Foslevodopa 2.4g/10ml / Foscarbidopa 120mg/10ml solution for infusion vials

BackgroundDevice-aided therapies, such as levodopa-and apomorphine-based infusion pumps, are widely used for managing patients with Parkinson's disease (PD) with symptoms inadequately controlled by oral medications. Cognitive impairment is a critical factor in selecting an appropriate therapy; however, the effects of levodopa/carbidopa intestinal gel (LCIG) and continuous subcutaneous apomorphine infusion (CSAI) on cognitive function remain debated.ObjectiveThe aim of this review is twofold: i) to provide a comprehensive analysis of the short-term benefits of device-aided infusion therapies on cognitive function, and ii) to evaluate their impact on long-term cognitive trajectories.MethodsA systematic literature search was conducted following PRISMA guidelines in PubMed, CINAHL, Cochrane, EMBASE, and MEDLINE. Narrative synthesis was applied to summarize results.ResultsOut of 1911 studies, 33 were included in this systematic review according to the selected criteria. No studies examined the effects of the newly introduced Foslevodopa/Foscarbidopa (LDp/CDp) nor levodopa/entacapone/carbidopa intestinal gel (LECIG) pump therapy. Seventeen studies addressed the short-term effects of CSAI; seven reported cognitive slowing and two were suggestive of positive effects. Only two studies assessed its impact on long-term cognitive trajectory, showing no significant changes. Thirteen studies examined LCIG's short-term effects; seven reported cognitive changes, with some decreases in executive functions. Two studies explored its long-term cognitive impact, with one reporting improvements.ConclusionsThe cognitive effects of device-aided treatments in PD show substantial variability, and their impact on cognitive function, processing speed, attention, and memory is inconsistent, with some studies reporting impairments and others indicating stability or slight improvements. The heterogeneity in study designs, neuropsychological assessments and coexisting vascular and amyloid pathology further complicates interpretation, underscoring the need for more controlled investigations.

Abstract licence: CC BY

BackgroundMany Parkinson's disease patients receiving oral levodopa/carbidopa experience a troublesome wearing off effect. Higher doses to mitigate OFF-time are limited by adverse effects occurring at peak dopamine levels, particularly dyskinesia. A novel strategy to reduce OFF-time without increasing peak dopamine levels is the continuous subcutaneous infusion of levodopa/carbidopa, or their prodrug equivalents foslevodopa/foscarbidopa.ObjectivesAssess whether subcutaneous infusion therapies safely reduce OFF-time and improve quality of life scores compared to oral levodopa/carbidopa.MethodsWe searched MEDLINE, Embase, CENTRAL and ICTRP up to 28th October 2024 for clinical trials comparing subcutaneous infusions of levodopa or foslevodopa to oral levodopa in Parkinson's disease.ResultsScreening of 1114 records identified seven studies in which 725 patients received subcutaneous infusion regimens of levodopa/carbidopa (ND0612) (407 patients) or foslevodopa/foscarbidopa (318 patients). Moderate quality evidence indicated subcutaneous infusion reduced the daily duration of OFF-time by 1.98 h (p = 0.0004). Moderate quality evidence indicated improvements in health-related quality of life score PDQ-39 (p = 0.0003) and sleep score PDSS-2 (p = 0.02), but an increase in the rate of treatment-emergent adverse events, mostly related to the infusion site (p = 0.04).ConclusionsSubcutaneous infusion therapies produce a clinically and statistically significant reduction in the duration of OFF-time experienced by patients with Parkinson's disease, compared to oral levodopa/carbidopa. Patient experience is improved by a statistically, but not clinically, significant degree. There are increased adverse events, mostly related to the infusion site. Overall, subcutaneous infusion regimens could provide a meaningful alternative for Parkinson's disease patients who experience severe motor fluctuations with existing levodopa formulations.

Abstract licence: CC BY

Abstract Background As Parkinson's disease (PD) progresses, managing symptoms becomes increasingly difficult. Foslevodopa/foscarbidopa (LDp/CDp), a 24‐hour/day continuous subcutaneous infusion of levodopa/carbidopa (LD/CD) prodrugs, improves motor complications. The feasibility and sustainability of LDp/CDp monotherapy warrants investigation. Objective The aim was to report the efficacy and safety of LDp/CDp monotherapy and combination therapy. Methods This post hoc analysis assessed patients with PD and ≥2.5 “Off” hours/day receiving LDp/CDp monotherapy or combination therapy in 3 trials: a 12‐week randomized active‐controlled trial (RCT) comparing LDp/CDp with oral immediate‐release LD/CD (NCT04380142), a 52‐week open‐label trial of LDp/CDp (NCT03781167), and its 96‐week open‐label extension study (OLE; NCT04379050). Monotherapy was defined as receiving LDp/CDp without concomitant PD medications; combination therapy was defined as receiving LDp/CDp with other PD medications. Results In the RCT, 74 of 141 patients received LDp/CDp. The 52‐week trial enrolled 244 patients; 129 entered the OLE. Of LDp/CDp‐treated patients, 19 of 74 (25.7%) in the RCT, 49 of 244 (20.1%) in the 52‐week trial, and 46 of 129 (35.7%) in the OLE received monotherapy. In the RCT, mean (standard deviation) change from baseline to week 12 in “Off” time was −4.5 (4.4) and −3.0 (3.5) hours for monotherapy and combination therapy, respectively; +4.1 (3.7) and +3.1 (3.6) hours for “On” time without troublesome dyskinesia; and +4.0 (3.6) and +4.0 (3.9) hours for “On” time without dyskinesia. Efficacy was similar in open‐label trials. Improvements in the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale Part II, 39‐item Parkinson's Disease Questionnaire, Parkinson's Disease Sleep Scale‐2 scores, and overall safety were comparable between monotherapy and combination therapy groups. Conclusions LDp/CDp monotherapy treatment may be suitable for up to 96 weeks.

Abstract licence: CC BY 4.0

INTRODUCTION: We evaluated continuous subcutaneously administered foslevodopa/foscarbidopa (LDp/CDp) in younger patients earlier within advanced Parkinson's disease (aPD). METHODS: This phase 3 trial included patients aged ≥ 30 years with levodopa-responsive PD, Mini-Mental State Examination score ≥ 24, and levodopa equivalent dose ≥ 400 mg/day. Patients were considered by the investigator as inadequately controlled on current oral/transdermal therapy and experienced ≥ 2.5 h/day "Off" time, with recognizable "On"/"Off" states. Patients were randomized (1:1) to LDp/CDp plus placebo capsules or orally administered immediate-release levodopa/carbidopa plus placebo infusion. This post hoc exploratory analysis focused on younger patients (≤ 65 years) earlier within aPD (Hoehn and Yahr stage ≤ 2 ["On" state], ≤ 5 years since motor fluctuations started). Outcomes included change from baseline (CFB) to week 12 in "Off" and "On" time, Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) II, 39-item PD Questionnaire (PDQ-39), and PD Sleep Scale-2 (PDSS-2). RESULTS: Twenty-six patients met subgroup criteria (LDp/CDp, n = 13; orally administered levodopa/carbidopa, n = 13). Despite small sample sizes, at week 12, LDp/CDp was associated with significantly greater improvements in "Off" time (mean [SD] CFB - 3.7 [3.1] vs - 1.6 [2.9] h; P = 0.0011), "On" time without troublesome dyskinesia (+ 3.9 [3.3] vs + 1.4 [3.8] h; P = 0.0011), and PDSS-2 (- 6.4 [4.6] vs - 1.8 [3.1]; P = 0.0220) vs orally administered levodopa/carbidopa. Mean (SD) CFB to week 12 (LDp/CDp vs orally administered levodopa/carbidopa) was + 4.2 (2.8) vs + 1.9 (4.6) h for "On" time without dyskinesia (P = 0.0878), - 3.0 (6.4) vs - 0.9 (3.5) for MDS-UPDRS II (P = 0.3539), and - 9.9 (7.4) vs - 1.9 (9.4) for PDQ-39 (P = 0.0534). For most assessments, treatment differences were numerically larger in the subgroup vs the overall population. Safety findings were consistent with the overall population. CONCLUSIONS: LDp/CDp was associated with significantly greater improvements in motor function and sleep vs orally administered levodopa/carbidopa in younger patients earlier within aPD whose symptoms were inadequately controlled by oral/transdermal therapies. Larger real-world studies are needed to confirm findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04380142.

Abstract licence: CC BY-NC 4.0

AbstractBackgroundParkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non‐motor symptoms, primarily because of the impairment of dopaminergic neurons. Long‐term use of levodopa, the standard PD treatment, often results in fluctuating therapeutic effects and dyskinesia, necessitating alternative therapies.ObjectivesThis review aims to synthesize current insights and clinical experiences with foslevodopa‐foscarbidopa, focusing on its pharmacokinetics, efficacy, and safety profile, to evaluate its potential in transforming PD therapy.MethodsA systematic literature search was conducted up to November 2023 using databases PubMed, Web of Science, and Cochrane Library. The search yielded eight eligible articles, including pharmacological studies, case reports, observational studies, and controlled trials. No language restrictions were applied.ResultsFoslevodopa and foscarbidopa, as prodrugs of levodopa and carbidopa, exhibited excellent chemical stability and solubility, facilitating continuous subcutaneous infusion. Clinical trials demonstrated that these prodrugs maintain stable levodopa levels, thereby addressing the limitations of oral levodopa therapy. Phase 1 and 3 studies indicated significant improvements in motor function and quality of life in advanced PD patients. However, a higher incidence of treatment‐emergent adverse events, mainly infusion site reactions, was observed compared to oral therapies.ConclusionsFoslevodopa‐foscarbidopa emerges as a promising alternative for advanced PD treatment, offering sustained symptom control. Its efficacy in managing motor fluctuations and dyskinesia makes it a viable option in the PD therapeutic spectrum. Future research should focus on long‐term safety, economic impact, and broader accessibility. Foslevodopa‐foscarbidopa is now commercially distributed in many countries in Europe and in Japan.

Abstract licence: CC BY-NC 4.0