Onasemnogene abeparvovec
Identification
- Summary
Onasemnogene abeparvovec is a gene therapy used to treat neonatal and infant patients with spinal muscular atrophy caused by bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.
- Brand Names
- Zolgensma Kit 2.6 - 3.0 Kg
- Generic Name
- Onasemnogene abeparvovec
- DrugBank Accession Number
- DB15528
- Background
Onasemnogene abeparvovec is an adeno-associated virus vector-based gene therapy that has been approved by the FDA in May 2019 for the treatment of infant patients (less than 2 years of age) with spinal muscular atrophy (SMA) and a specific mutation in the survival motor neuron 1 (SMN1) gene.5 SMA is a rare genetic disease that affects the survival and function of motor neurons, leading to debilitating and often fatal muscle weakness.1 As there is no cure for SMA, onasemnogene abeparvovec is a disease-modifying agent that decelerates the disease progression, improves motor function, and manages the symptoms. The use and effectiveness of onasemnogene abeparvovec in patients with advanced SMA, such as those with complete paralysis of the limbs and permanent dependence on ventilators, has not been evaluated. Onasemnogene abeparvovec is the first gene therapy that was approved for this indication in the USA. Nusinersen is another gene therapy that is currently approved by the FDA for the treatment of SMA in pediatric and adult patients.
Developed by AveXis, a Novartis company,2 onasemnogene abeparvovec is commonly marketed as Zolgensma®, which is available as a single-dose intravenous infusion.5 Onasemnogene abeparvovec for therapeutic use and marketing is currently being assessed by the EU and an intrathecal formulation of the drug is currently undergoing clinical development in the USA.2
- Type
- Biotech
- Groups
- Approved
- Biologic Classification
- Gene Therapies
Other gene therapies - Synonyms
- Onasemnogene abeparvovec
- onasemnogene abeparvovec-xioi
- External IDs
- AVXS-101
Pharmacology
- Indication
Onasemnogene abeparvovec is indicated for the treatment of pediatric patients less than 2 years of age (neonatal and infant patients) with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.5
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Spinal muscular atrophy •••••••••••• ••••••• ••••••••• ••••••••• •••••••••• ••••••••• •• ••• •••••••• ••••• •••••• • •••••• •••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Onasemnogene abeparvovec is a gene therapy that restores the levels of SMN protein in the spinal cord to promote the survival and function of motor neurons. Acute serious liver injury and elevated aminotransferases were observed with the treatment of onasemnogene abeparvovec in clinical trials.5
- Mechanism of action
Spinal muscular atrophy is a genetic disorder caused by mutations in the SMN gene, which encodes the SMN protein. SMN protein is found ubiquitously but it is highly expressed in the spinal cord where it is responsible for the survival and maintenance of specialized nerve cells called motor neurons.6 SMN1 and SMN2 genes encode the SMN protein but many mutations in the SMN1 gene have been found to cause spinal muscular atrophy,3,6 as SMN1 is the primary gene responsible for functional production of SMN protein.1 A common mutation that causes spinal muscular atrophy involves a bi-allelic deletion of exon 7 in the SMN1 gene.3 The number of copies of the SMN2 gene varies among individuals: while higher number of SMN2 gene copies may protect against SMN protein deficiency caused by SMN1 gene mutations,6 it is generally proposed that the bi-allelic mutation in the SMN1 gene cannot be compensated by the SMN2 gene.3 The mutation results in insufficient SMN protein expression and inefficient assembly of the machinery needed to process pre-mRNA for motor neuron development and survival. Spinal muscular atrophy involves a progressive degeneration and loss of lower motor neurons, leading to muscle weakness and atrophy.1,5
Onasemnogene abeparvovec is gene therapy that consists of a recombinant self-complementary adeno-associated virus serotype 9 (AAV9) as a gene delivery vector, which contains a transgene encoding the human survival motor neuron (SMN) protein.1,5 AAV9 is commonly used in gene therapy applications because it is capable of crossing the blood-brain barrier and transducing neurons in the CNS.4 After administration, this viral vector is shed and a copy of the gene encoding the human SMN protein is delivered, leading to cell transduction and expression of the SMN protein.5
- Absorption
There is limited pharmacokinetic information on onasemnogene abeparvovec.
- Volume of distribution
There is limited pharmacokinetic information on onasemnogene abeparvovec. When biodistribution was evaluated in autopsy studies, the highest levels of vector DNA were found in the liver. Vector DNA was also detected in the spleen, heart, pancreas, inguinal lymph node, skeletal muscles, peripheral nerves, kidney, lung, intestines, spinal cord, brain, and thymus.5
- Protein binding
There is limited pharmacokinetic information on onasemnogene abeparvovec.
- Metabolism
There is limited pharmacokinetic information on onasemnogene abeparvovec. The viral vector and the survival motor neuron (SMN) protein are expected to undergo normal nonspecific cellular degradation.
- Route of elimination
There is limited pharmacokinetic information on onasemnogene abeparvovec.
- Half-life
There is limited pharmacokinetic information on onasemnogene abeparvovec.
- Clearance
There is limited pharmacokinetic information on onasemnogene abeparvovec.
- Adverse Effects
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- Toxicity
The LD50 and information on overdose have not been evaluated with onasemnogene abeparvovec. In mice toxicology studies, dose-dependent cardiac and hepatic toxicities were observed following intravenous administration. Cardiac toxicity was characterized by mononuclear cell inflammation accompanied by edema, slight to mild fibrosis, and scattered myocardial cell degeneration/regeneration, as well as atrial thrombosis and dilation. Hepatotoxicity was characterized by hepatocellular hypertrophy, Kupffer cell activation, perinuclear vacuolation, and scattered hepatocellular necrosis.5
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAdenovirus type 7 vaccine live The therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Onasemnogene abeparvovec. Anthrax vaccine The therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Onasemnogene abeparvovec. Bacillus calmette-guerin substrain connaught live antigen The therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Onasemnogene abeparvovec. Bacillus calmette-guerin substrain russian BCG-I live antigen The therapeutic efficacy of Bacillus calmette-guerin substrain russian BCG-I live antigen can be decreased when used in combination with Onasemnogene abeparvovec. Bacillus calmette-guerin substrain tice live antigen The therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with Onasemnogene abeparvovec. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Zolgensma Injection, solution 20000000000000 vg/ml Intravenous Novartis Europharm Limited 2020-12-16 Not applicable EU Zolgensma Injection, solution 20000000000000 vg/ml Intravenous Novartis Europharm Limited 2020-12-16 Not applicable EU Zolgensma Injection, solution 20000000000000 vg/ml Intravenous Novartis Europharm Limited 2020-12-16 Not applicable EU Zolgensma Injection, solution 20000000000000 vg/ml Intravenous Novartis Europharm Limited 2020-12-16 Not applicable EU Zolgensma Injection, solution 20000000000000 vg/ml Intravenous Novartis Europharm Limited 2020-12-16 Not applicable EU - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Zolgensma Onasemnogene abeparvovec (20000000000000 1/1mL) + Onasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL) Intravenous Novartis Gene Therapies, Inc. 2019-05-24 Not applicable US Zolgensma Onasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL) Intravenous Novartis Gene Therapies, Inc. 2019-05-24 Not applicable US Zolgensma Onasemnogene abeparvovec (20000000000000 1/1mL) + Onasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL) Intravenous Novartis Gene Therapies, Inc. 2019-05-24 Not applicable US Zolgensma Onasemnogene abeparvovec (20000000000000 1/1mL) + Onasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL) Intravenous Novartis Gene Therapies, Inc. 2019-05-24 Not applicable US Zolgensma Onasemnogene abeparvovec (20000000000000 1/1mL) + Onasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL) Intravenous Novartis Gene Therapies, Inc. 2019-05-24 Not applicable US
Categories
- ATC Codes
- M09AX09 — Onasemnogene abeparvovec
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- MLU3LU3EVV
- CAS number
- 1922968-73-7
References
- General References
- Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L'Italien J, Sproule DM, Wells C, Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, Foust KD, Burghes AHM, Kaspar BK: Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1713-1722. doi: 10.1056/NEJMoa1706198. [Article]
- Hoy SM: Onasemnogene Abeparvovec: First Global Approval. Drugs. 2019 Jul;79(11):1255-1262. doi: 10.1007/s40265-019-01162-5. [Article]
- Hasanzad M, Golkar Z, Kariminejad R, Hadavi V, Almadani N, Afroozan F, Salahshurifar I, Shafeghati Y, Kahrizi K, Najmabadi H: Deletions in the survival motor neuron gene in Iranian patients with spinal muscular atrophy. Ann Acad Med Singapore. 2009 Feb;38(2):139-41. [Article]
- Wang D, Li S, Gessler DJ, Xie J, Zhong L, Li J, Tran K, Van Vliet K, Ren L, Su Q, He R, Goetzmann JE, Flotte TR, Agbandje-McKenna M, Gao G: A Rationally Engineered Capsid Variant of AAV9 for Systemic CNS-Directed and Peripheral Tissue-Detargeted Gene Delivery in Neonates. Mol Ther Methods Clin Dev. 2018 Mar 16;9:234-246. doi: 10.1016/j.omtm.2018.03.004. eCollection 2018 Jun 15. [Article]
- ZOLGENSMA® (onasemnogene abeparvovec-xioi) FDA Label [Link]
- SMN1 gene - Genetics Home Reference - NIH [Link]
- External Links
- KEGG Drug
- D11559
- 2170226
- Wikipedia
- Onasemnogene_abeparvovec
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Infantile Spinal Muscular Atrophy, Type I [Werdnig- Hoffman] / Spinal Muscular Atrophy (SMA) / Spinal Muscular Atrophy Type II / Spinal Muscular Atrophy Type III 1 3 Completed Treatment Gene Therapy / Spinal Muscular Atrophy (SMA) 1 3 Completed Treatment Infantile Spinal Muscular Atrophy, Type I [Werdnig- Hoffman] 1 3 Completed Treatment Spinal Muscular Atrophy (SMA) 2 3 Recruiting Treatment Spinal Muscular Atrophy (SMA) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Intravenous 20000000000000 vg/ml Solution Intravenous 20000000000000 vg / mL - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
Drug created at October 09, 2019 20:18 / Updated at June 03, 2022 07:24