FDA Issues Complete Response Letter to Amneal for Parkinson Agent IPX203


Reasons behind the CRL were not related to efficacy and do not impact Amneal’s 2023 financial guidance, which did not include IPX203 revenues.

Chintu Patel, Co-Chief Executive Officers at Amneal

Chintu Patel

The FDA has issued a complete response letter (CRL) to Amneal Pharmaceuticals for IPX203, an oral formulation of carbidopa/levodopa (CD/LD) extended-release capsules designed for the treatment of Parkinson disease. The reasons behind the decision were not based on efficacy or manufacturing for the agent, but rather established safety for an ingredient of the therapy.1

In its release, the agency noted that the pharmcokinectic data for the safety of one ingredient, levodopa, was sufficient; however, it felt it needed additional data for the second ingredient, carbidopa. Amneal plans to work closely with the FDA to address the comments and align on the best path forward.

"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,” Chirag and Chintu Patel, co-chief executive officers at Amneal, said in a statement. “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.”

The supporting data for IPX203's new drug application (NDA) submission came from the phase 3 RISE-PD clinical trial (NCT03007888) which consisted of a 3-week, open-label dose adjustment phase. The trial was followed by a 4-week open-label conversion to IPX203 and a 13-week double blind maintenance phase. In total, 419 patients with PD were enrolled and received treatment, with 384 (84%) completing the study. IPX203 was administered every 8 hours for most patients, although dosing intervals varied. In a follow-up analysis of the study, mean daily dosing frequency and most frequent LD dose were similar at the start and end of the conversion period, with stable dosing achieved in 1.6 (SD, 1.74) titration steps.

In November 2022, the FDA accepted Ameneal's NDA for IPX203.3 RISE-PD met its primary end point, demonstrating statistically significant improvement in good ON time relative to CD/LD immediate release capsules (0.53 hr; P = .0194). On secondary end points, treatment with the therapy resulted in significantly less OFF time compared with CD/LD immediate release (­–0.48 hr; P = .0252). For Patient Global Impression of Change scores, 29.7% of IPX203-treated patients were “much improve” or “very much improved” compared with 18.8% of those on CD/LD immediate release. Both groups demonstrated similar scores on Movement Disorder Society-Unified Parkinson’s Disease Rating scale.4

"The phase 3 RISE-PD clinical trial demonstrated that IPX203 provided significantly more 'Good On' time and less 'Off' time compared to immediate-release CD/LD, even when dosed less frequently, and was well tolerated. It appears that the FDA has requested additional pharmacokinetic information regarding the carbidopa component of IPX203. Hopefully, this information can be obtained in a timely fashion to allow this important medication to gain approval in the near future and provide benefit for our patients,” Robert A. Hauser, MD, director of the Parkinson’s Disease and Movement Disorders Center of the University of South Florida told NeurologyLive®.

Findings from an open-label extension trial of the RISE-PD study were presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, held April 22-27, in Boston, Massachusetts.2 In the study, IPX203 demonstrated a favorable safety and tolerability profile seen up to 9 months, with efficacy measures that were maintained from baseline to end of the study. Led by Alberto J. Espay, MD, MSc, director, James J. and Joan A. Gardner Family Center, and research chair, Parkinson’s Disease and Movement Disorders, University of Cincinnati Health, all efficacy measures were stable throughout the study period of 9 months. Among the 67 (16%) patients who discontinued treatment, the reasons included withdrawal (n = 22; 32.8%), adverse events (AEs)(n = 20; 29.9%), and lack of efficacy (n = 14; 20.9%).

Most treatment-emergent AEs were either mild or moderate in severity, and occurred within the first 90 days of treatment. Of them, the most common were dyskinesia (n = 21; 5.0%), fall (n = 21; 5.0%), urinary tract infection (n = 21; 5.0%), back pain (n = 15; 3.6%), constipation (n = 11; 2.6%), and COVID-19 (n = 10; 2.4%). The average daily dosing frequency of IPX203, 3.1 (standard deviation [SD], 0.45) times/day, was generally stable over the 9-month period, with most patients reaching a stable dosing regimen by 3 months of treatment. Additionally, the mean daily dose of IPX203 was 1539.61 (±630.83) and the median treatment duration was 271 (range, 16-369) days.

Presented at the 2022 Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress in Washington, DC, June 17-19, data on the pharmacodynamic and pharmacokinetic effects of IPX203 suggest—and according to the investigators, appear to confirm—that the novel design of the drug address some of the limitations of the current oral delivery levodopa options.5The pharmacokinetic data, collected from phase 2 of the RISE-PD study, showed that those with PD who were treated with IPX203 had rapid absorption followed by sustained plasma concentrations, with a maximum serum concentration (Cmax)­­ of 2.768 ng/mL (SD, 1.259) compared with 2.357 ng/mL (SD, 1.179) for immediate-release carbidopa-levodopa.

The time to maximum concentration (T­max) was 1.5 hours (min, 0.5; max, 6.0) compared with 0.5 hours (min, 0.5; max, 2.0) for immediate-release carbidopa-levodopa. This resulted in an area under the curve (AUC) of 11.214 (SD, 4.887) for IPX203 compared with 3,879 (SD, 1.744) for immediate-release carbidopa-levodopa. Notably, following the first dose on day 15, the duration of Cmax of at least 50% was markedly higher for IPX203, at 6.2 hours (SD, 1.9) compared with 3.9 hours (SD, 2.2) for immediate-release carbidopa-levodopa.

This study included 28 patients with advanced PD who were reporting motor fluctuations. They were randomly assigned 1:1 to 15 days of treatment with immediate-release carbidopa-levodopa followed by IPX203, or IPX203 followed by immediate-release carbidopa-levodopa, with a 1-week washout period between the two treatments. The investigational Amneal capsule product was supplied 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.

When comparing the predose Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) scores at day 1 with those at day 15, there was significant difference between IPX203 and immediate-release carbidopa-levodopa. On Day 1, the IPX203 group reported 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).

The investigators noted that levodopa, though the gold standard for the treatment of PD, has a short half-life that can result in pulsatile dopaminergic stimulation that can lead to motor complications. Additionally, there are limitations to achieving steady exposure to levodopa with oral treatments as gastric emptying is erratic and the window of absorption in the proximal small intestine is narrow. This is particularly true as PD progresses.

Further more, at the 2022 American Academy of Neurology (AAN) Annual Meeting, April 2-7, in Seattle, Washington, Hauser presented data from a pair of posters from the phase 3 RISE-PD trial (NCT03670953) on IPX203.6,7 In the first poster, overall, the data showed promise, with IPX-203 meeting the primary end point by showing statistically significant improvement in good ON time compared with immediate-release (IR) CD-LD (0.53 hours; P = .0194) in a cohort of 506 patients with Parkinson disease (PD) who experience motor fluctuations. The secondary end point—change from baseline in OFF time—displayed similar results, with IPX203 treatment resulting in significantly less OFF time compared with IR CD-LD (–0.48 hours; = .0252). The second poster, a post hoc analysis of the RISE-PD data, demonstrated similar promise in a modified intent-to-treat population (n = 495). At the end-of-study visit, 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 IR CD-LD (P <.0001).

1. Amneal Receives U.S. FDA Complete Response Letter for IPX203. News release. Amneal Pharmaceuticals. July 3, 2023. Accessed July 3, 2023. https://investors.amneal.com/news/press-releases/press-release-details/2023/Amneal-Receives-U.S.-FDA-Complete-Response-Letter-for-IPX203/default.aspx
2. Espay A, Hauser R, Dhall R, et al. Long-term safety and efficacy of IPX203 in Parkinson’s Disease patients with motor fluctuations: a 9-month open-label extension trial. Presented at: 2023 AAN Annual Meeting; April 22-27; in Boston, MA. Abstract 002472
3. Amneal announces US FDA filing acceptance of new drug application for IPX203 for the treatment of Parkinson disease. News release. November 11, 2022. Accessed June 28, 2023. 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
4. 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).
5. 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.
6. 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). Presented at: AAN Annual Meeting; April 2-7, 2022; Seattle, WA, and virtual. Abstract 001225.
7. 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.
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