Longitudinal evaluation of SMN levels as biomarker for spinal muscular atrophy: results of a phase IIb double-blind study of salbutamol

Abstract

BackgroundSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, due to the loss of function of the survival motor neuron (SMN1) gene. The first treatment for the condition, recently approved, is based on the reduction of exon 7 skipping in mRNAs produced by a highly homologous gene (SMN2). The primary objective of the present study was to evaluate the applicability of the dosage of SMN gene produts in blood, as biomarker for SMA, and the safety of oral salbutamol, a beta2-adrenergic agonist modulating SMN2 levels.MethodsWe have performed a 1-year multicentre, double-blind, placebo-controlled study with salbutamol in 45 adult patients with SMA. Patients assumed 4 mg of salbutamol or placebo/three times a day. Molecular tests were SMN2 copy number, SMN transcript and protein levels. We have also explored the clinical effect, by the outcome measures available at the time of study design.ResultsThirty-six patients completed the study. Salbutamol was safe and well tolerated. We observed a significant and progressive increase in SMN2 full-length levels in peripheral blood of the salbutamol-treated patients (p<0.00001). The exploratory analysis of motor function showed an improvement in most patients.ConclusionsOur data demonstrate safety and molecular efficacy of salbutamol. We provide the first longitudinal evaluation of SMN levels (both transcripts and protein) in placebo and in response to a compound modulating the gene expression: SMN transcript dosage in peripheral blood is reliable and may be used as pharmacodynamic marker in clinical trials with systemic compounds modifying SMN2levels.Trial registration numberEudraCT no. 2007-001088-32.

Biomarkers and the Development of a Personalized Medicine Approach in Spinal Muscular Atrophy

“…Similar results have been seen with salbutamol; a compound that increases SMN2 full length transcript and SMN protein. In this study, a subjective improvement of motor function was noted in all patients with a statistically significant improvement in validated functional scores in a proportion of patients (26). This suggests target engagement and a potential method of tracking treatment response.…”

Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment

“…While the reported CK/Crn dynamics suggest therapy response in our nusinersen-treated cohort, Tiziano et al reported an increase of CK associated with increasing SMN2-full length transcripts in SMA patients treated with salbutamol in a clinical trial. 45 Here, CK values were evaluated as part of safety assessment, because salbutamol and other beta2 agonists are known to increase CK levels 46 regardless of the underlying disease (also patients without neuromuscular diseases 47,48 ). This is of interest, as it shows that CK is influenced by different factors, which have to be properly controlled in further prospective studies.…”

Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review

“…Clinical trials which could address this issue require long durations and robust clinical outcome measures, drawing attention to the need for biomarkers which are sensitive to changes in disease progression and/or response to disease modifying agents [120]. Unlike studies in infants and children with SMA, in which circulating neurofilaments are emerging as potential measures to assess disease progression and response to nusinersen treatment [121], no studies in adults with SMA have yielded a robust, reliable measurement [86,88,[122][123][124][125][126]. A potential complexity in trying to detect elevated markers of axonal degradation in adults with SMA is again the slow rate of progression.…”