Levodopa/carbidopa intestinal gel

Levodopa/carbidopa intestinal gel (LCIG or Duodopa®) is a new formulation that utilizes a novel delivery system [1–3]. It utilizes a pump to deliver a gel formulation of levodopa/carbidopa via a gastrostomy tube into the duodenum to provide a steady, continuous release of levodopa, thereby reducing motor fluctuations and levodopa-induced dyskinesias (LIDs) [2, 4, 5]. The rationale, design, studies and effectiveness of LCIG are described extensively in Chapter 7 (this volume), so only a brief review of its status in the drug development pipeline will be described here.

Several large multinational clinical trials of LCIG have recently been completed. The use of LCIG is currently approved and in use in over 30 countries outside the USA. Compared with orally administered levodopa, LCIG shows reduced plasma levodopa fluctuations (14 vs 34%) [6]. The stabilization of plasma (and presumably brain levels) appears to correlate with reductions in “off” time and dyskinesias, and provides benefit for quality of life [7].

A 12-week, prospective, multicenter, placebo-controlled, parallel-group, double-blind, double-dummy, double-titration study comparing carbidopa/levodopa immediate release (IR) versus LCIG was recently completed in Germany, New Zealand and the USA [8]. Participants were patients with advanced PD experiencing a minimum of 3h of “off” time per day based on home diaries. In addition, patients were judged to be unsatisfactorily controlled despite optimized medical therapy.

From baseline to 12 weeks, mean “off” time decreased by 4.04h for 35 patients allocated to the LCIG group compared with a decrease of 2.14h for 31 patients allocated to carbidopa/levodopa IR (difference of –1·91h; P = 0·0015). In addition, a significant treatment benefit was seen in secondary efficacy measures including increased “on” time without troublesome dyskinesias (4.11h/day for LCIG vs 2.24h/day for carbidopa/levodopa IR, P = 0.0059) and “on” time without dyskinesias (3.37h/day for LCIG vs 1.09h/day for carbidopa/levodopa IR, P = 0.0142).

Quality-of-life measures using the 39-item Parkinson’s Disease Questionnaire (PDQ-39) were also significantly improved in favor of the LCIG group (–10.9 for LCIG vs –3.9 for carbidopa/levodopa IR, P = 0.0155). Adverse events in this 12-week prospective study frequently involved device complications (92% in the LCIG group vs 85% in the carbidopa/levodopa IR group). Other adverse events included abdominal pain (51% LCIG vs 32% carbidopa/levodopa IR), nausea (30% LCIG vs 21% carbidopa/levodopa IR) and procedural pain (30% LCIG vs 35% carbidopa/levodopa IR).

Side effects of LCIG are frequently related to the surgical procedure and hardware. In a multicenter, retrospective study of LCIG therapy with an average duration of 18 months, the following gastrointestinal/mechanical adverse events were observed: peritonitis, 4.3%; inner tube disconnection and leakage, 20%; inner tube pulled out, 18%; inner tube occlusion, 17%; and inner tube displacement and migration, 21% [1]. Interim results of an open-label study have also shown pain to be an issue. Abdominal pain was seen in 30.7%, and procedural pain was seen in 17.7% [9, 10]. For further details of this investigational approach to delivering levodopa, please refer to Chapter 7 (this volume).

IPX066

IPX066 is a novel, extended-release oral preparation of carbidopa/levodopa. It has been studied extensively for the treatment of PD in both early patients (“levodopa naïve”) as well as more advanced patients on commercially available formulations of levodopa, but with inadequate clinical response due to motor fluctuations. In an open-label study, both carbidopa/levodopa IR and IPX066 provided similar times to “on,” but IPX066 maintained significantly better motor score improvements from 3 to 6h after administration [11].

A phase 3, randomized, double-blind, double-dummy, parallel-group study comparing IPX066 with carbidopa/levodopa IR was performed in North America and Europe [12]. Parkinson’s disease patients were required to have at least 2.5h/day of “off” time in order to qualify for the study. Other inclusion criteria required subjects to be on a stable regimen of carbidopa/levodopa IR for at least 4 weeks prior to screening with a total daily dose of levodopa of at least 400mg along with a dosing frequency of at least four times per day. Patients were allowed to be receiving other agents including dopamine agonists, MAO-B inhibitors, amantadine and anticholinergic medications as long as they were maintained at stable doses of these medications during the study.

The study design required the patients undergo a 3-week open-label carbidopa/levodopa IR dose adjustment. During that time, investigators were allowed to adjust both the dose and the frequency, with the goal of achieving optimum motor function. This dose-adjustment period was followed by a 6-week open-label IPX066 dose conversion and optimization. Following this, patients were randomly allocated to 13 weeks of double-blind, double-dummy treatment with either IPX066 or carbidopa/levodopa IR using the dosage regimens achieved during the open-label optimization periods.

At the end of 22 weeks, the treatment group receiving IPX066 (mean of 3.6 doses per day) experienced 1.17h less “off” time per day compared with the individuals who received carbidopa/levodopa IR (mean of 5.0 doses per day) (P < 0.0001). In addition, “on” time without troublesome dyskinesia was also significantly more increased in the IPX066 group (by 0.93h). Other secondary efficacy measures, including global improvement scores and motor scores, were also significantly more improved with IPX066.

The most common adverse events reported during the study included insomnia, nausea, falls and dizziness, but these were of low frequency, between 1 and 3% for both groups. This study suggests that IPX066 may be considered as a replacement for conventional carbidopa/levodopa in patients with motor fluctuations.

IPX066 was also evaluated in early PD versus placebo in a multicenter, multinational, randomized, double-blind, parallel-group, fixed dose, 30-week study. Eligible subjects were randomized 1:1:1:1 to placebo or one of three different dosages of IPX066. The three doses in the active-treatment arm were 145, 245 or 390mg. Each of these doses was taken three times daily, approximately 6h apart [13]. Participants were required to be levodopa naïve. Some medications, including anticholinergics, amantadine and MAO-B inhibitors, were permitted, but the doses had to be stable for 4 weeks prior to study entry. The doses of these medications also had to remain unchanged throughout the study. A total of 361 patients were enrolled, and 300 patients completed the study.

The primary efficacy measure was a mean improvement in the Unified Parkinson’s Disease Rating Scale (UPDRS) II plus III at 30 weeks compared with baseline. Results demonstrated significant improvement in all three IPX066 treatment arms compared with placebo. The total improvement in the placebo arm was 0.6 points compared with 11.7, 12.9 and 14.9 points for the three IPX066 dosages, respectively. A secondary efficacy measure, the PDQ-39, was also improved for all IPX066 dosages compared with placebo. The most commonly reported adverse events in this study included nausea, headache, dizziness and insomnia. Overall, the 245mg three times daily dosage appeared to provide the best balance between efficacy and adverse events.

This study demonstrated the effectiveness and tolerability of IPX066 in patients with early PD [13]. There is interest as to whether IPX066 might be able to reduce the development of dyskinesias compared with carbidopa/levodopa IR by delivering levodopa in a smoother, more continuous fashion, but this remains to be evaluated in a prospective clinical trial.

XP21279

One of the challenges in the use of levodopa (l-DOPA) as a therapeutic agent in the management of PD is its limited geographical absorption. Levodopa is actively absorbed through amino acid transporters in the duodenum and jejunum, a relatively short segment of the small intestine. XP21279 is a levodopa prodrug that utilizes a nutrient moiety attached to levodopa and, when combined with carbidopa, has been shown to be absorbed throughout the entire gastrointestinal tract. This allows a greater proportion of the levodopa dose to be absorbed over a longer period of time.

A phase 2, randomized, double-blind, double-dummy, crossover study examining the efficacy, safety and pharmacokinetic profile of XP21279/carbidopa versus carbidopa/levodopa IR was performed in patients with PD who were experiencing motor fluctuations. A total of 35 patients were randomized, and 28 patients completed the study. There was an open-label dose, random-ordered optimization phase for carbidopa/levodopa IR and XP21279/carbidopa followed by a double-blind, double-dummy treatment phase in which subjects were on each active treatment for 2 weeks [14].

The primary efficacy measure was change from baseline in total daily “off” time at the end of each double-blinded treatment. The total reduction in “off” time was 2.7h with carbidopa/levodopa IR and 3.0h for XP21279/carbidopa (nonsignificant). However, XP21279/carbidopa was administered three times daily whereas carbidopa/levodopa IR was administered four or five times daily.

A secondary analysis that excluded outliers found that XP21279/carbidopa reduced “off” time by 0.9h more than carbidopa/levodopa IR (P = 0.016). In addition, there was a statistically significant improvement in the change in total “on” time without troublesome dyskinesias in favor of XP21279/carbidopa. Adverse events were mild and were similar between the two treatment arms. Participants at two sites also underwent pharmacokinetic analysis, the results of which demonstrated a significant reduction in the variability of levodopa concentrations with XP21279/carbidopa compared with carbidopa/levodopa IR [14]. These results suggest that XP21279/carbidopa may be a potential option for the management of advanced PD with motor fluctuations, but phase 3 studies are required.

Other levodopa formulations

Several additional novel methods of delivering levodopa are in development, including an accordion pill, a gastric-retentive pill and an intrapulmonary formulation for inhalation of levodopa. Phase 2 studies of all these agents have been published in abstract form.

Accordion Pill^TM (AP) carbidopa/levodopa incorporates a unique gastroretentive formulation to provide stable levodopa plasma levels analogous to those seen with LCIG. A phase II, multicenter, open-label, two-way randomized crossover, multiple-dose study with active control groups was completed in PD patients with motor fluctuations [15]. Twice daily administration of AP carbidopa-levodopa provided therapeutic plasma levels of levodopa. A total of 18 patients completed the study according to the protocol. In these patients, a statistically significant reduction in total daily “off” time was recorded using home diaries, from an average of 5.1h/day to 2.8h/day with AP carbidopa/levodopa (P < 0.0001). Adverse events were reported as “mild.”

A gastroretentive formulation, DM-1992, administered twice daily, was studied in comparison with carbidopa/levodopa IR given three to eight times daily (median of times per day) in an open-label, randomized, crossover design study involving 34 patients with PD [16, 17]. At baseline, patients recorded an average of 5.5h of “off” time per day. During the treatment phase, DM-1992 demonstrated a statistically significant reduction in “off” time of 0.9h/day compared with an increase of 0.1h/day of “off” time in the carbidopa/levodopa IR group (P = 0.047).

Pharmacokinetic studies on the final day using DM-1992 administered once daily compared with carbidopa/levodopa IR given multiple times per day demonstrated similar levodopa C_max and area-under-the-curve values. In addition, the ratio of C_max/C_min was significantly lower in the DM-1992 once daily group, consistent with a more stable levodopa plasma concentration. Adverse events were reported in 35% of the patients in the DM-1992 group compared with 14.7% in the carbidopa/levodopa IR group, although no consistent pattern of adverse events was demonstrated and most adverse events were reported as mild.

Finally, a novel method of administering levodopa has been developed as a “bridging” therapy. CVT-301 is an inhaled formulation of levodopa administered as a fine-particle dose (FPD). A double-blind, placebo-controlled, crossover study of CVT-301 was performed in 24 patients experiencing more than 2h/day of “off” time [18]. Patients were maintained on their usual doses of carbidopa/levodopa and the study drug versus placebo was administered approximately 4–5h after their first morning dose of carbidopa/levodopa. While two doses of CVT-301 (25 and 50mg of FPD) were studied in comparison with placebo, only the 50mg FPD resulted in statistically significant improvements in motor performance compared with placebo. However, these changes were seen within 5 min post-dose, suggestive of rapid increases in plasma and brain levodopa levels. There were no serious adverse events and no discontinuations. In addition, there were no changes in spirometry measures compared with baseline in either of the two CVT-301 dosages.

Istradefylline

Istradefylline (KW-6002) is the most extensively studied A_2a antagonist and is currently approved in Japan as an adjunct to levodopa. The complete history of this compound’s development was documented in a review published in 2013 [23]. Istradefylline consistently and significantly reduced “off” time in a series of exploratory and phase 2 studies in patients experiencing motor fluctuations on levodopa [24–26]. These were then followed by two large phase 3 studies that yielded mixed results [27, 28].

The KW-6002-US-013 study was a phase 3, 12-week, multicenter, placebo-controlled, double-blind, randomized study of istradefylline 20mg/day compared with placebo as an adjunct to levodopa in PD patients with motor fluctuations. Patients were required to be experiencing at least 3h of daily “off” time per day as documented in home diaries [27]. A total of 231 participants were randomized 1:1 to the addition of istradefylline or placebo. Total daily “off” time was reduced by 0.7h more in the istradefylline group compared with the placebo group (P = 0.03). Common reported adverse events included dyskinesias (istradefylline vs placebo: 22.6 vs 12.2%), light-headedness (7.8 vs 3.5%), decreased weight (6.1 vs 2.6%) and constipation (5.2 vs 0.9%). Overall, istradefylline provided a small but significant reduction in “off” time and was generally well tolerated.

The KW-6002-US-018 study was a phase 3, 12-week, North American, multicenter, placebo-controlled, double-blind, paralle-group, randomized study examining the efficacy of istradefylline 10, 20 and 40mg/day compared with placebo in patients with PD treated with levodopa and experiencing motor complications. A total of 610 patients were randomized 1:1:1:1 to the addition of placebo or one of the three different dosages of istradefylline [28]. Patients were required to be taking at least three doses/day of levodopa but were allowed to be receiving other adjunctive therapies including dopamine agonists, MAO-B inhibitors, COMT inhibitors and amantadine. The results demonstrated no statistically significant change from baseline to the end of the study in the primary efficacy measure of percentage of awake time per day spent in the “off” state. However, some of the secondary efficacy measures were significantly improved in favor of istradefylline, including UPDRS motor scores in the highest dose group, and the 36-Item Short Form Health Survey (SF-36) mental component score in the two highest dose groups. The most common reported adverse events (istradefylline 40mg vs placebo) included dyskinesia (26.3 vs 19.2%), headache (7.2 vs 4.2%) and light-headedness (7.2 vs 3.3%).

One possible explanation for the failure of istradefylline to demonstrate a significant difference in reduction in “off” time compared with placebo included a higher-than-average placebo effect. One factor that may have contributed to a large placebo effect was the relatively high number of active-treatment arms [3] and the relatively low likelihood of a patient being randomized to placebo (25%) [28].

Despite this result, a subsequent Japanese phase 3 study found a reduction in “off” time compared with placebo of 0.65h with istradefylline 20mg/day (P = 0.013) and 0.92h with 40mg/day (P < 0.001), and istradefylline was approved for the management of motor fluctuations in Japan in March 2013 [23].