Neurológia pre prax 2/2021

Orphan drugs in treatment of rare neuromuscular disorders

Rare disorders (RD) are a group of heterogeneous disorders in relation to their etiology, severity and geographical occurrence. RD are defined by the limit of their maximal prevalence in population, which has been fixed in Europe by 5 persons out of 10 000 inhabitants. Inherited and autoimmune neuromuscular disorders (NMD) belong to largest groups of RD. Current options of immunotherapy significantly improved the prognosis of rare autoimmune NMD. In myasthenia gravis at certain situations (refractory MG; treatment side effects) some new treatment options are available – complement inhibitors (eculizumab), B-cell directed therapy (rituximab) and neonatal Fc receptor antagonists (efgartigimod). New treatments improved significantly the prognosis of some inherited NMD which had in past unfavourable, mostly fatal, prognosis. Spinal muscular atrophy – nusinersen (antisense nucleotid), onasemnogene abeparvovec (gene therapy), risdiplam (splicing modifier). Hereditary amyloid transthyretin polyneuropathy – tafamidis (transthyretin stabilizer), patisiran (small interfering RNAs) and inotersen (antisense oligonucletide) resulting in gene silencing. Fabry disease – agalsidase alfa, agalsidase beta (enzyme replacement therapy), migalastat (chaperone). Lambert-Eaton myasthenic syndrome – amifampridine (blocker of presynaptic potassium channels). Duchenne muscular dystrophy – ataluren (promotes ribosomal readthrough for patients with nonsense DMD mutations), eteplirsen and golodirsen (exon skipping). Pompe disease – recombinant human alfa-glucosidase (enzyme replacement therapy). Malignant hyperthermia – dantrolene (RYR1 receptor blocker). In some rare NMD it will be important to identify biomarkers for tailoring and monitoring therapy in optimizing patient care, including differentiation of treatment responders and non-responders.

Keywords: rare hereditary and autoimmune NMD, orphan drugs, biomarkers