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Marketed as Crexont, the combination extended- and immediate-release treatment is indicated for treatment of PD, and is anticipated to be available in the United States in September 2024.
Robert A. Hauser, MD
(Credit: USF Health)
Richard D’Souza, PhD
(Credit: Amneal)
The FDA has approved Amneal Pharmaceuticals’ investigational agent IPX203, an oral formulation of carbidopa/levodopa (CD/LD) extended-release capsules, as a treatment for patients with Parkinson disease (PD), according to an announcement from the company. Marketed as Crexont, the therapy is an oral formulation CD/LD which includes immediate-release (IR) granules as well as extended-release (ER) pellets.1
The treatment is indicated for PD, PD caused by infection or inflammation of the brain, or PD-like symptoms that may result from carbon monoxide or manganese poisoning in adults. It is not recommended in combination with nonselective monoamine oxidase inhibitors, nor with other CD/LD preparations without consultation with a healthcare provider. Amneal noted its expectation is for the oral formulation to become available to patients in the United States in September 2024.
Robert A. Hauser, MD, a professor of neurology at the University of South Florida and the director of the Parkinson's Disease and Movement Disorders Center, said in a statement that "the treatment goals for people living with Parkinson’s disease include achieving a more robust duration of benefit per dose of LD, reducing OFF time, and simplifying dosing regimens. Crexont’s longer Good ON time per day and per dose represents a substantial advancement in managing motor symptoms and maintaining more consistent therapeutic effects, which is very encouraging for both patients and the Parkinson’s community."1
Amneal’s CD/LD ER capsule product was approved based on data from the phase 3 RISE-PD clinical trial (NCT0300788), a double-blind study published in JAMA Neurology in August 2023. In the study, those treated with IPX203 at least 3 times per day (n = 256) showed a statistically significant improvement of 0.53 hours (95% CI, 0.09-0.97; P = .02) in daily good ON time relative to those on IR CD/LD (n = 250), who were dosed 5 times per day.2
Richard D’Souza, PhD, the senior vice president of Research and Development for the Specialty Segment of Amneal, told NeurologyLive® that “any PD patient on IR CD/LD experiencing motor fluctuations will benefit from Crexont. We have not seen significant differences between different subgroups, potentially because the number of patients in each subgroup is small." He said that the treatment's label also allows for use in patients who are LD naive and those who are being treated with Amneal's CD and LD combination treatment known as Rytary.
The company’s new drug application, which featured data from RISE-PD, was originally accepted in November 2022; however, months later, in July 2023, the FDA issued a complete response letter (CRL) to Amneal, stating it needed additional data on the drug’s second ingredient, carbidopa. Earlier this year, in February 2024, the company presented its complete response resubmission, which featured additional information from a healthy volunteer study conducted in the fourth quarter of 2023. At the time, the FDA did not request any other studies.3
“The approval of Crexont is a seminal moment in the treatment paradigm for Parkinson’s disease. The burden of this incurable neurodegenerative disease increases with time. Some PD patients on IR CD/LD take up to 10 daily doses and still experience motor fluctuations. Crexont's innovative formulation provides a longer duration of 'Good ON' time with less frequent dosing compared to IR CD/LD. Amneal is so excited to introduce this meaningful new treatment for Parkinson’s patients in the US and soon internationally. We are committed to continuing to advance Parkinson’s research and development as a leader in the space,” Chirag and Chintu Patel, co-CEOs of Amneal, said in a statement.1
READ MORE: Transforming the Landscape of Parkinson Disease Care Through Patient-Centric Focus
RISE-PD, which was published months after the CRL was issued, consisted of a 4-week screening period, a 3-week open-label IR CD/LD dose-adjustment period, a 4-week open-label IPX203 dose-conversion period, and a 13-week double-blind, double-dummy treatment period. In addition to meeting its primary end point, IPX203 performed well on the secondary end point of change in OFF time hours per day. All told, treatment with the agent resulted in significantly less OFF time compared with IR CD/LD (difference in least square [LS] means, –0.48; 95% CI, –0.90 to –0.06; P = .03). In addition, 29.7% and 18.8% of patients on IPX203 and IR CD/LD, respectively, rated themselves as much improved or very much improved on Patient Global Impression of Change (P = .002).
In terms of safety, treatment-emergent adverse events (TEAEs) for IPX203-treated participants were most frequent in the double-blind period (42.2%) than the dose-conversion (38.9%) or dose-adjustment (18.7%) periods. Within this group, the most common TEAEs were nausea (4.3%), anxiety (2.7%), and dizziness (2.3%), while those on IR CD/LD mostly experienced fall (3.6%), urinary tract infection (3.2%), and back pain (2.8%). During the double-blind period, 8 patients treated with IPX203 (3.1%) and 4 treated with IR CD/LD (1.6%) experienced serious TEAEs.
At the 2024 American Academy of Neurology (AAN) Annual Meeting, data from RISE-PD revealed an association between longer exposure to IPX203 and a decrease in the occurrence of TEAEs. Overall, the findings demonstrated the safety and tolerability of IPX203 across various dosage ranges, even at the highest doses, over an extended period of use.
Led by William Ondo, MD, director of the Movement Disorders Clinic at the Houston Methodist Neurological Institute, the analysis included 179 patients with PD exposed to IPX203 continuously at a wide distribution of doses, with modal doses ranging from 140/560 mg CD/LD to 1260/5040 mg CD/LD a day. As participants were group into 4 quartiles (each quartile, n = 45), the modal dose ranges were 560 to <1050 mg, 1050 to <1470 mg, 1470 to <2100 mg, and 2100 to 5040 mg LD/day. All told, the data revealed a decrease in the number of patients with TEAEs as the exposure time increased compared with the number of patients with TEAEs by duration of exposure, at any modal dose range.4
