Safety of onasemnogene abeparvovec for patients with spinal muscular atrophy 8.5 kg or heavier in a Global Managed Access Program

BACKGROUND: Spinal muscular atrophy is a rare, neurodegenerative disorder caused by biallelic deletions in the survival motor neuron (SMN1) gene. Onasemnogene abeparvovec is a one-time, intravenous gene replacement therapy designed to deliver the SMN1 transgene. Although available in many geographies, it is not approved globally. The Global Managed Access Program (GMAP) expanded treatment access to patients in countries where treatment was not approved. Previous onasemnogene abeparvovec clinical trials included patients with body weight \u3c8.5 kg. Through GMAP, children weighing ≥8.5 kg received onasemnogene abeparvovec. We describe safety data for heavier patients in GMAP. METHODS: GMAP records were reviewed to identify patients weighing ≥8.5 kg at onasemnogene abeparvovec dosing. To obtain corresponding adverse event (AE) data, the Novartis ARGUS safety database was searched using patient identification numbers and birth dates/dosing dates for any reported AE for GMAP patients. RESULTS: As of September 2, 2021, 102 patients weighing ≥8.5 kg at time of dosing were identified. Fifty-four (53%) had one or more reported AEs. Three patients were reported to be deceased. All three deaths were assessed to be secondary to acute respiratory events. Most (62%) AEs were non-serious. The most frequently reported AEs included increases in hepatic laboratory values, decreased platelets and thrombocytopenia, pyrexia, vomiting, and decreased appetite. CONCLUSIONS: Safety findings for patients weighing ≥8.5 kg administered onasemnogene abeparvovec through GMAP were consistent with those described in clinical trials and included hepatotoxicity, thrombotic microangiopathy, and thrombocytopenia

Thrombotic microangiopathy following onasemnogene abeparvovec for spinal muscular atrophy: A case series

Spinal muscular atrophy is treated with onasemnogene abeparvovec, which replaces the missing survival motor neuron 1 gene via an adeno-associated virus vector. As of July 1, 2020, we had identified 3 infants who developed thrombotic microangiopathy following onasemnogene abeparvovec. Early recognition and treatment of drug-induced thrombotic microangiopathy may lessen mortality and morbidity

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy

INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated. RESULTS: The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients. CONCLUSIONS: Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity

Clinical trial and postmarketing safety of onasemnogene abeparvovec therapy

INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated. RESULTS: The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients. CONCLUSIONS: Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity

Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy

UNLABELLED:Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p<or=0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Delta7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p<or=0.0036) and maximum ulnar CMAP scores (p<or=0.0001) increased significantly. CONCLUSIONS:While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various candidate outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects. TRIAL REGISTRATION:ClinicalTrials.gov

SMA CARNI-VAL Trial Part I: Double-Blind, Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy

Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo.Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1) and an ambulatory group of "walkers" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures.At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007).This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials.Clinicaltrials.gov NCT00227266

ANÁLISIS ESPACIO-TEMPORAL DEL BROTE DE LA ENFERMEDAD DEL DENGUE EN EL ÁREA METROPOLITANA DE LA CD. DE MONTERREY, NUEVO LEÓN, MÉXICO (2007)

Se revisaron los archivos del Laboratorio Estatal de Salud Pública (LESPN) para realizar un análisis de lo ocurrido en el brote de la enfermedad del dengue durante todo el año 2007 en el área metropolitana de la Cd. de Monterrey N. L. Se clasificaron los criaderos, para las muestras positivas de Ae. aegypti en: diversos chicos, diversos grandes, botes y cubeta 20 L., menores de 200 L., tambos 200 L, mayores de 200 L., piletas y cisternas, plantas acuáticas, aire lavado y llantas, se observa la frecuencia y su productividad larval de cada uno de ellos. De las 3106 (89.66% del total) muestras positivas para Ae. eagypti, se determinaron 11575 (96.20%) de larvas. De los análisis de Virología se separan los casos positivos a la prueba serológica de ELISA, se dividieron por tipo de dengue (Clásico y Hemorrágico), grupos de edad y genero, además, se consideró la fecha de inicio de la sintomatología como una variable más a observar. De un total de 11045 muestras de suero procesadas para la determinación de dengue, 2829 (25.61%) resultaron positivas a la prueba de ELISA, Se determinaron 2341 (82.75%) del tipo de dengue clásico y 488 (17.25%) del hemorrágico. En las mujeres se presentaron 1610 (56.91%) de los casos, mientras que en los hombres fueron 1219 (43.08%), el grupo de edad más afectado fue el de 11-20 años. Los municipios que más casos presentaron fueron: Monterrey 889 (31.42%), Apodaca 757 (26.76%), San Nicolás de los Garza 568 (20.08%) y Escobedo 348 (12.30%) sumando un total de 2562 (90.56%) de los casos. Mediante el paquete estadístico SPSS v15, se realizaron tablas cruzadas para determinar las frecuencias del número de larvas de Aedes aegypti y recipientes por mes de muestreo. También se aplicó el mismo procedimiento para los casos de dengue (clásico y hemorrágico) respecto al mes de inicio de la sintomatología, género y edad de los pacientes. Abstract The State Public Health Laboratory (LESPN) files were revised to analyze the outbreak of dengue during 2007 in Monterrey, N. L. the metropolitan area Ae. aegypti breeding sites were classified to identify positive samples in different containers: small, large boats and 20 L bucket, less than 200 L, 200 L drums, over 200 L, sinks and tanks, aquatic plants, coolers and tires to determine the frequency and larval productivity of each of them. From 3106 (89.66%) positive samples for Ae. eagypti, were determinate 11 575 (96.20%) of larvae. According to the virology analysis, the positive cases were separated by the ELISA serological test, there were divided by type of classic dengue fever (DF) or dengue hemorrhagic fever (DHF), age group and gender, also was considered the date of onset of symptoms as a variable to analyze. From a total of 11,045 serum samples processed for dengue detection, 2829 (25.61%) were positives. There were determined 2341 (82.75%) of classical dengue and 488 (17.25%) from the hemorrhagic. Most cases occurred in women 1610 (56.91%), while 1219 cases (43.08%) occurred in men, the age group most affected was from 11 to 20 old. The highest occurrence in Monterrey was 889 (31.42%), followed by Apodaca 757 (26.76%), San Nicolas de los Garza 568 (20.08%) and Escobedo 348 (12.30%) for a total of 2562 (90.56 %) cases. Using SPSS v15, cross tables were conducted to determine the frequencies number of larvae ofAe. aegypti and containers per month of sampling. Also the same procedure was applied for cases of dengue (DF anf DHF) referring month of symptoms onset, gender and age of the patients. Palabras Clave: Aedes aegypti, Dengue, Monterrey, México

Comparative genomics of Cluster O mycobacteriophages

Mycobacteriophages - viruses of mycobacterial hosts - are genetically diverse but morphologically are all classified in the Caudovirales with double-stranded DNA and tails. We describe here a group of five closely related mycobacteriophages - Corndog, Catdawg, Dylan, Firecracker, and YungJamal - designated as Cluster O with long flexible tails but with unusual prolate capsids. Proteomic analysis of phage Corndog particles, Catdawg particles, and Corndog-infected cells confirms expression of half of the predicted gene products and indicates a non-canonical mechanism for translation of the Corndog tape measure protein. Bioinformatic analysis identifies 8-9 strongly predicted SigA promoters and all five Cluster O genomes contain more than 30 copies of a 17 bp repeat sequence with dyad symmetry located throughout the genomes. Comparison of the Cluster O phages provides insights into phage genome evolution including the processes of gene flux by horizontal genetic exchange