Onasemnogene abeparvovec, sold under the brand name Zolgensma, is a
gene therapy
Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
medication 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 genetic ...
(SMA).
It is used as a one-time
infusion into a vein.
Onasemnogene abeparvovec works by providing a new copy of the gene that makes the
human SMN protein.
The treatment must be accompanied by a course of corticosteroids of at least two months. Common side effects include vomiting and increased
liver enzymes.
Onasemnogene abeparvovec was first approved for medical use in the United States in 2019 as a treatment for children less than two years old.
[ ] It was later approved in other jurisdictions with similar scope.
The approval scope in certain jurisdictions, including the European Union and Canada, is somewhat different.
Medical uses
Onasemnogene abeparvovec has been developed 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 genetic ...
, 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, mi ...
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.
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 patients 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.
The medication is used with
corticosteroids
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involve ...
in an effort to
protect the liver.
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.
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.
Liver function should be monitored for three months after administration.
Mechanism of action
SMA is a
neuromuscular disorder caused by 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, mi ...
in the
''SMN1'' gene, which leads to a decrease in
SMN protein, a protein necessary for survival of
motor neuron
A motor neuron (or motoneuron or 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 or indirectl ...
s. Onasemnogene abeparvovec is a
biologic drug Biologic may refer to:
* biology
Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up ...
consisting of
AAV9 virus
capsids that contains a ''
SMN1''
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 was developed by the US biotechnology startup
AveXis, which was acquired by
Novartis
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
in 2018, based on the work at the Institut de Myologie in France.
The U.S.
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 respon ...
(FDA) granted the application for onasemnogene abeparvovec-xioi
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 "br ...
,
priority review, and
orphan drug
An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases.
The assignment of ...
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 the drug. 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 Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regarding ...
(CHMP) accelerated assessment program.
In May 2019, onasemnogene abeparvovec received US FDA approval as a treatment for children less than two years old.
Since 2019, the treatment has been reimbursed in Israel and Qatar. In March 2020, onasemnogene abeparvovec was granted regulatory approval in Japan with the label identical to the US one.
Also in March 2020, 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 medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
recommended a 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 fr ...
for use in people with SMA type 1 or with any SMA type and having no more than three copies of the ''
SMN2'' gene.
In May 2020, Onasemnogene abeparvovec was conditionally approved in Europe.
In August 2020, onasemnogene abeparvovec was granted regulatory approval in Brazil by the
Brazilian Health Regulatory Agency
Brazilian Health Regulatory Agency ( pt, Agência Nacional de Vigilância Sanitária, links=no, italics=yes, ''Anvisa'', literally National Health Surveillance Agency) is a regulatory body of the Brazilian government, created in 1999 during Presi ...
(ANVISA).
In December 2020, onasemnogene abeparvovec was approved for medical use in Canada.
Onasemnogene abeparvovec was approved for medical use in Australia in February 2021.
An official approval in Russia was granted in December 2021.
Society and culture
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 respon ...]
.
Novartis fired two AveXis executives it determined responsible for the alleged data manipulation but informed the FDA of the data integrity issue only in June 2019, a month after the drug's approval.