Onasemnogene abeparvovec, sold under the brand name Zolgensma, is a

gene therapy Gene therapy is Health technology, medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells. The first attempt at modifying human DNA ...

used to treat

spinal muscular atrophy Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common geneti ...

(SMA), a disease causing muscle function loss in children. It involves a one-time infusion of the medication into a vein. It works by providing a new copy of the SMN gene that produces the SMN protein. SMA stems from an

SMN1 Survival of motor neuron 1 (''SMN1''), also known as component of gems 1 or ''GEMIN1'', is a gene that encodes the SMN protein in humans. Gene ''SMN1'' is the telomeric copy of the gene encoding the SMN protein; the centromeric copy is ter ...

gene mutation, causing SMN protein deficiency vital for

motor neuron A motor neuron (or motoneuron), also known as efferent neuron is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly o ...

survival. Onasemnogene abeparvovec, a biologic drug utilizing AAV9 virus capsids containing an SMN1 transgene, is administered to motor neurons, boosting SMN protein levels. Common side effects include vomiting and elevated

liver enzymes Liver function tests (LFTs or LFs), also referred to as a hepatic panel or liver panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial t ...

, while more severe reactions involve liver issues and low platelet count. Developed by AveXis and acquired by

Novartis Novartis AG is a Swiss multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland. Novartis is one of the largest pharmaceutical companies in the world and was the eighth largest by re ...

, onasemnogene abeparvovec gained various

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

designations and approvals globally. Controversies included data manipulation concerns and delayed reporting to regulatory agencies. Onasemnogene abeparvovec's price is high, earning it the title of the world's most expensive medication at the time of commercial approval. This has later been exceeded by other gene therapies like Hemgenix. Several countries such as Japan, Netherlands, Canada, Brazil and others negotiated a lower price for Zolgensma for their public healthcare systems.

Medical uses

Onasemnogene abeparvovec was developed to treat

, a disease linked to a

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

in the ''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 In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of people less than two years of age with spinal muscular atrophy with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. The treatment is approved in the United States and certain other countries for use in children with spinal muscular atrophy up to the age of two, including at the presymptomatic stage of the disease. In the European Union and Canada, it is indicated for the treatment of people with spinal muscular atrophy who either have a clinical diagnosis of spinal muscular atrophy type 1 or have up to three copies of the ''SMN2'' gene.

Adverse effects

Common adverse reactions may include nausea and elevated

. Serious adverse reactions may include

liver problems Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground gla ...

and

low platelets In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coa ...

. 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 A neuromuscular disease is any disease affecting the peripheral nervous system (PNS), the neuromuscular junctions, or skeletal muscles, all of which are components of the motor unit. Damage to any of these structures can cause muscle atrophy and we ...

caused by a

in the ''SMN1'' gene, which leads to a decrease in SMN protein, a protein necessary for survival of

s. Onasemnogene abeparvovec is a biologic drug consisting of AAV9 virus

capsid A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or m ...

s that contains a ''

transgene A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...

along with synthetic promoters. Upon administration, the AAV9 viral vector delivers the ''SMN1'' transgene to the affected motor neurons, where it leads to an increase in SMN protein.

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 U.S. Food and Drug Administration (FDA) granted onasemnogene abeparvovec-xioi various designations including fast track,

breakthrough therapy Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "b ...

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

, and

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

designations. Additionally, the FDA awarded the manufacturer a rare pediatric disease priority review voucher and approved onasemnogene abeparvovec for AveXis Inc. In June 2015, the European Commission granted orphan designation to the drug. However, in July 2019, the drug was removed from the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...

(CHMP) accelerated assessment program. In May 2019, onasemnogene abeparvovec received US FDA approval as a treatment for children under two years old. Since 2019, the treatment has been reimbursed in Qatar and Israel. In March 2020, it gained regulatory approval in Japan with the same labeling as in the US. Additionally, the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

(EMA) recommended conditional

marketing authorization Marketing authorisation is the process of reviewing and assessing the evidence to support a medicinal product, such as a drug, in relation to its marketing, finalised by granting of a licence to be sold. This process is performed within a legal f ...

in March 2020, specifically for individuals with SMA type 1 or any SMA type with no more than three copies of the

SMN2 Survival of motor neuron 2 (''SMN2'') is a gene that encodes the SMN protein (full and truncated) in humans. Gene The ''SMN2'' gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four g ...

gene. This conditional approval was granted for Europe in May 2020. In August 2020, onasemnogene abeparvovec received regulatory approval in Brazil from the

Brazilian Health Regulatory Agency The Brazilian Health Regulatory Agency (, ''Anvisa'', literally National Health Surveillance Agency) is a regulatory body of the Brazilian government, created in 1999 during President Fernando Henrique Cardoso's term of office. It is responsible ...

(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.

Society and culture

Legal status

Initially approved in the United States in 2019 for children under two, onasemnogene abeparvovec's approval varies in different regions.

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.Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...