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FDA approves foslevodopa-foscarbidopa: a breakthrough continuous infusion therapy for advanced Parkinson’s disease

On October 17, 2024, AbbVie announced the U.S. Food and Drug Administration (FDA) approval of foslevodopa-foscarbidopa, marking the first and only subcutaneous 24-hour continuous infusion of levodopa-based therapy for motor fluctuations in advanced Parkinson’s disease (PD). Foslevodopa-foscarbidopa is set to provide a non-surgical option for patients facing the limitations of oral medications and offer continuous levodopa delivery throughout the day and night.1

Motor fluctuations in PD

Patients with advanced PD often experience fluctuations in motor control, switching between “on” periods, where motor symptoms are well-managed, and “off” periods, where symptoms return and hinder movement. Researchers believe these fluctuations stem from the declining ability of brain cells to store and release dopamine as dopamine-producing neurons degenerate. Although levodopa is an effective medication for replacing dopamine, it can cause fluctuating plasma levels, meaning patients may experience dyskinesia during periods of excessive dopamine and “off” periods when the medication wears off. Its effectiveness also diminishes over time, leading to shorter durations of symptom control.2

About foslevodopa-foscarbidopa

Motor fluctuations in PD are commonly managed by optimizing levodopa administration, which involves adjusting dosages, frequency, and combinations of medications. While effective, these strategies can complicate treatment regimens and challenge patient adherence due to the need for frequent dosing. Advanced treatment options like deep brain stimulation (DBS) and levodopa-carbidopa intestinal gel (LCIG) offer more stable symptom control; however, these are invasive procedures with associated risks and require specialized medical teams. Foslevodopa-foscarbidopa presents a novel alternative by delivering a prodrug combination of levodopa and carbidopa subcutaneously and continuously. This formulation aims to reduce troublesome “off” periods and enhance “on” time without dyskinesia, potentially alleviating the burdens of oral medication schedules and absorption delays while addressing the underlying motor fluctuations in advanced PD.3

We spoke to Angelo Antonini, MD, PhD, University of Padua, Padua, Italy, at the 2023 International Congress of Parkinson’s Disease and Movement Disorders. Prof. Antonini discussed the benefits of foslevodopa-foscarbidopa, stating that “the main advantage of this formulation is that you can bring into the syringe up to four grams of levodopa, so essentially covering the entire spectrum of doses possible in Parkinson’s disease. Also, it allows…delivery for 24-hours, at the same infusion rate or with different infusion rates according to the patient need, so it can be customized“.

Pivotal Phase III M15-736 and M15-741 studies

The FDA approval was supported by the pivotal Phase III M15-736 study (NCT04380142) in which foslevodopa-foscarbidopa was compared with oral immediate-release carbidopa-levodopa (CD-LD IR) in adults with advanced PD. 130 participants were randomized to receive continuous subcutaneous foslevodopa-foscarbidopa plus placebo oral capsules or CD-LD IR plus placebo subcutaneous injection over a 12-week treatment period. Patients’ motor symptoms were recorded in a home diary (the PD diary), with baseline values defined as the average “on” time in the three days before treatment initiation. The findings revealed that patients receiving foslevodopa-foscarbidopa experienced a significant increase from baseline in “on” time without troublesome dyskinesia – 2.72 hours compared with 0.97 hours in those treated with oral CD-LD IR (p=0.0083). Improvements were observed as early as the first week and were sustained throughout the study.1

Additionally, the 52-week open-label M15-741 study (NCT03781167) confirmed the long-term efficacy of foslevodopa-foscarbidopa. In this study, patients were treated with 24-hour infusions of foslevodopa-foscarbidopa at individually optimized doses for 52 weeks. Results demonstrated a mean reduction of 3.5 hours in “off” time, reflecting a 59% decrease from baseline (p ≤ 0.001). Concurrently, normalized “on” time without troublesome dyskinesia increased by 3.8 hours, marking a 41% improvement from baseline (p ≤ 0.001). 4.5% of patients discontinued treatment due to lack of efficacy; the discontinuation rate was notably higher in the initial 10 weeks.4

Safety profile

The long-term safety of foslevodopa-foscarbidopa was assessed in the M15-741 study. Of the 244 patients treated with foslevodopa-foscarbidopa, 94.3% experienced at least one adverse event (AE), with 91.8% of these considered associated with foslevodopa-foscarbidopa. Most AEs were mild to moderate and resolved with or without treatment, although 25.8% of patients experienced serious AEs, including severe infusion site reactions and severe hallucinations. Common non-serious AEs included infusion site erythema (52.0%), hallucinations (17.2%), and falls (16.8%). Notably, 26.2% of patients discontinued the study drug due to AEs, primarily related to hallucinations and infusion site issues. Although three treatment-emergent deaths occurred, none were deemed related to foslevodopa-foscarbidopa. Overall, the safety profile indicated a predominance of manageable infusion-related AEs, with no clinically relevant changes in any laboratory parameters, vital signs, or electrocardiogram values.4 These findings were supported by the 12-week M15-736 study, which found that AEs were mostly non-serious and mild or moderate in severity, with the most common being infusion site reactions, hallucinations, and dyskinesia.1

Looking ahead

Foslevodopa-foscarbidopa represents a major advancement in PD treatment, offering a non-surgical, individualized approach for patients with PD experiencing motor fluctuations. It has been approved in 35 countries, and over 4,200 patients worldwide have started treatment. With expected Medicare coverage in late 2025, patients will soon have greater access to this innovative therapy.1 This continuous, subcutaneous treatment option holds promise to improve motor functioning and the quality of life of patients with advanced PD.

Written by Hannah Elkheir

Reviewed by Henry Shippey and Katie Long

References

  1. AbbVie. U.S. FDA Approves VYALEV™ (foscarbidopa and foslevodopa) for Adults Living with Advanced Parkinson’s Disease. [Press Release]. 17th October 2024. Accessed 22nd October 2024.
  2. Parkinson’s Foundation. Motor Fluctuations and Parkinson’s “Off” Times. 2021. Accessed 22nd October 2024.
  3. Poplawska-Domaszewicz K, Batzu L, Falup-Pecurariu C , & Chaudhuri K. R. Subcutaneous levodopa: A new engine for the vintage molecule. Neurology and therapy. June 2024; 13(4):1055–1068.
  4. Aldred J, Freire-Alvarez E, Amelin A. V, et al. Continuous Subcutaneous Foslevodopa/Foscarbidopa in Parkinson’s Disease: Safety and Efficacy Results From a 12-Month, Single-Arm, Open-Label, Phase 3 Study. Neurology and therapy. August 2023; 26;12(6):1937–1958.