| Gene therapy | |
|---|---|
| Target gene | SMN1 |
| Vector | Adeno-associated virus serotype 9 |
| Clinical data | |
| Trade names | Zolgensma |
| Other names | AVXS-101, onasemnogene abeparvovec-xioi |
| AHFS/Drugs.com | Professional Drug Facts |
| License data | |
| Pregnancy category | |
| Routes of administration | Intravascular |
| ATC code | |
| Legal status | |
| Legal status | |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
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| KEGG | |
Onasemnogene abeparvovec, sold under the brand name Zolgensma, is a gene therapy used to treat spinal muscular atrophy (SMA), [6] [7] a disease causing muscle function loss in children. It involves a one-time infusion of the medication into a vein. [6] It works by providing a new copy of the SMN gene that produces the SMN protein. [6]
SMA stems from an SMN1 gene mutation, causing SMN protein deficiency vital for motor neuron 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, while more severe reactions involve liver issues and low platelet count. [6] [8]
Developed by AveXis and acquired by Novartis, onasemnogene abeparvovec gained various FDA 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. [10] This has later been exceeded by other gene therapies like Hemgenix. Japan negotiated a lower price for Zolgensma for its public healthcare system. [11] [12]
Onasemnogene abeparvovec has been developed to treat spinal muscular atrophy, a disease linked to a mutation in the SMN1 gene on chromosome 5q [7] and diagnosed predominantly in young children that causes progressive loss of muscle function and frequently death. The medication is administered as an intravenous infusion. [13]
In the United States, onasemnogene abeparvovec is indicated 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. [6]
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. [14] 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. [8] [15] [16]
Common adverse reactions may include nausea and elevated liver enzymes. [6] Serious adverse reactions may include liver problems and low platelets. [6] Transient elevated levels of cardiac troponin‑I were observed in clinical trials; the clinical importance of these findings is not known. [6] However, cardiac toxicity was seen in studies of other animals. [6]
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. [4] Upon administration, the AAV9 viral vector delivers the SMN1 transgene to the affected motor neurons, where it leads to an increase in SMN protein.[ citation needed ]
Onasemnogene abeparvovec, developed by the US biotechnology startup AveXis, which was acquired by Novartis in 2018, [17] is based on research conducted at the Institut de Myologie in France. [18]
The U.S. Food and Drug Administration (FDA) granted onasemnogene abeparvovec-xioi various designations including fast track, breakthrough therapy, priority review, and orphan drug designations. [14] Additionally, the FDA awarded the manufacturer a rare pediatric disease priority review voucher and approved onasemnogene abeparvovec for AveXis Inc. [14]
In June 2015, the European Commission granted orphan designation to the drug. [19] However, in July 2019, the drug was removed from the Committee for Medicinal Products for Human Use (CHMP) accelerated assessment program. [20]
In May 2019, onasemnogene abeparvovec received US FDA approval as a treatment for children under two years old. [14] Since 2019, the treatment has been reimbursed in Qatar [21] and Israel. [22] In March 2020, it gained regulatory approval in Japan with the same labeling as in the US. [23] Additionally, the European Medicines Agency (EMA) recommended conditional marketing authorization in March 2020, specifically for individuals with SMA type 1 or any SMA type with no more than three copies of the SMN2 gene. This conditional approval was granted for Europe in May 2020. [8] [24]
In August 2020, onasemnogene abeparvovec received regulatory approval in Brazil from the Brazilian Health Regulatory Agency (ANVISA). [25] Subsequently, it was approved for medical use in Canada in December 2020, [26] [27] in Australia in February 2021, [1] [2] [28] and in Russia in December 2021. [29]
According to the Health Sciences Authority register of Singapore, onasemnogene abeparvovec was approved in April 2023. [30]
Initially approved in the United States in 2019 for children under two, [14] [6] onasemnogene abeparvovec's approval varies in different regions. [23] [31] [32]
The drug carries a list price of US$2.125 million per treatment, making it the most expensive medication in the world as of 2019 [update] . [33] In its first full quarter of sales US$160 million of medication was sold. [34]
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. [10] The Central Social Insurance Medical Council, responsible for approving the universal drug fee schedule in Japan, has negotiated the price down to ¥167,077,222 (approx. USD 1,530,000) per patient. [11] [12]
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. [35] 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. [35] The delay drew strong condemnation from the FDA. [36] 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. [37] Due to data manipulation issue, the EMA withdrew their decision to allow an accelerated assessment of the medication. [38]
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, [39] was received with much criticism by the European Commission, [40] some European healthcare regulators [41] and patient groups who see it as emotionally burdening, suboptimal, and ethically questionable. [42] Novartis did not consult with families or doctors before announcing the scheme. [43] [44]
Novartis faced criticism for donating onasemnogene abeparvovec doses through a lottery system. [40] [41] [42]
Onasemnogene abeparvovec is the international nonproprietary name (INN) [45] and the United States Adopted Name (USAN). [46]
Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, United States specializing in the discovery, development, and delivery of therapies for the treatment of neurological diseases to patients worldwide. Biogen operates in Argentina, Brazil, Canada, China, France, Germany, Hungary, India, Italy, Japan, Mexico, Netherlands, Poland, Sweden, and Switzerland.
Spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of rare debilitating disorders characterised by the degeneration of lower motor neurons and subsequent atrophy (wasting) of various muscle groups in the body. While some SMAs lead to early infant death, other diseases of this group permit normal adult life with only mild weakness.
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Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.
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 cause of infant death. It may also appear later in life and then have a milder course of the disease. The common feature is progressive weakness of voluntary muscles, with arm, leg and respiratory muscles being affected first. Associated problems may include poor head control, difficulties swallowing, scoliosis, and joint contractures.
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.
Spinal disease refers to a condition impairing the backbone. These include various diseases of the back or spine ("dorso-"), such as kyphosis. Dorsalgia refers to back pain. Some other spinal diseases include spinal muscular atrophy, ankylosing spondylitis, scoliosis, lumbar spinal stenosis, spina bifida, spinal tumors, osteoporosis and cauda equina syndrome.
X-linked spinal muscular atrophy type 2, also known as arthrogryposis multiplex congenita X-linked type 1 (AMCX1), is a rare neurological disorder involving death of motor neurons in the anterior horn of spinal cord resulting in generalised muscle wasting (atrophy). The disease is caused by a mutation in UBA1 gene and is passed in an X-linked recessive manner by carrier mothers to affected sons.
Survival of motor neuron 2 (SMN2) is a gene that encodes the SMN protein in humans.
Ionis Pharmaceuticals, Inc. is a biotechnology company based in Carlsbad, California, that specializes in discovering and developing RNA-targeted therapeutics. The company has three commercially approved medicines: Spinraza (Nusinersen), Tegsedi (Inotersen), and Waylivra (Volanesorsen) and has four drugs in pivotal studies: tominersen for Huntington's disease, tofersen for SOD1-ALS, AKCEA-APO(a)-LRx for cardiovascular disease, and AKCEA-TTR-LRx for all forms of TTR amyloidosis.
Nusinersen, marketed as Spinraza, is a medication used in treating spinal muscular atrophy (SMA), a rare neuromuscular disorder. In December 2016, it became the first approved drug used in treating this disorder.
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Branaplam is a pyridazine derivative that is being studied as an experimental drug. It was originally developed by Novartis to treat spinal muscular atrophy (SMA); since 2020 it was being developed to treat Huntington's disease (HD) but the trial ended in 2023 with harmful side effects.
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Risdiplam, sold under the brand name Evrysdi, is a medication used to treat spinal muscular atrophy (SMA) and the first oral medication approved to treat this disease.
Novartis Gene Therapies, until 2020 known as AveXis, is a biotechnology company that develops treatments for rare neurological genetic disorders. It was founded in Dallas, Texas, United States in 2012 by John Carbona after reorganizing a company called BioLife Cell Bank founded by David Genecov and John Harkey. Work done at Nationwide Children's Hospital in the laboratory of Brian Kaspar was licensed to AveXis in October 2013. Unusual for the time, Nationwide Children's Hospital, in addition to upfront and milestone payments, also took an equity position in AveXis. Kaspar became paid consultant pari passu with the license agreement in 2013. The company was built specifically around a discovery of a novel method of treating spinal muscular atrophy using gene therapy.
Charlotte Jane Sumner is an American neurologist. She is a professor in the Departments of Neurology and Neuroscience at Johns Hopkins School of Medicine. Dr. Sumner cares for patients with genetically mediated neuromuscular diseases and directs a laboratory focused on developing treatments for these diseases. She co-directs the Johns Hopkins Muscular Dystrophy Association Care Center, the Spinal Muscular Atrophy (SMA), and the Charcot-Marie-Tooth (CMT) clinics, which deliver multidisciplinary clinical care, engage in international natural history studies, and provide cutting edge therapeutics.
Alberto Kornblihtt is an Argentine molecular biologist who specializes in alternative ribonucleic acid splicing. During his postdoctoral training with Francisco Baralle in Oxford, Kornblihtt documented one of the first cases of alternative splicing, explaining how a single transcribed gene can generate multiple protein variants. Kornblihtt was elected as a foreign associate of the National Academy of Sciences of the United States in 2011, received the Diamond Award for the most relevant scientist of Argentina of the decade, alongside physicist Juan Martin Maldacena, in 2013, and was incorporated to the Académie des Sciences of France in 2022.
Ricardo Dolmetsch, born Richard Carl Elciario Dolmetsch; is a Colombian-American neuroscientist, Stanford University professor and biotechnology entrepreneur. He is known for his research on calcium signaling in neurons and lymphocytes, and for his work in neuropsychiatric disease. He was an early developer of human stem cell models for studying diseases of the brain and heart, both in his laboratory at Stanford University and at the Allen Institute for Brain Science. As the Global Head of Neuroscience at Novartis, he helped create a drug pipeline for neuropsychiatric diseases, introduced human stem cell models as tools for drug discovery in neuroscience and contributed to the development of several treatments for brain disorders that are now in the clinic including Aimovig (Erenumab) for migraine and Kesimpta (Ofatumumab) for multiple sclerosis. Dolmetsch was also involved in early successes in gene therapy, including two approved therapies – Zolgensma and Hemgenix. Dolmetsch is currently the President of Tempero Bio, a biotech company seeking to cure substance use disorders, and an Adjunct Professor in Neurobiology at Stanford University.
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