† Compared to placebo
1. Xadago (safinamide). Summary of product characteristics. 2. Kulisevsky J. Safinamide - A Unique Treatment Targeting Both Dopaminergic and Non-Dopaminergic Systems. Eur Neurol Rev 2016;11(2):101-5. 3. Borgohain R, et al. Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations. Mov Disord. 2014;29(2):229-37. 4. Borgohain R, et al. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson’s disease. Mov Disord. 2014;29(10):1273-80. 5. Schapira AH, et al. Assessment of Safety and Efficacy of Safinamide as a levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurol. 2017;74(2):216-224.
The pathophysiology of Parkinson's disease
Parkinson’s disease is a slow, progressive, degenerative disorder largely characterised by striatal dopaminergic depletion. However, alterations in other neurochemical pathways are also implicated (Calabresi et al, 2017).
The degeneration of nigrostriatal dopaminergic neurons causes chain reactions, resulting in the overstimulation of glutamate (Jenner et al, 2019). Parkinson’s disease is associated with elevated levels of glutamate within the basal ganglia (Zhang et al, 2016).
Motor implications of glutamatergic overstimulation include:
(Jenner et al, 2019)
Apoptosis of dopaminergic neurons, contributing to levodopa-induced dyskinesia
Non-motor implications of glutamatergic overstimulation include:
(Jenner et al, 2019)
Mechanism of action
Xadago has a unique dual mechanism of action (Kulisevsky et al, 2016):
MAO-B, alongside COMT, is responsible for dopamine metabolism, and is found localised in glial cells (Caccia et al, 2006). Xadago selectively and reversibly inhibits MAO-B, which prolongs the lifetime activity of dopamine in the synaptic cleft (Calabresi et al, 2017).
Parkinson’s Disease is associated with elevated levels of glutamate within the basal ganglia (Zhang et al, 2016). Xadago inhibits sodium and calcium voltage-dependent channels, modulating glutamate release (Calabresi et al, 2017).
To what extent the non-dopaminergic effects contribute to the overall effect has not been established (Xadago (safinamide), Summary of Product Characteristics).
Watch Professor Peter Jenner, Emeritus Professor of Pharmacology at King’s College London, provide an overview of the pathophysiology of Parkinson's disease and the mechanism of action of Xadago.
The SYNAPSES study
The SYNAPSES trial was a European, multicenter, retrospective-prospective cohort StudY to observe the safiNAmide safety profile and pattern of use in clinical Practice during the firSt post commErcialisation phaSe.
The study was designed to investigate the use of safinamide in routine clinical practice, as recommended by the European Medicines Agency.
The trial reinforced the previously documented safety profile of safinamide even in special groups of patients, and showed clinically significant improvements in motor complications and motor scores in the UPDRS scale (Abbruzzese et al, 2021).