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Drug Safety Evaluation
1.
Introduction
2.
Chemistry, pharmacokinetics and pharmacodynamics
3.
Clinical efficacy
4.
Safety in clinical studies
5.
Safety in special populations
6.
Drug interactions with IPX066
7.
Conclusion
8.
Expert opinion
Safety of IPX066, an extended release carbidopa--levodopa formulation, for the treatment of Parkinson’s disease Meir Kestenbaum & Stanley Fahn† †
Columbia University, College of Physicians and Surgeons, Columbia University Medical Center, Center for Parkinson’ s Disease and Other Movement Disorders, Department of Neurology, New York, NY, USA
Introduction: Levodopa (LD) is the most effective treatment for Parkinson’s disease (PD). However, chronic use of LD commonly results in the development of motor complications, including wearing off and dyskinesia. The presumption that the short serum half-life of LD is associated with the development of motor complications has raised the need to develop treatments with increased durations of stable LD concentrations. Areas covered: We conducted a PubMed search for IPX066 articles and also reviewed abstracts from meetings that included this topic. IPX066 is a newly developed formulation of extended release carbidopa--LD (CD--LD) with a one to four ratio of CD to LD, that was approved by the FDA in January 2015 for the treatment of PD, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide or manganese intoxication. It will be marketed by the trade name Rytary. A Phase III clinical trial showed that IPX066 is efficacious in improving motor symptoms in early PD patients. In advanced PD patients with motor fluctuations, IPX066 reduced off time and increased on time without troublesome dyskinesia compared to CD--LD immediate release and CD--LD with entacapone. IPX066 had an acceptable safety profile. Adverse events of IPX066 from the different trials are presented. Expert opinion: IPX066 will probably have a role in the treatment of advanced PD with motor fluctuations. IPX066 could also be used initially when LD therapy is prescribed, but the question of whether this usage could reduce or prevent the development of motor complications is yet to be answered. Keywords: carbidopa--levodopa extended release, drug safety, IPX066, motor complications, Parkinson’s disease Expert Opin. Drug Saf. (2015) 14(5):761-767
1.
Introduction
Parkinson’s disease (PD) is a common neurodegenerative disease. Initially, PD had been viewed predominantly as a motor disorder. The cardinal early motor features of rigidity, bradykinesia and rest tremor mainly result from loss of dopaminergic nigrostriatal neurons, and these features can respond to levodopa (LD) therapy. Later in the disease, other motor symptoms develop, such as flexed posture, loss of postural reflexes and freezing of gait that do not respond well to LD, and thus are thought not to be related to loss of dopamine. Today, it is also recognized that PD is associated with many non-motor symptoms, including cognitive impairment, psychiatric disorders and autonomic dysfunction. These reflect involvement of the CNS beyond the nigrostriatal dopamine system.
10.1517/14740338.2015.1015986 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure
IPX066 -- Rytary III Parkinson’s disease Carbidopa--levodopa Oral O HO HO
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Pivotal trial(s)
OH NH2
[20-23]
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
So far, no treatment has been shown to cure PD and none has been approved for slowing the progression of the disease [1]. The early PD motor symptoms respond to dopamine-replacement therapy via its precursor LD. LD is combined with a peripheral DOPA decarboxylase inhibitor such as carbidopa (CD) or benserazide, to reduce nausea and vomiting due to peripheral metabolism of LD to dopamine and to increase its central bioavailability. LD is the most effective symptomatic treatment for PD. However, chronic use of LD commonly results in the development of motor complications, mainly wearing off and dyskinesia. Wearing off is defined as recurrence of motor and non-motor symptoms that precede scheduled doses of antiparkinsonian medication and usually improves after those doses are administered. Dyskinesia are involuntary movements, typically chorea and sometimes dystonia, which are twisting and more sustained movements and postures. Dyskinesias most commonly occur when LD-derived dopamine is peaking in the brain. Although classically considered late complications of LD therapy, wearing off and dyskinesias have been shown to emerge even after several months of treatment with CD--LD immediate release (CD--LD IR) [2]. The pathophysiology of wearing off and dyskinesia is complex, but appear to be linked to the short plasma half-life of LD, and is thought to be caused at least to some extent by nonphysiologic fluctuations in brain dopamine concentrations [3]. When LD is administered alone, it has a half-life of ~ 60 min, which reaches 90 min when administered as CD--LD IR [4]. Patients with relatively early PD have good response of motor symptoms to LD despite the short halflife. It is presumed that LD is taken up by dopaminergic and serotonergic neurons, decarboxylated to dopamine, stored intraneuronally and slowly released into the synapse [5]. With time, as dopaminergic neurons degenerate, storage and release of dopamine are impaired and patients experience a clinical response that mirrors peripheral pharmacokinetics of LD. The association of LD’s short half-life to wearing off has raised the need to develop treatments with increased durations 762
of stable LD concentrations. A longer acting LD formulation is expected to reduce the appearance of end of dose wearing off. Development of treatments with longer stable LD concentrations will hopefully reduce the development of dyskinesias as well. Over the years, numerous approaches have been tried with partial efficiency and significant shortcomings. Controlled release CD--LD formulations (also called extended release, CD--LD ER) have been shown to provide more sustained LD levels than CD--LD IR. However, this formulation has drawbacks because of the slower and less complete absorption rate, delayed time to clinical benefit compared with CD--LD IR and less consistent clinical response [6]. In addition, the hypothesis that controlled release CD--LD will be associated with a reduction in the development of motor complications has not been supported by studies [7]. Additional methods of prolonging the plasma half-life of LD include the administration of a catechol-O-methyltransferase (COMT) inhibitor, such as entacapone, to CD--LD. Entacapone acts mainly by blocking the peripheral metabolism of LD to 3-O-methyldopa by the enzyme COMT. Several studies reported that entacapone increases on time and reduces off time [8-10]. However, a recent evidence-based review reported that treatment with entacapone has been shown to be nonefficacious in preventing dyskinesia and motor fluctuations in PD subjects [1]. Co-administration of CD--LD with monoamine oxidase type B (MAO-B) inhibitors, such as rasagiline, prolongs the effect of dopamine by blocking the conversion of LD into 3,4-dihydroxyphenylacetic acid, and has been shown to reduce off times in PD patients [11,12]. Administration of dopamine agonists, including pramipexole, ropinirole, intermittent subcutaneous injections or continuous infusions of apomorphine have also been shown to reduce off times in PD patients [13-16]. Another method of prolonging LD levels and minimizing wearing off is continuous intrajejunal infusion of LD. This treatment is associated with reduced off times and dyskinesias [17]. However, this technique is invasive, requiring percutaneous endoscopic gastrostomy and has attendant surgical and postsurgical complications. Besides, there can be mechanical problems related to the pump and tube. Vitamin deficiency and polyneuropathies are other drawbacks [18]. The shortcomings of the treatments mentioned above are the basis for the genuine need for the development of a new increased duration LD treatment. An ideal LD formulation would reliably provide an initial rapid increase in LD plasma concentration, maintain clinically effective LD concentration for an extended duration, improve motor symptoms, reduce the frequency of motor complications, have an easy method of delivery, reduce the daily frequency of dosing and have a favorable adverse events (AEs) profile. IPX066 (Box 1) has been approved in January 2015 by the FDA for the treatment of all stages of PD; the drug will be marketed as Rytary.
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IPX066
Table 1. Summary of findings in CD--LD IR versus IPX066 study in advanced Parkinson’s disease with motor fluctuations.
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CD--LD IR
IPX066
Number of doses a day 5.00 3.60 Off time (h) -1.01 -2.18 On time without troublesome 0.80 1.88 dyskinesia (h) Adverse events during double blind maintenance period Insomnia 1% 3% Nausea 2% 3% Falls 2% 3% Dizziness 2% 1% Dyskinesia 2% 1%
3.
CD--LD IR: Carbidopa--levodopa immediate release.
Table 2. Summary of findings in CL + E versus IPX066 study in advanced Parkinson’s disease with motor fluctuations. CL + E
plasma LD concentrations increased at a similar rate. Time to reach 50% of peak LD concentration was 0.78 h for IPX066 compared to 0.76 h for CD--LD IR, but the duration of time with > 50% of maximal level was 4 h with IPX066 compared to only 1.4 h with CD--LD IR. Relative bioavailability of IPX066 was 74.5% of CD--LD IR. Following multiple doses (on day 8 of dosing), IPX066 showed lower variability of LD plasma concentrations despite a lower daily dosing frequency of a mean of 3.5 doses compared to 5.4 of CD--LD IR. In this study, the total LD exposure during IPX066 treatment was ~ 87% higher and the increase in LD peak concentration was 30% higher compared to CD--LD IR [22].
IPX066
Number of doses a day 5.00 3.00 Off time (h) -0.7 -2.10 On time without troublesome 0.2 1.40 dyskinesia (h) Adverse events during double blind maintenance period Insomnia 0 3.4% Nausea 0 1.1% Falls 2.3% 1.1% Dyskinesia 0 4.5% Confusional state 0 3.4% CL + E: Carbidopa--levodopa plus entacapone.
Chemistry, pharmacokinetics and pharmacodynamics
2.
IPX066 (Impax Pharmaceuticals, Inc., Hayward, CA, USA) is a newly developed formulation of combined immediate and ER CD--LD with a one to four ratio of CD to LD [19]. Each capsule consists of small beads containing CD--LD that dissolve at different rates. In clinical trials, the dose of CD per pill was 23.75, 36.25, 48.75, 61.25 and 97.5 mg, and the total LD dose per pill was 95, 145, 195, 245 and 390 mg, respectively [20,21]. These doses were selected to avoid confusion with the currently available CD--LD ER (the same generic name of Rytary). The pharmacokinetics of IPX066 were evaluated in a randomized, open-label, multicenter, crossover study that compared IPX066 and CD--LD IR in 27 subjects with advanced PD who were experiencing motor fluctuations while on LD therapy [22]. Subjects were randomized to treatment with CD--LD IR for 8 days followed by treatment with IPX066 for 8 days or the reverse order. Following administration of a single dose of IPX066 or CD--LD IR, peak
Clinical efficacy
Several large Phase III trials have elaborated IPX066’s efficacy in both early PD patients starting LD and in advanced PD patients with motor fluctuations. The ADVANCE-PD trial was a Phase III, randomized, double-blind, double-dummy study at 68 centers in North America and Europe that compared IPX066 to CD--LD IR in patients with advanced PD who had at least 2.5 h per day of off-time. Patients first underwent 3 weeks of open-label CD--LD IR dose adjustment followed by 6 weeks of open-label IPX066 dose conversion. Three-hundred-ninety-three patients were then randomized to 13 weeks of double-blind treatment of IPX066 or CD--LD IR. IPX066 reduced daily off time by an average of an extra 1.17 h compared with CD--LD IR with less daily doses, a mean of 3.6 versus 5, respectively. Mean on time without troublesome dyskinesia was increased by an average of extra 1.08 h in the IPX066 group compared to CD--LD IR, with a mild increase of on time with troublesome dyskinesia that did not differ between the groups (extra 0.05 h with IPX066). Mean Unified PD Rating Scale (UPDRS) parts II and III scores, PD Questionnaire (PDQ-39) (quality-of-life scale) and modified Rankin score were significantly better on IPX066 (Table 1) [21]. A recently published Phase III, randomized, double-blind, double-dummy, crossover study assessed the efficacy and safety of IPX066 versus CD--LD plus entacapone (CL + E) in advanced PD patients with a mean off time > 2.5 h a day, who had been taking CL + E or CD--LD--entacapone (CLE) combination tablets. This 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 (IPX066 and placebo CL + E or CL + E and placebo IPX066) separated by 1 week open-label IPX066 treatment. Ninety-one patients were randomized to the two treatment groups. Compared with CL + E treatment, IPX066 resulted in a mean of 1.4 h less daily off time and 1.4 h more daily on time without troublesome dyskinesia (both had p < 0.0001), without a difference in the mean on time with troublesome dyskinesia and fewer daily doses (median values of 3 vs 5) (Table 2) [23].
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Table 3. Summary of findings in IPX066 versus placebo study in early Parkinson’s disease. Placebo IPX066 IPX066 IPX066 145 mg t.i.d 245 mg t.i.d 390 mg t.i.d UPDRS II 0.2 UPDRS III -0.7 Adverse events Nausea 8.7% Headache 10.9% Dizziness 5.4% Insomnia 3.3%
-2.8 -8.9
-3.1 -9.8
-3.9 -11.0
13.8% 6.9% 9.2% 2.3%
19.2% 12.5% 19.2% 8.7%
15.7% 12.1% 11.8% 5.2%
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t.i.d: Three times daily; UPDRS: Unified PD rating scale.
IPX066 efficacy was also studied in early PD patients. A multicenter, randomized, double-blind, parallel-group, fixed-dose, placebo-controlled, 30-week study was recently published. Three hundred and eighty-one LD naı¨ve PD patients were assigned to placebo or IPX066 containing 145, 245 or 390 mg of LD administered 3 times daily (t.i.d). The primary efficacy measure was change from baseline in UPDRS activities of daily living (part II) and motor scores (part III). Secondary outcomes included patient and clinical global impressions and the PDQ-39. All three IPX066 dosages were superior to placebo, with mean improvement in UPDRS part II + III compared to baseline of 11.7, 12.9 and 14.9 points with higher doses of IPX066 associated with greater improvement in UPDRS compared to 0.6 points improvement in the placebo group. The total PDQ-39, patient and clinical global impressions were improved in each of the three active treatments groups compared to placebo (Table 3) [20]. A Phase II, open-label, crossover study of 27 advanced PD patients who were randomized to 8 days of treatment with either CD--LD IR followed by IPX066 or IPX066 followed by CD--LD IR showed that according to subjects diary results IPX066 was associated on average with 2 h of reduced off time (p < 0.0001) and 1.81 h more on time (p = 0.002) compared to CD--LD IR [22]. 4.
Safety in clinical studies
The AEs profile of CD--LD IR and controlled release CD--LD are well known, the most frequent being nausea, dizziness, abdominal pain and dyskinesia [7]. Since IPX066 is an ER CD--LD, the AE profile is expected to be similar. The Phase III and Phase II studies have provided the following data regarding the AEs of IPX066. In the placebo-controlled trial of early PD patients who were randomized to placebo versus three fixed doses of IPX066 (145, 245 or 390 mg t.i.d), 68.5% of the 381 patients evaluated experienced AEs. Surprisingly the overall AE rate in the 145 mg t.i.d group (56.3%) was notably lower than the placebo group (72.8%) and the 245 mg t.i.d (72.1%) and 764
390 mg t.i.d (71.4%) groups [20]. In general, the group treated with 145 mg t.i.d of IPX066 had the best AE profile and the frequency of AEs increased with increased IPX066 dose, clustering in the two higher dose groups of IPX066. The most common AEs were nausea, affecting 8.7% of placebo group, 13.8% in the 145 mg t.i.d group and reaching 20.4% in the 390 mg t.i.d group. Headache was reported in 10.9% of placebo group, only 6.9% in the 145 mg t.i.d group and 17.3% in the group treated with IPX066 390 mg t.i.d. Dizziness was reported almost twice as much in the IPX066 group treated with 145 mg t.i.d compared to placebo (9.2 vs 5.4%, respectively) with highest frequency reported in the intermediate dose of 245 mg t.i.d (19.2%). Insomnia was reported in 3.3% in the placebo group and reached as high as 8.7% in the intermediate dose treated with 245 mg t.i.d. All other AEs were not common and appeared in < 5% of treated patients. Fourteen serious AEs appeared during the study period. None of them were attributed to the study treatment and the numbers of patients experiencing serious AEs were similar across all treatment groups. Overall 39 (10.2%) of patients experienced AEs that contributed to early discontinuation of treatment, with a proportion of ~ 5% in the placebo and low-dose groups compared to ~ 15% in the groups treated with intermediate and high-dose IPX066. The most common AEs leading to early discontinuation were nausea, dizziness, vomiting, diarrhea and dyskinesia. In an open-label 9-month extension of this trial published as an abstract at the American Academy of Neurology (AAN) meeting in 2013 [24], 300 eligible patients were enrolled for treatment with IPX066. Safety and clinical utility were assessed at 1, 5 and 9 months. During the extension period, the most commonly reported AEs were nausea and insomnia (5.6% each), hypertension (4.1%) and headache (3.7% of patients). In the Phase III trial that compared IPX066 with CD--LD IR in advanced PD patients [21], during the 6 weeks of openlabel IPX066 dose conversion 206 (46%) of 450 patients reported AEs, the most common were dyskinesia (6%), nausea (5%), headache (4%) and dizziness (4%). Twenty-three patients (5%) discontinued treatment early because of AEs in this phase of the study. Fourteen patients (3%) had 22 serious AEs, including two deaths, one due to renal failure and the other had sudden death. Six of the serious side effects were regarded as related to IPX066. Two patients had gait disturbance, two had dyskinesia and the others had overdose (one patient) and acute psychosis (one patient). In the 13-week double-blind treatment period 43% of patients on IPX066 compared to 40% on CD--LD IR reported AEs. Overall, a similar number of patients in the two treatment groups reported AEs (87 in the IPX066 group compared to 76 in the CD--LD IR group), with three cases (1.5%) of early termination due to AEs in each group. The most common AEs in the IPX066 group were insomnia (3%), nausea (3%), falls (3%), dizziness (2%) and dyskinesia (2%). The other AEs were reported by up to 2% of the group. Eleven patients
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IPX066
(5%) in the IPX066 group reported 13 serious AEs. No specific serious AE was reported by more than one patient. One patient had anxiety and psychosis that were regarded as related to treatment with IPX066. In the CD--LD IR group, five patients (3%) reported eight serious AEs. It should be mentioned that three patients from the IPX066 group had impulse control symptoms (two patients had compulsive sexual behavior and one had gambling) assessed by the modified Minnesota impulsive disorders interview. One patient in the CD--LD IR group developed impulse control symptoms (excessive shopping). None of these four patients were taking concomitant dopamine agonists. The design of the Phase III trial comparing IPX066 with CL + E in advanced PD patients [23] included a 6-week conversion period from CL + E or CLE to IPX066 in which 30.9% of patients reported AEs. The most common AEs were nausea (7.3%), vomiting, falls and upper respiratory tract infections (2.7% each). During the double-blind treatment period (two 2-week periods), 20.2% of patients reported AEs on IPX066 compared to 13.6% on CL + E. The most common AEs during this period were dyskinesia (4.5%), insomnia and confusion (3.4% each) on IPX066, and falls, which appeared in 2.3% of patients on CL + E. During the open-label 1-week IPX066 treatment 13.5% of patients reported AEs that were not described in the paper. Overall, four patients reported a total of six serious AEs that included hypercalcemia, atrial fibrillation, constipation, chemical gastroenteritis, sciatica and dehydration. None of these were considered treatment-related AEs. One patient discontinued participation due to AEs that included dyspepsia, nausea and vomiting and one patient due to dyskinesia. No serious AEs were reported with the use of CL + E. Another abstract presented at the AAN in 2013 reported that 349 advanced PD patients who completed Phase II or III studies and exposed to IPX066 from 1 to 19 weeks were enrolled in a 9-month open-label extension trial treated with a median dose of 1450 mg IPX066 a day. During the extension period, the most frequently reported AEs were dyskinesia (6.9%), falls (6.6%), pain in extremities (3.7%) and hallucinations (3.4%) [25]. In the Phase II crossover trial of 27 advanced PD patients there were no serious AEs. Five subjects reported a total of nine mild or moderate AEs, none of which appeared in more than one subject [22]. 5.
Safety in special populations
Data regarding safety of IPX in special populations have been published. Two abstracts presented at the Movement Disorders Society Congress in 2013 reported higher frequency of at least one AEs in patients treated with IPX066 in females compared to males (63.3 vs 53.9%, respectively) [26], and in lighter weight patients (< 75 kg) compared to heavier patients (61.3 compared to 55.5%, respectively) [27]. Another abstract presented at the World Parkinson Congress in 2013 reported
higher frequency of at least one AE with IPX066 in patients older than 75 compared with patients younger than 65 (65 vs 54%, respectively) [28]. Differences in LD pharmacokinetics have been described with regard to gender. Women have been shown to require lower LD doses compared to men [29,30]. Whether these differences apply with regard to IPX066 is not known. 6.
Drug interactions with IPX066
No data has been published so far regarding potential drug interactions with IPX066. Drug interactions with IPX066 are expected to resemble drug interactions of LD [4]. 7.
Conclusion
IPX066 is an experimental newly developed formulation of ER CD--LD with a one to four ratio of CD to LD that was approved by FDA in January 2015 for the treatment of PD. Published Phase II and III studies shows that IPX066 improved UPDRS scores compared to placebo in early PD patients and reduced wearing off in advanced PD patients. It also has the advantage of a lower frequency of daily doses compared to CD--LD IR, and is on average taken 3 -- 4 times a day. Overall, IPX066 treatment was well tolerated and the frequency of AEs was similar to those of CD--LD IR. The most common AEs were nausea, dizziness, headache, falls, insomnia and dyskinesia. There is insufficient data regarding potential drug interactions but it is expected to be similar to those of LD. 8.
Expert opinion
IPX066 is a mixed formulation of immediate and ER CD--LD that was approved by FDA in January 2015 for the treatment of PD. IPX066 has an improved pharmacokinetic profile compared to CD--LD IR resulting in a similar initial absorption rate with more sustained plasma LD concentration. This pharmacokinetic advantage seems to result in an improved clinical response in advanced PD patients with motor fluctuations allowing motor improvements with less daily treatment doses. Reduction in the frequency of doses in advanced PD patients is important for patients’ convenience and has the potential to increase adherence to the recommended treatment schedule [31]. Studies comparing treatment with IPX066 to CD--LD IR or CL + E in advanced PD patients show that on average the added reduction in off times and increased on time without troublesome dyskinesia reached ~ 1.3 h/day. This additional reduction of ~ 25% of daily off time that PD patients experience has clinical significance and is reflected in the improved PDQ-39 total scores and could contribute to improvement in patients’ quality of life. Overall, treatment with IPX066 had good tolerability, and AEs profile was similar to those seen with CD--LD IR.
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It seems that IPX066 will have a role in the treatment of advanced PD patients with motor fluctuations. IPX066 does not solve the problem of motor complications but could help in reducing their severity. It is not surprising that IPX066, which has a LD component, showed improved UPDRS scores compared to placebo, as the effect of LD on motor symptoms of PD has been known for decades. The most important question that is yet to be answered is whether early treatment with IPX066, due to its sustained LD plasma concentration, could reduce and hopefully even eliminate the appearance of wearing off motor fluctuations and dyskinesia. A prospective, long-term study comparing treatment with CD--LD IR to IPX066 in early PD patients is needed to answer this question. If early treatment with IPX066 would be found to reduce development of motor complications, then IPX066 will cause a breakthrough in the management of PD, reducing the need for more expensive and invasive treatments of motor complications, for example, deep brain stimulation, continuous LD intestinal infusion and apomorphine continuous subcutaneous infusion. It would be interesting to see if combining IPX066 with other treatments such as COMT inhibitors such as entacapone or MAO inhibitors will have an additive value, causing Bibliography
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Declaration of interest S Fahn has received consulting or advisory board honoraria from Merz Pharma, PixarBio and Lundbeck. He has received Genervon Biotechnology and the Smart Family Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005;62(2):241-8
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Pahwa R, Stacy MA, Factor SA, et al. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Neurology 2007;68(14):1108-15 Olanow CW, Kieburtz K, Odin P, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol 2014;13(2):141-9 Jost WH. Unwanted effects and interaction of intrajejunal levodopa/ carbidopa administration. Expert Opin Drug Saf 2014;13(4):447-58 Ondo W. IPX066, a mixed immediate/ sustained-release levodopa preparation for Parkinson’s disease. Expert Opin Pharmacother 2014;15(14):2081-5 Pahwa R, Lyons KE, Hauser RA, et al. Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson’s disease. Parkinsonism Relat Disord 2014;20(2):142-8 Phase III study showing greater efficacy of IPX066 over placebo in early Parkinson’s disease. Hauser RA, Hsu A, Kell S, et al. Extended-release carbidopa-levodopa (IPX066) compared with immediaterelease carbidopa-levodopa in patients with Parkinson’s disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurol 2013;12(4):346-56 Phase III trial showing reduced off time and increased on time without troubling dyskinesia with
carbidopa-levodopa capsules. Mov Disord 2013;28(Suppl 1):P410
IPX066 compared to immediate release (IR) carbidopa--levodopa (CD--LD). 22.
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23.
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Hauser RA, Ellenbogen AL, Metman LV, et al. Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson’s disease. Mov Disord 2011;26(12):2246-52 Phase II trial demonstrating drug pharmacokinetics. Stocchi F, Hsu A, Khanna S, et al. Comparison of IPX066 with carbidopalevodopa plus entacapone in advanced PD patients. Parkinsonism Relat Disord 2014;20(12):1335-40 Phase III trial showing reduced off time and increased on time without troubling dyskinesia with IPX066 compared to IR CD-LD plus entacapone.
24.
Nausieda P, Rudzinska M, Kell S, et al. IPX066 Extended-release carbidopalevodopa capsules in patients with early Parkinson’s disease. AAN 2013;80:P01.064
25.
Ellenbogen A, Nauseida P, Pourcher E, et al. Long-term safety of IPX066 extended-release carbidopa-levodopa capsules in patients with motor fluctuations in advanced Parkinson’s disease. AAN 2013;80:P01.065
26.
Kell S, O’Connell M, Hsu D, et al. The effects of gender on adverse event reporting in Parkinson’s disease patients treated with IPX066 extended-release carbidopa-levodopa capsules. Mov Disord 2013;28(Suppl 1):P414
27.
Kell S, O’Connell M, Hsu D, et al. The effects of weight on adverse event reporting in Parkinson’s disease patients treated with IPX066 extended-release
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Kell S, O’Connell M, Hsu D, et al. The effects of age on adverse event reporting in Parkinson’s disease patients treated with IPX066 extended-release carbidopalevodopa capsules. J Parkinson’s Dis 2013;3(Suppl 1):P12.18
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Kompoliti K, Adler CH, Raman R, et al. Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics. Neurology 2002;58(9):1418-22
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Nyholm D, Karlsson E, Lundberg M, Askmark H. Large differences in levodopa dose requirement in Parkinson’s disease: men use higher doses than women. Euro J Neurol 2010;17(2):260-6
31.
Laliberte F, Bookhart BK, Nelson WW, et al. Impact of once-daily versus twice-daily dosing frequency on adherence to chronic medications among patients with venous thromboembolism. Patient 2013;6(3):213-24
Affiliation
Meir Kestenbaum1 MD & Stanley Fahn†2 MD † Author for correspondence 1 Movement Disorders Fellow, Columbia University, College of Physicians and Surgeons, Columbia University Medical Center, Department of Neurology, New York, NY, USA 2 Director Emeritus, Columbia University, College of Physicians and Surgeons, Columbia University Medical Center, Center for Parkinson’s Disease and Other Movement Disorders, Department of Neurology, 710 west 168 street, New York, NY, USA Tel: +1 212 305 3716; Fax: +1 212 305 3530; E-mail: [email protected]
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Drug Safety Evaluation
1.
Introduction
2.
Chemistry, pharmacokinetics and pharmacodynamics
3.
Clinical efficacy
4.
Safety in clinical studies
5.
Safety in special populations
6.
Drug interactions with IPX066
7.
Conclusion
8.
Expert opinion
Safety of IPX066, an extended release carbidopa--levodopa formulation, for the treatment of Parkinson’s disease Meir Kestenbaum & Stanley Fahn† †
Columbia University, College of Physicians and Surgeons, Columbia University Medical Center, Center for Parkinson’ s Disease and Other Movement Disorders, Department of Neurology, New York, NY, USA
Introduction: Levodopa (LD) is the most effective treatment for Parkinson’s disease (PD). However, chronic use of LD commonly results in the development of motor complications, including wearing off and dyskinesia. The presumption that the short serum half-life of LD is associated with the development of motor complications has raised the need to develop treatments with increased durations of stable LD concentrations. Areas covered: We conducted a PubMed search for IPX066 articles and also reviewed abstracts from meetings that included this topic. IPX066 is a newly developed formulation of extended release carbidopa--LD (CD--LD) with a one to four ratio of CD to LD, that was approved by the FDA in January 2015 for the treatment of PD, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide or manganese intoxication. It will be marketed by the trade name Rytary. A Phase III clinical trial showed that IPX066 is efficacious in improving motor symptoms in early PD patients. In advanced PD patients with motor fluctuations, IPX066 reduced off time and increased on time without troublesome dyskinesia compared to CD--LD immediate release and CD--LD with entacapone. IPX066 had an acceptable safety profile. Adverse events of IPX066 from the different trials are presented. Expert opinion: IPX066 will probably have a role in the treatment of advanced PD with motor fluctuations. IPX066 could also be used initially when LD therapy is prescribed, but the question of whether this usage could reduce or prevent the development of motor complications is yet to be answered. Keywords: carbidopa--levodopa extended release, drug safety, IPX066, motor complications, Parkinson’s disease Expert Opin. Drug Saf. (2015) 14(5):761-767
1.
Introduction
Parkinson’s disease (PD) is a common neurodegenerative disease. Initially, PD had been viewed predominantly as a motor disorder. The cardinal early motor features of rigidity, bradykinesia and rest tremor mainly result from loss of dopaminergic nigrostriatal neurons, and these features can respond to levodopa (LD) therapy. Later in the disease, other motor symptoms develop, such as flexed posture, loss of postural reflexes and freezing of gait that do not respond well to LD, and thus are thought not to be related to loss of dopamine. Today, it is also recognized that PD is associated with many non-motor symptoms, including cognitive impairment, psychiatric disorders and autonomic dysfunction. These reflect involvement of the CNS beyond the nigrostriatal dopamine system.
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description Route of administration Chemical structure
IPX066 -- Rytary III Parkinson’s disease Carbidopa--levodopa Oral O HO HO
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Pivotal trial(s)
OH NH2
[20-23]
Pharmaprojects -- copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline. citeline.com) and Citeline (http://informa.citeline.com).
So far, no treatment has been shown to cure PD and none has been approved for slowing the progression of the disease [1]. The early PD motor symptoms respond to dopamine-replacement therapy via its precursor LD. LD is combined with a peripheral DOPA decarboxylase inhibitor such as carbidopa (CD) or benserazide, to reduce nausea and vomiting due to peripheral metabolism of LD to dopamine and to increase its central bioavailability. LD is the most effective symptomatic treatment for PD. However, chronic use of LD commonly results in the development of motor complications, mainly wearing off and dyskinesia. Wearing off is defined as recurrence of motor and non-motor symptoms that precede scheduled doses of antiparkinsonian medication and usually improves after those doses are administered. Dyskinesia are involuntary movements, typically chorea and sometimes dystonia, which are twisting and more sustained movements and postures. Dyskinesias most commonly occur when LD-derived dopamine is peaking in the brain. Although classically considered late complications of LD therapy, wearing off and dyskinesias have been shown to emerge even after several months of treatment with CD--LD immediate release (CD--LD IR) [2]. The pathophysiology of wearing off and dyskinesia is complex, but appear to be linked to the short plasma half-life of LD, and is thought to be caused at least to some extent by nonphysiologic fluctuations in brain dopamine concentrations [3]. When LD is administered alone, it has a half-life of ~ 60 min, which reaches 90 min when administered as CD--LD IR [4]. Patients with relatively early PD have good response of motor symptoms to LD despite the short halflife. It is presumed that LD is taken up by dopaminergic and serotonergic neurons, decarboxylated to dopamine, stored intraneuronally and slowly released into the synapse [5]. With time, as dopaminergic neurons degenerate, storage and release of dopamine are impaired and patients experience a clinical response that mirrors peripheral pharmacokinetics of LD. The association of LD’s short half-life to wearing off has raised the need to develop treatments with increased durations 762
of stable LD concentrations. A longer acting LD formulation is expected to reduce the appearance of end of dose wearing off. Development of treatments with longer stable LD concentrations will hopefully reduce the development of dyskinesias as well. Over the years, numerous approaches have been tried with partial efficiency and significant shortcomings. Controlled release CD--LD formulations (also called extended release, CD--LD ER) have been shown to provide more sustained LD levels than CD--LD IR. However, this formulation has drawbacks because of the slower and less complete absorption rate, delayed time to clinical benefit compared with CD--LD IR and less consistent clinical response [6]. In addition, the hypothesis that controlled release CD--LD will be associated with a reduction in the development of motor complications has not been supported by studies [7]. Additional methods of prolonging the plasma half-life of LD include the administration of a catechol-O-methyltransferase (COMT) inhibitor, such as entacapone, to CD--LD. Entacapone acts mainly by blocking the peripheral metabolism of LD to 3-O-methyldopa by the enzyme COMT. Several studies reported that entacapone increases on time and reduces off time [8-10]. However, a recent evidence-based review reported that treatment with entacapone has been shown to be nonefficacious in preventing dyskinesia and motor fluctuations in PD subjects [1]. Co-administration of CD--LD with monoamine oxidase type B (MAO-B) inhibitors, such as rasagiline, prolongs the effect of dopamine by blocking the conversion of LD into 3,4-dihydroxyphenylacetic acid, and has been shown to reduce off times in PD patients [11,12]. Administration of dopamine agonists, including pramipexole, ropinirole, intermittent subcutaneous injections or continuous infusions of apomorphine have also been shown to reduce off times in PD patients [13-16]. Another method of prolonging LD levels and minimizing wearing off is continuous intrajejunal infusion of LD. This treatment is associated with reduced off times and dyskinesias [17]. However, this technique is invasive, requiring percutaneous endoscopic gastrostomy and has attendant surgical and postsurgical complications. Besides, there can be mechanical problems related to the pump and tube. Vitamin deficiency and polyneuropathies are other drawbacks [18]. The shortcomings of the treatments mentioned above are the basis for the genuine need for the development of a new increased duration LD treatment. An ideal LD formulation would reliably provide an initial rapid increase in LD plasma concentration, maintain clinically effective LD concentration for an extended duration, improve motor symptoms, reduce the frequency of motor complications, have an easy method of delivery, reduce the daily frequency of dosing and have a favorable adverse events (AEs) profile. IPX066 (Box 1) has been approved in January 2015 by the FDA for the treatment of all stages of PD; the drug will be marketed as Rytary.
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IPX066
Table 1. Summary of findings in CD--LD IR versus IPX066 study in advanced Parkinson’s disease with motor fluctuations.
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CD--LD IR
IPX066
Number of doses a day 5.00 3.60 Off time (h) -1.01 -2.18 On time without troublesome 0.80 1.88 dyskinesia (h) Adverse events during double blind maintenance period Insomnia 1% 3% Nausea 2% 3% Falls 2% 3% Dizziness 2% 1% Dyskinesia 2% 1%
3.
CD--LD IR: Carbidopa--levodopa immediate release.
Table 2. Summary of findings in CL + E versus IPX066 study in advanced Parkinson’s disease with motor fluctuations. CL + E
plasma LD concentrations increased at a similar rate. Time to reach 50% of peak LD concentration was 0.78 h for IPX066 compared to 0.76 h for CD--LD IR, but the duration of time with > 50% of maximal level was 4 h with IPX066 compared to only 1.4 h with CD--LD IR. Relative bioavailability of IPX066 was 74.5% of CD--LD IR. Following multiple doses (on day 8 of dosing), IPX066 showed lower variability of LD plasma concentrations despite a lower daily dosing frequency of a mean of 3.5 doses compared to 5.4 of CD--LD IR. In this study, the total LD exposure during IPX066 treatment was ~ 87% higher and the increase in LD peak concentration was 30% higher compared to CD--LD IR [22].
IPX066
Number of doses a day 5.00 3.00 Off time (h) -0.7 -2.10 On time without troublesome 0.2 1.40 dyskinesia (h) Adverse events during double blind maintenance period Insomnia 0 3.4% Nausea 0 1.1% Falls 2.3% 1.1% Dyskinesia 0 4.5% Confusional state 0 3.4% CL + E: Carbidopa--levodopa plus entacapone.
Chemistry, pharmacokinetics and pharmacodynamics
2.
IPX066 (Impax Pharmaceuticals, Inc., Hayward, CA, USA) is a newly developed formulation of combined immediate and ER CD--LD with a one to four ratio of CD to LD [19]. Each capsule consists of small beads containing CD--LD that dissolve at different rates. In clinical trials, the dose of CD per pill was 23.75, 36.25, 48.75, 61.25 and 97.5 mg, and the total LD dose per pill was 95, 145, 195, 245 and 390 mg, respectively [20,21]. These doses were selected to avoid confusion with the currently available CD--LD ER (the same generic name of Rytary). The pharmacokinetics of IPX066 were evaluated in a randomized, open-label, multicenter, crossover study that compared IPX066 and CD--LD IR in 27 subjects with advanced PD who were experiencing motor fluctuations while on LD therapy [22]. Subjects were randomized to treatment with CD--LD IR for 8 days followed by treatment with IPX066 for 8 days or the reverse order. Following administration of a single dose of IPX066 or CD--LD IR, peak
Clinical efficacy
Several large Phase III trials have elaborated IPX066’s efficacy in both early PD patients starting LD and in advanced PD patients with motor fluctuations. The ADVANCE-PD trial was a Phase III, randomized, double-blind, double-dummy study at 68 centers in North America and Europe that compared IPX066 to CD--LD IR in patients with advanced PD who had at least 2.5 h per day of off-time. Patients first underwent 3 weeks of open-label CD--LD IR dose adjustment followed by 6 weeks of open-label IPX066 dose conversion. Three-hundred-ninety-three patients were then randomized to 13 weeks of double-blind treatment of IPX066 or CD--LD IR. IPX066 reduced daily off time by an average of an extra 1.17 h compared with CD--LD IR with less daily doses, a mean of 3.6 versus 5, respectively. Mean on time without troublesome dyskinesia was increased by an average of extra 1.08 h in the IPX066 group compared to CD--LD IR, with a mild increase of on time with troublesome dyskinesia that did not differ between the groups (extra 0.05 h with IPX066). Mean Unified PD Rating Scale (UPDRS) parts II and III scores, PD Questionnaire (PDQ-39) (quality-of-life scale) and modified Rankin score were significantly better on IPX066 (Table 1) [21]. A recently published Phase III, randomized, double-blind, double-dummy, crossover study assessed the efficacy and safety of IPX066 versus CD--LD plus entacapone (CL + E) in advanced PD patients with a mean off time > 2.5 h a day, who had been taking CL + E or CD--LD--entacapone (CLE) combination tablets. This 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 (IPX066 and placebo CL + E or CL + E and placebo IPX066) separated by 1 week open-label IPX066 treatment. Ninety-one patients were randomized to the two treatment groups. Compared with CL + E treatment, IPX066 resulted in a mean of 1.4 h less daily off time and 1.4 h more daily on time without troublesome dyskinesia (both had p < 0.0001), without a difference in the mean on time with troublesome dyskinesia and fewer daily doses (median values of 3 vs 5) (Table 2) [23].
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Table 3. Summary of findings in IPX066 versus placebo study in early Parkinson’s disease. Placebo IPX066 IPX066 IPX066 145 mg t.i.d 245 mg t.i.d 390 mg t.i.d UPDRS II 0.2 UPDRS III -0.7 Adverse events Nausea 8.7% Headache 10.9% Dizziness 5.4% Insomnia 3.3%
-2.8 -8.9
-3.1 -9.8
-3.9 -11.0
13.8% 6.9% 9.2% 2.3%
19.2% 12.5% 19.2% 8.7%
15.7% 12.1% 11.8% 5.2%
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t.i.d: Three times daily; UPDRS: Unified PD rating scale.
IPX066 efficacy was also studied in early PD patients. A multicenter, randomized, double-blind, parallel-group, fixed-dose, placebo-controlled, 30-week study was recently published. Three hundred and eighty-one LD naı¨ve PD patients were assigned to placebo or IPX066 containing 145, 245 or 390 mg of LD administered 3 times daily (t.i.d). The primary efficacy measure was change from baseline in UPDRS activities of daily living (part II) and motor scores (part III). Secondary outcomes included patient and clinical global impressions and the PDQ-39. All three IPX066 dosages were superior to placebo, with mean improvement in UPDRS part II + III compared to baseline of 11.7, 12.9 and 14.9 points with higher doses of IPX066 associated with greater improvement in UPDRS compared to 0.6 points improvement in the placebo group. The total PDQ-39, patient and clinical global impressions were improved in each of the three active treatments groups compared to placebo (Table 3) [20]. A Phase II, open-label, crossover study of 27 advanced PD patients who were randomized to 8 days of treatment with either CD--LD IR followed by IPX066 or IPX066 followed by CD--LD IR showed that according to subjects diary results IPX066 was associated on average with 2 h of reduced off time (p < 0.0001) and 1.81 h more on time (p = 0.002) compared to CD--LD IR [22]. 4.
Safety in clinical studies
The AEs profile of CD--LD IR and controlled release CD--LD are well known, the most frequent being nausea, dizziness, abdominal pain and dyskinesia [7]. Since IPX066 is an ER CD--LD, the AE profile is expected to be similar. The Phase III and Phase II studies have provided the following data regarding the AEs of IPX066. In the placebo-controlled trial of early PD patients who were randomized to placebo versus three fixed doses of IPX066 (145, 245 or 390 mg t.i.d), 68.5% of the 381 patients evaluated experienced AEs. Surprisingly the overall AE rate in the 145 mg t.i.d group (56.3%) was notably lower than the placebo group (72.8%) and the 245 mg t.i.d (72.1%) and 764
390 mg t.i.d (71.4%) groups [20]. In general, the group treated with 145 mg t.i.d of IPX066 had the best AE profile and the frequency of AEs increased with increased IPX066 dose, clustering in the two higher dose groups of IPX066. The most common AEs were nausea, affecting 8.7% of placebo group, 13.8% in the 145 mg t.i.d group and reaching 20.4% in the 390 mg t.i.d group. Headache was reported in 10.9% of placebo group, only 6.9% in the 145 mg t.i.d group and 17.3% in the group treated with IPX066 390 mg t.i.d. Dizziness was reported almost twice as much in the IPX066 group treated with 145 mg t.i.d compared to placebo (9.2 vs 5.4%, respectively) with highest frequency reported in the intermediate dose of 245 mg t.i.d (19.2%). Insomnia was reported in 3.3% in the placebo group and reached as high as 8.7% in the intermediate dose treated with 245 mg t.i.d. All other AEs were not common and appeared in < 5% of treated patients. Fourteen serious AEs appeared during the study period. None of them were attributed to the study treatment and the numbers of patients experiencing serious AEs were similar across all treatment groups. Overall 39 (10.2%) of patients experienced AEs that contributed to early discontinuation of treatment, with a proportion of ~ 5% in the placebo and low-dose groups compared to ~ 15% in the groups treated with intermediate and high-dose IPX066. The most common AEs leading to early discontinuation were nausea, dizziness, vomiting, diarrhea and dyskinesia. In an open-label 9-month extension of this trial published as an abstract at the American Academy of Neurology (AAN) meeting in 2013 [24], 300 eligible patients were enrolled for treatment with IPX066. Safety and clinical utility were assessed at 1, 5 and 9 months. During the extension period, the most commonly reported AEs were nausea and insomnia (5.6% each), hypertension (4.1%) and headache (3.7% of patients). In the Phase III trial that compared IPX066 with CD--LD IR in advanced PD patients [21], during the 6 weeks of openlabel IPX066 dose conversion 206 (46%) of 450 patients reported AEs, the most common were dyskinesia (6%), nausea (5%), headache (4%) and dizziness (4%). Twenty-three patients (5%) discontinued treatment early because of AEs in this phase of the study. Fourteen patients (3%) had 22 serious AEs, including two deaths, one due to renal failure and the other had sudden death. Six of the serious side effects were regarded as related to IPX066. Two patients had gait disturbance, two had dyskinesia and the others had overdose (one patient) and acute psychosis (one patient). In the 13-week double-blind treatment period 43% of patients on IPX066 compared to 40% on CD--LD IR reported AEs. Overall, a similar number of patients in the two treatment groups reported AEs (87 in the IPX066 group compared to 76 in the CD--LD IR group), with three cases (1.5%) of early termination due to AEs in each group. The most common AEs in the IPX066 group were insomnia (3%), nausea (3%), falls (3%), dizziness (2%) and dyskinesia (2%). The other AEs were reported by up to 2% of the group. Eleven patients
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IPX066
(5%) in the IPX066 group reported 13 serious AEs. No specific serious AE was reported by more than one patient. One patient had anxiety and psychosis that were regarded as related to treatment with IPX066. In the CD--LD IR group, five patients (3%) reported eight serious AEs. It should be mentioned that three patients from the IPX066 group had impulse control symptoms (two patients had compulsive sexual behavior and one had gambling) assessed by the modified Minnesota impulsive disorders interview. One patient in the CD--LD IR group developed impulse control symptoms (excessive shopping). None of these four patients were taking concomitant dopamine agonists. The design of the Phase III trial comparing IPX066 with CL + E in advanced PD patients [23] included a 6-week conversion period from CL + E or CLE to IPX066 in which 30.9% of patients reported AEs. The most common AEs were nausea (7.3%), vomiting, falls and upper respiratory tract infections (2.7% each). During the double-blind treatment period (two 2-week periods), 20.2% of patients reported AEs on IPX066 compared to 13.6% on CL + E. The most common AEs during this period were dyskinesia (4.5%), insomnia and confusion (3.4% each) on IPX066, and falls, which appeared in 2.3% of patients on CL + E. During the open-label 1-week IPX066 treatment 13.5% of patients reported AEs that were not described in the paper. Overall, four patients reported a total of six serious AEs that included hypercalcemia, atrial fibrillation, constipation, chemical gastroenteritis, sciatica and dehydration. None of these were considered treatment-related AEs. One patient discontinued participation due to AEs that included dyspepsia, nausea and vomiting and one patient due to dyskinesia. No serious AEs were reported with the use of CL + E. Another abstract presented at the AAN in 2013 reported that 349 advanced PD patients who completed Phase II or III studies and exposed to IPX066 from 1 to 19 weeks were enrolled in a 9-month open-label extension trial treated with a median dose of 1450 mg IPX066 a day. During the extension period, the most frequently reported AEs were dyskinesia (6.9%), falls (6.6%), pain in extremities (3.7%) and hallucinations (3.4%) [25]. In the Phase II crossover trial of 27 advanced PD patients there were no serious AEs. Five subjects reported a total of nine mild or moderate AEs, none of which appeared in more than one subject [22]. 5.
Safety in special populations
Data regarding safety of IPX in special populations have been published. Two abstracts presented at the Movement Disorders Society Congress in 2013 reported higher frequency of at least one AEs in patients treated with IPX066 in females compared to males (63.3 vs 53.9%, respectively) [26], and in lighter weight patients (< 75 kg) compared to heavier patients (61.3 compared to 55.5%, respectively) [27]. Another abstract presented at the World Parkinson Congress in 2013 reported
higher frequency of at least one AE with IPX066 in patients older than 75 compared with patients younger than 65 (65 vs 54%, respectively) [28]. Differences in LD pharmacokinetics have been described with regard to gender. Women have been shown to require lower LD doses compared to men [29,30]. Whether these differences apply with regard to IPX066 is not known. 6.
Drug interactions with IPX066
No data has been published so far regarding potential drug interactions with IPX066. Drug interactions with IPX066 are expected to resemble drug interactions of LD [4]. 7.
Conclusion
IPX066 is an experimental newly developed formulation of ER CD--LD with a one to four ratio of CD to LD that was approved by FDA in January 2015 for the treatment of PD. Published Phase II and III studies shows that IPX066 improved UPDRS scores compared to placebo in early PD patients and reduced wearing off in advanced PD patients. It also has the advantage of a lower frequency of daily doses compared to CD--LD IR, and is on average taken 3 -- 4 times a day. Overall, IPX066 treatment was well tolerated and the frequency of AEs was similar to those of CD--LD IR. The most common AEs were nausea, dizziness, headache, falls, insomnia and dyskinesia. There is insufficient data regarding potential drug interactions but it is expected to be similar to those of LD. 8.
Expert opinion
IPX066 is a mixed formulation of immediate and ER CD--LD that was approved by FDA in January 2015 for the treatment of PD. IPX066 has an improved pharmacokinetic profile compared to CD--LD IR resulting in a similar initial absorption rate with more sustained plasma LD concentration. This pharmacokinetic advantage seems to result in an improved clinical response in advanced PD patients with motor fluctuations allowing motor improvements with less daily treatment doses. Reduction in the frequency of doses in advanced PD patients is important for patients’ convenience and has the potential to increase adherence to the recommended treatment schedule [31]. Studies comparing treatment with IPX066 to CD--LD IR or CL + E in advanced PD patients show that on average the added reduction in off times and increased on time without troublesome dyskinesia reached ~ 1.3 h/day. This additional reduction of ~ 25% of daily off time that PD patients experience has clinical significance and is reflected in the improved PDQ-39 total scores and could contribute to improvement in patients’ quality of life. Overall, treatment with IPX066 had good tolerability, and AEs profile was similar to those seen with CD--LD IR.
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It seems that IPX066 will have a role in the treatment of advanced PD patients with motor fluctuations. IPX066 does not solve the problem of motor complications but could help in reducing their severity. It is not surprising that IPX066, which has a LD component, showed improved UPDRS scores compared to placebo, as the effect of LD on motor symptoms of PD has been known for decades. The most important question that is yet to be answered is whether early treatment with IPX066, due to its sustained LD plasma concentration, could reduce and hopefully even eliminate the appearance of wearing off motor fluctuations and dyskinesia. A prospective, long-term study comparing treatment with CD--LD IR to IPX066 in early PD patients is needed to answer this question. If early treatment with IPX066 would be found to reduce development of motor complications, then IPX066 will cause a breakthrough in the management of PD, reducing the need for more expensive and invasive treatments of motor complications, for example, deep brain stimulation, continuous LD intestinal infusion and apomorphine continuous subcutaneous infusion. It would be interesting to see if combining IPX066 with other treatments such as COMT inhibitors such as entacapone or MAO inhibitors will have an additive value, causing Bibliography
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Declaration of interest S Fahn has received consulting or advisory board honoraria from Merz Pharma, PixarBio and Lundbeck. He has received Genervon Biotechnology and the Smart Family Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005;62(2):241-8
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further reduction in wearing off. Additional clinical trials are needed to answer this question. Overall, the clinical efficacy in reducing off times in advanced PD and improving motor symptoms in early PD patients, the lower frequency of daily doses compared to other oral LD preparations, and the relatively good AEs profile will probably make IPX066 an important player in the treatment of PD, assuming cost will not be limiting. Further studies assessing the ability of early IPX066 treatment to reduce development of motor complications, and long-term studies assessing clinical efficacy and safety are needed.
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Affiliation
Meir Kestenbaum1 MD & Stanley Fahn†2 MD † Author for correspondence 1 Movement Disorders Fellow, Columbia University, College of Physicians and Surgeons, Columbia University Medical Center, Department of Neurology, New York, NY, USA 2 Director Emeritus, Columbia University, College of Physicians and Surgeons, Columbia University Medical Center, Center for Parkinson’s Disease and Other Movement Disorders, Department of Neurology, 710 west 168 street, New York, NY, USA Tel: +1 212 305 3716; Fax: +1 212 305 3530; E-mail: [email protected]
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