Novartis' Zolgensma Receives Positive CHMP Opinion for Treatment of Spinal Muscular Atrophy in the EU

March 28, 2020 /Bio ValleyBIOON/ --Novartis(Novartis) recently announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion, recommending the approval of 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 clinicalDiagnosis(1) Patients 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. 5q-SMA is the most common form 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 located on chromosome 5, hence the name 5q-SMA. The CHMP’s opinion will now be submitted to the European Commission (EC) for review, which typically issues a final decision within approximately two months.

Spinal muscular atrophy (SMA) is a rare hereditary neuromuscular disorder caused by the absence of a functional SMN1 gene. SMA leads to rapid and irreversible loss of motor neurons, impairing muscle function, including breathing, swallowing, and basic movement. SMN2 serves as a backup gene for SMN1; the two are nearly identical. The copy number of SMN2 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), whereas 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 and young children under the age of two.HereditySMA killer, with Type 1 SMA being the most common type, accounting for approximately 60% of all cases. Without treatment, more than 90% of patients will die or require permanent ventilation by the age of 2.

Zolgensma was approved in the United States in May 2019FDAApproved for marketing, it has become the world’s first gene therapy for the treatment of spinal muscular atrophy (SMA). This medication is a one-time gene therapy designed to address the genetic root cause of 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 the 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 provides clinically significant therapeutic benefits in both symptomatic and presymptomatic SMA patients, including prolonged event-free survival and the achievement of motor milestones not observed in the natural history of the disease.

The CHMP’s positive opinion recommending approval of Zolgensma was 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 1–2 copies and 2 copies of the SMN2 backup gene, respectively. All patients were under 6 months of age at the time of dosing, and the studies evaluated the efficacy and safety of a single intravenous infusion of Zolgensma. Zolgensma demonstrated: (1) survival rates unprecedented in the natural history of the disease; (2) rapid improvement in motor function, typically within one month after dosing; and (3) achievement of milestones, including the ability to sit unsupported, a milestone never attained in untreated patients. Patients from the long-term follow-up study of START are now 5 years old.

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

These data reinforce the importance of early intervention in patients with spinal muscular atrophy (SMA), which must be initiated as early as possible.DiagnosisSMA and initiate treatment, including active 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, with those having pre-existing liver impairment potentially 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 be monitored for at least three months post-infusion.

SMA is a motor neuron disease that causes muscle weakness and atrophy. It is an autosomal recessive genetic disorder caused by genetic defects, affecting muscles throughout the patient's 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 the age of two.GeneticsDisease Killer: This condition is a relatively common "rare disease," with an incidence rate 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 and its partner Ionis Pharmaceuticals, was approved, becoming the first drug worldwide for the treatment of SMA. This medication is an antisense oligonucleotide (ASO) administered via intrathecal injection, which delivers the drug 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 patients with SMA.

May 2019,NovartisZolgensma (onasemnogene abeparvovec) Gene Therapy Approved as the World’s First Gene Therapy for SMA. By enabling sustained expression of the SMN protein following a single, one-time intravenous infusion, this therapy halts 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.FDApriority review, with the review results expected in May this year. If approved, risdiplam will become the first oral medication for the treatment of 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 for the treatment of SMA in the Chinese market. (Bioon.com)

Original Source:AveXis receives positive CHMP opinion for Zolgensma®, the only gene therapy for spinal muscular atrophy (SMA)