Novartis' Zolgensma Receives Conditional EU Approval as First-Ever Gene Therapy for Spinal Muscular Atrophy

May 20, 2020 News /BioonBIOON/ --Novartis(Novartis) subsidiaryGene TherapyAveXis recently announced that the European Commission (EC) has granted conditional approval for the gene therapy Zolgensma (onasemnogene abeparvovec) for the treatment of patients with 5q spinal muscular atrophy (SMA), specifically: (1) those with biallelic mutations in SMN1 and clinicalDiagnosispatients with type 1 SMA among those with 5q SMA; (2) patients with 5q SMA who have biallelic mutations in the SMN1 gene and up to three copies of the SMN2 gene. According to the approved dosing guidelines, this approval includes infants and young children weighing up to 21 kg. Zolgensma was approved in the United States in May 2019FDAApproved for market launch, becoming the world's first gene therapy for treating SMA.

5q-SMA is the most common type of SMA, accounting for approximately 95% of all SMA cases. This type of SMA is caused by mutations in the SMN1 (Survival Motor Neuron 1) gene on chromosome 5, hence the name 5q-SMA. In Europe, approximately 550–600 infants are born with SMA each year.SMA represents a significant burden on European healthcare systems, with the cumulative medical costs for each child with SMA estimated at €2.5–4 million within the first 10 years alone.

Spinal Muscular Atrophy (SMA) is a rare hereditary neuromuscular disorder caused by the lack of a functional SMN1 gene. SMA can lead to rapid and irreversible loss of motor neurons, affecting muscle function, including breathing, swallowing, and basic movements. SMN2 is a backup gene for SMN1; the two are nearly identical. The number of SMN2 copies is negatively correlated with the severity of the SMA phenotype. Patients with two copies of the SMN2 gene may develop infantile-onset SMA (also known as Type 1 SMA), while those with three or four copies of the SMN2 gene may develop later-onset SMA (Type 2 and Type 3 SMA). SMA is the leading cause of death in infants under the age of two.GeneticsInfantile killer, with SMA type 1 being the most common form, accounting for approximately 60% of all cases. Without treatment, over 90% of patients will die or require permanent ventilation by the age of two.

Zolgensma is a revolutionary and highly innovative one-time gene therapy designed to address the genetic root cause of spinal muscular atrophy (SMA) by replacing the function of the missing or nonfunctional SMN1 gene. Following a single intravenous (IV) infusion, Zolgensma delivers a functional copy of the SMN1 gene into patients’ cells, enabling sustained expression of functional SMN protein to halt disease progression and thereby improve patients’ quality of life over the long term. Clinical studies have demonstrated that single-infusion treatment with Zolgensma yields clinically meaningful therapeutic benefits in both symptomatic and presymptomatic SMA patients, including prolonged event-free survival and achievement of motor milestones not observed in the natural history of the disease.

Dave Lennon, President of AveXis, stated, “The European Union’s approval of Zolgensma marks a significant milestone for the SMA community, further underscoring the substantial clinical value of Zolgensma as the only gene therapy for SMA and bringing new hope to patients affected by this rare but devastating disease. Even amid the current pandemic, access pathways for Zolgensma have been established in France and Germany due to the urgent need for SMA treatment. Furthermore, we have engaged with more than 100 stakeholder organizations across Europe to discuss our ‘Day One’ access program, which aims to enable rapid patient access to Zolgensma through customizable options operating within local pricing and reimbursement frameworks.”

SMA Boy (Image Source: drpgx.com).png

The European Commission approved Zolgensma based on the completed Phase I START trial and the Phase III STR1VE-US trial. The START and STR1VE-US trials were conducted in symptomatic patients with Type 1 spinal muscular atrophy (SMA) carrying one to two copies and two copies of the SMN2 backup gene, respectively. These patients were under six months of age at the time of dosing. The efficacy and safety of a single intravenous infusion of Zolgensma were evaluated. Zolgensma demonstrated: (1) survival rates unprecedented in the natural history of the disease; (2) rapid improvement in motor function, typically within one month after administration; and (3) achievement of milestones, including the ability to sit unsupported, a milestone never achieved in untreated patients. Patients from the long-term follow-up study of the START trial are now five years old.

Other supportive data include the interim results from the ongoing SPR1NT trial, an open-label, single-arm Phase III study conducted in presymptomatic SMA patients genetically defined by biallelic SMN1 deletion and carrying 2–3 copies of the SMN2 backup gene, who were <6 weeks of age at dosing. The study evaluated the efficacy and safety of a single one-time intravenous infusion of Zolgensma. Interim results from the SPR1NT trial demonstrated that Zolgensma treatment yielded rapid, age-appropriate benefits in achieving major developmental milestones.

These data reinforce the importance of early intervention for patients with spinal muscular atrophy (SMA), which must be initiated as early as possible.DiagnosisSMA and initiate treatment, including aggressive supportive care, to halt irreversible motor neuron loss and disease progression.

In clinical studies, the most common adverse reactions following Zolgensma treatment were elevated liver enzymes and vomiting. Patients may experience acute severe liver injury and elevated transaminases; those with pre-existing liver impairment may be at higher risk. Prior to infusion, physicians should assess hepatic function in all patients through clinical evaluation and laboratory testing. All patients should receive systemic corticosteroid therapy before and after treatment, and liver function should continue to be monitored for at least three months post-infusion.

Spinal Muscular Atrophy (SMA) is a motor neuron disease that causes muscle weakness and atrophy. It is an autosomal recessive genetic disorder caused by gene defects, affecting muscles throughout the body. Patients primarily present with generalized muscle atrophy and weakness, progressively losing various motor functions, including breathing and swallowing. SMA is the leading cause of death in infants under 2 years of age.GeneticsSMA Killer: This disease is a relatively common "rare disease," with a prevalence of 1 in 6,000 to 1 in 10,000 among newborns. According to relevant reports, there are currently approximately 30,000 to 50,000 SMA patients in China.

To date, two drugs have been approved for the treatment of spinal muscular atrophy (SMA). In December 2016, Spinraza (nusinersen), developed by Biogen in partnership with Ionis Pharmaceuticals, was approved as the first-ever therapy for SMA worldwide. This drug is an antisense oligonucleotide (ASO) administered via intrathecal injection, delivering the medication directly into the cerebrospinal fluid (CSF) surrounding the spinal cord. It modifies the splicing of SMN2 pre-messenger RNA (pre-mRNA), thereby increasing the production of full-length, functional SMN protein. In patients with SMA, insufficient levels of SMN protein lead to the degeneration of motor neuron function in the spinal cord. Clinical studies have demonstrated that treatment with Spinraza significantly improves motor function in SMA patients.

May 2019,NovartisZolgensma (onasemnogene abeparvovec) gene therapy approved, becoming the world’s first gene therapy for SMA. Administered as a single, one-time intravenous infusion, it enables sustained expression of the SMN protein to halt disease progression, addresses the root cause of SMA, and holds promise for long-term improvement in patients’ quality of life.

Currently, Roche is also developing an oral therapy, risdiplam, a splicing modifier of the survival motor neuron 2 (SMN2) gene, for the treatment of all types (Type 1, Type 2, and Type 3) of spinal muscular atrophy (SMA). The drug is currently under review by the U.S.FDAreview, with results expected in August this year. If approved, risdiplam will become the first oral medication for treating all three types of SMA.

In the Chinese market, Spinraza was approved in late February 2019 for the treatment of patients with 5q spinal muscular atrophy (5q-SMA). This approval made Spinraza the first drug approved to treat SMA in China. (Bioon.com)

Original Source: AveXis Receives ECapproval and activates “Day One” access program for Zolgensma, the only gene therapy for spinal muscular atrophy (SMA)