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7 June 2019

Zolgensma for the Treatment of Spinal Muscular Atrophy

Zolgensma® (onasemnogene abeparvovec-xioi) is a gene replacement therapy indicated for the treatment of spinal muscular atrophy (SMA) in paediatric patients.
Zolgensma® (onasemnogene abeparvovec-xioi) is the first gene therapy indicated to treat spinal muscular atrophy in paediatric patients. Credit: Novartis Pharmaceuticals.
Zolgensma® is an AAV9-based gene therapy designed to deliver a copy of SMN1 gene encoding human SMN protein. Credit: Novartis Pharmaceuticals.
SMA is caused due to the insufficient expression of survival motor neuron (SMN) protein. Credit: Emw.

Zolgensma® (onasemnogene abeparvovec-xioi) is a gene replacement therapy indicated for the treatment of spinal muscular atrophy (SMA) in paediatric patients.

Originally developed by Avexis, the drug became a part of Novartis’ portfolio after it acquired Avexis in May 2018.

Novartis submitted a biologics license application (BLA) for the drug to the US Food and Drug Administration (FDA) in September 2018, accepted for priority review status in December 2018. The FDA approved the drug in May 2019.

The therapy holds FDA breakthrough therapy and European priority medicines (PRIME) designations. It is being reviewed under accelerated assessment procedure by the European Medicines Agency (EMA) for approval in the EU.

The Japanese Ministry of Health, Labour and Welfare (MHLW) provided SAKIGAKE designation to the Zolgensma drug for the treatment of SMA type 1. The drug is expected to receive regulatory approvals in Europe and Japan by the end of 2019.

Priced at $2.1m for five years, the drug is one of the most expensive drugs to be approved. Avexis’ OneGene Program will provide personalised support to the patients’ families, including treatment information and financial assistance during the treatment period.

Spinal muscular atrophy causes and symptoms

SMA is a rare genetic disease that deteriorates the neuromuscular functioning of the body by causing motor neurons loss and associated muscle weakness and paralysis.

The disease is caused by a genetic defect in the survival motor neuron (SMN) gene, which encodes the SMN protein essential for the survival of motor neurons. An estimated one in 10,000 babies is born with the disease.

“Out of the 21 patients, 19 no longer needed permanent ventilation.”

SMA is categorised into SMA type 1 and SMA type 2. The first form is a more severe variant, causing rapid motor neuron loss and resulting in death or permanent ventilation support requirement in more than 90% of patients if left untreated. SMA type 2 leads to mortality in more than 30% of patients by 25 years of age.

Some common symptoms of SMA are muscle loss and weakening in infants after birth and difficulty in feeding and breathing.

Zolgensma’s mechanism of action

Zolgensma is an adeno-associated virus (AAV) 9 based gene therapy designed to deliver a copy of the SMN1 gene to encode for human SMN protein.

It is a recombinant form of self-complementary AAV9, which contains human SMN protein-encoding transgene. The Zolgensma drug will be available in single-use vials, each containing a nominal concentration of 2.0 × 1013 vector genomes (vg) per millilitre for intravenous infusion.

Clinical studies on Zolgensma

FDA approval of the drug was based on the positive outcomes of two open-label, non-randomised, single-group, single-dose clinical studies named STR1VE and START. STR1VE is an ongoing Phase III clinical trial enrolling 21 patients with infant-onset SMA, while START is a Phase I clinical trial.

START, a 24-month clinical study, was conducted to evaluate the safety and efficacy of the drug in 15 patients. Three subjects enrolled in a low-dose cohort, while the remaining three enrolled in a high-dose group. The primary endpoint of the study was survival without permanent ventilation.

At the end of the 24 months, 12 patients that received a high dose no longer required permanent ventilation, representing event-free survival. During the trial, approximately 91.7% of the evaluated patients were able to hold their heads erect, while 83.3% achieved the ability to sit without support for more than ten seconds, 75% for more than 30 seconds. Furthermore, 16.7% of patients were able to stand alone and walk with assistance.

Event-free survival and support-free sitting of patients for at least 30 seconds were the primary endpoints of the 24-month STR1VE trial. Out of the 21 patients, 19 no longer needed permanent ventilation and 47.6% were able to sit without support for at least 30 seconds.

The most common adverse events (AE) reported in the patients were increased aminotransferases and vomiting.

AveXis also reported positive interim data from the Phase I / II STRONG trial, assessing the intrathecal formulation of the drug in SMA patients aged two to five years.

In October 2019, the FDA placed a partial clinical hold on studies of intrathecal Zolgensma, after AveXis reported safety events in a pre-clinical study.

During animal tests, the Zolgensma drug was observed to be associated with dorsal root ganglia (DRG) mononuclear cell inflammation and also neuronal cell body degeneration or loss in some cases.

The FDA also received a report from AveXis in August 2019, highlighting a manipulation issue with some data obtained from animal testing. The US regulator is assessing the data while recommending the continued market availability of the drug.

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