Mechanism Of Action
ZOLGENSMA 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 Pharmacokinetics].
There are no clinically relevant pharmacodynamics data
Vector shedding after infusion with ZOLGENSMA was
investigated at multiple time points during the completed clinical trial.
Samples of saliva, urine and stool were collected the day after infusion,
weekly through Day 30, and then monthly through Month 12 and every 3 months
thereafter. Samples from 5 patients were used for ZOLGENSMA vector DNA shedding
analysis through the Month 18 visit. 10
Vector DNA was shed in saliva, urine and stool after
infusion of ZOLGENSMA, with much higher concentrations of vector DNA found in
stool than in saliva or urine. The vector DNA concentration in saliva was low
on Day 1 after infusion and declined to undetectable levels within 3 weeks. In
urine, the vector DNA concentration was very low on Day 1 after infusion and
declined to undetectable levels within 1 to 2 weeks. In stool, the vector DNA
concentration was much higher than in saliva or urine for 1 to 2 weeks after
infusion and declined to undetectable levels by 1 to 2 months after infusion.
Biodistribution was evaluated 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 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.
Immunostaining for SMN protein showed generalized SMN expression in spinal
motor neurons, neuronal and glial cells of the brain, and in the heart, liver,
skeletal muscles, and other tissues evaluated.
Animal Toxicology And/Or Pharmacology
In toxicology studies conducted in neonatal mice,
dose-dependent cardiac and hepatic toxicities were observed following
intravenous administration of ZOLGENSMA. ZOLGENSMA-related findings in the
myocardium, at doses of 7.9 Ã 1013 vg/kg and higher, included slight
to mild mononuclear cell inflammation accompanied by edema, slight to mild
fibrosis, and scattered myocardial cell degeneration/regeneration. Additional
cardiac findings at dose levels of 1.5 Ã 1014 vg/kg and higher
included minimal to moderate atrial thrombosis and slight to marked atrial
dilation. Liver findings included hepatocellular hypertrophy, Kupffer cell
activation, perinuclear vacuolation, and scattered hepatocellular necrosis.
Target organ toxicity in the heart and liver was associated with mortality at
dose levels of 2.4 Ã 1014 vg/kg and above, approximately 2.2-fold
higher than the recommended clinical dose level.
The efficacy of ZOLGENSMA in pediatric patients less than
2 years of age with SMA with bi-allelic mutations in the SMN1 gene was
evaluated in an open-label, single-arm clinical trial (ongoing) and an
open-label, single-arm, ascending-dose clinical trial (completed). Patients
experienced onset of clinical symptoms consistent with SMA before 6 months of
age. All patients 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 milder phenotype). 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 motor milestones such as sitting without support.
Survival was defined as time from birth to either death or permanent
ventilation. Permanent ventilation was defined as requiring invasive
ventilation (tracheostomy), or respiratory assistance for 16 or more hours per
day (including noninvasive ventilatory support) continuously for 14 or more
days in the absence of an acute reversible illness, excluding perioperative
ventilation. Efficacy was also supported by assessments of ventilator use,
nutritional support and scores on the Children's Hospital of Philadelphia
Infant Test of Neuromuscular Disorders (CHOP-INTEND). CHOP-INTEND is an
assessment of motor skills in patients with infantile-onset SMA.
The ongoing clinical trial enrolled 21 patients (10 male
and 11 female) with infantile-onset SMA. Before treatment with ZOLGENSMA, none
of the 21 patients required non-invasive ventilator (NIV) support, and all
patients could exclusively feed orally (i.e., no need for non-oral nutrition).
The mean CHOP-INTEND score at baseline was 31.0 (range 18 to 47). All the
patients received 1.1 Ã 1014 vg/kg of ZOLGENSMA. The mean age of the
21 patients at the time of 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 trial, while one patient died at age 7.8 months due to disease
progression, and one patient withdrew from the study at age 11.9 months. The 19
surviving patients who were continuing in the trial ranged in age from 9.4 to
18.5 months. By the data cutoff, 13 of the 19 patients continuing in the trial
reached 14 months of age without permanent ventilation, one of the study's
co-primary efficacy endpoints. In addition to survival, assessment of the other
co-primary efficacy endpoint found that 10 of the 21 patients (47.6%) achieved
the ability to sit without support for ≥ 30 seconds between 9.2 and 16.9
months of age (mean age was 12.1 months). Based on the natural history of the
disease, patients who met the study entry criteria would not be expected to
attain the ability to sit without support, and only approximately 25% of these
patients would be expected to survive (i.e., being alive without permanent
ventilation) beyond 14 months of age. In addition, 16 of the 19 patients had
not required daily NIV use.
Comparison of the results of the ongoing clinical trial
to available natural history data of patients with infantile-onset SMA provides
primary evidence of the effectiveness of ZOLGENSMA.
The completed clinical trial enrolled 15 patients (6 male
and 9 female) with infantile-onset SMA, 3 in a low-dose cohort and 12 in a
high-dose cohort. At the time of treatment, the mean age of patients in the
low-dose cohort was 6.3 months (range 5.9 to 7.2 months), and 3.4 months (range
0.9 to 7.9 months) in the high-dose cohort. The dosage received by patients in
the low-dose cohort was approximately one-third of the dosage received by
patients in the high-dose cohort. However, the precise dosages of ZOLGENSMA
received by patients in this completed clinical trial are unclear due to a
change in the method of measuring ZOLGENSMA concentration, and to decreases in
the concentration of stored ZOLGENSMA over time. The retrospectively-estimated
dosage range in the high-dose cohort is approximately 1.1 Ã 1014 to
1.4 Ã 1014 vg/kg.
By 24 months following ZOLGENSMA infusion, one patient in
the low-dose cohort met the endpoint of permanent ventilation; all 12 patients
in the high-dose cohort were alive without permanent ventilation. None of the
patients in the low-dose cohort were able to sit without support, or to stand
or walk; in the high-dose cohort, 9 of the 12 patients (75.0%) were able to sit
without support for ≥ 30 seconds, and 2 patients (16.7%) were able to
stand and walk without assistance. Comparison of the results of the low-dose
cohort to the results of the high-dose cohort shows a dose-response
relationship that supports the effectiveness of ZOLGENSMA.