olesoxime and Spinal-Muscular-Atrophies-of-Childhood

Great progress has been made in the clinical translation of several therapeutic strategies for spinal muscular atrophy (SMA), including measures to selectively address Survival Motor Neuron (SMN) protein deficiency with SMN1 gene replacement or modulation of SMN2 encoded protein levels, as well as neuroprotective approaches and supporting muscle strength and function. This review highlights these novel therapies. This is particularly vital with the advent of the first disease modifying therapy, which has brought to the fore an array of questions surrounding who, how and when to treat, and stimulated challenges in resource limited healthcare systems to streamline access for those eligible for drug therapy. The overhaul of the landscape for all those involved in SMA extends to the design of further drug trials and the necessity of multidisciplinary supportive care to potentiate the effects of disease modifying medications. The impact of respiratory complications in SMA is central to management in the current era of emerging novel therapies. These fundamental changes in our knowledge and management approach to those with SMA are explored further in this review.

Topics: Cholestenones; Genetic Therapy; Humans; Imidazoles; Neuroprotective Agents; Oligonucleotides; Physical Therapy Modalities; Pyrazines; Respiration, Artificial; Spinal Muscular Atrophies of Childhood; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein

The 32-item Motor Function Measure (MFM32) is an assessment of motor function, and its measurement properties were established in a broad neuromuscular disease population. This study sought to investigate the reliability, validity, and ability to detect change of MFM32 in individuals with Type 2 and non-ambulant Type 3 spinal muscular atrophy (SMA). Data were used from the Phase 2 study assessing the efficacy and safety of olesoxime. A total of 110 individuals with Type 2 or 3 SMA were included in the analyses. Test-retest reliability (intraclass-correlation coefficient in global impression-defined stable individuals), internal consistency (Cronbach's alpha), convergent validity (Spearman rank order correlations with other measures), known-groups validity (analysis of covariance comparing Hammersmith Functional Motor Scale -defined groups), and ability to detect change (analysis of covariance comparing global impression-defined groups) were calculated. Strong evidence of test-retest reliability (intraclass-correlation coefficient = 0.93-0.95), internal consistency (Cronbach's alpha = 0.89), convergent validity (Hammersmith Functional Motor Scale: rho = 0.87; forced vital capacity: rho = 0.61), known-groups validity (all p<0.0001), and ability to detect change (all p<0.001) were demonstrated. These results provide evidence of the MFM32's measurement properties, supporting its use in longitudinal research in individuals with Type 2 and non-ambulant Type 3 SMA.

Topics: Adolescent; Adult; Child; Child, Preschool; Cholestenones; Female; Humans; Longitudinal Studies; Male; Motor Activity; Psychomotor Performance; Retrospective Studies; Severity of Illness Index; Spinal Muscular Atrophies of Childhood; Young Adult

In a previous Phase 2 study, olesoxime had a favorable safety profile. Although the primary endpoint was not met, analyses suggested that olesoxime might help in the maintenance of motor function in patients with Types 2/3 SMA. This open-label extension study (OLEOS) further characterizes the safety, tolerability and efficacy of olesoxime over longer therapy durations. In OLEOS, no new safety risks were identified. Compared to matched natural history data, patients treated with olesoxime demonstrated small, non-significant changes in motor function over 52 weeks. Motor function scores were stable for 52 weeks but declined over the remainder of the study. The greatest decline in motor function was seen in patients ≤15 years old, and those with Type 2 SMA had faster motor function decline versus those with Type 3 SMA. Previous treatment with olesoxime in the Phase 2 study was not protective of motor function in OLEOS. Respiratory outcomes were stable in patients with Type 3 SMA >15 years old but declined in patients with Type 2 SMA and in patients with Type 3 SMA ≤15 years old. Overall, with no stabilization of functional measures observed over 130 weeks, OLEOS did not support significant benefit of olesoxime in patients with SMA.

Topics: Adolescent; Adult; Child; Cholestenones; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Motor Activity; Spinal Muscular Atrophies of Childhood; Young Adult

Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA.. This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3-25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in all patients who received one or more doses of the study drug. The trial is registered with ClinicalTrials.gov, number NCT01302600.. The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and -1·82 for placebo (treatment difference 2·00 points, 96% CI -0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment.. Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed.. AFM Téléthon and Trophos SA.

Topics: Adolescent; Adult; Child; Child, Preschool; Cholestenones; Double-Blind Method; Female; Humans; Male; Mobility Limitation; Neuroprotective Agents; Outcome Assessment, Health Care; Spinal Muscular Atrophies of Childhood; Young Adult

We propose a mathematical model to empirically describe spinal muscular atrophy (SMA) progression assessed by the 3 domains of the motor function measure (MFM) scale. The model implements development and deterioration of muscle function.. Nonlinear mixed-effects modeling was applied to data from 2 observational studies and 1 prospective clinical efficacy study comprising 190 healthy participants and 277 patients with type 2/3 SMA.. The model evidenced correlations between parameter estimates for different MFM domains. Slower development in MFM domain D1 (standing and transfers) was associated with faster deterioration for MFM domains D2 (proximal and axial motricity) and D3 (distal motor function).. The model describes all individual data well, although sparseness and variability of observational data prevented numerically stable estimation of parameters. Treatment duration in clinical studies was too limited to determine a proper drug-effect model that could differentiate between symptomatic and disease modifying effects. Muscle Nerve 58: 528-535, 2018.

Topics: Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; Cholestenones; Clinical Trials, Phase II as Topic; Disease Progression; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Models, Theoretical; Nonlinear Dynamics; Observational Studies as Topic; Spinal Muscular Atrophies of Childhood; Young Adult