Extended Use of Investigational Agent IPX203 Safe in Parkinson Disease

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Even at the highest modal dose range, findings from the phase 3 RISE-PD trial showed that IPX203 did not increase safety risks for patients with Parkinson disease over time.

William Ondo, MD, director of the Movement Disorders Clinic at the Houston Methodist Neurological Institute

William Ondo, MD

Credit: PD Wise

New data from the phase 3 RISE-PD clinical trial (NCT0300788) assessing IPX203 (Amneal Pharmaceuticals), an oral formulation of carbidopa/levodopa (CD/LD) extended-release capsules, revealed an association between longer exposure to IPX203 and a decrease in the occurrence of treatment emergent adverse events (TEAEs).1 These findings demonstrated the safety and tolerability of IPX203 across various dosage ranges, even at the highest doses, over an extended period of use.

For at least 12 months, investigators had 179 patients with PD exposed to IPX203 continuously at a wide distribution of doses, with modal doses ranging from 140/560 mg CD-LD to 1260/5040 mg CD-LD a day. As participants were grouped into 4 quartiles (each quartile, n ≈ 45), the modal dose ranges were 560-<1050 mg, 1050-<1470 mg, 1470-<2100 mg and 2100-5040mg LD/day. Findings showed a decrease in the number of patients with TEAEs as the exposure time increased compared with the number of patients with TEAEs by duration of exposure, at any modal dose range.

Top Clinical Takeaways

  • Continuous exposure to IPX203 in patients with Parkinson disease led to a decrease in the occurrence of adverse events over time.
  • The study involved patients across a range of modal doses, from 560 mg to 5040 mg of LD per day, showcasing IPX203's safety across different dosage levels.
  • The trial design included a comprehensive approach: open-label dose adjustments, conversion, and randomization phases, culminating in a 9-month open-label extension.

These findings were presented at the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, by lead author William Ondo, MD, director of the Movement Disorders Clinic at the Houston Methodist Neurological Institute, and colleagues. RISE-PD was a randomized, double-blind, phase 3 study that assessed the safety and efficacy of IPX203 compared with immediate-release (IR) CD-LD in patients with PD who had motor fluctuations. In the trial, participants went through a 3-week open-label IR CD-LD dose adjustment, followed by a 4-week open-label conversion to IPX203. Patients were then randomized to a 13-week double-blind treatment period with IR CD-LD or IPX203, followed by a 9-month open-label extension study. In this analysis of the trial, investigators calculated modal dose for patients who were exposed continuously to the treatment for at least 12 months.

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After receiving a complete response letter (CRL) from the FDA in July 2023, Amneal Pharmaceuticals announced in February 2024 it presented its complete response resubmission to the FDA for IPX203as a potential treatment for PD.2 In the original CRL, the agency noted that the pharmacokinetic data for the safety of 1 ingredient, levodopa, was sufficient; however, it felt it needed additional data for the second ingredient, carbidopa. The resubmitted package now included additional information from a healthy volunteer study which was conducted in the further quarter of 2023. Amneal noted that the FDA did not request any other studies.

IPX203’s new drug application (NDA) was supported by findings from RISE-PD which demonstrated the therapy’s ability to provide significantly more ON time per day than IR CD/LD. The NDA was originally accepted in November 2022 and the full results of the trial were published in JAMA Neurology in August 2023, months after the CRL was issued.3

Robert A. Hauser, MD, director of the Parkinson’s and Movement Disorders Center at the University of South Florida

Robert A. Hauser, MD

Credit: Research Gate

Results from the trial showed that the agent met its primary end points, as those dosed with IPX203 (n = 256) 3 times per day had a statistically significant improvement of 0.53 hours (95% CI, 0.09-0.97; P = .02) in daily good ON time relative to those on IR CD/LD (n = 250), who were dosed 5 times per day.3 Led by Robert A. Hauser, MD, director of the Parkinson’s and Movement Disorders Center at the University of South Florida, 449 patients (88.7%) completed the study.

The secondary end point of change from baseline in OFF-time in hours per day showed that IPX203 treatment resulted in significantly less OFF-time compared with IR CD/LD (difference in least square [LS] means, –0.48; 95% CI, –0.90 to –0.06; P = .03). Between the groups, 29.7% and 18.8% of patients on IPX203 and IR CD/LD, respectively, rated themselves as much improved or very much improved on PGI-C (P = .002).

Among those treated with IPX203, the most frequently reported treatment emergent adverse events were nausea (4.3%), anxiety (2.7%), and dizziness (2.3%), while those on IR CD/LD mostly experienced fall (3.6%), urinary tract infection (3.2%), and back pain (2.8%). No clinically relevant treatment group differences were noted for laboratory parameters, vital signs, and electrocardiogram results. There were no deaths reported as well.

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REFERENCES
1. William Ondo, Stanley Fisher, Ghazal Banisadr, Richard D'Souza, Robert Hauser. Safety Profile of IPX203 in Patients Exposed for 12 Months in a Phase 3 Study in PD by Modal Dose Distribution. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO.
2. Amneal Announces Complete Response Resubmission for IPX203 New Drug Application. News release. Amneal Pharmaceuticals. February 8, 2024. Accessed April 12, 2024. https://finance.yahoo.com/news/amneal-announces-complete-response-resubmission-210500452.html
3. Hauser RA, Espay AJ, Ellenbogen AL, et al. IPX203 vs immediate-release carbidopa-levodopa for the treatment of motor fluctuations in Parkinson disease: the RISE-PD randomized clinical trial. JAMA Neurol. Published online August 14, 2023. doi:10.1001/jamaneurol.2023.2679
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