The pharmacodynamic and pharmacokinetic effects of the novel Amneal Pharmaceuticals therapy suggest that it can overcome the current absorption and exposure limitations of the oral levodopa therapies used to treat those with Parkinson disease motor fluctuations.
Data on the pharmacodynamic and pharmacokinetic effects of IPX203, an investigational oral extended-release formulation of carbidopa-levodopa from Amneal Pharmaceuticals for the treatment of Parkinson disease (PD), suggest—and according to the investigators, appear to confirm—that the novel design of the drug address some of the limitations of the current oral delivery levodopa options.1
The pharmacokinetic data, collected from a phase 2 study in those with PD (NCT03007888), showed that those with PD who were treated with IPX203 had rapid absorption followed by sustained plasma concentrations, with a maximum serum concentration (Cmax) of 2.768 ng/mL (SD, 1.259) compared with 2.357 ng/mL (SD, 1.179) for immediate-release carbidopa-levodopa.
The time to maximum concentration (Tmax) was 1.5 hours (min, 0.5; max, 6.0) compared with 0.5 hours (min, 0.5; max, 2.0) for immediate-release carbidopa-levodopa. This resulted in an area under the curve (AUC) of 11.214 (SD, 4.887) for IPX203 compared with 3,879 (SD, 1.744) for immediate-release carbidopa-levodopa. Notably, following the first dose on day 15, the duration of Cmax of at least 50% was markedly higher for IPX203, at 6.2 hours (SD, 1.9) compared with 3.9 hours (SD, 2.2) for immediate-release carbidopa-levodopa.
“The design of IPX203 provides rapid absorption and prolonged steady concentrations of [levodopa] which lead to sustained pharmacodynamic effect in patients with PD who exhibit motor fluctuations on conventional [immediate-release carbidopa-levodopa] formulations,” Rohit Dhall, MD, MSPH, associate professor of neurology, and director, Neurodegenerative Disorders, University of Arkansas for Medical Sciences, and colleagues wrote. Dhall et al presented the data in a poster at the 2022 Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress in Washington, DC, June 17-19.
This study included 28 patients with advanced PD who were reporting motor fluctuations. They were randomly assigned 1:1 to 15 days of treatment with immediate-release carbidopa-levodopa followed by IPX203, or IPX203 followed by immediate-release carbidopa-levodopa, with a 1-week washout period between the two treatments. The investigational Amneal capsule product was supplied in 2 doses of 45/180 mg or 67.5/270 mg carbidopa/levodopa, while the comparator was supplied as a 25/100 mg carbidopa/levodopa capsule.
“The dosing regimen for IPX203 was expected to be as infrequent as 3 times days (at intervals of approximately 7 to 8 hours),” Dhall et al wrote. “During the first 9 days of each treatment period, investigators were permitted to adjust the dose regimens of [immediate-release carbidopa-levodopa] and IPX203 for optimal therapeutic effect. Thereafter, dosing regimens were unchanged.”
When comparing the predose Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) scores at day 1 with those at day 15, there was significant difference between IPX203 and immediate-release carbidopa-levodopa. On Day 1, the IPX203 group reported scores of 42.8 compared with 41.4 in the comparator group, with those dropping at day 15 to 33.5 in the IPX203 group compared with 41.6 in the comparator group, which was a significant change (P = .0087). The mean difference in MDS-UPDRS scores between the treatments was 8.1 points (SD, 25.0), which was also significant (P = .0255).
The investigators noted that levodopa, though the gold standard for the treatment of PD, has a short half-life that can result in pulsatile dopaminergic stimulation that can lead to motor complications. Additionally, there are limitations to achieving steady exposure to levodopa with oral treatments as gastric emptying is erratic and the window of absorption in the proximal small intestine is narrow. This is particularly true as PD progresses.
“IPX204 contains immediate-release granules (carbidopa and levodopa with a disintegrant polymer to allow for rapid dissolution) and extended-release beads (levodopa coated with a controlled-release polymer to allow for slow release of the drug, a mucoadhesive polymer to keep the granules anchored to the area of absorption longer, and an enteric coating to prevent the granules from disintegrating too early in the stomach,” Dhall et al wrote.
Earlier this year, at the 2022 American Academy of Neurology (AAN) Annual Meeting, April 2-7, in Seattle, Washington, Robert A. Hauser, MD, MBA, professor of neurology, and director, Parkinson’s Disease and Movement Disorder Center, University of South Florida, presented data from a pair of posters from the phase 3 RISE-PD trial (NCT03670953) on IPX203.2,3 These data showed notable efficacy among those treated with the investigational drug, and, in August 2021, Amneal stated that the data will serve as the supporting basis for a new drug application.4
Hauser, speaking with NeurologyLive® at the AAN Annual Meeting, stressed the importance of the dosing regimen of IPX203, and the advantages it can offer patients with PD. “[With] the primary outcome measure of the increase in good ON time, many people look at it and say, ‘Well 0.53 hours is a half an hour increase in ON time, it’s not that much per day.’ But you have to keep in mind that patients received IPX-203 three times per day, compared to IR CD-LD an average of five times per day,” he said at the time.
In the first poster, overall, the data showed promise, with IPX-203 meeting the primary end point by showing statistically significant improvement in good ON time compared with immediate-release (IR) CD-LD (0.53 hours; P = .0194) in a cohort of 506 patients with Parkinson disease (PD) who experience motor fluctuations.2,3 The secondary end point—change from baseline in OFF time—displayed similar results, with IPX203 treatment resulting in significantly less OFF time compared with IR CD-LD (–0.48 hours; P = .0252).2
The second poster, a post hoc analysis of the RISE-PD data, demonstrated similar promise in a modified intent-to-treat population (n = 495). At the end-of-study visit, those in the IPX-203 group (n = 249) had 3.76 hours of good ON time per dose, compared with 2.21 hours for those on IR CD-LD (P <.0001).3