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April 05, 2016; 86 (14 Supplement 1) Article

Advances in levodopa therapy for Parkinson disease

Review of RYTARY (carbidopa and levodopa) clinical efficacy and safety

Rohit Dhall, David L. Kreitzman
First published April 4, 2016, DOI: https://doi.org/10.1212/WNL.0000000000002510
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Abstract

Parkinson disease (PD) is a slowly progressive, incurable, neurodegenerative disorder with progressive motor symptoms that can be managed with treatments. Levodopa is generally recognized as the most effective and widely used treatment for PD. It improves function and quality of life, morbidity, and mortality, and therefore reduces individual and societal costs. Levodopa has a relatively short half-life, however, and is quickly metabolized in the plasma, leading to fluctuations, including wearing-off of effect and inconsistent symptomatic relief as well as development of dyskinesias, with both wearing off and dyskinesias worsening with advancing disease. Immediate-release and controlled-release formulations have been used with success, but motor fluctuations remain a problem. RYTARY (levodopa and carbidopa, IPX066) is an oral extended-release therapy composed of carbidopa–levodopa microbeads designed to dissolve at various rates that allows for quick absorption and sustained levodopa release over an extended period. In development studies, RYTARY improved symptoms in patients with both early and advanced PD and offered significantly improved Unified Parkinson Disease Rating Scale scores and “on” times, without worsening troublesome dyskinesias when compared to other levodopa formulations. Tolerability and safety were comparable to other formulations. This section reviews the data that support the use of RYTARY in the treatment of PD.

GLOSSARY

ADVANCE-PD=
A Study to Evaluate the Safety and Efficacy of IPX066 in Advanced Parkinson's Disease;
AE=
adverse event;
APEX-PD=
A Study to Evaluate the Safety and Efficacy of IPX066 in Subjects with Parkinson's Disease;
ASCEND-PD=
Comparison of IPX066, a Novel Carbidopa-Levodopa Extended-Release Formulation, and CD-LD-Entacapone in Advanced Parkinson's Disease;
CD=
carbidopa;
CGI-C=
Clinician Global Impression of Change;
CLE=
carbidopa-levodopa + entacapone;
CR=
controlled release;
DDC=
dopa decarboxylase;
EQ-5D=
EuroQoL 5-dimension quality of life scale;
FDA=
Food and Drug Administration;
IR=
immediate release;
LD=
levodopa;
PDQ-39=
39-item Parkinson's Disease Questionnaire;
PD=
Parkinson disease;
PGI-C=
Patient Global Impression of Change;
PK=
pharmacokinetics;
SAE=
serious adverse event;
SF-36=
Short Form Health Survey;
UPDRS=
Unified Parkinson's Disease Rating Scale

Parkinson disease (PD) is the second most common neurodegenerative disorder in the United States. PD pathology in the form of Lewy bodies is found in the brain and spinal cord, as well as in the peripheral nervous system, and presents a wide range of clinical manifestations, both motor and nonmotor. Dopamine modulated circuits are at the core of motor dysfunction in PD. Motor symptoms of rigidity and bradykinesia respond well to dopaminergic treatment in early PD, with levodopa (LD) being one of the most effective and widely used treatments for PD.1,–,4 The use of LD therapy for PD is supported by the American Academy of Neurology Practice Guidelines5 because it improves function and quality of life, reduces morbidity and mortality, and, therefore, reduces individual and societal costs. Patients with early PD can derive significant benefits from simple regimens initially, but treatment regimens become more complex with advancing PD, and there is progressive increase in disability from motor and nonmotor impairment as well as complications of dopaminergic therapy including development of motor fluctuations in advanced PD.6

LD has a relatively short half-life (∼1.5 hours), however, and is quickly and extensively metabolized in plasma.7,8 A number of formulations have been developed that combine LD with a dopa decarboxylase (DDC) inhibitor, such as carbidopa (CD), which inhibits peripheral LD metabolism and allows an increase in LD CNS availability.7 Combining LD with a DDC inhibitor improves tolerability by reducing nausea and other adverse effects from peripheral decarboxylation, making oral use of LD practical. A number of well-controlled, large-scale, long-term clinical trials have consistently demonstrated symptomatic control of PD with the CD-LD formulation.9,–,11

Many of these CD-LD formulations have limitations. Immediate release (IR) CD-LD has a short half-life so it must be taken frequently, and at regular intervals, to be effective. Although effective, over time there is a shortening of clinical response and higher, more frequent dosing to compensate for the change in pharmacodynamics of CD-LD is required.8,12,13 As PD progresses, the conversion of LD to dopamine, as well as its subsequent storage and release, becomes unpredictable.8 The short half-life of LD coupled with more frequent dosing causes intermittent or pulsatile release of dopamine in the striatum, producing changes in the postsynaptic receptors. These downstream changes due to intermittent LD use, as well as progression of disease severity, lead to motor complications and dyskinesias.8,12,14,15

Many patients (between 40% and 100%) have been reported to develop fluctuating motor and nonmotor symptoms (wearing-off and on-off phenomena) and dyskinesias with continued use of LD.16,–,20 Motor fluctuations can be noted as soon as 5–6 months after treatment initiation, particularly with large doses (≥600 mg/d).21 After 2 years of CD-LD therapy, as few as 20% of patients experience sustained benefits.22 More than 70% of patients experience on-off fluctuations and dyskinesias after 5 years.20,23 As wearing-off becomes more frequent, LD doses need to be given in increasing frequency to achieve a sufficient clinical response. The fluctuation of pharmacodynamic response to LD between wearing-off and LD-induced dyskinesias leads to a narrower optimal therapeutic window with increasing probability of overdosage and underdosage.12 Thus, research has focused on an oral PD drug that provides a rapid onset of effect and more stable plasma LD levels, resulting in less “off” time and more “on” time.

Controlled-release (CR) or sustained-release formulations of CD-LD that use a degradable polymer matrix to slow the release of LD into the gut have been developed as alternatives to IR formulations. However, a 5-year comparison study noted no difference in the degree of motor fluctuations and dyskinesias between CR and IR formulations in patients with moderate to severe motor fluctuations.24 Patients transferred to CR CD-LD from an IR formulation have not consistently experienced significant “off” time reduction.25,–,29 Absorption is delayed (4–6 hours)30 and symptom relief is less predictable with CR than with IR.31,–,33 This often requires coadministration of IR with CR, particularly for the first morning dose, and increases the burden or complexity of the medication schedule for patients.34,35 CR use is often restricted to nighttime administration.

CD-LD+ entacapone (CLE) increases total exposure of IR by 35%–40% and prolongs LD half-life to 2.4 hours. Entacapone inhibits peripheral LD metabolism and allows more LD to enter the CNS.36 However, CLE has been shown to produce LD plasma profiles similar to CR CD-LD, with higher LD fluctuations.37

INTRODUCTION TO RYTARY

RYTARY (IPX066), an oral formulation of CD-LD that received US Food and Drug Administration (FDA) approval in early 2015, was designed to meet the need for better LD pharmacokinetics (PK) over existing preparations. Each RYTARY capsule contains CD-LD microbeads designed to dissolve at various rates, allowing for release and absorption of LD over a longer timeframe. The CD:LD ratio is 1:4. Summaries of the key clinical trials for RYTARY are provided in the sections below.

Phase 1 research.

A key phase 1 study38 in healthy volunteers assessed the PK of RYTARY vs IR, CR, and CLE formulations using a randomized, single-dose, open-label, crossover design in 24 individuals. The mean plasma concentration of both LD and CD were greater and more sustained with RYTARY than with the other treatments. An initial LD plasma peak occurred at 1 hour, with a median Tmax of 4.5 hours. Unlike the plasma concentrations of the other formulations, which decreased to <10% of peak at 5–7.5 hours, RYTARY plasma concentrations remained above 10% of peak until 10.1 hours (figure 1A). The PK profile for CD was similarly extended (figure 1B). Another study utilized a randomized open-label, crossover design to assess the dose proportionality of 4 doses of RYTARY in 28 subjects. Statistical analysis of the PK parameters demonstrated that the Cmax and AUC0–∞ values for LD and CD increased in an approximately dose-proportional manner over the range of doses studied.39

Figure 1
Figure 1 Mean levodopa and carbidopa plasma concentration profile38

Mean levodopa (A) and carbidopa (B) plasma concentration time profiles following a single dose of 2 capsules of extended-release (ER) carbidopa-levodopa (CD-LD) (total dose 97.5 mg CD–390 mg LD), immediate-release (IR) CD-LD (25–100 mg), controlled-release (CR) CD-LD (25–100 mg), and CD-LD-entacapone (25–100–200 mg) under fasting conditions. Source: Hsu A, et al. J Clin Pharmacol 2015;55:995–1003.

The effects of a high-fat, high-calorie meal, as well as sprinkling the capsule contents on applesauce on the PK of RYTARY, were examined in a randomized, single-dose, open-label, 3-sequence, 3-treatment, crossover study39 in healthy volunteers. Subjects were randomized to receive 2 capsules of RYTARY 61.25–245 mg (CD-LD) 30 minutes after ingestion of an FDA-standardized, high-fat, high-calorie breakfast. They were asked to swallow, without chewing and in a fasted state, 2 tablespoons of applesauce onto which the contents of 2 capsules of RYTARY 61.25–245 mg (CD-LD) had been sprinkled, or were asked to take 2 capsules of RYTARY 61.25–245 mg in a fasted state. No “dose dumping” was noted with the high-fat, high-calorie breakfast; however, the meal increased LD AUC0–∞ by ∼13% and decreased Cmax by ∼21% relative to values in the fasted state. Sprinkling the RYTARY capsule contents on applesauce did not affect the PK of LD compared with the intact capsule.39

Phase 2 research.

A single phase 2 study examined the effects of RYTARY in 27 patients with advanced PD experiencing motor fluctuations while on IR CD-LD therapy.40 Patients were Hoehn & Yahr stages I–IV during “on” time, with a Mini-Mental State Examination score ≥26, and had predictable wearing-off with at least 3 hours of “off” time per day. In this randomized, open-label, crossover study, patients received either RYTARY followed by IR CD-LD or IR CD-LD followed by RYTARY. PK and motor evaluations were performed for 8 hours on day 1 (single-dose evaluation) and for 12 hours on day 8 (multiple-dose evaluation) during each treatment period. Mean daily LD doses were 816.7 mg with IR CD-LD and 2,054.4 mg with RYTARY. Mean daily dosing frequency decreased from 5.4 doses to 3.5 doses during RYTARY treatment, but were unchanged with IR CD-LD.40

LD plasma concentrations reached 50% of Cmax at approximately the same rate; 50% of Cmax was 0.78 hours for RYTARY and 0.76 hours for IR CD-LD (p = 0.90). However, LD plasma concentration was sustained above 50% of Cmax for 4 hours with RYTARY compared with 1.4 hours with IR CD-LD (p < 0.0001). During multiple-dose administration (day 8), RYTARY had a significantly lower fluctuation index (1.5 vs 3.2; p < 0.0001) and Cmax/Cmin ratio (p < 0.0001) compared with IR CD-LD (12.0 vs 82.2). LD bioavailability of RYTARY was 74.5% relative to IR CD-LD (table).40

View this table:
Table

LD PK values (mean ± SD)40

On day 1, motor symptoms improved rapidly for the first 2 hours following both treatments. After 3, 4, 5, and 6 hours, motor disability as measured by Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score was reduced significantly (p < 0.05) more with RYTARY compared with IR CD-LD treatment. Even after 6 hours, 68% of RYTARY-treated patients were reported to be “on” without troublesome dyskinesia compared with 4% following IR CD-LD treatment; the average amount of time spent in the “off” state after RYTARY was significantly less than with IR CD-LD (1.9 vs 4.4 hours; p < 0.0001). The amount of “on” time with troublesome dyskinesia did not significantly differ between the treatment groups.40

After repeated dosing (day 8), Cmax for RYTARY was 30% higher and LD AUC was 87% higher than for IR CD-LD. Walking times (predose and postdose on day 8, p < 0.02), UPDRS part III scores (predose and postdose day 8, p ≤ 0.03), and “on” time without troublesome dyskinesias (p = 0.04) were significantly improved with RYTARY, as well. Patient diaries noted a 2.11-hour improvement in “off” time for RYTARY compared with 0.11 for IR CD-LD (p < 0.0001). “On” time without troublesome dyskinesia was also significantly (p = 0.002) greater for RYTARY (1.38 vs 0.43 hours). There were no serious adverse events (SAEs) and few drug-related adverse events (AEs). Five subjects reported a total of 9 mild or moderate treatment-emergent AEs, approximately equally split between treatment groups.40

The authors concluded that RYTARY was rapidly absorbed and provided more sustained plasma LD concentrations with less fluctuation compared with IR CD-LD. Consistent with its PK profile, RYTARY produced a similar clinical onset and had a longer duration of reduced motor symptoms (less “off” time).40

Phase 3 research.

Five phase 3 studies (1 in early PD, 3 in advanced PD, and 1 open-label extension in both early and advanced PD) examined the safety and efficacy of RYTARY in patients with PD.

A STUDY TO EVALUATE THE SAFETY AND EFFICACY OF IPX066 IN SUBJECTS WITH PARKINSON'S DISEASE (APEX-PD)

APEX-PD was a randomized, double-blind, fixed-dose, placebo-controlled study that examined the safety and efficacy of RYTARY in 381 LD-naive patients with early PD.41 Patients were not to have been exposed to LD for >30 days, or have received LD within 4 weeks of study entry. Treatment with dopamine agonists was also an exclusion criterion. Patients were initiated onto RYTARY using a fixed titration schedule, starting with 95 mg RYTARY 3 times/day (TID). Patients were increased to their randomized RYTARY dose (145 mg TID, 245 TID, or 390 mg TID) over the 4-week titration period. RYTARY or placebo was administered 3 times/day and patients were followed for a total of 30 weeks. The primary efficacy endpoint was the change from baseline at week 30 in the sum of the UPDRS parts II and III.41

All 3 doses of RYTARY significantly (p < 0.0001) improved UPDRS part II + III scores by study end (figure 2).41 Decreases from baseline in UPDRS were also significantly (p < 0.0001) greater at each week for all RYTARY doses relative to placebo. Concordance was seen in the individual parts of the UPDRS (except part IV; p < 0.0001), changes in the 39-item Parkinson's Disease Questionnaire (PDQ-39) total scores (p ≤ 0.034), and the Patient Global Impression of Change (PGI-C) and Clinician Global Impression of Change (CGI-C) scores (p < 0.0001), with all indicating significant improvement for all 3 doses of RYTARY compared with placebo. AEs were reported in 56.3% of 145 mg, 72.1% of 245 mg, 71.4% of 390 mg RYTARY treatment groups compared with 72.8% in the placebo group. The most commonly reported AEs (>5%) across all treatment groups were nausea (15.7%), headache (12.1%), dizziness (11.8%), and insomnia (5.2%). None of the 14 SAEs were attributed to study treatment; the number of patients experiencing SAEs was similar across all treatment groups. Discontinuations due to AEs were higher in the 245- and 390-mg treatment groups.41

Figure 2
Figure 2 Mean (SE) Unified Parkinson's Disease Rating Scale (UPDRS) II + III over 30 weeks41

TID = 3 times daily. Source: Pahwa R, et al. Parkinsonism Relat Disord 2014;20:142–148.

RYTARY at 145, 245, and 390 mg of LD was safe and well-tolerated, as well as effective for improving PD symptoms in LD-naive patients with PD as measured by UPDRS, PDQ-39, and patient and clinician global impressions. The best balance between efficacy and safety among LD-naive patients in this trial was achieved with 145 mg of RYTARY 3 times daily.41

A STUDY TO EVALUATE THE SAFETY AND EFFICACY OF IPX066 IN ADVANCED PARKINSON'S DISEASE (ADVANCE-PD)

The ADVANCE-PD42 study was a randomized, double-blind, parallel-group trial comparing RYTARY to IR CD-LD in patients with advanced PD. Patients were required to have Hoehn & Yahr stage I–IV in the “on” state, Mini-Mental State Examination score ≥26, predictable “off” time, and be on a stable (≥4 weeks) treatment regimen with IR CD-LD. Patients initially underwent a 3-week adjustment period to maximize the treatment response to IR CD-LD, followed by a 6-week RYTARY dose-conversion period; 95.5% (n = 450) completed the 3-week open-label adjustment period and 83.4% (n = 393) completed the 6-week open-label RYTARY dose conversion. The initial dose of RYTARY was based on each patient's total daily dose of IR CD-LD at the end of the IR dose adjustment period. Patients were to start on 3 times/day dosing with RYTARY, but the dose and dose frequency could be adjusted by the investigator, with the intention of reducing “off” time and minimizing adverse effects. After the 6-week dose conversion period, patients were randomly assigned to double-blind treatment with either RYTARY (186 patients completed) or IR CD-LD (183 patients completed) for 13 weeks. Four dose strengths of RYTARY were available for use.42

The 471 patients enrolled in this study had a mean age of 63.2 years, PD duration of 7.4 years, and mean daily “off” time of 5.97 hours.42 The primary efficacy endpoint, “off” time as percent of waking hours, was significantly (p < 0.0001) reduced with RYTARY (1.17 hours greater reduction) compared with the IR formulation by study end. Mean daily IR CD-LD dose was 825.4 mg/d and the mean RYTARY dose was 1,621 mg/d; the mean dosing frequency was 5.2 doses per day for IR CD-LD and 3.6 doses per day for RYTARY. Sixty percent of patients required higher doses of and 16% required lower doses of RYTARY compared to the dose at the start of conversion; the dose ratio of RYTARY to IR CD-LD was 2.05. Mean daily “off” time is shown in figure 3 for the duration of the study. Mean “on” time without troublesome dyskinesia was increased with RYTARY. Mean changes in PGI-C, CGI-C, UPDRS parts II and III, PDQ-39 total score and mobility subscores, modified Rankin Scale, components of the Short Form Health Survey (SF-36), EuroQoL 5-dimension quality of life scale (EQ-5D), and Scales for Outcomes in Parkinson's Disease–Sleep Scale favored RYTARY.42

Figure 3
Figure 3 Mean daily “off” time was significantly (p < 0.0001) reduced with RYTARY42

ANCOVA = analysis of covariance; CD-LD = carbidopa-levodopa; DB = double-blind; EOS = end of study; IR = immediate release; OL = open-label; V = visit. Source: Hauser RA, et al. Lancet Neurol 2013;12:346–356. *p = 0.0004 vs IR CD-LD group, ANCOVA. **p < 0.0001 vs IR CD-LD group, ANCOVA.

During the 13-week double-blind period, 43% and 40% of patients taking RYTARY and IR CD-LD, respectively, reported AEs, mostly insomnia, nausea, falls, dizziness, and dyskinesia. In the RYTARY treatment group, 15 (7%) patients withdrew from the study, compared with 10 (5%) in the IR CD-LD group. Five percent of RYTARY and 3% of IR CD-LD patients reported an SAE. Four patients overall, 3 taking RYTARY and 1 taking IR CD-LD, developed impulse control disorders, none of whom were taking concomitant dopamine agonists.

Overall, ADVANCE-PD showed that patients could be safely switched from standard IR CD-LD to RYTARY with reduced “off” time and improved motor function and quality of life.42

COMPARISON OF IPX066, A NOVEL CARBIDOPA-LEVODOPA EXTENDED-RELEASE FORMULATION, AND CD-LD-ENTACAPONE IN ADVANCED PARKINSON'S DISEASE (ASCEND-PD)

ASCEND-PD43 was a randomized, double-blind, crossover study comparing RYTARY with CLE in patients with advanced PD previously treated with a stable dose of CLE (≥4 times/day dosing frequency) and having mean “off” time ≥2.5 h/d. After screening, there was an open-label, 6-week dose conversion period (from CLE to RYTARY), during which the RYTARY dose and dose frequency could be adjusted to the maximum benefit of the patient. As with the ADVANCE-PD trial,42 the initial RYTARY dose was based on each patient's baseline LD dose (from CLE). Dosing with RYTARY was not to exceed 5 times/day. After dose conversion, patients were randomized and underwent two 2-week crossover treatment periods where they received either active RYTARY with placebo CLE or active CLE with placebo RYTARY, separated by a 1-week open-label RYTARY washout period. Due to the crossover design, all patients were to receive both active treatments, one during each period.43

Eighty-four patients completed both crossover periods. Mean daily LD dosage was 1,723 mg for RYTARY and 652 mg for CLE, which reflects an approximately 22% higher daily LD exposure with RYTARY and accounts for the differences in bioavailability. Patients taking RYTARY received a mean of 3.5 daily doses compared with 4.7 for CLE.43 Thirty-one percent of patients had no change in their daily LD dose, 56% increased, and 13% decreased compared to the dose at the start of conversion.44 Mean percent “off” time during waking hours (based on patient diaries) during the last 3 days of each double-blind treatment period (primary efficacy endpoint) was significantly (p < 0.0001) lower during RYTARY treatment (24.0%) relative to CLE treatment (32.5%; figure 4A).43 Mean “off” time during waking hours per day was significantly (p < 0.0001) lower for RYTARY (3.8 hours) compared with CLE (5.2 hours; figure 4B), with a comparable increase in mean “on” time without troublesome dyskinesia during waking hours per day for RYTARY (11.4 vs 10.0; p < 0.0001; figure 4C). There was no significant increase in “on” time with troublesome dyskinesia during treatment with RYTARY compared to CLE, and no treatment period effect was observed.43

Figure 4
Figure 4 Mean percent “off” time during waking hours, mean “off” time during waking hours/day, and mean “on” time without troublesome dyskinesia during waking hours/day43

(A) Mean percent “off” time during waking hours. (B) Mean “off” time during waking hours/day. (C) Mean “on” time without troublesome dyskinesia during waking hours/day. CLE = carbidopa-levodopa + entacapone. Source: Stocchi F, et al. Parkinsonism Relat Disord 2014;20:1335–1340.

At study end, UPDRS II + III scores in the “on” state were significantly lower with RYTARY (p = 0.023), and patients reported a significant (p = 0.0008) preference for RYTARY (52.4%) vs CLE (27.4%) or no preference (20.2%). The anxiety/depression scale of the EQ-5D, visual-analog scale, and the SF-36 Physical Component Summary score all favored RYTARY over CLE.43

More AEs occurred during the dose conversion period with RYTARY (n = 34) compared with the crossover treatment period with RYTARY (n = 18) or CLE (n = 12) or during the open-label washout period with RYTARY (n = 12). SAEs occurred in 4 RYTARY-treated patients while none occurred with CLE. No SAEs were considered treatment-related. The more common AEs (reported in at least 2 patients) with RYTARY were nausea (7.3%), vomiting (2.7%), fall (2.7%), and upper respiratory tract infections (2.7%) during dose conversion; dyskinesia (4.5%), insomnia (3.4%), and confusional state (3.4%) were reported during double-blind treatment. Only falls were reported in at least 2 patients (n = 2) taking CLE.43

RYTARY was well-tolerated and demonstrated improved symptom reduction (decreased percent “off” time by 34% and increase in “on” time by 1.4 hours) without increasing troublesome dyskinesia compared with CLE in patients with advanced PD. This improvement was achieved with reduced dosing frequency. The findings were clinically meaningful as indicated by the higher percentage of patients showing preference for RYTARY.43

Conversion from CR CD-LD.

One study45 examined the conversion to RYTARY from CR CD-LD, followed by long-term treatment with RYTARY in advanced PD. Patients had been previously treated with CR CD-LD alone or in combination with IR CD-LD. The study design included a 6-week open-label conversion to RYTARY, followed by 6 months (extension 1) of open-label treatment with RYTARY and a possible second 6-month period of open-label RYTARY treatment (extension 2). As with the previously described studies in advanced PD, conversion to RYTARY was based on the total daily dose of LD that patients were taking at study entry. Initial RYTARY dosing was 3 times/daily and the RYTARY dose and dosing schedule could be adjusted with the goal of minimizing “off” time without causing troublesome dyskinesia. The suggested initial total daily LD dose from RYTARY was approximately 2 to 1; RYTARY was generally taken at 4- to 6-hour intervals during the patient's waking day.45

Participants had a mean age of 58.4 years at PD onset and a mean disease duration of 8 years; 65% were Hoehn & Yahr stage I or II and 35% were stage III and IV. Mean years of LD treatment was 6.6. Of the 46 patients screened, 33 completed dose conversion, 25 completed extension 1, and 12 completed extension 2 (of 12 enrolled). For the total period under study, 35 patients (81.4% of the 43 treated patients) reported AEs including urinary tract infection, nausea, anxiety, fall, dyskinesia, viral upper respiratory tract infection, hallucination, orthostatic hypotension, and tremor (each reported by ≥7.0%). Of the 12 patients remaining in the study at completion (58 weeks), 9 reported AEs (1 each anxiety and tremor; 2 each fall, viral upper respiratory tract infection, and orthostatic hypotension).45 AEs during long-term treatment with RYTARY were consistent with that of an older population receiving dopaminergic pharmacotherapy for advanced PD and were similar to those reported previously in patients with advanced PD receiving RYTARY or IR CD-LD.46,47

PGI-C and CGI-C scales were used to determine patient and clinical perception of improvement.45 At the end of initial 6-week dose conversion period, 60.5% (26 of 43) of all enrolled patients and 78.8% (26 of 33) of conversion completers rated themselves as being at least minimally improved. Clinicians gave similar ratings to 67.4% (29 of 43) of all enrolled and 84.8% (28 of 33) of conversion completers. At the end of the extension 1, 68.8% (22 of 32) of all patients enrolled in the extension rated themselves as being at least minimally improved. Clinicians gave such ratings to 75.0% of these patients. More than half of the patients were rated much improved or very much improved by both scales. No significant differences in PDQ-8 mean total score were noted at either time point.45

Of the 33 patients who completed the initial 6-week dose conversion period, 78.8% preferred RYTARY to their previous treatment, 9.1% preferred their previous treatment, and 12.1% had no preference. Of the 25 completers of the first 6-month extension period, 80.0% preferred RYTARY to their previous treatment, 4.0% preferred their previous treatment, and 16.0% had no preference (figure 5). The authors concluded that patients with advanced PD using CR CD-LD, alone or with IR CD-LD, can be safely switched to a stable RYTARY dosing regimen within 6 weeks, with an overall patient and clinician perception of clinical improvement.45

Figure 5
Figure 5 Patient preference of treatment45

Source: Tetrud J, et al. Mov Disord 2014;29:727 (poster).

Integrated safety data analyses from RYTARY clinical trials.

An integrated analysis (N = 978) summarized the AE profile of patients with advanced and early PD treated with RYTARY in phase 2 and 3 trials, which revealed that a greater proportion of patients with advanced PD experienced AEs and withdrew from the studies compared with patients with early PD.48 The most common AEs in patients with early PD were nausea, dizziness, and headache, compared with dyskinesias, nausea, and falls in patients with advanced PD. With the exception of dyskinesias and falls, AEs tended to decrease with duration of RYTARY exposure.48 Another analysis49 compared low- and high-dose groups across 2 studies: ADVANCE-PD42 and ASCEND-PD.43 Dose appeared to affect AE occurrence as well. Dyskinesias were reported more often in high-dose groups, whereas insomnia was reported more frequently in low-dose groups. Dyskinesias, which led to discontinuation, occurred only in the high-dose group.49 Sex (higher rates in females), weight (higher rates in lighter patients),50 and age (greater AE rates in patients ≥75 years of age)51 may also play a role in rate of AE incidence.

Long-term safety and efficacy of RYTARY.

The last study covered in this review52 reported the long-term safety and efficacy of RYTARY in patients with early and advanced PD. The 9-month, open-label extension study enrolled patients with early PD from APEX-PD and patients with advanced PD from ADVANCE-PD and the open-label crossover study comparing RYTARY and IR CD-LD. Patients with early PD were titrated by the investigator to an appropriate RYTARY dose, while patients with advanced PD started with regimens established in the previous studies. Patients' RYTARY dose and dose frequency could be adjusted during the extension study at the investigator's discretion. A total of 617 patients were enrolled and 567 completed the study.52

Patients had a mean age of 64.1 years, with mean PD duration of 2.7 for early and 7.9 years for advanced PD. The majority of patients had a Hoehn & Yahr stage II rating. For patients with early PD, 53.4% experienced at least one AE, most often nausea (5.6%), insomnia (5.6%), headache (3.7%), back pain (3.4%), falls (3.4%), dizziness (3.4%), and tremor (3.0%). Dyskinesia was reported by 1.9% of patients in the early PD group. In the advanced PD group, 210 (60.2%) experienced at least one AE, most often dyskinesia (6.9%), falls (6.6%), pain in the extremity (3.7%), hallucinations (3.4%), arthralgia (3.2%), urinary tract infections (3.2%), and nausea (2.9%).52

Clinical efficacy, as measured by UPDRS II + III scores in patients with early PD, indicated maintenance of improvement in the extension study to month 9 regardless of previous treatment with placebo (24.9) or RYTARY (24.0). In patients with advanced PD, no difference in mean scores was noted between patients previously treated with IR CD-LD (28.1) and RYTARY (28.2) at 9 months. The majority of patients with early PD (83.4%) and patients with advanced PD (80%) were satisfied with RYTARY treatment at 9 months as indicated by PGI ratings. PDQ-39, SF-36, and EQ-5D values were maintained at 9 months.52

Tolerability and efficacy were sustained with extended treatment with RYTARY in this study, both in early and advanced PD. No new safety signals were noted during the extension. In early PD, most patients took RYTARY 3 times/day with a median dose of 720 mg/d equivalent to 500 mg/d of IR LD doses.52 The patients with advanced PD who completed the extension most commonly took RYTARY 3–4 times/day with a median daily dose of 1,450 mg/d.52

DISCUSSION

RYTARY, a formulation of CD-LD containing both immediate-release and extended-release components, has been shown to produce an onset of clinical effect similar to IR CD-LD while prolonging the duration of LD's symptomatic benefits. Plasma LD levels were maintained for up to 6 hours, which resulted in sustained improvements in patients with PD and motor fluctuations.42 Studies included in this review support the use of RYTARY as initial choice of LD therapy, as well as to reduce the “off” time without a significant increase in troublesome dyskinesias in patients with advanced PD.42,–,44

Summary of efficacy and safety findings.

As indicated by measures of clinical improvement, RYTARY led to significant improvement in UPDRS II + III, PGI-C, and CGI-C in patients with early PD compared to placebo.39,51 Among patients with advanced PD, RYTARY resulted in similar improvements in measures of motor disability and global outcomes, along with significantly greater reductions in “off” time and increases in “on” time compared with IR formulations.42,43,53 Patients with advanced PD reported a significant preference for RYTARY over CLE.53 The safety profile of RYTARY is consistent with the known effects of CD-LD in the treatment of PD.53,54 The most frequent AEs noted with RYTARY were nausea, dizziness, dyskinesias, falls, headache, and insomnia,48 which tended to be dose-dependent in patients with PD in low-dose groups.49 AEs, except for dyskinesias and falls, tended to decrease over time45 and were generally consistent between RYTARY and IR CD-LD.54

Summary of PK findings.

PK data from Hsu et al.38 in healthy adults indicated that the profile for RYTARY is substantially different from other LD products such as IR CD-LD, CR CD-LD, and CLE. Following oral dosing, a sustained concentration defined as >50% of Cmax was attained and maintained for 1.9–2.5 hours longer than other CD-LD products. Due to its formulation, RYTARY did not require supplemental IR doses to quickly reach the “on” state. The variability in the LD plasma concentration as measured by the percent coefficient of variation was lower with RYTARY (64.9%) than with IR CD-LD (121.4%), CR CD-LD (101.7%), and CLE (92.4%). Additionally, the slower decline in LD plasma concentration from peak to 6 hours (Cmax/C6 hr), lower dose-normalized LD Cmax values, and smaller deviation from average LD concentration compared with other agents suggests RYTARY could offer more constant LD CNS concentrations. This may result in longer “on” periods without an increase in the incidence of dyskinesias compared with the frequent cycles of “on” and “off” periods seen with the existing IR and CR formulations.

Summary of open-label conversion to RYTARY findings.

The ADVANCE-PD42 and ASCEND-PD43 studies in advanced PD reported that RYTARY significantly decreased “off” time and increased “on” time without troublesome dyskinesia, while a long-term open-label study45 showed conversion to RYTARY from CR CD-LD with or without IR improved PGI-C and CGI-C ratings. Patients preferred RYTARY relative to other LD agents. However, because RYTARY has a substantially different LD plasma profile, changes in LD dose and dosing schedules are required when switching from standard forms of CD-LD to RYTARY. The initial total daily LD dose from RYTARY was approximately 2 to 1; RYTARY was generally taken at 4- to 6-hour intervals during the patient's waking day.42,–,44

Both ADVANCE-PD and ASCEND-PD showed that the majority of patients required a higher daily dose of RYTARY than indicated in the dose conversion.42,43 However, adjusting for bioavailability, the total systemic LD exposure (AUC) was 30%–40% higher with RYTARY than IR CD-LD.40 The median dosing frequency was 3 times/day after conversion compared with 5 times daily before conversion. In Nausieda et al.,44 the only AE with ≥5% incidence was nausea, which was mild or moderate. There were few discontinuations due to AEs. At the end of the studies, 86.4% of patients were successfully and safely converted to a stable RYTARY dosage within a 6-week conversion period.44

Potential role of RYTARY among marketed oral LD formulations.

These clinical results demonstrated that RYTARY produced significant improvements in motor disability as well as activities of daily living and quality of life in early PD vs placebo, and reduced “off” time compared with other LD formulations, while reducing the frequency of dosing, in patients with advanced PD not adequately controlled by other LD formulations. Incidence and prevalence of troublesome dyskinesias remained low in the initial clinical trials41,–,43 and throughout the open-label extension study.52 In early PD, a low dose (145 mg TID) provided the best balance between efficacy and safety in the initial study.41 For patients with advanced PD on IR CD-LD, the majority (>85%) completed the 6-week open-label RYTARY dose conversion,42 suggesting that a similar conversion period may be appropriate in clinical practice. Optimization of therapy can be effectively obtained in patients with PD with motor fluctuations due to RYTARY's rapid onset and prolonged action.

AUTHOR CONTRIBUTIONS

R. Dhall: drafting/revising the manuscript for content, contribution of vital reagents/tools/patents, and acquisition of data. D.L. Kreitzman: drafting/revising the manuscript for content, including medical writing for content, and acquisition of data.

DISCLOSURES

Dr. Dhall has been an investigator in clinical trials sponsored by Impax Laboratories, Inc. and has been a consultant for Impax, Merz, Teva, and Acadia Pharmaceuticals. He has participated on speakers bureaus for Impax, Teva Pharmaceuticals, and UCB. Dr. Kreitzman has been a principal investigator (PI) for several IPX066 trials and has served on one Impax Laboratories, Inc., advisory board, for which he received compensation by the sponsor for these activities. He currently is a PI, and has been so over the past 5 years, for several ongoing clinical trials sponsored by Adamas Pharmaceuticals, Teva Pharmaceuticals, Pharma Two B Ltd., Impax Laboratories, Inc., Neuraltus Pharmaceuticals, Inc., Chelsea Therapeutics, US WorldMeds, LLC, Ipsen Biopharmaceuticals, and ACADIA Pharmaceuticals Inc. In addition, he currently is a speaker and consultant, and has been so over the past 5 years, for several pharmaceutical companies, including Teva Pharmaceuticals, Impax, US WorldMeds, LLC, XenoPort, Boehringer Ingelheim, Novartis, and UCB.

ACKNOWLEDGMENT

Editorial assistance was provided by Maria B. Vinall of The Curry Rockefeller Group, LLC, Tarrytown, NY, and was funded by Impax Laboratories, Inc. All authors contributed substantially to the analysis and interpretation of data and/or the drafting and critical revision of the manuscript. All authors gave final approval for submission.

Footnotes

  • Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • This Neurology® supplement was not peer-reviewed. Information contained in this Neurology supplement represents the opinions of the authors. These opinions are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology.

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