IPX066 (Rytary

)
A New Medication for Parkinson’s Disease
Robert A. Hauser, MD, MBA
Parkinson’s Disease and Movement Disorders Center University of South Florida Tampa, FL
8/22/12

Introduction IPX066 is an investigational, extended release formulation of carbidopa/levodopa. It is designed to achieve therapeutic levodopa levels as quickly as carbidopa/levodopa immediate release (IR), but to maintain therapeutic levodopa levels for a significantly longer time (1). For patients who are experiencing motor fluctuations on carbidopa/levodopa IR (Sinemet), this translates to a longer duration of benefit from each administration of medication. There is also interest as to whether use of IPX066 in early Parkinson’s disease will decrease the development of dyskinesia compared to carbidopa/levodopa IR, although this has not yet been tested. Phase 3 trials have been completed in both early and moderate to advanced disease, and safety and efficacy data are now being reviewed by the FDA. The proposed brand name for IPX066 is Rytary.

Pharmacokinetics

IPX066 is manufactured as tablets filled with beads that contain carbidopa/levodopa that dissolve at various rates to allow absorption from the gut over a longer period of time than occurs with carbidopa/levodopa IR. The bioavailability of levodopa from IPX066 compared to carbidopa/levodopa IR in terms of AUC (total amount absorbed) is approximately 70% (1). However, the shape of the concentration curve is substantially altered, with the peak (Cmax) being 30% of carbidopa/levodopa IR and levodopa levels sustained significantly longer. Therefore, for patients who are experiencing motor fluctuations on carbidopa/levodopa IR, when switching to IPX066, the initial individual milligram dose is approximately three times higher (to match the carbidopa/levodopa IR peak concentration) but it is only administered 2/3 as often (typically three times per day). Thus, the total daily levodopa mg dose for IPX066 is typically twice that of carbidopa/levodopa IR (approximately 40% higher after adjusting for lower bioavailability) as this additional levodopa is necessary to “fill in” the levodopa troughs from carbidopa/levodopa IR and to smooth the clinical response. After an initial switch is made according to dosing guidelines, further adjustments are often necessary to optimize the clinical response.

Clinical Trials In a phase 3 clinical trial (2,3), patients with moderate to advanced Parkinson’s disease and motor fluctuations on carbidopa/levodopa IR, initially underwent a 3 week open-label carbidopa/levodopa IR dose adjustment. They were then converted to open-label IPX066 which was adjusted over 6 weeks. Patients were then randomized to double-blind treatment with their optimized regimen of carbidopa/levodopa IR plus placebo for IPX066 or IPX066 plus placebo

for carbidopa/levodopa IR for 13 weeks. Results demonstrated that IPX066 administered an average of 3.6 times per day reduced mean daily OFF time by 1.18 hours more (p <0.001) than carbidopa/levodopa IR administered an average of 5.0 times per day. In addition, quality of life (PDQ-39) scores were significantly more improved with IPX066, and 39% of patients treated with IPX066 rated themselves as much or very much improved compared with 17% for carbidopa/levodopa IR (p<0.0001). IPX066 was well tolerated and troublesome dyskinesia was not significantly increased. In another phase 3 trial in moderate to advanced Parkinson disease patients with motor fluctuations (2, 4), IPX066 was compared to carbidopa/levodopa IR plus entacapone. In this double-blind, double-dummy, cross-over trial, IPX066 administered an average of 3.5 times per day reduced OFF time 1.4 hours more (p<0.0001) than carbidopa/levodopa IR plus entacapone administered an average of 5.0 times per day. IPX066 was also demonstrated to provide benefit in early Parkinson’s disease compared to placebo. In a phase 3 double-blind trial (2,5), levodopa naïve patients were randomized to TID (three times daily) treatment with IPX066 145 mg, 245 mg, 390 mg or placebo for 30 weeks. Results demonstrated significant improvement in Parkinson (UPDRS motor plus Activity of Daily Living) scores in patients treated with each dosage of IPX066 compared to placebo (P≤0.0001). All dosages of IPX066 also provided significant improvement in quality of life (PDQ-39 scores). IPX066 was generally well tolerated. There was a dose response with higher daily dosages providing more benefit, but there were also more side effects with the higher dosages, including nausea and headache. Therefore, results from this study suggest that for IPX066, 145 mg TID might provide the best balance between efficacy and side effects for treatment if early Parkinson’s disease.

Use in Clinical Practice Clinical trial results suggest that IPX066 will be useful for patients with moderate to advanced Parkinson’s disease who are experiencing motor fluctuations on carbidopa/levodopa IR or carbidopa/levodopa IR plus entacapone. Patients on these levodopa formulations 4 or 5 times per day will likely be able to switch to IPX066 3 or 4 times per day and experience a reduction in OFF time. Many such patients will also be on adjunctive medications or these can also be considered. Although it has not been tested in clinical trials, patients taking carbidopa/levodopa IR 3 times a day who begin to experience motor fluctuations can probably switch to IPX066 3 times per day and reduce or eliminate their OFF time. For many such patients the alternative would be to go to carbidopa/levodopa IR 4 times per day or to add an adjunctive medication such as entacapone, an MAO-B inhibitor, or dopamine agonist. The relative pros and cons, including price, of each of these options will have to be considered on an individual basis. IPX066 will often offer the advantage of allowing fewer dosings per day, thereby enhancing convenience and helping to maintain compliance and predictability of the clinical response.

IPX066 may also be useful as a bedtime medication to provide antiparkinsonian efficacy further into the night than carbidopa/levodopa IR (with or without entacapone). This effect might be optimized by having the patient take IPX066 at bedtime along with food, which slows absorption but is also expected to prolong the clinical benefit. This has not yet been evaluated in clinical trials.

IPX066 is clearly effective in early Parkinson’s disease, but its advantage over carbidopa/levodopa IR is unproven. These two formulations have not been compared in a headto-head trial and carbidopa/levodopa IR is also very effective in early Parkinson’s disease. The main drawback of carbidopa/levodopa IR is that over time, patients develop dyskinesia, a sensitivity to dopamine medication that is expressed clinically as peak-dose chorea (twisting, turning movements). Dyskinesia appears to represent an essentially irreversible intrinsic change in the brain that can become very difficult to manage. Some patients develop troublesome dyskinesias that interfere with function or cause discomfort. Even when dysknesias are not that severe, they often create a barrier that limits better treatment of parkinsonian motor features and fluctuations. If dyskinesias could be avoided, levodopa could be used more liberally to better treat motor features of Parkinson’s disease. The Continuous Dopaminergic Hypothesis suggests that it is the fluctuating concentrations of brain dopamine derived from fluctuating concentrations of levodopa from carbidopa/levodopa IR that create the sensitivity that causes dyskinesia. The hypothesis suggests that if we deliver levodopa to the brain in a smoother, more continuous fashion, we might reduce the development of dyskinesias, or perhaps avoid them altogether. Thus, there is interest in whether by using IPX066 as the initial levodopa formulation one might be able to reduce or avoid the development of dyskinesia. This is an important area of research and will require a multi-year clinical trial to assess. Information to date indicates that at least with carbidopa/levodopa IR, the higher the dosage that is used, the higher the risk of dyskinesia. Therefore, unnecessarily high dosages should be avoided. The same may be true for IPX066, and there is appeal to using a low dose of IPX066 three times daily when levodopa is first introduced, pending additional information from clinical trials.

Conclusion IPX066 is an extended release formulation of carbidopa/levodopa. Compared to carbidopa/levodopa IR, it provides benefit as quickly and improvement is maintained significantly longer. IPX066 has demonstrated efficacy in early Parkinson’s disease compared to placebo. In moderate to advanced disease, patients can be switched from carbidopa/levodopa IR or carbidopa/levodopa IR plus entacapone at a lower dosing frequency and still experience a reduction in OFF time.

References 1) Hauser RA, Ellenbogen AL, Verhagen Metman L, et al. Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson’s disease. Mov Disord 2011; 26: 2246– 52. 2) Hauser RA. IPX066: a novel carbidopa–levodopa extended-release formulation. Expert Rev Neurother 2012; 12; 133–140. 3) Hauser RA, Nausieda P, Ondo W et al. Double-blind, controlled trial of IPX066, a novel carbidopa–levodopa extended-release formulation, in advanced Parkinson’s disease (ADVANCE-PD trial). Presented at: Movement Disorder Society Meeting 2011. Toronto, ON, Canada, 5–7 June 2011 (Abstract LB9). 4) Stocchi F, Dillmann U, Mahler A, Ellenbogen A, Liang G, Hsu A, Khanna S, Rubens R, Gupta S. Comparison of IPX066, a novel investigational carbidopa-levodopa (CD-LD) extended-

release formulation, and CD-LD-entacapone (CLE) in advanced Parkinson’s disease (ASCENDPD trial). Presented at: Movement Disorder Society Meeting 2012. Dublin, Ireland. 5) Pahwa R, Ellenbogen A, Jankovic J, Hauser R, Fahn S; Clinical Team at Impax Pharmaceuticals. Efficacy and safety of IPX066, a new carbidopa–levodopa (CD–LD) extendedrelease formulation, in LD-naive early Parkinson’s disease (APEX-PD trial). Mov. Disord. 26(Suppl. 2), S137 (2011).

--------------------------------------------------------------------------------------------------------------------All rights reserved. No part of this publication may be reproduced without the author’s express written permission. The brand name for carbidopa/levodopa immediate release (IR) is Sinemet ------------------------------------------------------------------------------------------------------------------Conflict of Interest Disclosure Dr. Hauser serves as a consultant and advisor to Impax Pharmaceuticals, makers of IPX066. Dr. Hauser has participated in clinical trials of IPX066. Dr. Hauser did not receive any payments for writing this paper. There were no ghost authors. Impax pharmaceuticals, its employees, and agents had no input into the content of this paper. Dr. Hauser is solely responsible for the content of this paper and the locations in where it legitimately appears.