Abstract
Background:
IPX203 is a novel oral extended-release formulation of carbidopa/levodopa (CD/LD) developed to address the short half-life of immediate-release CD/LD. In the phase 3 RISE-PD trial, IPX203 significantly improved “Good On” time in patients with Parkinson disease compared with immediate-release CD/LD.
Objectives:
To evaluate the safety and efficacy of IPX203 in an open-label extension of the pivotal phase 3 study.
Methods:
This 9-month extension enrolled patients who completed the randomized, double-blind trial. Key efficacy endpoints included MDS-UPDRS and Patient and Clinical Global Impression scores. Adverse events (AEs) were recorded.
Results:
Improvements in efficacy were maintained, and dosing frequency and total daily dose remained stable through the trial. 52.7% of patients experienced ≥1 treatment-emergent AE, mostly mild or moderate and occurred within the first 90 days of treatment.
Conclusions:
In this phase 3 open-label extension, IPX203 exhibited a favorable safety and tolerability profile and sustained efficacy of comparable magnitude to the end of the double-blind study.
Introduction
Levodopa/carbidopa (LD/CD) has been a standard for treating motor symptoms of Parkinson disease (PD) for nearly 50 years.1 However, immediate-release (IR) formulations of CD/LD have short half-lives, and long-term use of IR CD/LD is complicated by development of motor fluctuations.2 IPX203 is an investigational oral ER CD/LD that was designed to prolong plasma concentrations of LD. A double-blind, randomized, active-controlled phase 3 trial (RISE-PD) assessed the efficacy and safety of IPX203 versus IR CD/LD in patients with PD and motor fluctuations (ClinicalTrials.gov identifier: NCT03670953).3 Compared with patients who received IR CD/LD, IPX203 when given 3 times per day, compared with 5 times per day for IR CD/LD, led to significant improvement in “Good On” time per dose (LS mean difference [95% CI], 1.55 [1.37–1.73] hours; P<0.001)3 and “Good On” time per day (least squares [LS] mean difference [95% CI], 0.53 [0.09–0.97] hours; P=0.02).3 Treatment with IPX203 (mean [SD], 1488.05 [592.78] mg LD per day) was well tolerated during the double-blind treatment period.3 Here, we present the safety and efficacy of IPX203 during the open-label extension of the RISE-PD trial.
Methods
Study Design and Participants
This 9-month, multicenter, open-label extension trial was conducted at 94 sites in the United States, Italy, Spain, France, United Kingdom, Czech Republic, Poland, and Germany between April 2019 and March 2022 (ClinicalTrials.gov Identifier: NCT03877510). All patients who completed the RISE-PD trial could enroll in the open-label extension trial. The extension trial consisted of a baseline visit (visit 1) and 3 follow-up visits at approximately 3-month intervals (visits 2–4). The baseline visit of this study occurred at the same time as the end-of-study visit of the RISE-PD trial.
The trial was conducted in accordance with standards set out by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice. The study protocol and relevant documents were reviewed and approved by an institutional review board before the start of the study. All patients provided informed consent; patients enrolled in the United States also signed Health Insurance Portability and Accountability Act authorization.
Treatments and Dosing
Patients were started on the final IPX203 dosing regimen that was determined during the IPX203 dose-conversion period of RISE-PD, as previously described.3 Investigators could adjust the dosing regimen of IPX203 to achieve the optimal balance of efficacy and safety. Patients were advised to take the dose approximately every 8 hours and no more frequently than every 6 hours.
Assessments
Efficacy was assessed at every visit and included the Movement Disorder Society‒Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part I to IV,4 Patient (PGI-S) and Clinician (CGI-S) Global Impression of Severity.
Safety, including adverse event (AE) reporting, was assessed at each visit. Clinical laboratory tests, vital signs, electrocardiogram, and physical examinations were also performed. AEs were considered treatment emergent if the date of onset was on or after the date of the first open-label study drug administration and no later than 1 day after the last dose of study drug.
Study drug exposure was assessed as frequency of daily dose administration (i.e., number of administrations per day), total daily dose (TDD) of IPX203 in mg, and most frequently used dose of IPX203 in mg, as well as changes from the dosage initiated at visit 1 at the start of the open-label extension.
Statistical Analysis
There was no prespecified sample size determination. All patients who successfully completed the randomized lead-in trial could enroll in the open-label extension. A total of 300 patients were estimated to enroll, but enrollment was not capped at 300.
Efficacy data were analyzed in the intent-to-treat (ITT) population, which included all patients who received open-label study drug and had ≥1 post-baseline efficacy assessment. Safety was analyzed in the safety analysis set, which included all patients who received open-label study drug. Missing data were not imputed, with the exception of missing MDS-UPDRS data.
Results
Study Participants
Between April 03, 2019, and March 21, 2022, 419 patients were enrolled and received treatment, and 352 (84.0%) completed the trial (Supplementary Figure 1). A total of 67 patients (16.0%) discontinued; the most common reasons for discontinuation were withdrawal by patient (22 patients [32.8%]), AEs (20 [29.9%]), and lack of efficacy (14 [20.9%]). Among patients who received IPX203 in the double-blind trial, the rate of discontinuation was stable over the 9-month extension (4%‒5%); among patients switching from IR CD/LD to IPX203, the rate of discontinuation was higher in the first 6 months after switching (8%–8.5% vs 2.3% at month 9 [visit 4]). Overall, mean (SD) age was 66.9 (8.9) years, and most patients (66.6%) were male (Supplementary Table 1).
Dosing Regimen
The daily dosing frequency was stable over the 9-month trial; mean daily dosing frequency was approximately 3 doses a day at each visit (Supplementary Table 2; Supplementary Figure 2A). Over the 9-month trial, the mean (SD) TDD of LD in IPX203 was 1539.6 (630.8) mg (Supplementary Figure 2B).
Efficacy
Efficacy and quality of life (QoL) measures were unchanged throughout the 9-month open-label extension (Table 1). No notable changes were observed in mean MDS-UPDRS Total and Parts I–IV from baseline to visit 4. Similarly, no changes were observed in PGI-S or CGI-S scores.
Table 1.
Summary of Efficacy Endpoints (ITT Analysis Set)
| Endpoint Score | RISE-PD Baseline* | Visit 1 (Trial Baseline†) | Visit 2 (Month 3) | Visit 3 (Month 6) | Visit 4 (Month 9) | Change From Baseline to Visit 4 |
|---|---|---|---|---|---|---|
|
| ||||||
| MDS-UPDRS Total, n | 412 | 409 | 379 | 355 | 351 | 349 |
| Mean (SD) | 60.2 (27.0) | 56.7 (28.6) | 56.5 (30.1) | 56.0 (28.9) | 58.8 (29.6) | 2.3 (16.7) |
| MDS-UPDRS Part I, n | 412 | 410 | 390 | 362 | 351 | 350 |
| Mean (SD) | 9.9 (5.4) | 9.9 (6.3) | 10.6 (6.4) | 10.7 (6.2) | 11.0 (6.8) | 1.2 (4.7) |
| MDS-UPDRS Part II, n | 412 | 409 | 390 | 362 | 351 | 349 |
| Mean (SD) | 13.3 (7.3) | 12.8 (7.8) | 13.0 (8.0) | 12.8 (7.7) | 13.5 (8.1) | 0.8 (4.9) |
| MDS-UPDRS Part III, n | 412 | 410 | 379 | 357 | 351 | 350 |
| Mean (SD) | 29.6 (17.2) | 27.5 (17.2) | 26.8 (17.9) | 26.6 (17.5) | 27.9 (17.1) | 0.4 (11.4) |
| MDS-UPDRS Part IV, n | 412 | 410 | 382 | 358 | 351 | 350 |
| Mean (SD) | 7.5 (2.6) | 6.6 (3.0) | 6.0 (3.2) | 6.0 (3.1) | 6.3 (3.2) | −0.1 (2.6) |
| PGI-S, n | 412 | 409 | 390 | 363 | 351 | 349 |
| Mean (SD) | 3.8 (0.9) | 3.7 (1.0) | 3.8 (1.0) | 3.7 (1.0) | 3.7 (1.1) | 0 (1.1) |
| CGI-S, n | 412 | 409 | 383 | 358 | 350 | 348 |
| Mean (SD) | 3.9 (0.8) | 3.8 (0.9) | 3.8 (0.9) | 3.7 (0.9) | 3.7 (1.0) | −0.1 (0.8) |
| PDQ-39 Total, n | 411 | 406 | 392 | 364 | 348 | 343 |
| Mean (SD) | 44.9 (26.9) | 41.7 (27.7) | 42.7 (27.7) | 42.8 (28.2) | 44.4 (28.7) | 4.1 (18.8) |
| PAS Total, n | 410 | 408 | 390 | 365 | 350 | 347 |
| Mean (SD) | 10.7 (7.8) | 10.4 (8.2) | 10.3 (8.2) | 10.3 (7.7) | 10.9 (8.3) | 0.8 (6.3) |
| NMSS Total, n | 412 | 407 | 388 | 362 | 349 | 346 |
| Mean (SD) | 34.9 (27.5) | 32.0 (29.0) | 32.5 (28.5) | 33.4 (29.2) | 35.0 (30.2) | 3.9 (22.4) |
| PDSS-2, n | 412 | 410 | 389 | 363 | 344 | 343 |
| Mean (SD) | 17.4 (9.4) | 16.6 (9.7) | 15.8 (9.2) | 16.1 (9.3) | 16.1 (9.2) | −0.1 (8.8) |
| TSA, n | N/A | N/A | 392 | 365 | 350 | N/A |
| Mean (SD) | N/A | N/A | 5.2 (1.3) | 5.4 (1.2) | 5.4 (1.3) | N/A |
| ZBI-12 Total, n | N/A | 153 | 149 | 141 | 135 | 124 |
| Mean (SD) | N/A | 9.2 (7.8) | 10.5 (8.4) | 11.0 (9.0) | 10.6 (8.9) | 1.3 (7.6) |
| EMSQ Total Severity, n | 411 | 406 | 388 | 362 | 349 | 345 |
| Mean (SD) | 9.5 (4.3) | 8.4 (5.2) | 8.1 (5.4) | 8.0 (5.1) | 8.4 (5.5) | 0.4 (4.5) |
CGI-S, Clinical Global Impression of Severity; EMSQ, Early Morning Symptoms Questionnaire; ITT, intent to treat; MDS-UPDRS, Movement Disorders Society–Unified Parkinson’s Disease Rating Scale; N/A, not applicable; NMSS, Non-Motor Symptom Assessment Scale; PAS, Parkinson Anxiety Scale; PDQ-39, 39-item Parkinson’s Disease Questionnaire; PDSS-2, Parkinson’s Disease Sleep Scale-2; PGI-S, Patient Global Impression of Severity; TSA, Treatment Satisfaction Assessment; ZBI-12, 12-Item Zarit Burden Interview.
Defined as the last assessment before the first dose of study drug during the dose-adjustment period.
Defined as the last assessment before the first dose of open-label drug
Mean PDQ-39, PAS, NMSS, PDSS-2, and EMSQ scores were unchanged throughout the trial with no differences observed from baseline to visit 4 (Table 1). Overall, 80.4% of patients reported being at least somewhat satisfied with treatment (score of 5, 6, or 7 on the TSA) at 3 months; 84.4% and 81.7% reported being at least somewhat satisfied with treatment at 6 and 9 months, respectively.
Safety
Among the 419 patients who entered the open-label extension, 221 (52.7%) patients experienced ≥1 treatment-emergent AE (TEAE), and 42 (10.0%) experienced ≥1 serious AE (Table 2). In general, TEAEs more commonly occurred within the first 90 days of the trial, with 17.7% of patients experiencing a TEAE within 30 days of trial start and 16.9% of patients experiencing a TEAE between 30 and 90 days (Supplementary Figure 3). TEAEs were considered treatment related in 66 patients (15.8%); the most commonly reported treatment-related TEAEs (occurring in ≥1% of patients) were dyskinesia (4.5%) and nausea (1.0%). A total of 25 patients (6.0%) discontinued the trial due to a TEAE. Six patients died during the trial. All serious AEs (SAEs) leading to death were deemed not related to study drug, with the exception of 1 patient who had a severe SAE of drowning that was considered by the investigator to be related to study drug.
Table 2.
Summary of TEAEs (Safety Analysis Set)
| Patients, n (%) | Overall N=419 |
|---|---|
|
| |
| ≥1 TEAE | 221 (52.7) |
| ≥1 treatment-related TEAE | 66 (15.8) |
| ≥1 serious TEAE | 42 (10.0) |
| TEAE leading to study drug discontinuation | 25 (6.0) |
| TEAE leading to death | 6 (1.4) |
| TEAEs reported in ≥2% of patients | |
| Dyskinesia | 21 (5.0) |
| Fall | 21 (5.0) |
| Urinary tract infection | 21 (5.0) |
| Back pain | 15 (3.6) |
| Constipation | 11 (2.6) |
| COVID-19 | 10 (2.4) |
TEAE, treatment-emergent adverse event.
No clinically meaningful changes from trial baseline (visit 1) to visit 4/early termination were observed in clinical laboratory parameters, vital signs, electrocardiogram parameters, and physical examination. As measured by the C-SSRS, a small percentage of patients had any suicidal ideation at baseline (0.5%) and at visit 4 (0.8%); no patient had any suicidal behavior at any visit. No clinically meaningful differences were seen from baseline to visit 4 in GCSI questionnaire scores.
Discussion
During 9 months of open-label treatment, IPX203 was associated with sustained efficacy and acceptable safety and tolerability profiles in patients with PD experiencing motor fluctuations. TEAEs were generally mild to moderate in intensity and mostly occurred within the first 90 days of treatment.
IR CD/LD formulations are limited by their short half-lives, and when motor fluctuations emerge, doses or dosing frequency are commonly increased to circumvent this limitation. However, increasing the amount of LD can lead to, or worsen, LD-induced dyskinesia.2 ER CD/LD has shown a more stable pharmacokinetic profile with less fluctuations in plasma LD concentrations compared with IR CD/LD5,6 and sustained efficacy; however, it must still be dosed at least 4 times a day in advanced PD. In the RISE-PD trial, patients taking IPX203 dosed an average of 3 times a day experienced 0.53 hours more “Good On” time per day than patients taking IR CD/LD dosed an average of 5 times a day.3 IPX203 also increased the “Good On” time per dose by 1.55 hours compared to IR CD/LD.3 At the end of the double-blind RISE-PD trial, mean (SD) MDS-UPDRS Part III scores were 27.8 (17.7) and 28.0 (16.6) for patients in the IPX203 and IR CD/LD groups, respectively. Mean (SD) MDS-UPDRS Part IV was 6.6 (3.3) for patients in the IPX203 group and 6.9 (2.8) for patients in the IR CD/LD group. In this extension trial, patients taking IPX203 dosed an average of 3 times a day experienced unchanged MDS-UPDRS Part III and IV scores throughout the 9-month open-label trial, suggesting stable control of motor symptoms. MDS-UPDRS Part III and IV scores were also similar between patients previously receiving IPX203 and patients switching from IR CD/LD to IPX203. All other efficacy outcomes were unchanged throughout the trial, providing further evidence for maintained efficacy with IPX203. In the double-blind trial, a significantly greater proportion of patients (P=0.002) reported themselves “much improved” or “very much improved” with IPX203 treatment (29.7%) compared with IR CD-LD treatment (18.8%).3 Patient-reported outcomes remained stable throughout the open-label extension.
Changes in dosing regimens were more likely to occur within the first 90 days of the trial, suggesting that dosing regimens can be relatively quickly stabilized.
The most commonly reported TEAEs in this open-label extension trial were dyskinesia and nausea, which are commonly associated with PD therapies. Dyskinesia was reported in 5.0% of patients during the open-label extension compared with 2.0% of patients receiving IPX203 in the double-blind period of the lead-in trial.3 Nausea was reported in 1.9% of patients in the open-label extension, whereas 4.3% of patients receiving IPX203 in the double-blind period of the lead-in trial reported nausea. Rates of treatment-related AEs in the open-label extension were generally lower for patients continuing on IPX203 than for patients switching from IR CD/LD, and AEs were more common within the first 30 days of treatment, suggesting that AEs may improve over time as the dosing regimen is stabilized.
Overall, in this phase 3 open-label extension trial of IPX203, most patients achieved a stable dosing regimen within 3 months. Trial results suggest that treatment with IPX203 given an average of 3 times a day for 9 months provides maintained efficacy and is generally safe and well tolerated in patients with PD and motor fluctuations.
Supplementary Material
Acknowledgments
Copyediting and graphic services were provided by The Curry Rockefeller Group, LLC, a communications agency, and funded by Amneal Pharmaceuticals.
Funding Sources:
Amneal Pharmaceuticals provided funding for the study and for medical writing and editorial support for preparation of this manuscript.
Financial Disclosures (Preceding 12 Months)
Alberto J. Espay has received consulting fees, payment, or honoraria from Neuroderm, Amneal Pharmaceuticals, Acadia, Avion Pharmaceuticals, Acorda, Kyowa Kirin, Sunovion, Supernus Pharmaceuticals, and Herantis Pharma; has received research support (paid to his institution) from Michael J. Fox Foundation and National Institutes of Health; has received royalties from Cambridge University Press, Lippincott Williams & Wilkins, and Springer; is co-owner of a patent that covers synthetic soluble nonaggregating peptide analogues as replacement treatment in proteinopathies; and is cofounder of REGAIN Therapeutics.
Robert A. Hauser has received consulting fees from AbbVie, Amneal Pharmaceuticals, BlueRock Therapeutics, Global Kinetics, Inhibikase, Jazz Pharmaceuticals, Kyowa Kirin, Merz, Neurocrine Biosciences, NeuroDerm, Ovid Therapeutics, PD Neurotechnology, Pharma Two B, Regenxbio, Sage Therapeutics, Scion Neurostim, Supernus Pharmaceuticals, Tris Pharma, UCB, and Vivifi Biotech; is a speaker for Acorda, Amneal Pharmaceuticals, Cerevel, Inhibikase, Kyowa Kirin, Neurocrine Biosciences, and Supernus Pharmaceuticals; has received royalties from USF for licensing a PD diary; has received research support (paid to his institution) from Abbvie, AEON Biopharma, Biogen, Bukwang Pharmaceuticals, Cavion, Centogene, Cerevance, Cerevel Therapeutics, Covance/Sun Pharmaceuticals, Enterin, Genentech, Global Kinetics, Impax, IRLAB, Lundbeck, Michael J. Fox Foundation, Neuraly, NeuroDerm, Parkinson’s Foundation (Center of Excellence Grant), Pharma Two B, Revance, Roche, Sanofi, Scion Neurostim, and UCB; and owns stock or stock options in Axial Therapeutics, Enterin, Inhibikase, and Revance.
Rohit Dhall has received research support (paid to his institution) from Abbvie, Aeon Biopharma, Alexion, Amneal Pharmaceuticals, Cerevel Therapeutics, Neurocrine, Neuroderm, Neuraly, Parkinson’s Foundation, Pharma Two B, Praxis Precision Medicines, Sage Therapeutics, Sun Pharma, and the National Institutes of Health (parent grant #UL1TR003107); has received consulting fees from CALA Health and Best Doctors; and reports stock ownership (all at <$10,000) in Enliven Therapeutics, Gilead, Gossamer Bio, and Moderna.
Sandeep Thakkar is a speaker for Amneal.
Leslie Cloud has been a consultant for Abbvie; has served on an advisory board and speakers bureau for Kyowa Kirin; is employed by Virginia Commonwealth University (VCU)/VCU Health System; has clinical trial contracts (paid to her institution) with Bukwang and Cerevel; has received honoraria from HMP Global, M3 Global Research, MedLink Neurology, and Qessential Medical Market Research; has grants (paid to her institution) from the Michael J. Fox Foundation, National Institute of Neurological Disorders and Stroke of the National Institutes of Health (1R01NS120560-01), Parkinson’s Foundation, and Virginia Catalyst Fund; is the inventor of the Gastrointestinal Symptoms in Neurodegenerative Disease (GIND) scale (VCU Office of Technology Transfer #CLO-11-0R67) and Recognize and Deploy Vibration for Mitigation of Freezing of Gait (VCU Office of Technology Transfer #PRE-21-137F; 322203-8130); and has filed a patent application (provisional patent #PRE-21-137F; 322203-8130; filed July 2022).
Leonid Zeitlin is a consultant for Quartesian, LLC, a company that provides clinical data services to Amneal.
Ghazal Banisadr, Stanley Fisher, and Hester Visser are employees of Amneal and may hold stock or ownership interest in Amneal.
Footnotes
Financial Disclosure/Conflict of Interest:
Alberto J. Espay is a study investigator for, has received honoraria and travel support from, and serves as a consultant and on the Speakers’ Bureau for Amneal.
Robert A. Hauser is a study investigator for, has received honoraria and travel support from, and serves as a consultant and on the Speakers’ Bureau for Amneal.
Rohit Dhall is a study investigator for Amneal.
Sandeep Thakkar is a study investigator for and has received honoraria and travel support from Amneal.
Leslie Cloud is a study investigator for Amneal.
Leonid Zeitlin is a consultant for Quartesian, LLC, a company that provides clinical data services to Amneal.
Ghazal Banisadr, Stanley Fisher, and Hester Visser are employees of Amneal and may hold stock or ownership interest in Amneal.
Data Availability Statement
Data from this study will be shared according to regulatory guidelines and timelines (e.g., on ClinicalTrials.gov) and as determined by Amneal Pharmaceuticals. Deidentified patient data can only be shared by people other than Amneal Pharmaceuticals after written approval from Amneal Pharmaceuticals.
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Associated Data
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Supplementary Materials
Data Availability Statement
Data from this study will be shared according to regulatory guidelines and timelines (e.g., on ClinicalTrials.gov) and as determined by Amneal Pharmaceuticals. Deidentified patient data can only be shared by people other than Amneal Pharmaceuticals after written approval from Amneal Pharmaceuticals.