"The FDA filing acceptance of IPX203 marks another important milestone for Amneal as we strive to improve the lives and care of people living with Parkinson’s disease” Gustavo Pesquin, chief commercial officer, Amneal Specialty, said in a statement.¹ "We look forward to engaging in conversations with the FDA as we advance the application. We believe the data in our RISE-PD study supports the important benefit IPX203 can offer to this community by providing longer duration of symptom control with the benefit of fewer doses."

RISE-PD, a multicenter, randomized, double-blind, active-controlled, parallel-group trial (NCT03670953), was the basis for IPX203’s submission. Published in Neurology earlier this year, the study consisted of a 3-week open-label dose adjustment phase, followed by a 4-week open-label conversion to IPX203, and a 13-week double-blind maintenance phase. A total of 506 individuals with PD aged 40 years and older were randomly assigned, and required to have at least 2.5 hours daily OFF time during waking hours.²

All told, the study met its primary end point, demonstrating statistically significant improvement in good ON time for IPX203 relative to CD/LD immediate release (IR) capsules (0.53 hr; P = .0194). On secondary end points, treatment with IPX203 resulted in significantly less OFF time compared with CD/LD IR (–0.48 hr; P = .0252). For Patient Global Impression of Change scores, 29.7% of IPX203-treated patients were “much improved” or “very much improved” compared with 18.8% of those on CD/LD IR (P = .0015). Both groups demonstrated similar scores on Movement Disorder Society-Unified Parkinson’s Disease Rating scale.

Data from RISE-PD was also presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, by Robert A. Hauser, MD, MBA, professor of neurology, and director, Parkinson’s Disease and Movement Disorder Center. In the second of his 2 posters, a post-hoc analysis showed that those in the IPX-203 group (n = 249) had 3.76 hours of good ON time per dose, compared with 2.21 hours for those on CD/LD IR (P <.0001).³

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In a planned superiority analysis, the between-group difference of the 12-month change in MDS-UPDRS part III score was not statistically significant.

At the time, Hauser told NeurologyLive^® "[With] the primary outcome measure of the increase in good ON time, many people will look at it and say ‘well, 0.53 hours is a half an hour increase in ON time, it’s not that much per day.’ But you have to keep in mind that patients received IPX-203 three times per day, compared with CD/LR IR an average of five times per day."

The pharmacodynamic and pharmacokinetic effects of IPX203 also appeared to confirm that the novel design of the drug may address some of the limitations of the current oral delivery levodopa options. Collected from a phase 2 study of those with PD (NCT03007888), the pharmacokinetic findings showed that patients on IPX203 had rapid absorption followed by sustained plasma concentrations, with a maximum serum concentration of 2.768 ng/mL (standard deviation [SD], 1.259) compared with 2.357 ng/mL (SD, 1.179) for CD/LD IR.⁴

The phase 2 trial included 28 patients with advanced PD who were reporting motor fluctuations. Individuals were assigned 1:1 to 15 days of treatment with CD/LD IR followed by IPX203, or IPX203 followed by CD/LD IR, with a 1-week washout period between the 2 treatments. The investigational Amneal capsule product was suppled in 2 doses of 45/180 mg or 67.5/270 mg carbidopa/levodopa, while the comparator was supplied as a 25/100 mg carbidopa/levodopa capsule. On Day 1, the IPX203 group reported MDS-UPDRS scores of 42.8 compared with 41.4 in the comparator group, with those dropping at day 15 to 33.5 in the IPX203 group compared with 41.6 in the comparator group, which was a significant change (P = .0087). The mean difference in MDS-UPDRS scores between the treatments was 8.1 points (SD, 25.0), which was also significant (P = .0255).

REFERENCES
1. Amneal announces US FDA filing acceptance of new drug application for IPX203 for the treatment of Parkinson disease. News release. November 11, 2022. Accessed November 11, 2022. https://www.businesswire.com/news/home/20221109005842/en/Amneal-Announces-U.S.-FDA-Filing-Acceptance-of-New-Drug-Application-for-IPX203-for-the-Treatment-of-Parkinson%E2%80%99s-Disease
2. Hauser RA, Espay AJ, LeWitt P, et al. A phase 3 trial of IPX203 vs CD-LD IR in Parkinson’s disease patients with motor fluctuations (RISE-PD). Neurology. 2022;98(18 supplement).
3. Hauser RA, Fernandez HH, Klos K, et al. Duration of Benefit Per Dose: Post Hoc Analysis of ”Good On” Time Per Dose for IPX203 vs CD-LD IR in the RISE-PD Phase 3 Trial. Presented at: AAN Annual Meeting; April 2-7, 2022; Seattle, WA, and virtual. Abstract 001231.
4. Dhall R, Agarwal P, Kilbane C, et al. Design of better levodopa delivery: formulation strategy of OPX203, an investigational extended-release carbidopa-levodopa. Presented at: ATMRD Congress; June 17-19, 2022; Washington, DC.