AveXis, a Novartis company, announced the U.S. FDA has approved Zolgensma (onasemnogene abeparvovec-xioi) 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. Zolgensma is designed to address the genetic root cause of SMA by providing a functional copy of the human SMN gene to halt disease progression through sustained SMN protein expression with a single, one-time intravenous (IV) infusion. Zolgensma is the first and only gene therapy approved by the FDA for the treatment of SMA, including those who are pre-symptomatic at diagnosis.

The FDA approval of Zolgensma was based on the STRIVE and START clinical trials. Efficacy was established based on 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.

STRIVE, an ongoing, open-label, single-arm clinical trial, evaluated Zolgensma in pediatric patients less than 2 years of age with SMA with bi-allelic mutations in the SMN1 gene. Patients experienced onset of clinical symptoms consistent with SMA before 6 months of age. All patients had genetically confirmed bi-allelic SMN1 gene deletions, two 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.

STR1VE has 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. The mean CHOP-INTEND score at baseline was 31.0 (range 18 to 47). All the patients received 1.1 × 10[1][4] 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 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.

START 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. 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.

About Spinal Muscular Atrophy (SMA)
SMA is a severe neuromuscular disease characterized by the loss of motor neurons leading to progressive muscle weakness and paralysis. SMA is caused by a genetic defect in the SMN1 gene that codes SMN, a protein necessary for survival of motor neurons. The incidence of SMA is approximately 1 in 10,000 live births and it is the leading genetic cause of infant mortality. The most severe form of SMA is Type 1, a lethal genetic disorder characterized by rapid motor neuron loss and associated muscle deterioration, resulting in mortality or the need for permanent ventilation support by 24 months of age for more than 90 percent of patients if left untreated.

About Zolgensma (onasemnogene abeparvovec-xioi)
Zolgensma (onasemnogene abeparvovec-xioi) is a proprietary gene therapy designed to address the genetic root cause of SMA by providing a functional copy of the human SMN gene to halt disease progression through sustained SMN protein expression with a single, one-time intravenous (IV) infusion.

Zolgensma is also under regulatory review in Japan and the European Union, with approval expected later this year.

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