Objectives Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/RYTARY/NUMIENT) produces improvements in “off” time, “on” time without troublesome dyskinesia, and Unified Parkinson Disease Rating Scale scores compared with immediate-release (IR) CD-LD or IR CD-LD plus entacapone (CLE). Post hoc analyses of 2 ER CD-LD phase 3 trials evaluated whether the efficacy and safety of ER CD-LD relative to the respective active comparators were altered by concomitant medications (dopaminergic agonists, monoamine oxidase B [MAO-B] inhibitors, or amantadine). Methods ADVANCE-PD (n = 393) assessed safety and efficacy of ER CD-LD versus IR CD-LD. ASCEND-PD (n = 91) evaluated ER CD-LD versus CLE. In both studies, IR- and CLE-experienced patients underwent a 6-week, open-label dose-conversion period to ER CD-LD prior to randomization. For analysis, the randomized population was divided into 3 subgroups: dopaminergic agonists, rasagiline or selegiline, and amantadine. For each subgroup, changes from baseline in PD diary measures (“off” time and “on” time with and without troublesome dyskinesia), Unified Parkinson Disease Rating Scale Parts II + III scores, and adverse events were analyzed, comparing ER CD-LD with the active comparator. Results and Conclusions Concomitant dopaminergic agonist or MAO-B inhibitor use did not diminish the efficacy (improvement in “off” time and “on” time without troublesome dyskinesia) of ER CD-LD compared with IR CD-LD or CLE, whereas the improvement with concomitant amantadine failed to reach significance. Safety and tolerability were similar among the subgroups, and ER CD-LD did not increase troublesome dyskinesia. For patients on oral LD regimens and taking a dopaminergic agonist, and/or a MAO-B inhibitor, changing from an IR to an ER CD-LD formulation provides approximately an additional hour of “good” on time.

Evaluate the effect of concomitant Parkinson's disease (PD) medications on the dosing and efficacy of extended-release (ER) vs. immediate-release (IR) carbidopa-levodopa (CD-LD) using post hoc subgroup analyses.

Background: IPX066 (Rytary (R); carbidopa and levodopa [CD-LD] extended-release capsules) was designed to achieve therapeutic LD plasma concentrations within 1 h of dosing and maintain LD concentrations for a prolonged duration in early or advanced Parkinson's disease (PD).Methods: In this open-label study, patients underwent 6 weeks of conversion to IPX066 from their prior controlled-release (CR) +/- immediate-release (IR) CD-LD therapy and 6 months of maintenance (with an additional 6 months of IPX066 at some sites). Clinical utility was assessed at both the end of conversion and maintenance.Results: Among 43 patients initiated on IPX066, 33 completed conversion. The mean LD conversion ratio was 1.8 among 30 patients previously on CR plus IR (and 1.5 among 3 previously taking CR alone). The mean IPX066 dosing frequency was 3.5 times/day compared with 2.6 times/day for CR plus 4.6 times/day for IR previously (and 4.7 times/day for CR alone). By patient and clinician global improvement ratings after 6-month maintenance,>= 43.8% of patients were much or very much improved from their previous treatment, and >= 68.8% were at least minimally improved. Adverse events were consistent with those reported in prior IPX066 studies.Conclusions: These results suggest that advanced PD patients using CR CD-LD +/- IR can be safely converted to IPX066, with high likelihood of achieving a stable regimen, less frequent LD dosing, and improved overall clinical benefit. (C) 2016 The Authors. Published by Elsevier B.V.

Objective: Describe the characteristics of advanced Parkinson's disease (PD) patients who discontinued treatment during conversion to IPX066 Background: IPX066 is a multiparticulate, extended-release formulation of carbidopa-levodopa (CD-LD) that achieves stable plasma LD levels within an hour of dosing and maintains plasma levels for 4-5 hours. IPX066 improved motor symptoms and activities of daily living in advanced PD patients. Methods: ADVANCE-PD examined the efficacy and safety of IPX066 compared to immediate-release (IR) CD-LD in advanced PD patients with motor fluctuations. Prior to randomization, patients underwent a 6-week conversion from IR to IPX066. Results: Out of 450 patients who started conversion to IPX066, 57 (12.7[percnt]) discontinued during the conversion period. Patients who discontinued had a longer duration of PD compared to those who completed conversion (mean±SD: 9.1±6.2 vs. 7.4±4.5 yrs, respectively) and a higher proportion of patients with more advanced disease (Hoehn & Yahr Stage III-IV, 56.1[percnt] vs. 43.0[percnt], respectively). Patients who discontinued had a higher IR dose (874.6±356.9 mg/day) and dose frequency (5.7±2.2 doses/day) at study entry than those who completed conversion (775.8±353.3 mg/day, 5.0±1.6 doses/day, respectively). Less than 10[percnt] of patients taking 400-799 mg/day of IR at study entry discontinued, while 19.1[percnt] on ≥1000 mg/day discontinued. Similarly, 10.9[percnt] of patients taking IR 4-6 times/day at study entry discontinued vs. 25.0[percnt] taking IR >6 times/day. A higher proportion of patients who discontinued were taking IPX066 ≥5 times/day (21.1[percnt]) than those who completed dose conversion (8.1[percnt]). Of the discontinuations, 23 (40.4[percnt]) were due to adverse events (AE) and 13 (22.8[percnt]) were due to lack of efficacy. The most common AEs leading to discontinuation were dyskinesia (n=5), anxiety (n=4), and dizziness, nausea, and somnolence (n=3 each). Conclusions: Patients with higher IR CD-LD dose and dose frequency and with later stage disease tended to have higher rates of discontinuation during conversion to IPX066.

Background: Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications.IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours.Objective: To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting.Methods: Patients had ≥2.5 hours/day of "off" time despite a stable IR or CLE regimen.Suggested initial dosing conversion tables based on prior LD daily dosage were provided.Results: Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively.At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1 ± 0.6 for IR CD-LD and 2.8 ± 0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies.After conversion, daily "off" time significantly decreased, with no significant increase in troublesome dyskinesia.The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE. Conclusions: Among PD patients with substantial "off" time, a majority were safely converted to IPX066.The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia.

IPX066 is a multiparticulate extended-release formulation of carbidopa–levodopa, designed to produce prolonged therapeutic levodopa plasma concentrations. This 9-month open-label extension study assessed its long-term safety and clinical utility in early and advanced Parkinson’s disease (PD).

April 20, 2015April 6, 2015Free AccessSummary of safety from clinical trial experience with IPX066, extended-release carbidopa-levodopa, in Parkinson’s disease (P1.184)Margery Mark, Rohit Dhall, David Kreitzman, Sherron Kell, Sarita Khanna, Ann Hsu, and Suneel GuptaAuthors Info & AffiliationsApril 6, 2015 issue84 (14_supplement)https://doi.org/10.1212/WNL.84.14_supplement.P1.184 Letters to the Editor

OBJECTIVE: To summarize the safety profile of IPX066 versus the comparator arms in the Phase 3 clinical trials in Parkinson's disease (PD) BACKGROUND: IPX066 is an investigational, extended-release formulation of carbidopa-levodopa (CD-LD) designed to provide rapid absorption, similar to immediate-release CD-LD (IR), but with extended duration of therapeutic LD plasma concentrations to permit ~q6h dosing. IPX066 has demonstrated significant improvement in PD motor symptoms compared to placebo, IR, and CD-LD+entacapone (CL+E). DESIGN/METHODS: Adverse events (AEs) were recorded during the double-blind periods of three phase 3 studies: APEX-PD (IPX066 145 mg, 245 mg, or 390 mg vs. placebo TID in LD-naïve, early patients [n=381]); ADVANCE-PD (IPX066 vs. IR in advanced patients [n=393]); and ASCEND-PD (IPX066 [n=89] vs. CL+E in advanced patients [n=88]). RESULTS: In APEX-PD, the most common AEs occurred less frequently in the placebo and 145 mg IPX066 groups than in the higher dose groups: nausea (8.7[percnt], 13.8[percnt], 19.2[percnt], 20.4[percnt]), dizziness (5.4[percnt], 9.2[percnt], 19.2[percnt], 12.2[percnt]), and headache (10.9[percnt], 6.9[percnt], 12.5[percnt], 17.3[percnt]) were reported in the placebo, 145 mg, 245 mg, and 390 mg IPX066 groups, respectively. In ADVANCE-PD, 43.3[percnt] of IPX066 (87/201) and 39.6[percnt] of IR (76/192) patients reported AEs. The most frequent AEs for IPX066 were insomnia (3.5[percnt]), nausea, and falls (each 3.0[percnt]), which for IR occurred in 1.0[percnt], 1.6[percnt], and 2.1[percnt], respectively. In ASCEND-PD, AEs were reported by 20.2[percnt] (IPX066, n=89) and 13.6[percnt] (CL+E, n=88) of patients during double-blind treatment. Most frequent AEs on IPX066 were dyskinesia (4.5[percnt]), insomnia (3.4[percnt]), and confusional state (3.4[percnt]). Falls (2.3[percnt]) were most frequent in the CL+E group. CONCLUSIONS: In early PD patients, 145 mg IPX066 had the best tolerability profile among IPX066 doses. During the double-blind periods, AE rates in ADVANCE-PD were similar between IPX066 and IR, but were lower for CL+E than IPX066 in ASCEND-PD. SUPPORT: Impax

OBJECTIVE: Summarize the efficacy of IPX066 across three phase 3 clinical trials in Parkinson's disease (PD) BACKGROUND: IPX066 is an investigational, extended-release formulation of carbidopa-levodopa (CD-LD) with an initial absorption rate similar to immediate-release CD-LD (IR), but which also provides an extended duration of therapeutic LD plasma concentrations allowing ~q6h dosing. DESIGN/METHODS: IPX066 was examined in LD-naïve patients (APEX-PD: 145mg, 245mg, or 390mg TID vs. placebo for 30 weeks, N=381) and in advanced patients (ADVANCE-PD: IPX066 vs. IR for 13 weeks, N=393; ASCEND-PD: IPX066 vs. CD-LD+entacapone [CL+E] using a 2 week/period crossover, N=91). Efficacy endpoints included Unified Parkinson's Disease Rating Scale (UPDRS) Parts II+III (all trials); PD diary (ADVANCE-PD/ASCEND-PD); Patient, Clinician Global Impression (PGI, CGI; APEX-PD/ADVANCE-PD); and Subject Preference of Treatment (ASCEND-PD). RESULTS: In APEX-PD, improvements from baseline on UPDRS Parts II+III were ˗11.7 to ˗14.9 points for IPX066 dose groups vs. ˗0.6 for placebo (all P<.0001 vs. placebo) and were maintained throughout the study. IPX066 improved UPDRS Part II+III by ˗5.7 points vs. ˗2.1 by IR (P<.0001) in ADVANCE-PD, and by ˗2.7 points vs. ˗0.3 by CL+E (P=.0233) in ASCEND-PD. IPX066 produced a significantly greater reduction from baseline in "off" time compared to IR (˗2.2 vs. ˗1.0 hr, P<.0001) and CL+E (˗2.1 vs. ˗0.7 hr, P<.0001). "On" time with troublesome dyskinesia did not differ from comparators (P=.6047 vs. IR, P=.3051 vs CL+E). PGI and CGI were significantly improved by all doses of IPX066 vs. placebo (all P<.0001) and vs. IR (P<.0001). In ASCEND-PD, more patients preferred IPX066 (52.4[percnt]) than CL+E (27.4[percnt], P<.001). Across studies, 57.5[percnt] of patients reported 蠅1 adverse event. The most frequent were nausea (10.4[percnt]), dizziness (7.6[percnt]), headache (7.1[percnt]), and dyskinesia (5.4[percnt]). CONCLUSIONS: IPX066 significantly improved PD symptoms with an adverse event profile similar to other dopaminergic therapies. A low proportion of patients reported dyskinesia. SUPPORT: Impax

OBJECTIVE: To evaluate IPX066 dosing regimens in three trials. BACKGROUND: IPX066 is an oral investigational extended-release formulation of carbidopa-levodopa (CD-LD; 1:4 ratio) designed to provide rapid increase in LD plasma concentrations followed by sustained concentrations allowing dosing interval of ~6h. IPX066 was studied in 2 active-controlled double-blind studies with immediate-release CD-LD (IR) and CD-LD+entacapone (CLE) as active controls, respectively, and in 1 open-label study in patients previously treated with controlled-release CD-LD (CR) alone or with IR. DESIGN/METHODS: Studies enrolled advanced PD patients with 蠅2.5h “Off” time. All dose conversion to IPX066 was not blinded. The recommended initial IPX066 LD conversion dose was ~30% higher for CLE than for IR regimens with or without CR. All patients were started with IPX066 approximately every 6 hours. IPX066 dosing >5X/day was not permitted. IPX066 regimen was individually adjusted for 6 weeks. IR rescue was not allowed in the 2 double-blind studies. RESULTS: The final IPX066 LD daily dose averaged ~2X IR LD dose when converting from IR alone, and ~2.7X when converting from CLE. The ~35% higher conversion ratio with CLE regimen is consistent with higher LD exposure (35-40%) when IR is dosed with entacapone. The conversion ratios were ~1.8X when converting from IR+CR, and ~1.5X from CR alone; these lower conversion ratios are generally consistent with reduced bioavailability of CR relative to IR in PD patients. The dosing frequency of IPX066 (median 3X/day) was similar regardless of patients’ previous LD regimens. The higher dose of IPX066 represents ~30% higher LD exposures than the controls after adjusting for lower bioavailability of IPX066. CONCLUSIONS: Conversion ratios from various LD regimens to IPX066 are generally consistent with the pharmacokinetic profiles of IPX066 and LD regimens presented above. IPX066 dosing frequency is similar (median:3X/day) regardless of previous LD regimen. Study Supported by: Impax Disclosure: Dr. Hsu has received personal compensation for activities with Impax Laboratories. Dr. Hsu holds stock and/or stock options in Impax Laboratories which sponsored research in which Dr Hsu was involved as an investigator. Dr. Hsu holds stock and/or stock options in other pharmaceutical companies. Dr. Khanna has received personal compensation for activities with Impax Pharma as an employee. Dr. Khanna holds stock and/or stock options in Impax Pharma which sponsored research in which Dr. Khanna was involved as an investigator. Dr. Kell has received personal compensation for activities with Impax Laboratories. Dr. Kell holds stock and/or stock options in Impax Laboratories which sponsored research in which Dr Kell was involved as an investigator. Dr. Rubens has received personal compensation for activities with Impax Laboratories. Dr. Rubens holds stock and/or stock options in Impax Laboratories which sponsored research in which Dr. Rubens was involved as an investigator. Dr. Gupta has received personal compensation for activities with Impax Laboratories as an employee. Dr. Gupta holds stock and/or stock options in Impax Laboratories which sponsored research in which Dr. Gupta was involved as an investigator. Dr. Gupta has received research support from Impax Laboratories.

Objective: IPX066 is an extended release carbidopa/levodopa formulation designed to rapidly attain and maintain therapeutic plasma concentrations for a prolonged duration, allowing dosing intervals of approximately 6 h. The objective was to assess the efficacy, safety, and impact on quality of life of IPX066 in the treatment of levodopa-naive Parkinson's disease (PD) patients.Methods: This was a randomized, double-blind, placebo-controlled, 30-week study of 381 levodopanaive patients assigned to placebo or IPX066 containing 145, 245 or 390 mg of levodopa administered three times daily (TID). The primary efficacy measure was change from Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (Part II) + motor scores (Part III), at 30 weeks. Secondary outcome measures included UPDRS total and subscores, patient and clinician global impressions (PGI-I, CGI-I), and the Parkinson's Disease Questionnaire (PDQ-39).Results: All IPX066 dosages were superior to placebo throughout the study and at 30 weeks (P < 0.0001). The mean improvement in UPDRS Parts II + III at 30 weeks compared to baseline was 11.7,12.9, and 14.9 points for the three dosages and 0.6 points for placebo (P < 0.0001, all dosages). PDQ-39 total scores improved with IPX066 (P <= 0.034, all dosages). The most commonly reported adverse events with IPX066 included nausea, dizziness, and headache. No unexpected drug-related serious adverse events were reported.Conclusion: IPX066 provided significant clinical benefits at the three dosages tested compared to placebo and was well tolerated in levodopa-naive PD patients. Of the dosages tested, IPX066 145 mg TID appeared to provide the best overall balance between efficacy and safety. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

Background: IPX066, an investigational extended-release carbidopa-levodopa (CD-LD) preparation, has demonstrated a rapid attainment and prolonged maintenance of therapeutic LD plasma concentrations in advanced Parkinson's disease (PD). This phase-3 crossover study assessed its efficacy and safety vs. CDLD plus entacapone (CL + E).Methods: At baseline, all patients had motor fluctuations despite a stable regimen of CL + E or CD-LDentacapone combination tablets (CLE). The study included a 6-week conversion from CL + E or CLE to IPX066, followed by two 2-week, double-blind crossover treatment periods in randomized order, one on IPX066 (and placebo CL + E), the other on CL + E (and placebo IPX066), separated by 1-week open-label IPX066 treatment. The primary efficacy measure was mean percent daily "off" time during waking hours (from patient diaries).Results: Of 91 randomized patients, 84 completed the study. Their median daily LD dosage was 1495 mg from IPX066 and 600 mg from CL + E, corresponding, after correction for bioavailability, to an approximately 22% higher LD exposure on IPX066. Compared with CL + E, IPX066 demonstrated a lower percent "off' time (24.0% vs. 32.5%; p < 0.0001), lower "off' time (3.8 vs. 5.2 h/day; p < 0.0001), and higher "on" time without troublesome dyskinesia (11.4 vs. 10.0 h/day; p < 0.0001). Other endpoints, including patient-reported treatment preference, also favored IPX066 (p < 0.05). During double-blind treatment, 20.2% and 13.6% of patients reported adverse events on IPX066 and CL + E, respectively. The most common were dyskinesia (4 patients), insomnia (3), and confusional state (3) for IPX066, and fall (2) for CL + E.Conclusions: In advanced PD, IPX066 showed improved efficacy, compared with CL + E, and appeared to be well tolerated. (C) 2014 The Authors. Published by Elsevier Ltd.

OBJECTIVE: To evaluate the long-term safety of IPX066 in early Parkinson's disease (PD).