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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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
Adverseeffects
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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.
DrugInteraction
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Onasemnogene abeparvovec.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Onasemnogene abeparvovec.
Bacillus calmette-guerin substrain connaught live antigenThe 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 antigenThe 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 antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with Onasemnogene abeparvovec.
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Onasemnogene abeparvovec.
Human adenovirus e serotype 4 strain cl-68578 antigenThe therapeutic efficacy of Human adenovirus e serotype 4 strain cl-68578 antigen can be decreased when used in combination with Onasemnogene abeparvovec.
PexidartinibOnasemnogene abeparvovec may increase the hepatotoxic activities of Pexidartinib.
Rubella virus vaccineThe therapeutic efficacy of Rubella virus vaccine can be decreased when used in combination with Onasemnogene abeparvovec.
Typhoid Vaccine LiveThe therapeutic efficacy of Typhoid Vaccine Live can be decreased when used in combination with Onasemnogene abeparvovec.
Interactions
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Food Interactions
No interactions found.

Products

Products2
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dosage, form, labeller, route of administration, and marketing period.
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZolgensmaInjection, solution20000000000000 vg/mlIntravenousNovartis Gene Therapies Eu Limited2020-12-16Not applicableEU flag
ZolgensmaInjection, solution20000000000000 vg/mlIntravenousNovartis Gene Therapies Eu Limited2020-12-16Not applicableEU flag
ZolgensmaInjection, solution20000000000000 vg/mlIntravenousNovartis Gene Therapies Eu Limited2020-12-16Not applicableEU flag
ZolgensmaInjection, solution20000000000000 vg/mlIntravenousNovartis Gene Therapies Eu Limited2020-12-16Not applicableEU flag
ZolgensmaInjection, solution20000000000000 vg/mlIntravenousNovartis Gene Therapies Eu Limited2020-12-16Not applicableEU flag
ZolgensmaInjection, solution20000000000000 vg/mlIntravenousNovartis Gene Therapies Eu Limited2020-12-16Not applicableEU flag
ZolgensmaInjection, solution20000000000000 vg/mlIntravenousNovartis Gene Therapies Eu Limited2020-12-16Not applicableEU flag
ZolgensmaInjection, solution20000000000000 vg/mlIntravenousNovartis Gene Therapies Eu Limited2020-12-16Not applicableEU flag
ZolgensmaInjection, solution20000000000000 vg/mlIntravenousNovartis Gene Therapies Eu Limited2020-12-16Not applicableEU flag
ZolgensmaInjection, solution20000000000000 vg/mlIntravenousNovartis Gene Therapies Eu Limited2020-12-16Not applicableEU flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
ZolgensmaOnasemnogene abeparvovec (20000000000000 1/1mL) + Onasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL)IntravenousNovartis Gene Therapies, Inc.2019-05-24Not applicableUS flag
ZolgensmaOnasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL)IntravenousNovartis Gene Therapies, Inc.2019-05-24Not applicableUS flag
ZolgensmaOnasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL)IntravenousNovartis Gene Therapies, Inc.2019-05-24Not applicableUS flag
ZolgensmaOnasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL)IntravenousNovartis Gene Therapies, Inc.2019-05-24Not applicableUS flag
ZolgensmaOnasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL)IntravenousNovartis Gene Therapies, Inc.2019-05-24Not applicableUS flag
ZolgensmaOnasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL)IntravenousNovartis Gene Therapies, Inc.2019-05-24Not applicableUS flag
ZolgensmaOnasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL)IntravenousNovartis Gene Therapies, Inc.2019-05-24Not applicableUS flag
ZolgensmaOnasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL)IntravenousNovartis Gene Therapies, Inc.2019-05-24Not applicableUS flag
ZolgensmaOnasemnogene abeparvovec (20000000000000 1/1mL) + Onasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL)IntravenousNovartis Gene Therapies, Inc.2019-05-24Not applicableUS flag
ZolgensmaOnasemnogene abeparvovec (20000000000000 1/1mL) + Onasemnogene abeparvovec (20000000000000 1/1mL) + Isopropyl alcohol (0.7 mL/1mL)IntravenousNovartis Gene Therapies, Inc.2019-05-24Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
MLU3LU3EVV
CAS number
1922968-73-7

References

General References
  1. 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]
  2. Hoy SM: Onasemnogene Abeparvovec: First Global Approval. Drugs. 2019 Jul;79(11):1255-1262. doi: 10.1007/s40265-019-01162-5. [Article]
  3. 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]
  4. 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]
  5. ZOLGENSMA® (onasemnogene abeparvovec-xioi) FDA Label [Link]
  6. SMN1 gene - Genetics Home Reference - NIH [Link]
KEGG Drug
D11559
RxNav
2170226
Wikipedia
Onasemnogene_abeparvovec

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Enrolling by InvitationPreventionSMA / Spinal Muscular Atrophy Type I / Spinal Muscular Atrophy Type II / Spinal Muscular Atrophy Type III1
3CompletedTreatmentSMA1
3CompletedTreatmentSpinal Muscular Atrophy (SMA)1
3CompletedTreatmentSpinal Muscular Atrophy (SMA) / Therapy, Gene1
3CompletedTreatmentSpinal Muscular Atrophy Type I1
2CompletedTreatmentAlzheimer's Disease (AD)1
2CompletedTreatmentIdiopathic Parkinson's Disease1
1CompletedTreatmentRetinal Diseases / Retinitis Pigmentosa (RP)1
1CompletedTreatmentSpinal Muscular Atrophy 11
1SuspendedTreatmentSpinal Muscular Atrophy (SMA)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous20000000000000 vg/ml
SolutionIntravenous20000000000000 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 November 28, 2021 11:56