Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

The clinical, economic, and humanistic burden of Dravet syndrome - A systematic literature review.

Dravet syndrome (DS) is a developmental and epileptic encephalopathy with evolving disease course as individuals age. In recent years, the treatment landscape of DS has changed considerably, and a comprehensive systematic review of the contemporary literature is lacking. Here we synthesized published evidence on the occurrence of clinical impacts by age, the economic and humanistic (health-related quality-of-life [HRQoL]) burden, and health state utility. We provide an evidence-based, contemporary visualization of the clinical manifestations, highlighting that DS is not limited to seizures; non-seizure manifestations appear early in life and increase over time, contributing significantly to the economic and humanistic burden of disease. The primary drivers of HRQoL in DS include seizure severity, cognition, and motor and behavioral problems; in turn, these directly affect caregivers through the extent of assistance required and consequent impact on activities of daily living. Unsurprisingly, costs are driven by seizure-related events, hospitalizations, and in-home medical care visits. This systematic review highlights a paucity of longitudinal data; most studies meeting inclusion criteria were cross-sectional or had short follow-up. Nonetheless, available data illustrate the substantial impact on individuals, their families, and healthcare systems and establish the need for novel therapies to address the complex spectrum of DS manifestations.

An updated cost-utility model for onasemnogene abeparvovec (Zolgensma®) in spinal muscular atrophy type 1 patients and comparison with evaluation by the Institute for Clinical and Effectiveness Review (ICER).

Background: Recent cost-utility analysis (CUA) models for onasemnogene abeparvovec (Zolgensma®, formerly AVXS-101) in spinal muscular atrophy type 1 (SMA1) differ on key assumptions and results. Objective: To compare the manufacturer's proprietary CUA model to the model published by the Institute for Clinical and Economic Review (ICER), and to update the manufacturer's model with long-term follow-up data and some key ICER assumptions. Study design: We updated a recent CUA evaluating value for money in cost per incremental Quality-adjusted Life Year (QALY) of onasemnogene abeparvovec versus nusinersen (Spinraza®) or best supportive care (BSC) in symptomatic SMA1 patients, and compared it to the ICER model. Setting/Perspective: USA/Commercial payer Participants: Children aged <2 years with SMA1. Interventions: Onasemnogene abeparvovec, a single-dose gene replacement therapy, versus nusinersen, an antisense oligonucleotide, versus BSC. Main outcome measure: Incremental-cost effectiveness ratio and value-based price using traditional thresholds for general medicines in the US. Results: Updated survival (undiscounted) predicted by the model was 37.60 years for onasemnogene abeparvovec compared to 12.10 years for nusinersen and 7.27 years for BSC. Updated quality-adjusted survival using ICER's utility scores and discounted at 3% were 13.33, 2.85, and 1.15 discounted QALYs for onasemnogene abeparvovec, nusinersen, and BSC, respectively. Using estimated net prices, the discounted lifetime cost/patient was $3.93 M for onasemnogene abeparvovec, $4.60 M for nusinersen, and $1.96 M for BSC. The incremental cost per QALY gained for onasemnogene abeparvovec was dominant against nusinersen and $161,648 against BSC. These results broadly align with the results of the ICER model, which predicted a cost per QALY gained of $139,000 compared with nusinersen, and $243,000 compared with BSC (assuming a placeholder price of $2 M for onasemnogene abeparvovec), differences in methodology notwithstanding. Exploratory analyses in presymptomatic patients were similar. Conclusion: This updated CUA model is similar to ICER analyses comparing onasemnogene abeparvovec with nusinersen in the symptomatic and presymptomatic SMA populations. At a list price of $2.125 M, onasemnogene abeparvovec is cost-effective compared to nusinersen for SMA1 patients treated before age 2 years. When compared to BSC, cost per QALY of onasemnogene abeparvovec is higher than commonly used thresholds for therapies in the USA ($150,000 per QALY).

Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients.

Background: Spinal muscular atrophy type 1 (SMA1) is a devastating genetic disease for which gene-replacement therapy may bring substantial survival and quality of life benefits. Objective: This study investigated the cost-effectiveness of onasemnogene abeparvovec (AVXS-101) gene-replacement therapy for SMA1. Study design: A Markov model was used to estimate the incremental cost-effectiveness ratio (ICER), expressed as cost/quality-adjusted life year ($/QALY), of AVXS-101 versus nusinersen over a lifetime. Survival, healthcare costs and QALYs were estimated using natural history data for SMA patients who achieved motor milestones (sitting/walking). Health utility weights were obtained from the CHERISH trial. Setting: USA; commercial payer perspective Participants: SMA1 infants Interventions: AVXS-101 was compared to nusinersen. Main outcome measure: The primary outcome was the ICER. Results: Expected survival (undiscounted) over a lifetime predicted by the model was 37.20 life years for AVXS-101 and 9.68 for nusinersen (discounted QALYs, 15.65 and 5.29, respectively). Using a potential AVXS-101 price range ($2.5-5.0M/treatment), the average lifetime cost/patient was $4.2-6.6M for AVXS-101 and $6.3M for nusinersen. The ICER range was (-$203,072) to $31,379 per QALY gained for AVXS-101 versus nusinersen, indicating that AVXS-101 was cost-effective with prices of ≤$5M. Conclusion: Single-dose AVXS-101 was cost-effective compared to chronic nusinersen for SMA1 patients.

Survival, Motor Function, and Motor Milestones: Comparison of AVXS-101 Relative to Nusinersen for the Treatment of Infants with Spinal Muscular Atrophy Type 1.

INTRODUCTION: Infants with spinal muscular atrophy (SMA) type 1 typically face a decline in motor function and a severely shortened life expectancy. Clinical trials for SMA type 1 therapies, onasemnogene abeparvovec (AVXS-101) and nusinersen, demonstrated meaningful improvements in efficacy (e.g., overall survival) but there were no head-to-head clinical trials assessing comparative efficacy. This study estimated the treatment effects of AVXS-101 relative to nusinersen for the treatment of SMA type 1. METHODS: Overall survival, event-free survival (no death or need to use permanent assisted ventilation), improvement in motor function [increase of ≥ 4 points in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score from baseline], and motor milestone achievements (head control, rolling over, and sitting unassisted) reported in the onasemnogene abeparvovec (AVXS-101-CL-101; NCT02122952) and nusinersen (ENDEAR; NCT02193074) clinical trials were indirectly compared using frequentist and Bayesian approaches. RESULTS: Among symptomatic infants with SMA type 1, the number needed to treat (NNT) to prevent one more death with AVXS-101 instead of nusinersen was 6.2 [95% confidence intervals (CI) = 4.1-12.2], and the probability of preventing death was 20% higher for patients treated with AVXS-101 than nusinersen [risk ratio (RR) = 1.2, 95% CI 1.1-1.3]. For event-free survival, the NNT to prevent one more event was 2.6 (95% CI 2.0-3.6) and RR was 1.6 (95% CI 1.4-1.9). For improvement in motor function, NNT was 3.5 (95% CI 2.6-5.3) and RR was 1.4 (95% CI 1.2-1.6). For milestone achievements, the NNTs were 1.4 (95% CI 1.1-1.9), 1.5 (95% CI 1.1-2.5), and 1.2 (95% CI 1.0-1.5); RRs 4.2 (95% CI 2.6-6.7), 7.8 (95% CI 3.6-17.0), and 11.2 (95% CI 5.1-24.5) for head control, rolling over, and sitting unassisted, respectively. Results were similar using the Bayesian approach. CONCLUSION: This indirect comparison (AVXS-101-CL-101 vs. ENDEAR) among symptomatic SMA type 1 infants suggests that AVXS-101 may have an efficacy advantage relative to nusinersen for overall survival, independence from permanent assisted ventilation, motor function, and motor milestones. FUNDING: AveXis.

Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy.

BACKGROUND: Spinal Muscular Atrophy type 1 (SMA1) is a rare genetic neuromuscular disease where 75% of SMA1 patients die/require permanent-ventilation by 13.6 months. This study assessed the health outcomes of SMA1 infants treated with AVXS-101 gene replacement therapy. METHODS: Twelve genetically confirmed SMA1 infants with homozygous deletions of the SMN1 gene and two SMN2 gene copies received a one-time intravenous proposed therapeutic dose of AVXS-101 in an open label study conducted between December 2014 and 2017. Patients were followed for 2-years post-treatment for outcomes including (1) pulmonary interventions; (2) nutritional interventions; (3) swallow function; (4) hospitalization rates; and (5) motor function. RESULTS: All 12 patients completed the study. Seven infants did not require noninvasive ventilation (NIV) by study completion. Eleven patients had stable or improved swallow function, demonstrated by the ability to feed orally; 11 patients were able to speak. The mean proportion of time hospitalized was 4.4%; the mean unadjusted annualized hospitalization rate was 2.1 (range = 0, 7.6), with a mean length of stay/hospitalization of 6.7 (range = 3, 12.1) days. Eleven patients achieved full head control and sitting unassisted and two patients were walking independently. CONCLUSIONS: AVXS-101 treatment in SMA1 was associated with reduced pulmonary and nutritional support requirements, improved motor function, and decreased hospitalization rate over the follow-up period. This contrasts with the natural history of progressive respiratory failure and reduced survival. The reduced healthcare utilization could potentially alleviate patient and caregiver burden, suggesting an overall improved quality of life following gene replacement therapy. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02122952.

Successful treatment of a patient with severe atopic dermatitis and severe asthma by centrifugal therapeutic plasma exchange.

This is a case of a 42-year-old atopic man with severe atopic dermatitis and asthma who despite long-term immunosuppression was not well controlled. He had a very high IgE at 7897 Iu/mL prior to treatment. He underwent two therapeutic plasma exchanges (TPEs) through two peripheral lines in our outpatient department, which led to an absolute decrease of 44.1% and 37% in his plasma IgE for each exchange, and immediate sustained improvement in shortness of breath, and atopic dermatitis, and hence led to a vast improvement in his quality of life. TPE offers a new exciting adjunctive treatment option for severe atopic individuals, where it may provide a novel role to reduce health burden and improve clinical symptoms. Further studies need to be performed to establish an optimal protocol and potential maintenance with recently available targeted anti-IgE biologics.

Potential use of an estrogen-glucocorticoid receptor chimera as a drug screen for tissue selective estrogenic activity.

SERMs act as ER agonists in bone despite their antagonistic properties in other tissues. As well as inhibiting bone remodelling, this effect may involve stimulation of osteoblast activity, in light of evidence from recent in vivo studies. However, progress in exploring this action has been hampered by a lack of accurate in vitro models. For example, ER antagonists are reported to stimulate reporter assays based on estrogen target genes in osteoblasts, contrary to their inhibitory effects in vivo. We examined whether evaluating global aspects of ER function provides a more accurate reflection of ER activation in osteoblasts, based on the use of morphological and/or transcriptional read-outs with green fluorescent protein (GFP)-receptor chimeras. Osteoblast-like (ROS and U2OS) and breast cancer (MCF7) cells were transfected with a human ERalpha-GFP fusion protein, and treated with ER agonists (17beta-estradiol, and dienestrol), antagonists (ICI 182,780 and ZK 164015) and SERMs (tamoxifen, raloxifene, 4-hydroxytamoxifen (4-HT) and hexestrol). We investigated cellular compartmentalisation of these constructs by fluorescence microscopy, nuclear mobility by fluorescence recovery after photobleaching (FRAP), and global activation of estrogenic transcription using a ERE-luc reporter. SERMs caused a modest increase in ERE-luc activity in osteoblast-like cells (but not in breast cells), and a reduction in nuclear mobility in breast (but not osteoblast-like) cells. These studies were then repeated using a GFP chimera where the human GR ligand binding domain (LBD) was replaced by the human ERalpha LBD (ERGR-GFP), combined with a GRE-luc reporter. Interestingly, SERMs increased both cytoplasmic to nuclear translocation of ERGR-GFP, and GRE-luc reporter activity, in osteoblast-like (but not breast) cells. Indeed, transcriptional responses to SERMs in osteoblast-like cells were considerably greater with the ERGR/GRE-luc than the ERalpha/ERE-luc system, 4-HT inducing 300 and 25% increases in reporter activity respectively. ER antagonists were entirely without effect. We conclude that evaluation of global estrogenic activity, as opposed to activation of a specific target gene, provides a more accurate read-out for osteoblast stimulation. In particular, ERGR-mediated GRE-luc activity provides a high signal response to estrogen agonists and SERMs, in a cell context dependent manner closely resembling that observed in vivo. Further studies utilising this system are justified to explore the mechanistic basis for estrogenic stimulation of osteoblast activity, and to identify newer SERMs capable of targeting this activity.