Advancing Parkinson Disease Care: Nonsurgical Continuous Carbidopa/Levodopa Infusion Therapy

By Clinical Content Hub

Parkinson disease (PD) is a chronic, progressive, neurodegenerative disorder primarily characterized by the degeneration of dopaminergic neurons.1 It is the second most common neurodegenerative disorder worldwide, affecting more than 10 million people, with prevalence increasing in aging populations.1,2 PD manifests through a complex array of motor and non-motor symptoms that significantly impact patients’ quality of life (QOL).1,3 While levodopa (LD) has been the cornerstone of PD treatment since the 1960s, its long-term use presents challenges, including motor fluctuations and dyskinesias, necessitating the development of alternative treatment strategies.4 Figure 1 presents the prevalence and progression of PD.1-3

Motor and Non-Motor Complications and Their Impact on QOL

PD is primarily defined by hallmark motor symptoms, including bradykinesia (slowness of movement), muscle rigidity, resting tremor, and postural instability. These symptoms typically emerge after approximately 60% to 80% of dopamine-producing neurons are lost and progressively worsen over time. While initially responsive to LD therapy, the disease eventually leads to motor complications due to fluctuating dopamine levels, disrupting daily functioning.2

Motor Fluctuations and Dyskinesias

Motor fluctuations and dyskinesia are significant challenges in long-term PD management2,5:

  • Motor fluctuations: characterized by alternating periods of good mobility (“on” time) and poor mobility (“off” time) requiring frequent medication adjustments. Approximately 50% of patients develop motor fluctuations 2 to 5 years after diagnosis, and 80% to 100% experience them after a decade.
  • Dyskinesias: involuntary, choreiform movements that typically occur during peak-dose “on” periods. Over time, these movements become more severe, hindering daily activities and reducing QOL.

These complications arise from the progressive loss of striatal dopaminergic neurons and fluctuating plasma LD levels, making treatment optimization crucial.5,6

Non-Motor Symptoms and Their Impact on QOL

Non-motor symptoms also have a profound effect but are often overlooked. They can precede or accompany motor deficits and include autonomic dysfunction, neuropsychiatric disturbances, and sleep disorders. Many of these symptoms, only partially responsive to dopaminergic therapy, pose further treatment challenges.5,6

Sleep Disturbances and Nocturnal Treatment Gaps

Over 90% of advanced PD patients experience sleep disturbances, which significantly impair health-related QOL (HRQOL).3 Common issues include:(1) insomnia and fragmented sleep leading to excessive daytime sleepiness and impaired daily functioning; and(2) early morning “off” (EMO) periods resulting from the short half-life of LD and exacerbating mobility challenges upon waking and affecting daily performance.3

Since most PD medications are administered during waking hours, a nocturnal treatment gap remains, worsening sleep disturbances and impacting both patients and caregivers. Optimized nighttime treatment strategies are essential for improving overall disease management.3

Limitations of Oral LD Therapy

Oral LD therapy, combined with carbidopa (CD), remains the gold standard in PD management. However, as the disease progresses, limitations in oral LD therapy become more apparent, necessitating the development of non-oral, continuous drug delivery (CDD) strategies4,5:

  • Short half-life and absorption issues:
    • The short half-life of LD requires frequent dosing.
    • Impaired gastric motility in patients with PD leads to unpredictable absorption and plasma fluctuations, contributing to inconsistent symptom control.
  • Complex medication regimens:
    • As PD progresses, patients often require increased LD dosing frequency, sometimes up to 4 to 5 times per day.
    • This complexity leads to poor compliance, increased caregiver burden, and a higher risk of adverse events (AEs).
  • Pulsatile dopaminergic stimulation:
    • Intermittent dosing results in non-physiological dopamine delivery, exacerbating motor fluctuations and dyskinesias over time.
    • This pulsatile stimulation is a key contributor to long-term complications associated with oral LD therapy.

The Need for Non-Oral, LD-Based CDD

Given the limitations of oral LD therapy, non-oral, LD-based CDD strategies have gained prominence. These approaches aim to maintain stable LD plasma concentrations, thereby reducing motor fluctuations, improving QOL, and addressing non-motor symptoms.4

Managing PD symptoms with oral treatments alone can be challenging, but continuous therapy — rather than intermittent dosing — can help improve symptom control. Approaches such as deep brain stimulation (DBS), LD/CD intestinal gel (LCIG), and continuous subcutaneous apomorphine infusion (CSAI) require medical devices, which, despite their efficacy, are not always acceptable to patients. Concerns about invasiveness, surgical risks, cosmetic impact, and potential side effects often deter patients from pursuing these options. Additionally, access to these advanced therapies is limited in some regions, as their availability depends on specialized centers and regional adherence to international guidelines.5

Certain patient factors further restrict the use of these therapies. For example, DBS is generally not recommended for elderly individuals or those with dementia or psychotic disorders. Similarly, CSAI may lose effectiveness over time due to panniculitis-related reductions in apomorphine absorption. While LD remains the cornerstone of PD treatment due to its strong efficacy and favorable safety profile, the benefits of continuous delivery (eg, LCIG) are offset by the need for a surgical procedure. These limitations highlight an unmet need for a nonsurgical therapeutic option that offers stable LD plasma concentrations and continuous symptom relief throughout the day.5

The Importance of 24-Hour Continuous Dopaminergic Stimulation

A key consideration in developing new treatments is the need for 24-hour dopaminergic stimulation. Nocturnal symptoms, such as EMO periods and sleep disturbances, are often undertreated, as most current non-oral therapies are designed for daytime use (approximately 16-hour formulations).2,3 A 24-hour delivery system could improve nighttime mobility and sleep quality, reduce EMO episodes, and provide more physiological dopaminergic stimulation while minimizing dopamine agonist-related side effects.2,3

Benefits of foslevodopa/ foscarbidopa for advanced PD
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Foslevodopa/foscarbidopa is the first continuous subcutaneous infusion of an LD-based formulation approved for adults with advanced PD. It helps reduce motor fluctuations and dyskinesia, thus improving motor control.

Continuous Subcutaneous Infusion of Foslevodopa/Foscarbidopa in Advanced PD

The continuous subcutaneous infusion of foslevodopa/foscarbidopa represents a significant advancement in the management of advanced PD. Approved by the US Food and Drug Administration (FDA) on October 17, 2024, foslevodopa/foscarbidopa is the first and only 24-hour subcutaneous infusion of a LD-based formulation for adults with advanced PD.2 By maintaining stable plasma LD levels, foslevodopa/foscarbidopa effectively reduces motor fluctuations and dyskinesia, improving patients’ overall motor control.1,5

Evolution of Continuous LD Infusion Therapy

The idea of continuous LD infusion began in the 1980s but was initially hindered by logistical challenges, including issues with systemic volume overload. The development of foslevodopa/foscarbidopa addressed these concerns by leveraging the enhanced solubility of foslevodopa and foscarbidopa. This innovation enables a smaller infusion volume compared to LCIG, resulting in a more practical and patient-friendly delivery system. Having overcome prior limitations, foslevodopa/foscarbidopa offers a more manageable solution for patients with advanced PD.4 Table 1 describes the indications, mechanism of action, dosage, and adverse reactions of foslevodopa/foscardidopa.7

Mechanism of Action and Pharmacology

Foslevodopa and foscarbidopa are prodrugs of LD and CD, respectively. These phosphate ester derivatives exhibit excellent chemical stability, maintaining degradation of less than 2% in solution over a year, even at high concentrations (240/12 mg/mL and 360/18 mg/mL) and across a wide pH range, including physiological pH (7.4). Upon administration, these prodrugs are rapidly hydrolyzed by alkaline phosphatases in the liver and other tissues, releasing the active forms of LD and CD. This enzymatic conversion ensures consistent drug levels, optimizing dopaminergic stimulation and reducing motor fluctuations.1

Foslevodopa/foscarbidopa is delivered via a compact, portable, subcutaneous infusion pump significantly smaller than the LCIG pump. This continuous 24-hour delivery method provides stable dopaminergic stimulation, potentially improving both motor and non-motor symptoms, including nocturnal issues such as sleep disturbances.4 However, while HRQOL improvements suggest potential benefits, objective studies examining its direct impact on sleep remain limited.

Clinical Efficacy and Safety

Foslevodopa/foscarbidopa’s approval was supported by several pivotal studies. Notably, a phase 3, 12-week study evaluated its efficacy in adult patients with advanced PD, comparing it with oral, immediate-release CD/LD (CD/LD IR).2 Additionally, a 52-week open-label study assessed its long-term safety and efficacy.5,6

Clinical Studies

A randomized, double-blind, phase 3 trial (ClinicalTrials.gov identifier: NCT04380142) involving 141 patients demonstrated foslevodopa/foscarbidopa’s superior efficacy over oral CD/LD IR. Patients in the study had motor fluctuations inadequately controlled by their current medications, with at least 2.5 hours of daily “off” time as recorded in PD diaries. Participants were randomly assigned to receive either 24-hour continuous subcutaneous foslevodopa/foscarbidopa with oral placebo or oral CD/LD IR with subcutaneous placebo. The study population had a mean age of 66.4 years. Most (93%) were White and (70%) male. At baseline, 74% of patients in the foslevodopa/foscarbidopa group and 66% in the oral CD/LD IR group were on additional PD medications.7

The primary endpoint, which measured the change in total daily “on” time without troublesome dyskinesia, showed significant improvements in the foslevodopa/foscarbidopa group compared to the oral CD/LD IR group (P =.0083). Additionally, foslevodopa/foscarbidopa significantly reduced “off” time compared to oral CD/LD IR (P =.0054). These findings highlight foslevodopa/foscarbidopa’s ability to improve motor fluctuations, with increased “on” time without troublesome dyskinesia and decreased “off” time.7

Long-Term Efficacy and Safety

Findings from the 52-week, open-label, phase 3 study (ClinicalTrials.gov identifier: NCT03781167) further supported foslevodopa/foscarbidopa’s long-term efficacy and safety. At week 52, 62.2% of patients awoke in the “on” state without dyskinesia, a significant improvement from 17.5% at baseline. Additionally, foslevodopa/foscarbidopa led to substantial improvements in motor experiences of daily living and HRQOL.3,5

Safety Profile

The safety profile of foslevodopa/foscarbidopa was generally consistent with that of oral LD. Most adverse reactions (ARs) were mild or moderate in severity, with the most common ARs (incidence ≥10%) being infusion site reactions (pain, swelling, redness, and infections requiring medical attention).1,7 Other ARs included hallucinations, dyskinesia, impulse-control disorders, sudden sleep episodes, and cardiovascular concerns.7 Infusion site reactions were the most frequent AEs. Monitoring is recommended for patients with prior hypertension or tachycardia.7

References

1. Aubignat M, Tir M. Continuous subcutaneous foslevodopa-foscarbidopa in Parkinson’s disease: a mini-review of current scope and future outlook. Mov Disord Clin Pract. 2024;11(10):1188-1194. doi:10.1002/mdc3.14161

2. U.S. FDA approves VYALEV™ (foscarbidopa and foslevodopa) for adults living with advanced Parkinson’s disease. News release. AbbVie, Inc. October 17, 2024. Accessed March 11, 2025. https://news.abbvie.com/2024-10-17-U-S-FDA-Approves-VYALEV-TM-foscarbidopa-and-foslevodopa-for-Adults-Living-with-Advanced-Parkinsons-Disease

3. Chaudhuri KR, Facheris MF, Bergmans B, et al. Improved sleep correlates with improved quality of life and motor symptoms with foslevodopa/foscarbidopa. Mov Disord Clin Pract. 2024;11(7):861-866. doi:10.1002/mdc3.14018

4. Poplawska-Domaszewicz K, Batzu L, Falup-Pecurariu C, Chaudhuri KR. Subcutaneous levodopa: a new engine for the vintage molecule. Neurol Ther. 2024;13:1055-1068. doi:10.1007/s40120-024-00635-4

5. Aldred J, Freire-Alvarez E, Amelin AV, 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. Neurol Ther. 2023;12:1937-1958. doi:10.1007/s40120-023-00533-1.

6. Fung VSC, Aldred J, Arroyo MP, et al. Continuous subcutaneous foslevodopa/foscarbidopa infusion for the treatment of motor fluctuations in Parkinson’s disease: considerations for initiation and maintenance. Clin Park Relat Disord. 2024;10:100239. doi:10.1016/j.prdoa.2024.100239

7. Vyalev™. Prescribing Information. AbbVie, Inc; 2024. Accessed March 9, 2024. https://www.rxabbvie.com/pdf/vyalev_pi.pdf

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Reviewed June 2025