Novartis Gene Therapies, Inc. (United States)

INTRODUCTION: We sought to evaluate the cost-effectiveness of newborn screening (NBS) versus no NBS for 5q spinal muscular atrophy (SMA) in England. METHODS: A cost-utility analysis using a combination of decision tree and Markov model structures was developed to estimate the lifetime health effects and costs of NBS for SMA, compared with no NBS, from the perspective of the National Health Service (NHS) in England. A decision tree was designed to capture NBS outcomes, and Markov modeling was used to project long-term health outcomes and costs for each patient group following diagnosis. Model inputs were based on existing literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess the robustness of the model and the validity of the results. RESULTS: The introduction of NBS for SMA in England is estimated to identify approximately 56 (96% of cases) infants with SMA per year. Base-case results indicate that NBS is dominant (less costly and more effective) than a scenario without NBS, with a yearly cohort of newborns accruing incremental savings of £62,191,531 and an estimated gain in quality-adjusted life-years of 529 years over their lifetime. Deterministic and probabilistic sensitivity analyses demonstrated the robustness of the base-case results. CONCLUSIONS: NBS improves health outcomes for patients with SMA and is less costly compared with no screening; therefore, it is a cost-effective use of resources from the perspective of the NHS in England.

BACKGROUND: Improvement and maintenance of bulbar function are goals of disease-modifying treatments for spinal muscular atrophy (SMA). Lack of standardized measures and a widely accepted definition of bulbar function represents a gap in SMA care. OBJECTIVE: A multidisciplinary team conducted post-hoc analyses of pooled data from one phase 1 (START) and two phase 3 (STR1VE-US, STR1VE-EU) studies to define and evaluate bulbar function of infants with SMA type 1 after receiving one-time gene replacement therapy, onasemnogene abeparvovec. METHODS: We defined bulbar function as the ability to meet nutritional needs while maintaining airway protection and the ability to communicate verbally. Four endpoints represented adequate bulbar function: (1) absence of clinician-identified physiologic swallowing impairment, (2) receiving full oral nutrition, (3) absence of adverse events indicating pulmonary instability, and (4) the ability to vocalize at least two different, distinct vowel sounds. We descriptively assessed numbers/percentages of patients who achieved each endpoint and all four collectively. Patients were followed until 18 months old (STR1VE-US and STR1VE-EU) or 24 months (START) post-infusion. RESULTS: Overall, 65 patients were analyzed for swallowing, nutrition intake, and adverse events, and 20 were analyzed for communication. At study end, 92% (60/65) of patients had a normal swallow, 75% (49/65) achieved full oral nutrition, 92% (60/65) had no evidence of pulmonary instability, 95% (19/20) met the communication endpoint, and 75% (15/20) achieved all four bulbar function components in the composite endpoint. CONCLUSIONS: In these three clinical trials, patients with SMA type 1 who received onasemnogene abeparvovec achieved and maintained the bulbar function criteria utilized within this investigation.

Objective: Uniform data collection is fundamental for multicentre clinical trials. We aim to determine the variability, between ALS trial centers, in the prevalence of unexpected or implausible improvements in the revised ALS functional rating scale (ALSFRS-R) score, and its associations with individual patient and item characteristics.Methods: We used data from two multicentre studies to estimate the prevalence of an unexpected increase or implausible improvement in the ALSFRS-R score, defined as an increase of 5 points or more between two consecutive, monthly visits. For each patient with a 5-point or more increase, we evaluated the individual contribution of each ALSFRS-R item.Results: Longitudinal ALSFRS-R scores, originating from 114 trial centers enrolling a total of 1,240 patients, were analyzed. A 5-point or more increase in ALSFRS-R total score was found in 151 (12.2%) patients, with prevalence per study center ranging from 0% to 83%. Bulbar onset, faster disease progression at enrollment, and a lower ALSFRS-R score at baseline were associated with a sudden 5-point or more increase in the ALSFRS-R total score. ALSFRS-R items 2 (saliva), 9 (stairs), 10 (dyspnea), and 11 (orthopnea) were the primary drivers when a 5-point or more increase occurred.Conclusions: Sudden 5-point or more increases in ALSFRS-R total scores between two consecutive visits are relatively common. These sudden increases were not found to occur with equal frequency in trial centers; which underscores the need for amending existing standard operating procedures toward a universal version and monitoring of data quality during the study, in multicentre research.

Bulbar function in spinal muscular atrophy has been defined as the ability to meet nutritional needs by mouth while maintaining airway protection and communicate verbally. The effects of disease-modifying treatment on bulbar function are not clear. A multidisciplinary team conducted post-hoc analyses of phase 3 SPR1NT trial data to evaluate bulbar function of infants at risk for spinal muscular atrophy who received one-time gene replacement therapy (onasemnogene abeparvovec) before symptom onset. Three endpoints represented adequate bulbar function in SPR1NT: (1) absence of physiologic swallowing impairment, (2) full oral nutrition, and (3) absence of adverse events indicating pulmonary instability. Communication was not assessed in SPR1NT. We descriptively assessed numbers/percentages of children who achieved each endpoint and all three collectively. SPR1NT included infants <6 postnatal weeks with two (n = 14) or three (n = 15) copies of the survival motor neuron 2 gene. At study end (18 [two-copy cohort] or 24 [three-copy cohort] months of age), 100% (29/29) of patients swallowed normally, achieved full oral nutrition, maintained pulmonary stability, and achieved the composite endpoint. When administered to infants before clinical symptom onset, onasemnogene abeparvovec allowed children at risk for spinal muscular atrophy to achieve milestones within published normal ranges of development and preserve bulbar function.

To understand providers’ assessment of outcomes following disease-modifying therapy (DMT; onasemnogene abeparvovec or nusinersen monotherapy, or onasemnogene abeparvovec following nusinersen) in patients with spinal muscular atrophy (SMA).

Evaluate long-term safety/efficacy of patients previously treated in the onasemnogene abeparvovec (formally AVXS-101) clinical development program who electively enrolled into LTFU studies LT-001 (NCT03421977) and LT-002 (NCT04042025).

ABSTRACT Introduction We sought to evaluate the cost effectiveness of newborn screening (NBS) versus no NBS for 5q spinal muscular atrophy (SMA) in England. Methods A cost-utility analysis using a combination of decision tree and Markov model structures was developed to estimate the lifetime health effects and costs of NBS for SMA, compared with no NBS, from the perspective of the National Health Service (NHS) in England. A decision tree was designed to capture NBS outcomes, and Markov modelling was used to project long-term health outcomes and costs for each patient group following diagnosis. Model inputs were based on existing literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess the robustness of the model and the validity of the results. Results The introduction of NBS for SMA in England is estimated to identify approximately 56 (96% of cases) infants with SMA per year. Base-case results indicate that NBS is dominant (less costly and more effective) than a scenario without NBS, with a yearly cohort of newborns accruing incremental savings of £62,191,531 and an estimated gain in quality-adjusted life-years of 529 years over their lifetime. Deterministic and probabilistic sensitivity analyses demonstrated the robustness of the base-case results. Conclusions NBS improves health outcomes for patients with SMA and is less costly compared with no screening; therefore, it is a cost-effective use of resources from the perspective of the NHS in England.

To investigate dosing patterns in patients with spinal muscular atrophy (SMA) type 1 treated with nusinersen in the United States.

Quantify strength longitudinally in patients with ALS and variants using ATLIS and compare these changes to ALSFRS-R and forced vital capacity (FVC). Identify putative markers of upper motor neuron (UMN) involvement.