Overview
11 DESCRIPTION ZOLGENSMA is a suspension of an adeno-associated viral vector-based gene therapy for intravenous infusion. It is a recombinant self-complementary AAV9 containing a transgene encoding the human survival motor neuron (SMN) protein, under the control of a cytomegalovirus enhancer/chicken-β-actin hybrid promoter. ZOLGENSMA has a nominal concentration of 2.0 × 10 13 vg/mL.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Onasemnogene abeparvovec is a recombinant AAV9-based gene therapy designed to deliver a copy of the gene encoding the human SMN protein. SMA is caused by a bi-allelic mutation in the SMN1 gene, which results in insufficient SMN protein expression. Intravenous administration of ZOLGENSMA that results in cell transduction and expression of the SMN protein has been observed in two human case studies [see Clinical Pharmacology ( 12.3 )] . 12.2 Pharmacodynamics There are no clinically relevant pharmacodynamics data for onasemnogene abeparvovec. 12.3 Pharmacokinetics Vector shedding after infusion with onasemnogene abeparvovec was investigated at multiple time points during Study 2.
Indications
- 1 INDICATIONS AND USAGE ZOLGENSMA is an adeno-associated virus (AAV) vector-based gene therapy indicated for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. Limitations of Use The safety and effectiveness of repeat administration of ZOLGENSMA have not been evaluated [see Adverse Reactions ( 6.2 )] . The use of ZOLGENSMA in patients with advanced SMA (e.g., complete paralysis of limbs, permanent ventilator-dependence) has not been evaluated [see Clinical Studies ( 14 )] .
Common Doses
- 1 mg
Dosage
2 DOSAGE AND ADMINISTRATION For single-dose intravenous infusion only. For single-dose intravenous infusion only ( 2 ). The recommended dosage of ZOLGENSMA is 1.1 × 10 14 vector genomes (vg) per kg of body weight. ( 2.1 ) Administer ZOLGENSMA as an intravenous infusion over 60 minutes. ( 2.1 , 2.3 ) Postpone ZOLGENSMA in patients with infections until the infection has resolved and the patient is clinically stable. ( 2.1 , 5.
Black Box Warning
WARNING: SERIOUS LIVER INJURY and ACUTE LIVER FAILURE Cases of acute liver failure with fatal outcomes have been reported. Acute serious liver injury and elevated aminotransferases can also occur with ZOLGENSMA [see Warnings and Precautions ( 5.1 )]. Patients with preexisting liver impairment may be at higher risk [see Warnings and Precautions ( 5.1 )]. Prior to infusion, assess liver function of all patients by clinical examination and laboratory testing. Administer systemic corticosteroid to all patients before and after ZOLGENSMA infusion.
Contraindications
- 4 CONTRAINDICATIONS None. None. ( 4 )
Side Effects
- 6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥ 5%) were elevated aminotransferases and vomiting. The most common adverse reactions (incidence ≥ 5%) were elevated aminotransferases and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Gene Therapies at 1-833-828-3947 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another...
Interactions
- 7 DRUG INTERACTIONS Where feasible, adjust a patient’s vaccination schedule to accommodate concomitant corticosteroid administration prior to and following ZOLGENSMA infusion [see Dosage and Administration ( 2.1 )] . Certain vaccines, such as measles, mumps, and rubella (MMR) and varicella, are contraindicated for patients on a substantially immunosuppressive steroid dose (i.e., ≥ 2 weeks of daily receipt of 20 mg or 2 mg/kg body weight of prednisone or equivalent). Seasonal RSV prophylaxis is recommended (General Best Practice Guidelines for Immunization [ www.cdc.