e for anti-AAV9 antibodies.
The safety of ZOLGENSMA was studied in pediatric patients who received ZOLGENSMA
infusion at age 0.3 to 7.9 months (weight range 3.0 kg to 8.4 kg) [see Adverse Reactions (6)].
The efficacy of ZOLGENSMA was studied in pediatric patients who received ZOLGENSMA
infusion at age 0.5 to 7.9 months (weight range 3.6 kg to 8.4 kg) [see Clinical Studies (14)].
8.6 Hepatic Impairment
One patient who received ZOLGENSMA developed acute serious liver injury; that patient hadelevated aminotransferase levels prior to ZOLGENSMA infusion. In clinical trials, elevation ofaminotransferases was observed in patients following ZOLGENSMA infusion [see Warningsand Precautions (5.1)].
11 DESCRIPTION
ZOLGENSMA is a suspension of an adeno-associated viral vector-based gene therapy forintravenous infusion. It is a recombinant self-complementary AAV9 containing a transgeneencoding the human survival motor neuron (SMN) protein, under the control of acytomegalovirus enhancer/chicken-β-actin hybrid promoter.ZOLGENSMA has a nominal concentration of 2.0 × 1013 vg/mL. Each vial contains anextractable volume of not less than either 5.5 mL or 8.3 mL and the excipients 20 mM Tris(pH 8.0), 1 mM magnesium chloride (MgCl2), 200 mM sodium chloride (NaCl) and0.005% poloxamer 188. ZOLGENSMA is packaged as a sterile suspension and contains no
preservative.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ZOLGENSMA is a recombinant AAV9-based gene therapy designed to deliver a copy of thegene encoding the human SMN protein. SMA is caused by a bi-allelic mutation in the SMN1gene, which results in insufficient SMN protein expression. Intravenous administration ofZOLGENSMA that results in cell transduction and expression of the SMN protein has beenobserved in two human case studies [see Pharmacokinetics (12.3)].
12.2 Pharmacodynamics
There are no clinically relevant pharmacodynamics data for ZOLGENSMA.
12.3 Pharmacokinetics
Vector shedding after infusion with ZOLGENSMA was investigated at multiple time pointsduring the completed clinical trial. Samples of saliva, urine and stool were collected the day afterinfusion, weekly through Day 30, and then monthly through Month 12 and every 3 monthsthereafter. Samples from 5 patients were used for ZOLGENSMA vector DNA shedding analysisthrough the Month 18 visit.
Vector DNA was shed in saliva, urine and stool after infusion of ZOLGENSMA, with muchhigher concentrations of vector DNA found in stool than in saliva or urine. The vector DNAconcentration in saliva was low on Day 1 after infusion and declined to undetectable levelswithin 3 weeks. In urine, the vector DNA concentration was very low on Day 1 after infusionand declined to undetectable levels within 1 to 2 weeks. In stool, the vector DNA concentrationwas much higher than in saliva or urine for 1 to 2 weeks after infusion and declined toundetectable levels by 1 to 2 months after infusion.
Biodistribution was eva luated in two patients who died 5.7 months and 1.7 months, respectively,after infusion of ZOLGENSMA at the dose of 1.1 x 1014 vg/kg. Both cases showed that thehighest levels of vector DNA were found in the liver. Vector DNA was also detected in thespleen, heart, pancreas, inguinal lymph node, skeletal muscles, peripheral nerves, kidney, lung,intestines, spinal cord, brain, and thymus. Immunostaining for SMN protein showed generalizedSMN expression in spinal motor neurons, neuronal and glial cells of t |
