Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised, placebo-controlled, dose-finding trial followed by 24 months of treatment.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations in the SMN1 gene. Risdiplam is an orally administered molecule that modifies SMN2 pre-mRNA splicing to increase functional SMN protein. METHODS: SUNFISH Part 1 was a dose-finding study conducted in 51 individuals with types 2 and 3 SMA aged 2-25 years. A dose-escalation method was used to identify the appropriate dose for the subsequent pivotal Part 2. Individuals were randomized (2:1) to risdiplam or placebo at escalating dose levels for a minimum 12-week, double-blind, placebo-controlled period, followed by treatment for 24 months. The dose selection for Part 2 was based on safety, tolerability, pharmacokinetic, and pharmacodynamic data. Exploratory efficacy was also measured. RESULTS: There was no difference in safety findings for all assessed dose levels. A dose-dependent increase in blood SMN protein was observed; a median twofold increase was obtained within 4 weeks of treatment initiation at the highest dose level. The increase in SMN protein was sustained over 24 months of treatment. Exploratory efficacy showed improvement or stabilization in motor function. The pivotal dose selected for Part 2 was 5 mg for patients with a body weight ≥20 kg or 0.25 mg/kg for patients with a body weight <20 kg. CONCLUSIONS: SUNFISH Part 1 demonstrated a twofold increase in SMN protein after treatment with risdiplam. The observed safety profile supported the initiation of the pivotal Part 2 study. The long-term efficacy and safety of risdiplam are being assessed with ongoing treatment.

Natural history of Type 1 spinal muscular atrophy: a retrospective, global, multicenter study.

BACKGROUND: ANCHOVY was a global, multicenter, chart-review study that aimed to describe the natural history of Type 1 spinal muscular atrophy (SMA) from a broad geographical area and provide further contextualization of results from the FIREFISH (NCT02913482) interventional study of risdiplam treatment in Type 1 SMA. METHODS: Data were extracted from medical records of patients with first symptoms attributable to Type 1 SMA between 28 days and 3 months of age, genetic confirmation of SMA, and confirmed survival of motor neuron 2 copy number of two or unknown. The study period started on 1 January 2008 for all sites; study end dates were site-specific due to local treatment availabilities. Primary endpoints were time to death and/or permanent ventilation and proportion of patients achieving motor milestones. Secondary endpoints included time to initiation of respiratory and feeding support. RESULTS: Data for 60 patients from nine countries across Asia, Europe and North and South America were analyzed. The median age (interquartile range [IQR]) for reaching death or permanent ventilation was ~ 7.3 (5.9-10.5) months. The median age (IQR) at permanent ventilation was ~ 12.7 (6.9-16.4) months and at death was ~ 41.2 (7.3-not applicable) months. No patients were able to sit without support or achieved any level of crawling, standing or walking. INTERPRETATION: Findings from ANCHOVY were consistent with published natural history data on Type 1 SMA demonstrating the disease's devastating course, which markedly differed from risdiplam-treated infants (FIREFISH Part 2). The results provide meaningful additions to the literature, including a broader geographical representation.

Distribution of weight, stature, and growth status in children and adolescents with spinal muscular atrophy: An observational retrospective study in the United States.

INTRODUCTION/AIMS: Data regarding weight, height/length, and growth status of patients with spinal muscular atrophy (SMA) who have received only supportive care are limited. This cross-sectional study describes these measurements in patients with Type 1 and Types 2/3 SMA and compares them with reference values from typically developing children. METHODS: Retrospective baseline data from three sites in the Pediatric Neuromuscular Clinical Research Network (Boston, New York, Philadelphia) were used. Descriptive statistics for weight, height/length, body mass index-for-age, as well as weight-for-length and absolute and relative deviations from reference values (ie, 50th percentile from World Health Organization/Centers for Disease Control growth charts) were calculated. Furthermore, growth status was reported. RESULTS: A total of 91 genetically confirmed patients with SMA receiving optimal supportive care and without any disease-modifying treatment were stratified into Types 1 (n = 28) and 2/3 SMA (n = 63). Patients with Type 1 SMA weighed significantly less (median = -7.5%) compared with reference values and patients with Types 2/3 SMA were significantly shorter (mean = -3.0%) compared with reference values. The median weight was considerably below the 50th percentile in both groups of patients, even if they received a high standard of care and proactive feeding support. DISCUSSION: More research is needed to understand which factors influence growth longitudinally, and how to accurately capture growth in patients with SMA. Further research should investigate the best time to provide feeding support to avoid underweight, especially in patients with Type 1, and how to avoid the risk of overfeeding, especially in patients with Types 2/3 SMA.

The influence of sample size on preferences from experience.

People often learn from experience about the distribution of outcomes of risky options. Typically, people draw small samples, when they can actively sample information from risky gambles to make decisions. We examine how the size of the sample that people experience in decision from experience affects their preferences between risky options. In two studies (N = 40 each), we manipulated the size of samples that people could experience from risky gambles and measured subjective selling prices and the confidence in selling price judgements after sampling. The results show that, on average, sample size influenced neither the selling prices nor confidence. However, cognitive modelling of individual-level learning showed that around half of the participants could be classified as Bayesian learners, whereas the other half adhered to a frequentist learning strategy and that if learning was cognitively simpler more participants adhered to the latter. The observed selling prices of Bayesian learners changed with sample size as predicted by Bayesian principles, whereas sample size affected the judgements of frequentist learners much less. These results illustrate the variability in how people learn from sampled information and provide an explanation for why sample size often does not affect judgements.

How environmental regularities affect people's information search in probability judgments from experience.

In everyday life, people encounter smaller rewards with higher probability than larger rewards. Do people expect this reward-probability regularity to hold in experimental settings? To answer this question, we tested whether people's behavior in probability judgment tasks is affected by the correlation between reward size and reward probabilities. In Study 1, we asked people to judge reward probabilities under uncertainty. In line with the ecological reward-probability correlation, people assumed that larger rewards were less likely than smaller rewards. In Study 2, we tested the prediction that people's information search and integration depend on the representativeness of the environment. Participants performed an experience-based probability judgment task in which they sampled outcomes from unknown gambles until they felt confident to estimate the probabilities of the gambles' outcomes. We manipulated the reward-probability relationship of the gambles in 3 experimental groups. Rewards and reward probabilities were negatively correlated, positively correlated, or not correlated at all. A negative correlation mimics the ecological reward-probability relationship often present in real life. We analyzed people's search effort and whether they integrated sample-based uncertainty into their judgments. We found that people sampled fewer outcomes in the ecologically representative condition than in the other 2 conditions. However, people did not integrate sample-based uncertainty in their judgments: In all conditions people treated the observed outcomes as representative of the underlying outcome distribution. People's prior beliefs about regularities in environments provides a potential explanation of why people often rely on small sample sizes when making judgments and decisions from experience. (PsycINFO Database Record (c) 2019 APA, all rights reserved).