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12th December 2022
Deferiprone, which is an iron chelating agent, failed to delay the progression of symptoms in patients diagnosed with Parkinson’s disease prior to treatment with levodopa according to a recent randomised trial by French researchers.
Globally, Parkinson’s disease is estimated to affect around 10 million people. It is a neurodegenerative disorder that mostly presents in later life, with generalised slowing of movements (bradykinesia) and at least one other symptom of resting tremor or rigidity, due to the loss of dopaminergic activity in the substantia nigra. Within the central nervous system, iron is present in several proteins involved in important processes such as oxygen transportation, oxidative phosphorylation and the synthesis and metabolism of neurotransmitters. However, during ageing, different iron complexes accumulate in brain regions and changes in iron homoeostasis result in altered cellular iron distribution and accumulation in diseases such as Alzheimer’s and Parkinson’s disease. It has therefore been proposed that a moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for Parkinson’s disease. Deferiprone is the only orally active iron-chelating drug to be used therapeutically in conditions of trans fusional iron overload. Moreover, early data suggests that deferiprone use in early Parkinson’s disease, did lead to a reduction in substantia nigra iron levels in a small number of patients. As a result, in the current trial, the French team undertook, a phase 2, randomised, double-blind trial involving participants with newly diagnosed Parkinson’s disease who had never received levodopa. Participant were randomised 1:1 to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. The team set the primary outcome as the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and which ranges from 0 to 260, with higher scores indicating more severe impairment, at 36 weeks.
Deferiprone and outcomes in early Parkinson’s disease
A total of 372 participants with a mean age of 62.5 years (37% female) were randomised to deferiprone (186) or placebo. The mean MDS-UPDRS baseline score was 34.3 and 33.2 in the deferiprone and placebo groups respectively.
At week 36, the MDS-UPDRS score increased by 15.6 points (i.e., worsened) in the deferiprone group and by 6.3 points with placebo. (mean difference = 9.3, 95% CI 6.3 – 12.2, p < 0.001).
When the researchers looked at iron levels in the brain among a subgroup of 148 patients (70 in the placebo arm), there was a greater decrease among those assigned to deferiprone (-0.65 vs -0.17).
Based on these findings, the authors concluded that despite reducing iron brain levels, deferiprone use was associated with worse scores in measures of Parkinsonism than in those with placebo over a period of 36 weeks.
Devos D et al. Trial of Deferiprone in Parkinson’s Disease. N Engl J Med 2022
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.
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.