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.
Spinal muscular atrophy (SMA) is an autosomal recessive, childhood-onset motor neuron disease. Onasemnogene abeparvovec (OA) is a gene therapy designed to address SMA's root cause. In pivotal mouse ...toxicology studies, the liver was identified as a major site of OA toxicity. Clinical data reflect elevations in serum aminotransferase concentrations, with some reports of serious acute liver injury. Prophylactic prednisolone mitigates these effects. Herein, we aim to provide pragmatic, supportive guidance for identification, management, and risk mitigation of potential drug-induced liver injury.
Data from 325 patients with SMA who had received OA through 31 December 2019, in 5 clinical trials, a managed access program (MAP), and a long-term registry (RESTORE), and through commercial use, were analyzed. Liver-related adverse events, laboratory data, concomitant medications, and prednisolone use were analyzed.
Based on adverse events and laboratory data, 90 of 100 patients had elevated liver function test results (alanine aminotransferase, and/or aspartate aminotransferase, and/or bilirubin concentrations). Of these, liver-associated adverse events were reported for 34 of 100 (34%) and 10 of 43 (23%) patients in clinical trials and MAP/RESTORE, respectively. Two patients in MAP had serious acute liver injury, which resolved completely. While all events in the overall population resolved, prednisolone treatment duration varied (range: 33–229 days), with a majority receiving prednisolone for 60–120 days. More than 60% had elevations in either alanine aminotransferase, aspartate aminotransferase, or bilirubin concentrations prior to dosing. Greater than 40% received potentially hepatotoxic concomitant medications.
Hepatotoxicity is a known risk associated with OA use. Practitioners should identify contributing factors and mitigate risk through appropriate monitoring and intervention.
Onasemnogene abeparvovec is a type of medicine called a “gene therapy,” which is used to treat babies and young children who have a rare, serious inherited condition called “spinal muscular atrophy” (SMA). It works by supplying a fully functioning copy of the survival motor neuron or SMN gene, which then helps the body produce enough SMN protein. However, it can cause an immune response that could lead to an increase in enzymes produced by the liver. This article provides information about the liver injury and how to prevent and recognize if it happens, so that it may be treated properly.
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•Onasemnogene abeparvovec is an approved gene therapy for spinal muscular atrophy.•Hepatotoxicity is a known risk associated with onasemnogene abeparvovec.•Liver-related data for 325 patients who received onasemnogene abeparvovec were analyzed and are presented.•The risk of hepatotoxicity can be serious if not recognized.•Practitioners should mitigate risk through appropriate monitoring and intervention.
Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene ...abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy.
STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes per kg) for 30–60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed).
From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36–100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79–100) survived free from permanent ventilation at age 14 months (vs 6 26%, 8–44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus).
Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit–risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1.
Novartis Gene Therapies.
Human gene replacement therapies such as onasemnogene abeparvovec (OA) use recombinant adeno-associated virus (rAAV) vectors to treat monogenic disorders. The heart and liver are known target organs ...of toxicity in animals; with cardiac and hepatic monitoring recommended in humans after OA dosing. This manuscript provides a comprehensive description of cardiac data from preclinical studies and clinical sources including clinical trials, managed access programs and the post-marketing setting following intravenous OA administration through 23 May 2022. Single dose mouse GLP-Toxicology studies revealed dose-dependent cardiac findings including thrombi, myocardial inflammation and degeneration/regeneration, which were associated with early mortality (4-7 weeks) in the high dose groups. No such findings were documented in non-human primates (NHP) after 6 weeks or 6 months post-dose. No electrocardiogram or echocardiogram abnormalities were noted in NHP or humans. After OA dosing, some patients developed isolated elevations in troponin without associated signs/symptoms; the reported cardiac adverse events in patients were considered of secondary etiology (e.g. respiratory dysfunction or sepsis leading to cardiac events). Clinical data indicate cardiac toxicity observed in mice does not translate to humans. Cardiac abnormalities have been associated with SMA. Healthcare professionals should use medical judgment when evaluating the etiology and assessment of cardiac events post OA dosing so as to consider all possibilities and manage the patient accordingly.
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 <8.5 kg. Through GMAP, children weighing ≥8.5 kg received onasemnogene abeparvovec. We describe safety data for heavier patients in GMAP.
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.
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.
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.
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.
Epidemiologic studies of physical activity among pediatric hemodialysis (HD) patients are lacking. A sedentary lifestyle in End-Stage Kidney Disease is associated with a higher cardiovascular ...mortality risk. In those patients receiving HD, time spent on dialysis and restrictions on physical activity due to access also contribute. No consensus exists regarding physical activity restrictions based on vascular access type. The aim of this study was to describe the patterns of physical activity restrictions imposed by pediatric nephrologists on pediatric HD patients and to understand the basis for these restrictions.
We conducted a cross-sectional study involving US pediatric nephrologists using an anonymized survey through Pediatric Nephrology Research Consortium. The survey consisted of 19 items, 6 questions detailed physician characteristics with the subsequent 13 addressing physical activity restrictions.
A total of 35 responses (35% response rate) were received. The average years in practice after fellowship was 11.5 years. Significant restrictions were placed on physical activity and water exposure. None of the participants reported accesses damage or loss that was attributed to physical activity and sport participation. Physicians practice is based on their personal experience, standard practice at their HD center, and clinical practices they were taught.
There is no consensus among pediatric nephrologists about allowable physical activity in children receiving HD. Due to the lack of objective data, individual physician beliefs have been utilized to restrict activities in the absence of any deleterious effects to accesses. This survey clearly demonstrates the need for more prospective and detailed studies to develop guidelines regarding physical activity and dialysis access in order to optimize quality of care in these children.
The care of children with end-stage renal disease (ESRD) is highly specialized and often poorly understood by nonpediatric providers and facility/institution administrators. As such, this position ...paper has been created to offer provider, facility, and institutional guidance regarding the components of care necessary for children receiving dialysis. Key differences between adult and pediatric dialysis units are highlighted. Responsibilities and expectations of the members of the interdisciplinary dialysis team are outlined as they pertain specifically to the care of pediatric dialysis patients. Physical and staffing requirements of the dialysis facility are reviewed, again focusing on unique needs and challenges faced by the pediatric dialysis care team. Among these, vascular access options and proper planning of ESRD care are underscored. Pediatric quality-of-life metrics differ significantly from adult quality variables, and proper tools for assessment must be used. Endorsed by the Council of the American Society of Pediatric Nephrology (ASPN), this position paper serves as a reference tool for the provision of care to pediatric patients with ESRD.
This research examined the impact of school location on teaching and learning through a case study of two urban, two rural and two remote Fijian secondary schools. A total of 48 semi-structured ...interviews were conducted: 16 from each category of urban, rural and remote. Each school was represented by three teachers, three heads of department and two administrators. The study established that rural and remote schools often face different challenges to their urban counterparts: geography, poverty and funding influence the quality of education. Leadership support and adequate resources are the key to breaking the overreliance on traditional methods of teaching and enhancing student classroom interest and participation. Finally, just as schools serve different communities, geographical location impacts on external links, cooperation and professional exchange and development. Understanding the impact of school locality on teaching and learning in Fiji should benefit other developing nations and the educational community at large.
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