Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy

Kichula, Elizabeth; Proud, Crystal; Farrar, Michelle A.; Kwon, Jennifer M.; Saito, Kayoko; Desguerre, Isabelle; McMillan, Hugh J.

doi:10.1002/mus.27363

Cited by 45 publications

(56 citation statements)

References 77 publications

(201 reference statements)

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“…Two patients had infections before developing TMA. Thus, waiting for illness to resolve prior to treatment with onasemnogene abeparvovec was recently recommended [16]. Encapsulated bacteria can trigger TMA because the capsular polysaccharide is a virulence factor, enabling immune evasion.…”

Section: Discussionmentioning

confidence: 99%

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy

et al. 2021

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“…In recent years, several newborn screening (NBS) programs for SMA have been implemented [44]. NBS is expected to play an increasingly important role in the management of SMA, allowing for early diagnosis and treatment during the pre-symptomatic stage, and potentially leading to improved outcomes [1,9].…”

Section: Place Of Onasemnogene Abeparvovec In the Management Of Smamentioning

confidence: 99%

“…In a small US survey (n = 18), parents of children with NBS-diagnosed SMA chose onasemnogene abeparvovec (72%) over risdiplam (11%) and nusinersen (6%) as first-line treatment for reasons such as frequency of treatment and method of administration [56]. Of note, access to long-term multidisciplinary care (including rehabilitation, ventilatory and nutritional support) continues to be important after gene therapy in order to maximize the effectiveness of onasemnogene abeparvovec [9,19,24]. While there is increasing interest in combinatorial therapies for SMA, they are not currently recommended due to a lack of clinical evidence regarding their efficacy and safety [8,57].…”

Section: Place Of Onasemnogene Abeparvovec In the Management Of Smamentioning

confidence: 99%

“…SMA types 2 and 3 have a later onset and a less severe course, while SMA type 4, the mildest form of the disease, occurs in early adulthood [3]. Pre-symptomatic SMA is diagnosed based on SMN2 copy number alone [9]. This presymptomatic stage provides a therapeutic window for starting treatment before the occurrence of significant motor neuron loss [10].…”

Section: Introductionmentioning

confidence: 99%

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Onasemnogene Abeparvovec: A Review in Spinal Muscular Atrophy

Blair

2022

CNS Drugs

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Onasemnogene abeparvovec (Zolgensma ® ) is a gene therapy approved for the treatment of spinal muscular atrophy (SMA). Administered as a one-time intravenous infusion, onasemnogene abeparvovec uses the adeno-associated virus vector to deliver a functional copy of the human survival motor neuron (SMN) gene to motor neuron cells. SMN1 encodes survival motor neuron protein, which is responsible for the maintenance and function of motor neurons. In clinical trials, onasemnogene abeparvovec improved event-free survival, motor function and motor milestone outcomes in patients with SMA, with these improvements maintained over the longer term (up to a median of ≈ 5 years). Onasemnogene abeparvovec was also associated with rapid age-appropriate achievement of motor milestones and improvements in motor function in children with pre-symptomatic SMA, indicating the benefit of early treatment. Onasemnogene abeparvovec was generally well tolerated. Hepatotoxicity is a known risk that can generally be mitigated with prophylactic prednisolone. In conclusion, onasemnogene abeparvovec represents an important treatment option for patients with SMA, particularly when initiated early in the course of the disease. Plain Language SummarySpinal muscular atrophy (SMA) is a rare genetic condition that causes muscle weakness and wasting. Infants with SMA type 1, the most common form of the disease, are unable to sit without support and usually die before the age of 2 years if untreated. SMA is caused by a defect in the survival motor neuron 1 (SMN1) gene. This gene provides instructions for making survival motor neuron protein, which is essential for the health and normal function of the nerves that control muscles. Onasemnogene abeparvovec (Zolgensma ® ) is a gene therapy that replaces the missing SMN1 gene and is given as a one-time infusion into a vein. In patients with SMA, onasemnogene abeparvovec improved event-free survival (alive without breathing support), motor function and achievement of motor milestones. Patients maintained these improvements for up to ≈ 5 years after treatment. Onasemnogene abeparvovec also helped pre-symptomatic children reach motor milestones at ages similar to healthy children. Onasemnogene abeparvovec is generally well tolerated and is an important treatment option for patients with SMA, including those who are yet to develop symptoms.

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“…as an episome in their nuclei. The formulation also includes chicken-β-actin promoter, which enables permanent transgene expression [3]. Clinical studies show the greatest efficacy of gene therapy in infants with type 1 SMA below 6 months of age [3].…”

Section: Case Reportmentioning

confidence: 99%

Is gene therapy in spinal muscular atrophy safe? A casereport of thrombotic microangiopathy following onasemnogene abeparvovec

Ziółkiewicz¹,

Bielak²,

Welian³

et al. 2022

J Pre Clin Clin Res.

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Spinal muscular atrophy is a neuromuscular disorder caused by a mutation in the survival of SMN1 gene. Diagnosis of the disease is based mainly on the presence of hypotonia and symmetrical [1]. A five-month-old male with SMA type 1 was admitted to the Children's Neurology Clinic for gene therapy with onasemnogene abeparvovec. He was diagnosed with spinal muscular atrophy in newborn screening.Neurological examination of the patient revealed abolition of deep tendon reflexes. Administration of the medication proceeded without complications. Two weeks after gene therapy, abnormal test results were observed. The patient experienced several adverse effects of the therapy, which indicated thrombotic microangiopathy (TMA). Gene therapy with onasemnogene abeparvovec provides many hopes for patients with SMA. On the other hand, its safety remains uncertain and patients require comprehensive long-term monitoring for possible side-effects.

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Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy

Cited by 45 publications

References 77 publications

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy

Onasemnogene Abeparvovec: A Review in Spinal Muscular Atrophy

Is gene therapy in spinal muscular atrophy safe? A casereport of thrombotic microangiopathy following onasemnogene abeparvovec

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