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12th January 2024
The subcutaneous drug foslevodopa-foscarbidopa (brand name Produodopa) has been launched in the European Union (EU) for the treatment of advanced Parkinson’s disease, its manufacturer AbbVie has announced.
It becomes the first-and-only subcutaneous 24-hour infusion of levodopa-based therapy available in the EU for the treatment severe motor fluctuations and hyperkinesia (excessive movement) or dyskinesia (involuntary movement) in people living with advanced Parkinson’s disease and whose symptoms are inadequately controlled by other therapies.
The continuous delivery of foslevodopa-foscarbidopa provides levodopa 24-hours a day, which AbbVie said may help patients by extending the period when symptoms are well-controlled – often referred to as ‘On’ time.
‘On’ time signifies when symptoms are controlled, whereas ‘Off’ time occurs when symptoms return between medication doses.
Foslevodopa-foscarbidopa gained marketing authorisation through the European Medicine’s Agency’s decentralised procedure in the third quarter of 2022. The Vyafuser pump for the drug’s subcutaneous delivery received Conformité Européenne (CE) Mark in November of 2023.
Angelo Antonini, professor of neurology at the Department of Neuroscience, University of Padua, Italy, said: ‘This approval represents a significant advancement for those with Parkinson’s disease who have historically had limited treatment options for advanced stages.
‘When oral treatment no longer sufficiently helps with improvement in motor fluctuations, patients need alternative options. Produodopa’s around-the-clock infusion allows for continuous delivery of levodopa, the gold standard of treatment.’
The launch was supported by three studies, including the Phase 3, 12-month open-label M15-741 study in which the primary endpoint was to evaluate the safety and tolerability of foslevodopa-foscarbidopa.
Secondary endpoints included changes from baseline in normalised ‘Off’ and ‘On’ time, the percentage of patients reporting morning akinesia – defined as ‘Off’ time upon waking – and total scores from quality-of-life surveys.
Eligible patients included adults 30 years or older diagnosed with levodopa-responsive idiopathic Parkinson’s disease experiencing an average of greater than or equal to 2.5 hours of ‘Off’ time per day, as assessed by patient’s Parkinson’s disease diaries.
The results, published in the Journal of Neurology & Therapy, observed a reduction in motor fluctuations as early as Week 1 and persisted through Week 52, and the percentage of patients experiencing morning akinesia dropped from 77.7% at baseline to 27.8% at week 52.
The researchers concluded that there was a favourable benefit/risk profile and sustained improvements in ‘Off’ time and ‘On’ time without dyskinesia, and morning akinesia as measured by the percentage of patients in early morning ‘Off’ time.
The 12-week Phase 3 M15-736 study and a Phase 1 pharmacokinetic comparability study also supported the launch.
The majority of adverse events (AEs) with foslevodopa-foscarbidopa were non-serious and mild or moderate in severity. The most frequent AEs (greater than or equal to 10%) were infusion site events (infusion site erythema, infusion site cellulitis, infusion site nodule, infusion site pain, infusion site oedema, infusion site reaction, and infusion site infection), hallucination, fall, and anxiety.
Foslevodopa-foscarbidopa was recommended by the UK’s National Institute of Health and Care Excellence in autumn 2023 for treating advanced Parkinson’s with motor symptoms and the final technology appraisal guidance was published on 29 November 2023.
8th November 2023
The drug foslevodopa-foscarbidopa (brand name Produodopa) has been recommended in final draft guidance by the National Institute for Health and Care Excellence (NICE) for people with advanced Parkinson’s disease who experience motor fluctuations.
Foslevodopa-foscarbidopa is a solution of carbidopa and levodopa prodrugs for continuous subcutaneous delivery via a portable infusion pump that can be refilled at home by the patient.
As foslevodopa and foscarbidopa are released into the body, foslevodopa is turned into dopamine, which is then used to transmit messages between the parts of the brain and nerves that control movement.
Taking foslevodopa with foscarbidopa increases the availability of foslevodopa in the brain, said NICE.
Oral treatment with levodopa and carbidopa is the standard initial treatment for Parkinson’s, but other treatments may be added as the disease progresses. Non-oral treatments used in advanced Parkinson’s that is responsive to levodopa include apomorphine, deep brain stimulation through surgery or levodopa–carbidopa intestinal gel.
Foslevodopa-foscarbidopa was under consideration by NICE as an alternative to standard oral treatment and levodopa–carbidopa intestinal gel for people who cannot have apomorphine or deep brain stimulation surgery, or for when these treatments no longer control symptoms.
NICE has previously published clinical guidelines and medtech innovation briefings for the condition but this is the first technology appraisal to look at Parkinson’s disease treatments.
Once available on the NHS, foslevodopa-foscarbidopa is set to benefit around 900 patients with advanced Parkinson’s, according to NICE.
Helen Knight, director of medicines evaluation at NICE, said: ’Foslevodopa-foscarbidopa represents an important new treatment for people with advanced Parkinson’s, providing an easy-to-use option that can help them manage their symptoms more reliably and effectively.
’This is the first time NICE has approved a treatment for Parkinson’s and comes after NICE was able to work with [AbbVie] to address the issues that had initially prevented a positive recommendation. We are determined to get the best care to patients fast and ensure value for the taxpayer.’
The charity Parkinson’s UK welcomed the news and said: ’Although Produodopa won’t be suitable for everyone, it is really positive to have another effective treatment for people whose complex movement symptoms are making life difficult.’
It added: ’Now that NICE has approved this life-changing treatment we want to see as many people with Parkinson’s benefit from it. We’ll be encouraging the NHS across England, Northern Ireland and Wales to make sure it’s commissioned.
’It can take up to three months after NICE approves a treatment for it to be commissioned, so we’ll be monitoring this closely.
’We also want [Produodopa] to be available in Scotland, so we’ll be working with AbbVie and the Scottish Medicines Consortium to make sure that everyone with Parkinson’s can benefit from it.’
8th December 2022
A subcutaneous infusion of foslevodopa and foscarbidopa to patients with advanced Parkinson’s disease, led to an increase in treatment ‘on time’ and a reduction in ‘off time’ but without troublesome dyskinesia according to the results of a randomised, double-blind, double-dummy, active-controlled trial by US and Australian researchers.
Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease characterised by both motor and non-motor features with the former symptoms attributed to the loss of striatal dopaminergic neurons. The incidence of Parkinson’s disease increases with age and globally, there are an estimated 10 million people living with the condition.
The gold standard treatment is levodopa (L-dopa) which has been used in clinical practice since the 1960’s and is a precursor of dopamine which crosses the blood-brain barrier, thus increasing dopamine production in the brain and helping to manage Parkinsonism symptoms. In addition, carbidopa, a decarboxylase inhibitor, is added to levodopa formulations to decrease the peripheral conversion of L-dopa to dopamine, reduce gastrointestinal side effects and increase central nervous system levodopa bioavailability. However, as PD progresses higher and more frequent doses of treatment are required, and this leads to dyskinesias at high dopamine concentrations and increased “off” time when levels fall back. Consequently, patients with advanced Parkinson’s experience periods where they have good disease control (referred to as ‘on time’) and times of poor motor control and mobility (i.e., ‘off time’). In an effort to mitigate these fluctuations in levodopa, researchers examined a soluble levodopa-carbidopa phosphate prodrug (foslevodopa foscarbidopa) and which releases the two main treatments once in the circulation, as a continuous, subcutaneous infusion. This early study demonstrated consistent and stable LD plasma exposure, supporting further studies of this treatment.
For the current study, researchers undertook a 12-week randomised, double-blind, double-dummy, active-controlled study in patients with levodopa-responsive advanced Parkinson’s disease that was inadequately controlled on current therapy, including at least 2·5 hours of average daily off time. Participants were randomly assigned 1:1, to either continuous subcutaneous infusion of foslevodopa foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. The primary efficacy endpoint was the change from baseline to week 12 in hours of average on time without troublesome dyskinesia and off time.
Foslevodopa foscarbidopa and treatment outcome
A total of 141 participants with a mean age of 66.4 years (30% women) were randomised to foslevodopa foscarbidopa (74) or oral levodopa carbidopa and the mean duration of PD was 8.58 years.
Compared to oral levodopa-carbidopa, participants assigned to foslevodopa foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (mean change from baseline = 2·72 vs 0·97 hours) and this mean difference (MD) of 1.75 hours was statistically significant (p = 0.0083). There was also a significantly reduced ‘off time’ compared to oral therapy (MD = -1.79, p = 0.0054).
The most frequent adverse events in the foslevodopa foscarbidopa group were infusion site adverse events including erythema (27%), pain (26%), cellulitis (19%) and oedema (12%), most of which were non-serious and mild-moderate in severity.
The authors concluded that foslevodopa foscarbidopa has a favourable benefit-risk profile and represented a potential non-surgical alternative for patients with advanced Parkinson’s disease.
Citation
Soileau MJ et al. Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson’s disease: a randomised, double-blind, active-controlled, phase 3 trial. Lancet Neurol 2022.
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