Onasemnogene abeparvovec

Onasemnogene abeparvovec, sold under the trade name Zolgensma, is a gene therapy medication used to treat spinal muscular atrophy (SMA). It is used with corticosteroids as a one-time injection into a vein. It was approved in the United States in 2019 for children less than two years old.

Common side effects include vomiting and increased liver enzymes. Serious side effects may include liver problems, low platelets, and heart damage. Onasemnogene abeparvovec works by providing a new copy of the gene that makes the human SMN protein.

Onasemnogene abeparvovec was developed by AveXis, which was acquired by Novartis, based on the work of Martine Barkats from the Institut de Myologie in France. It carries a list price of  per treatment, making it the most expensive medication in the world as of 2019. A formulation that is injected into the spinal canal is being studied in people under six years old; however, this study was put on hold in October 2019.

Medical use 
Onasemnogene abeparvovec is used to treat spinal muscular atrophy linked to a mutation in the survival motor neuron 1 (SMN1) gene, a genetic disorder diagnosed predominantly in young children that causes progressive loss of muscle function and frequently death.

In an intravenous formulation, it is approved in the United States for use in children up to the age of two with SMA, including before symptoms occur.

The medication is used with corticosteroids in an effort to protect the liver. The use of corticosteroids is recommended for a least two months starting the day before onasemnogene abeparvovec is given. If liver abnormalities persist, longer use of corticosteroids is recommended.

While marketed as a one-time treatment for SMA, it is unknown how long the onasemnogene abeparvovec-delivered transgene will persist in people. Since motor neurons do not divide, it is expected that the transgene may have long-term stability.

Adverse effects
Common adverse reactions may include nausea and increased liver enzymes. Serious adverse reactions may include liver problems, low platelets, and heart damage. It is recommended to check liver function for three months after administration.

As the medication may reduce the platelet count, platelets may need to be checked before the medication is started, then weekly for the first month and every two weeks for the next two months until the level is back to baseline.

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 drug consisting of AAV9 virus capsids that contains a SMN1 transgene 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
The U.S. Food and Drug Administration (FDA) granted the application for onasemnogene abeparvovec-xioi for fast track, breakthrough therapy, priority review, and orphan drug designations. The FDA also awarded the manufacturer a rare pediatric disease priority review voucher, and granted the approval of Zolgensma to AveXis Inc.

In June 2015, the European Commission granted orphan designation for onasemnogene abeparvove. In July 2019, onasemnogene abeparvovec was removed from the Committee for Medicinal Products for Human Use (CHMP) accelerated assessment program.

Society and culture

Terminology
Onasemnogene abeparvovec is the international nonproprietary name (INN) and US adopted name (USAN). The medication is known under compound name AVXS-101 in countries where it is not approved for marketing.

Cost
It carries a list price of  per treatment, making it the most expensive medication in the world as of 2019. In its first four months of sales  of medication was sold.

Approval
Onasemnogene abeparvovec was approved for medical use in the United States in 2019. , it is in the approval process for the European Union and for Japan.

Controversies
In the months leading up to the drug's approval by the FDA, a whistleblower informed Novartis that certain studies of the drug had been subject to data manipulation. Novartis fired two AveXis executives it determined responsible but informed the FDA of the data integrity issue only in June 2019, a month after the drug's approval. The delay drew strong condemnation of the FDA. In October 2019, the company 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.

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 patient groups (e.g. the UK's TreatSMA, SMA Europe) who see it as emotionally burdening, suboptimal, and ethically questionable. Novartis did not consult with families or doctors before announcing the scheme. Alan Regenberg, a bioethicist at Johns Hopkins Berman Institute of Bioethics, said that the scheme was perhaps the best available since it may be impossible to reliably establish prognosis for children under two years of age. Also not all the SMA community opposes it.

Research
AveXis is also developing an intrathecal formulation of onasemnogene abeparvovec; however, trials in humans were halted by the US Food and Drug Administration (FDA) in October 2019 due to observed animal toxicity.

See also 
 Vectors in gene therapy

References

External links
 

Category:Breakthrough therapy
Category:Drug discovery
Category:Experimental drugs
Category:Novartis brands
Category:Gene therapy
Category:Orphan drugs
Category:Spinal muscular atrophy