he brain, and in the heart,liver, skeletal muscles, and other tissues eva luated.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies have been performed to eva luate the effects of ZOLGENSMA oncarcinogenesis, mutagenesis or impairment of fertility.
13.2 Animal Toxicology and/or Pharmacology
In toxicology studies conducted in neonatal mice, dose-dependent cardiac and hepatic toxicitieswere observed following intravenous administration of ZOLGENSMA. ZOLGENSMA-relatedfindings in the myocardium, at doses of 7.9 × 1013 vg/kg and higher, included slight to mildmononuclear cell inflammation accompanied by edema, slight to mild fibrosis, and scatteredmyocardial cell degeneration/regeneration. Additional cardiac findings at dose levels of1.5 × 1014 vg/kg and higher included minimal to moderate atrial thrombosis and slight to markedatrial dilation. Liver findings included hepatocellular hypertrophy, Kupffer cell activation,
perinuclear vacuolation, and scattered hepatocellular necrosis. Target organ toxicity in the heartand liver was associated with mortality at dose levels of 2.4 × 1014 vg/kg and above,approximately 2.2-fold higher than the recommended clinical dose level.
14 CLINICAL STUDIES
The efficacy of ZOLGENSMA in pediatric patients less than 2 years of age with SMA withbi-allelic mutations in the SMN1 gene was eva luated in an open-label, single-arm clinical trial(ongoing) and an open-label, single-arm, ascending-dose clinical trial (completed). Patientsexperienced onset of clinical symptoms consistent with SMA before 6 months of age. Allpatients had genetically confirmed bi-allelic SMN1 gene deletions, 2 copies of the SMN2 gene,and absence of the c.859G>C modification in exon 7 of SMN2 gene (which predicts a milderphenotype). All patients had baseline anti-AAV9 antibody titers of ≤ 1:50, measured by ELISA.
In both trials, ZOLGENSMA was delivered as a single-dose intravenous infusion.
Efficacy was established on the basis of survival, and achievement of developmental motormilestones such as sitting without support. Survival was defined as time from birth to eitherdeath or permanent ventilation. Permanent ventilation was defined as requiring invasiveventilation (tracheostomy), or respiratory assistance for 16 or more hours per day (includingnoninvasive ventilatory support) continuously for 14 or more days in the absence of an acutereversible illness, excluding perioperative ventilation. Efficacy was also supported byassessments of ventilator use, nutritional support and scores on the Children's Hospital ofPhiladelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). CHOP-INTEND is anassessment of motor skills in patients with infantile-onset SMA.
The ongoing clinical trial enrolled 21 patients (10 male and 11 female) with infantile-onsetSMA. Before treatment with ZOLGENSMA, none of the 21 patients required non-invasiveventilator (NIV) support, and all patients could exclusively feed orally (i.e., no need for non-oralnutrition). The mean CHOP-INTEND score at baseline was 31.0 (range 18 to 47). All thepatients received 1.1 × 1014 vg/kg of ZOLGENSMA. The mean age of the 21 patients at the timeof treatment was 3.9 months (range 0.5 to 5.9 months).
As of the March 2019 data cutoff, 19 patients were alive without permanent ventilation (i.e.,event-free survival) and were continuing in the t |
