Onasemnogene abeparvovec

Onasemnogene abeparvovec was developed to treat spinal muscular atrophy, a disease linked to a mutation in the survival motor neuron 1 (SMN1) gene on chromosome 5q and diagnosed predominantly in young children that causes progressive loss of muscle function and frequently death. The medication is administered as an intravenous infusion. In the United States, onasemnogene abeparvovec is indicated for the treatment of children with spinal muscular atrophy with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. Spinal muscular atrophy is an autosomal-recessive neurodegenerative disorder caused by mutations in the SMN1 gene, characterized by irreversible and progressive motor neuron loss, leading to progressive muscle atrophy and weakness, and subsequent paralysis and death in the most severe cases. Spinal muscular atrophy has an incidence of approximately 4-10 per 10,000 live births. ==Adverse effects==

Common adverse reactions may include nausea and elevated liver enzymes. Serious adverse reactions may include liver problems and low platelets. Transient elevated levels of cardiac troponin‑I were observed in clinical trials; the clinical importance of these findings is not known. However, cardiac toxicity was seen in studies of other animals. ==Mechanism of action==

SMA is a neuromuscular disorder caused by a mutation in the SMN1 gene, which leads to a decrease in SMN protein, a protein necessary for survival of motor neurons. Onasemnogene abeparvovec is a biologic medication consisting of AAV9 virus capsids that contains a SMN1 transgene along with synthetic promoters. ==History==

Onasemnogene abeparvovec, developed by the US biotechnology startup AveXis, which was acquired by Novartis in 2018, is based on research conducted at the Institut de Myologie in France. The US Food and Drug Administration (FDA) granted onasemnogene abeparvovec fast track, breakthrough therapy, priority review, and orphan drug designations. However, in July 2019, the drug was removed from the Committee for Medicinal Products for Human Use (CHMP) accelerated assessment program. In May 2019, onasemnogene abeparvovec received US FDA approval as a treatment for children under two years old. and Israel. In March 2020, it gained regulatory approval in Japan with the same labeling as in the US. In August 2020, onasemnogene abeparvovec received regulatory approval in Brazil from the Brazilian Health Regulatory Agency (ANVISA). Subsequently, it was approved for medical use in Canada in December 2020, in Australia in February 2021, and in Russia in December 2021. According to the Health Sciences Authority register of Singapore, onasemnogene abeparvovec was approved in April 2023. The US Food and Drug Administration expanded the availability of onasemnogene abeparvovec, sold under the brand name Itvisma, for the treatment of spinal muscular atrophy in people aged two years of age and older who have a confirmed mutation in the survival motor neuron 1 gene. Onasemnogene abeparvovec (Itvisma) demonstrated substantial evidence of effectiveness for the treatment of spinal muscular atrophy in children aged two years of age and older with a confirmed mutation in the SMN1 gene based on primary evidence of effectiveness from the adequate and well controlled phase III study, and the confirmatory evidence of effectiveness from data characterizing the mechanism of the product's action, as well as efficacy findings from onasemnogene abeparvovec (Zolgensma) which contains the same active ingredient in an intravenous formulation. The applicant provided adequate justification to support expanding the indication beyond the pivotal study population to include adults with spinal muscular atrophy, however, warnings and precautions are warranted due to the potentially increased risks of adverse events of special interest (e.g., hepatotoxicity and cardiotoxicity) in adult patients with preexisting chronic medical conditions. ==Society and culture==

Legal status Initially approved in the United States in 2019 for children under two years of age, Economics The drug carries a list price of per treatment, making it the most expensive medication in the world . In its first full quarter of sales of medication was sold. In Japan, the drug was made available through the public health care system on 20 May 2020, making it the most expensive drug covered by the Japanese public health care system. The Central Social Insurance Medical Council, responsible for approving the universal drug fee schedule in Japan, has negotiated the price down to (approx. USD ) per patient. Controversy In the months leading up to the medication's approval by the US Food and Drug Administration (FDA), a whistleblower informed Novartis that certain studies of the medication had been subject to data manipulation. In a filing to the FDA, Novartis said that two executives, brothers Brian and Allan Kaspar manipulated the data, pressured others into manipulating data and then attempted to cover it up. In October 2019, Novartis admitted to not having informed the FDA and the European Medicines Agency (EMA) for seven months about toxic effects of the intravenous formulation observed in laboratory animals. Due to the data manipulation issue, the EMA withdrew their decision to allow an accelerated assessment of the medication. In December 2019, Novartis announced that it would donate 100 doses of onasemnogene abeparvovec per year to children outside the US through a global lottery. The decision, which has been claimed by Novartis to be based on a recommendation by unnamed bioethicists, was received with much criticism by the European Commission, some European healthcare regulators and patient groups who see it as emotionally burdening, suboptimal, and ethically questionable. Novartis did not consult with families or doctors before announcing the scheme. Names Onasemnogene abeparvovec is the international nonproprietary name (INN) and the United States Adopted Name (USAN). Onasemnogene abeparvovec is sold under the brand names Zolgensma and Itvisma. == References ==