First steps in the treatment of advanced Parkinson's disease with foslevodopa/foscarbidopa continuous subcutaneous infusion

First steps in the treatment of advanced Parkinson’s disease with foslevodopa/ foscarbidopa continuous subcutaneous infusion Karina Atanasova-Ivanova1,2 , Nevena Kamenova1,2 , Sonya Hristova1,2 , Ivan Milanov1,2 1 Department of Neurology, Medical Faculty, Medical University, Sofia, Bulgaria 2 University Hospital for Active Treatment in Neurology and Psychiatry “St. Naum”, Sofia, Bulgaria Corresponding author: Karina Atanasova-Ivanova (karyatan[email protected]m) Received 25 August 2025♦ Accepted 13 October 2025♦ Published 6 November 2025 Citation: Atanasova-Ivanova K, Kamenova N, Hristova S, Milanov I (2025) First steps in the treatment of advanced Parkinson’s disease with foslevodopa/foscarbidopa continuous subcutaneous infusion. Pharmacia 72: 1–4. https://doi.org/10.3897/pharmacia.72.e169712 Abstract Aim: The aim of this study was to evaluate the efficacy and safety of this new therapy in Bulgaria. The second objective was to determine whether foslevodopa/foscarbidopa infusion improves the quality of life of patients. Materials and methods: This study observed 24 patients with advanced Parkinson’s disease. Neurological examination, MDS– UPDRS, Parkinson’s Disease Sleep Scale, Parkinson’s Disease Quality of Life Questionnaire, and the Bulgarian version of EQ–5D–5L were used. Results: All patients showed improvement in motor fluctuations, nocturnal akinesia, and quality of life. In almost 68% of patients, monotherapy was not possible, and a dopamine agonist had to be added. The main side effects were non-serious skin reactions. Conclusion: Foslevodopa/foscarbidopa is a new method for the treatment of advanced Parkinson’s disease. The therapy improves motor function and has a positive effect on nocturnal akinesia and quality of life. Overall, the drug demonstrates a good safety profile and tolerance. Keywords Parkinson’s disease, subcutaneous therapies Introduction Parkinson’s disease is a progressive neurodegenerative disorder with ever-increasing frequency and importance. In the advanced stage of the disease, motor fluctuations occur as a result of prolonged treatment with levodopa. They include the wearing-off phenomenon, on–off phenomenon, delayed on, peak-dose dyskinesia, and, in some cases, biphasic dyskinesia. Motor fluctuations appear in 40% of patients after 4–6 years of disease duration (Regensburger et al. 2025). Non-motor symptoms such as pain, gastrointestinal symptoms, orthostatic hypotension, sleep disturbance, cognitive symptoms, and anxiety may affect 60–97% of patients with Parkinson’s disease and occur in 50.5% of them simultaneously with motor fluctuations (Mujahid et al. 2025). This condition has a significant impact on patients’ quality of life and healthcare resources. In recent years, current therapies for advanced Parkinson’s disease have included deep brain stimulation, continuous subcutaneous infusion of apomorphine hydrochloride, Copyright Atanasova-Ivanova K et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Pharmacia 72: 1–4 DOI 10.3897/pharmacia.72.e169712 Research Article Atanasova-Ivanova K et al.: Foslevodopa/foscarbidopa subcutaneous infusion2 intestinal infusion of levodopa/carbidopa, and intestinal infusion of levodopa/carbidopa/entacapone. A new device-assisted therapy has been developed to help patients with motor complications. Foslevodopa/foscarbidopa continuous subcutaneous infusion represents a combination of prodrugs of levodopa and carbidopa. Once administered, the prodrugs are rapidly hydrolyzed to their active forms. The solution contains a foslevodopa concentration of 240 mg/ml, for a total of 2400 mg foslevodopa and 120 mg foscarbidopa, which is equivalent to approximately 1700 mg levodopa and 89 mg carbidopa. The product is delivered subcutaneously via a pump system. The total daily dose consists of three possible individually adjusted rates: the basic rate, the lower rate, and the higher rate. An extra bolus dose can be administered to control any repetitive OFF symptoms. The base infusion rate is determined by calculating the total dose of foslevodopa/foscarbidopa required, based on a patient’s oral levodopa-containing medications and COMT inhibitors, using a provided conversion calculator. In such cases, the levodopa equivalent daily dose should be determined. In the phase III randomized controlled trial by Soileau et al. (2022), the medication demonstrated improvements in ON time without troublesome dyskinesia and reductions in OFF time. Similar results were confirmed in a 12-month open-label, phase III study by Aldred et al. (2023). The authors observed a 59% average reduction in OFF periods from baseline and a 58% increase in ON periods without dyskinesia compared to baseline. The percentage of patients with morning akinesia decreased from 77.7% at baseline to 27.8%. Improvements were also reported in the Parkinson’s Disease Sleep Scale–2 (PDSS-2), 39-item Parkinson’s Disease Questionnaire (PDQ-39), and EuroQol 5-Dimension Questionnaire (Aldred et al. 2023). This product represents a new therapeutic approach aimed at addressing the disabling motor fluctuations observed in the advanced stages of Parkinson’s disease. Its clinical effectiveness has yet to be evaluated. Aim The aim of this study is to evaluate the efficacy and safety of this new therapy for advanced Parkinson’s disease in Bulgaria. The second objective is to determine whether foslevodopa/foscarbidopa infusion improves the quality of life of patients. Materials and methods An ongoing observational study was conducted on the first patients to start foslevodopa/foscarbidopa infusion at the Clinic of Movement Disorders, Department for Parkinson’s Disease, MHATNP St. Naum, Sofia, Bulgaria. Included were patients in the advanced stage of Parkinson’s disease according to the 5–2–1 criteria (Milanov et al. 2023). Exclusion criteria included patients with atypical parkinsonism. Twenty-four patients (7 females and 17 males) were enrolled. Five of them discontinued treatment. Nineteen patients continued with foslevodopa/foscarbidopa infusion (4 females and 15 males). The patients’ demographic data were recorded, including date of birth, duration of disease, sex, and previous treatment. The median age was 66 years, and the median duration since PD diagnosis was 10 years. The patients’ profiles were similar in sex, age, and duration of Parkinson’s disease compared with those in the 52-week, open-label, phase III registrational trial (Aldred et al. 2023) (Table 1). Previously, 68% of patients had taken 1000 mg or more of levodopa, while 32% were treated with doses between 700 and 900 mg. Three patients were switched from apomorphine infusion. To evaluate the influence of motor and non-motor symptoms of the disease, neurological examination and the MDS–Unified Parkinson’s Disease Rating Scale (MDS– UPDRS) were used. For sleep assessment, the Parkinson’s Disease Sleep Scale (PDSS-2) was applied. To assess quality of life, we used the Parkinson’s Disease Quality of Life Questionnaire (PDQ-39) and the Bulgarian version of EQ–5D–5L. All scales were assessed at the start of treatment with foslevodopa/foscarbidopa and approximately 1 month thereafter. Results This is an ongoing observational study of the first patients treated with foslevodopa/foscarbidopa in our clinic, and statistical analysis of the data has not yet been performed due to the small number of patients. Since September 2024, 24 patients have started treatment with foslevodopa/foscarbidopa infusion. Five of them were excluded—one for personal reasons related to pump servicing, one due to a feeling of swelling and palpitations, and two for insufficient improvement in motor symptoms and a prolonged period of rigidity and bradykinesia associated with a low body mass index. One patient died due to a suspected infection with Clostridium difficile. Nineteen patients continue therapy. All patients were on a basic rate during the day and a lower rate at night. In cases of continuous OFF periods, a higher rate was used. Median ranges of the pump at the Table 1. Comparison of characteristics of the initial treatment group and the registrational trial. Characteristics Our group 52-week, openlabel, phase III registrational trial Number of patients 24 244 Sex Males > females Males > females Age, mean 66 63.9 Parkinson’s disease duration 10 years 10.7 years Daily OFF times, mean (h) 7.3 5.9 Daily ON time with troublesome dyskinesia, mean (h) 1.5 1.0 Pharmacia 72: 1–4 3 start of treatment were 0.35 ml/h for the basic rate, 0.30 ml/h for the lower rate, and 0.40 ml/h for the higher rate. During treatment, some patients required an increased foslevodopa/foscarbidopa dose, with a coefficient increase of 0.14. Median ranges after adjustment were 0.40 ml/h for the basic rate, 0.36 ml/h for the lower rate, and 0.44 ml/h for the higher rate. All patients reported improvement in the PDSS total score and all domain scores beginning within the first days of treatment (Table 2). Patients stated that the pump did not disturb their sleep. There were also improvements in the PDQ-39 Summary Index and the EQ VAS score (Table 2). The frequency of OFF periods decreased according to the MDS–UPDRS, and no worsening of dyskinesias was observed. However, in 68% of patients, monotherapy could not be achieved. Regarding side effects, six patients experienced non-serious skin reactions, including erythema and nodules. In two patients, the complaints developed into serious adverse reactions—one patient had abscesses twice and required surgical treatment, and another developed necrosis and also underwent surgery (Table 3). All of these patients continue treatment. Discussion In our observation, 74% of patients experienced deterioration of motor symptoms approximately 2 weeks after starting treatment. During this period, we adjusted the doses. In 26% of patients, no correction was needed at that time. In almost 68% of patients, monotherapy was not possible, and a dopamine agonist had to be added. In comparison, more than 30% of patients were able to achieve monotherapy with foslevodopa/foscarbidopa after previously being on one or more concomitant medications (Poplawska-Domaszewicz et al. 2024). Rescue levodopa and concomitant medications such as dopamine agonists are not included in the conversion algorithm when starting treatment (Fung et al. 2024). This may result in insufficient control of motor symptoms and a need for dose adjustment. Another problem is that, in Bulgaria, there are certain limitations on the number of vials prescribed. As expected, 24 h dopaminergic stimulation improves sleep and nocturnal akinesia, which was also observed in our study. Sakuramoto et al. (2024) reported an improvement in sleep architecture with an increased duration of stage 3 sleep. The authors used a nocturnal rate of 88% of the daytime infusion rate, with a minimum of 0.15 ml/h (Sakuramoto et al. 2024). In our group, the median nocturnal lower rate was 0.36 ml/h. The main side effects were non-serious skin reactions. In only two patients, the complaints developed into serious adverse reactions that required surgical treatment; however, this did not lead to discontinuation. Aubignat and Tir (2024) suggested that more frequent changes of the subcutaneous catheter—once per day—could help prevent this adverse effect. We propose administering the medication in regions other than the periumbilical area, such as the hands, waist, and thighs, and maintaining good skin care practices. Topical treatment with potent corticosteroids may be beneficial and is recommended (Koeglsperger et al. 2025). In a 12-week randomized, double-blind trial, the most frequent adverse events in 85% of patients in the foslevodopa/foscarbidopa group were infusion site reactions, including erythema, pain, and cellulitis, most of which were non-serious (Soileau et al. 2022). In the registrational trial, the most common adverse event leading to study drug discontinuation was hallucination; in contrast, in our group, no patient experienced this (Aldred et al. 2023). In our patients, the main side effect leading to discontinuation was the lack of effect on motor symptoms in two individuals with a low body mass index, probably due to non-absorption of the medication. This highlights the importance of selecting the appropriate patient profile. One patient receiving treatment died due to an underlying probable Clostridium infection. At present, it is difficult to identify a specific microbiota composition associated with Parkinson’s disease because of varying research standards. In general, most studies support the finding that pro-inflammatory and harmful bacteria increase, whereas anti-inflammatory bacteria decrease (Chen et al. 2021). There is currently no evidence of a direct link between treatment with foslevodopa/foscarbidopa and an increased risk of clostridial infection. Given the theory that the pathogenesis of Parkinson’s disease may originate in the gut and the gastrointestinal symptoms observed in these patients, further research is needed to explore the relationship between the two conditions (Zeng et al. 2022). Conclusion Foslevodopa/foscarbidopa is a promising new nonsurgical method for the treatment of advanced Parkinson’s disease. The product improves motor function and has a positive effect on nocturnal akinesia and quality of life. Overall, the drug shows a good safety profile and tolerance. Long-term clinical observations are needed. Table 3. Most common non-serious and serious adverse events during treatment. Adverse events Number of patients Infusion site erythema and nodules 6 Serious adverse events Number of patients Infusion site abscesses 1 Infusion site necrosis 1 Table 2. Comparison of PDSS, PDQ-39, and EQ VAS mean values before and after the start of treatment. Before treatment After treatment PDSS total score, mean 23.6 11.5 PDQ-39 Summary Index, mean 48.6 21.9 EQ VAS score, mean 26 61 Atanasova-Ivanova K et al.: Foslevodopa/foscarbidopa subcutaneous infusion4 Acknowledgements This research was supported by the Bulgarian Ministry of Education and Science under the Young Scientists and Postdoctoral Students 2 National Program (No. GD-158/01.10.2024). Additional information Conflict of interest The authors have declared that no competing interests exist. Ethical statements The authors declared that no clinical trials were used in the present study. The authors declared that no experiments on humans or human tissues were performed for the present study. The authors declared that no informed consent was obtained from the humans, donors or donors’ representatives participating in the study. The authors declared that no experiments on animals were performed for the present study. The authors declared that no commercially available immortalised human and animal cell lines were used in the present study. Use of AI No use of AI was reported. Funding No funding was reported. Author contributions All authors have contributed equally. Author ORCIDs Karina Atanasova-Ivanova https://orcid.org/0009-0007-05189606 Nevena Kamenova https://orcid.org/0009-0008-8595-0545 Sonya Hristova https://orcid.org/0000-0001-9695-8632 Ivan Milanov https://orcid.org/0000-0002-4522-4070 Data availability All of the data that support the findings of this study are available in the main text. References Aldred J, Freire-Alvarez E, Amelin AV, Antonini A, Bergmans B, Bergquist F, Bouchard M, Budur K, Carroll C, Chaudhuri KR, Criswell SR, Danielsen EH, Gandor F, Jia J, Kimber TE, Mochizuki H, Robieson WZ, Spiegel AM, Standaert DG, Talapala S, Facheris MF, Fung VSC (2023) 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 12: 1937–1958. https://doi.org/10.1007/s40120-023-00533-1 Aubignat M, Tir M (2024) Continuous subcutaneous foslevodopa-foscarbidopa in Parkinson’s disease: A mini-review of current scope and future outlook. Movement Disorders Clinical Practice 11: 1188– 1194. https://doi.org/10.1002/mdc3.14161 Chen Z-J, Liang C-Y, Yang L-Q, Ren S-M, Xia Y-M, Cui L, Li X-F, Gao B-L (2021) Association of Parkinson’s disease with microbes and microbiological therapy. Frontiers in Cellular and Infection Microbiology 11. https://doi.org/10.3389/fcimb.2021.619354 Fung VSC, Aldred J, Arroyo MP, Bergquist F, Boon AJW, Bouchard M, Bray S, Dhanani S, Facheris MF, Fisseha N, Freire-Alvarez E, Hauser RA, Jeong A, Jia J, Kukreja P, Soileau MJ, Spiegel AM, Talapala S, Tarakad A, Urrea-Mendoza E, Zamudio J, Pahwa R (2024) Continuous subcutaneous foslevodopa/foscarbidopa infusion for the treatment of motor fluctuations in Parkinson’s disease: Considerations for initiation and maintenance. Clinical Parkinsonism & Related Disorders 10: 100239. https://doi.org/10.1016/j.prdoa.2024.100239 Koeglsperger T, Berberovic E, Dresel C, Haferkamp S, Kassubek J, Müller R, Oehlwein C, Paus S, Urban PP (2025) Real-world experience with continuous subcutaneous foslevodopa/foscarbidopa infusion: insights and recommendations. Journal of Neural Transmission (Vienna, Austria: 1996). https://doi.org/10.1007/s00702-025-02911-5 Milanov I, Traykov L, Tarnev I, Haralanov L, Vasileva E, Maslarov D, Atanasova P, Kaprelyan A, Genov K, Ivanova S, Bogdanova D, Danovska M (2023) National consensus on the diagnostics and treatment of Parkinson’s disease. Journal of Movement Disorders 20(3): 32–36. Mujahid BIM, Holla VV, Kamble N, Yadav R, Pal PK, Mahale RR (2025) Non-motor fluctuations in Parkinson’s disease: frequency and clinical correlate. Journal of Neural Transmission. https://doi.org/10.1007/ s00702-025-02908-0 Poplawska-Domaszewicz K, Batzu L, Falup-Pecurariu C, Chaudhuri KR (2024) Subcutaneous Levodopa: A New Engine for the Vintage Molecule. Neurology and Therapy 13: 1055–1068. https://doi. org/10.1007/s40120-024-00635-4 Regensburger M, Csoti I, Jost WH, Kohl Z, Lorenzl S, Pedrosa DJ, Lingor P (2025) Motor and non-motor fluctuations in Parkinson’s disease: the knowns and unknowns of current therapeutic approaches. Journal of Neural Transmission. https://doi.org/10.1007/s00702-025-02990-4 Sakuramoto H, Fujita H, Ogaki K, Suzuki K (2024) A patient with Parkinson’s disease whose sleep status improved after the introduction of continuous subcutaneous foslevodopa/foscarbidopa infusion. Clinical Parkinsonism & Related Disorders 11: 100292. https://doi.org/10.1016/j.prdoa.2024.100292 Soileau MJ, Aldred J, Budur K, Fisseha N, Fung VS, Jeong A, Kimber TE, Klos K, Litvan I, O’Neill D, Robieson WZ, Spindler MA, Standaert DG, Talapala S, Vaou EO, Zheng H, Facheris MF, Hauser RA (2022) Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson’s disease: a randomised, double-blind, active-controlled, phase 3 trial. The Lancet Neurology 21: 1099–1109. https://doi.org/10.1016/ S1474-4422(22)00400-8 Zeng J, Wang X, Pan F, Mao Z (2022) The relationship between Parkinson’s disease and gastrointestinal diseases. Frontiers in Aging Neuroscience 14: 955919. https://doi.org/10.3389/fnagi.2022.955919