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15th April 2024
The glucagon-like peptide 1 receptor agonist (GLP-1 RA) lixisenatide, commonly used to treat type 2 diabetes, may slow the progression of Parkinson’s disease symptoms, research suggests.
Investigators evaluating lixisenatide reported less progression of motor disability over a 12-month period in patients taking the drug compared with placebo.
But writing in the New England Journal of Medicine, they said lixisenatide was associated with gastrointestinal side effects in the phase two study and longer and larger trials are now needed to determine the impact and safety of the drug.
It is the second trial of a GLP-1 RA diabetes drug to show an effect in Parkinson’s disease with a 2017 study reporting improvement in motor symptoms in patients taking exenatide.
A larger phase three trial of exenatide, led by UK researchers, is due to report later this year.
The latest study enrolled 156 people with early Parkinson’s disease and no motor complications. All of the patients were taking their usual medication, but half also had a daily injection of lixisenatide and half were given a placebo.
After a year, those given lixisenatide showed no progression of motor problems while those on placebo dropped around three points on the assessment scale – classed as a moderate difference but likely to be clinically meaningful.
The difference was still apparent two months after the trial stopped, the researchers said, suggesting a neuroprotective effect.
Gastrointestinal side effects occurred in more than half the participants receiving lixisenatide, and often led to the dose of the drug being halved, but nausea did not appear to be associated with the magnitude of effect of the drug, they said.
The UK researchers said the study was important given it supports what had previously been found with exenatide.
Professor Tom Foltynie, professor of neurology, at the University College London (UCL) Queen Square Institute of Neurology, said: ‘This cumulative clinical data therefore strongly supports the earlier laboratory and epidemiological data, that GLP1 receptor stimulation in the brain has neuroprotective effects relevant to the neurodegenerative processes of Parkinson’s disease.’
But he said the beneficial effects are likely to be restricted to those GLP1 receptor agonists that can cross the blood-brain barrier which ruled out liraglutide and semaglutide.
Yet it is still not clear whether the drugs simply improve dopaminergic signalling to provide symptom relief or have a neuroprotective effect.
‘Phase 3 trial data of the effects of two years exposure to exenatide in patients with Parkinson’s disease will hopefully address this question and will be available in the second half of 2024,’ Professor Foltynie added.
Professor Masud Husain, who co-leads the dementia research team at the University of Oxford, said the results around lixisenatide were ‘really encouraging‘ for people with Parkinson’s disease.
‘However, the findings do not provide conclusive evidence that the drug has a protective effect on the brain to effectively slow down disease progression. We also have to bear in mind the side effects. Nausea occurred in nearly half and vomiting in 13% of people on the medication.’
Last summer, machine learning models accurately predicted sub-types of Parkinson’s disease based on images of patient-derived stem cells.
A version of this article was originally published by our sister publication Pulse.
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.’
11th September 2023
Retinal thinning appears to a consistent finding in patients with Parkinson‘s disease and questions have arisen over whether this serves as an early biomarker for the subsequent onset of the disease. Clinical writer Rod Tucker delves into the evidence.
Parkinson’s disease (PD) is estimated to affect at least 1% of people over the age of 60. The neurodegenerative condition affects both movement and cognition and is linked with the loss of dopaminergic neurons in the substantia nigra together with the presence of Lewy bodies.
Symptoms and progression of PD depend on the subtype, but patients with PD commonly experience tremor, bradykinesia and muscle stiffness, and up to 70% also have recurrent visual complaints and visual hallucinations.
But what is responsible for the visual dysfunction, and is it somehow linked to direct dopaminergic impairment within the eyes?
The fact that dopaminergic neurotransmission occurs within retina has been known since 1982, and the first evidence that patients with PD could experience visual problems emerged in 1987. Researchers observed a loss in both flicker sensitivity and near the peak of the spatial contrast sensitivity in those with the disease. But whether these visual deficits was causally related to PD remained unknown.
Definitive proof linking visual dysfunction with PD finally arrived, but from a rather unusual source. Canadian researchers decided to measure the level of dopamine in the retinas of eight patients with PD who died.
They stratified their findings based on each individual‘s last dose of levodopa therapy. While the retinal dopamine content in five patients who received levodopa therapy before death was similar to that in the controls, the levels were significantly lower in those who had not received the drug within the last five days before death.
As it became widely acknowledged that retinal levels of dopamine were often reduced in patients with PD, whether this was also associated with a concurrent loss of retinal tissue was less clear. Establishing such a relationship became much easier in 1994, following the introduction of optical coherence tomography (OCT).
This technique, which uses near-infrared light, enabled an assessment of nerve fibre thickness in the eye. In 2004, using OCT, researchers were able to show there was reduced thickness of the circumpapillary retinal nerve fibre layer in patients with PD.
Later work quantified this reduction in comparison to healthy controls and established that retinal thinning of the inner retinal layer was significantly greater in those with PD.
Although there was an emerging consensus that retinal thinning was a hallmark of PD, it wasn‘t actually a universal finding. For instance, other work was unable to detect a difference in comparison to healthy controls. A second study, which also failed to detect differences with PD and healthy controls, called for further work to define the role of OCT as a diagnostic biomarker.
Nevertheless, in a 2018 study, Korean researchers not only re-affirmed the presence of retinal thinning in patients with PD but provided the first evidence that there was a correlation between retinal thinning and nigral dopaminergic neuronal loss within the brains of patients who were at an early stage of their disease.
The relationship between retinal changes and PD was further strengthened in a 2021 meta-analysis of 27 studies that included 1,470 patients. The authors concluded that whole thickness – the thickness of the combination of ganglion cell layer and inner plexiform layer – and nerve fibre layer of central retina are significantly reduced in PD patients.
With confirmation of the relationship between retinal thinning and nigral dopaminergic neuronal loss, researchers sought to address a further pertinent question. If retinal thinning could be detectable in those without overt PD, could it serve as a prognostic marker for the disease?
This was the question posed in a recent study in the journal Neurology. Researchers assessed retinal thinning in two separate cohorts: one in patients with established PD and one in a second prospective cohort where retinal imaging had been performed.
The team looked at several aspects of retinal tissue including the ganglion cell-inner plexiform layer (GCIPL) and inner nuclear layer (INL) thicknesses, which had been measured in the two cohorts with OCT.
As expected, individuals in the first cohort with prevalent PD had thinner GCIPL and INL when compared to healthy controls. But what was more intriguing was how, in the prospective cohort in which patients had undergone OCT imaging approximately 2,653 days before the onset of PD, there was also significant GCIPL and INR thinning in those who went on to develop PD.
For example, the hazard ratio for a thinner GCIPL was 0.62 per standard deviation increase. In other words, for each standard deviation increase in GCIPL thickness, the risk of developing PD was reduced by 38%. In fact, the relationship remained significant even after excluding patients who developed PD within the first 24 months after their retinal imaging.
Taken together, the findings from the current study suggest that retinal thinning can be detected almost seven years before the onset of PD.
With the recognition that visual dysfunction in patients with PD is a harbinger of cognitive decline and greater white matter damage over time, it seems that the retina could become a potential imaging target.
There is still much more work that needs to be done, in particular, establishing the sensitivity and specificity of these changes, before the results can be used to predict whether an individual will develop PD. But if retinal thinning does turn out to be an effective biomarker, it could be used to support the early diagnosis of PD, thereby allowing for more effective treatment planning in those deemed to be at risk of developing the condition.
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.
Citation
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.
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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