AveXis, a Novartis company, announced the European Commission (EC) granted conditional approval for Zolgensma? (onasemnogene abeparvovec) for the treatment of patients with 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of SMA Type 1; or for patients with 5q SMA with a bi-allelic mutation in the SMN1 gene and up to three copies of the SMN2 gene. The approval covers babies and young children with SMA up to 21 kg according to the approved dosing guidance.

In Europe each year, approximately 550–600 infants are born with SMA, a rare, genetic neuromuscular disease caused by a lack of a functional SMN1 gene, resulting in the rapid and irreversible loss of motor neurons, affecting muscle functions, including breathing, swallowing and basic movement. Zolgensma is a one-time gene therapy designed to address the genetic root cause of the disease by replacing the function of the missing or nonworking SMN1 gene. Administered during a single, intravenous (IV) infusion, Zolgensma delivers a new working copy of the SMN1 gene into a patient’s cells, halting disease progression. According to Pediatric Neuromuscular Clinical Research (PNCR) natural history study of SMA, almost all patients under the age of five years of age will be under 21kg with some patients at 6, 7 or 8 weighing below 21 kg. AveXis is planning a product presentation that allows for treatment of patients weighing up to 21 kg and is working with the European Medicines Agency (EMA) to finalize supply timelines.

“The EC approval of Zolgensma is a significant milestone for the SMA community, and further underscores the substantial clinical value of the only gene therapy for SMA, bringing new hope to those impacted by this rare, but devastating disease.” said Dave Lennon, president of AveXis. “Even under the current pandemic conditions, the urgent need to treat SMA has resulted in access pathways in France and Germany for Zolgensma, a potentially life-saving medicine delivered in a single dose. Additionally, we have met with more than 100 stakeholder organizations across Europe to discuss our “Day One” access program to enable rapid access with customizable options designed to work within local pricing and reimbursement frameworks.”

SMA is a significant burden to the healthcare system in Europe with cumulative estimated healthcare costs per child ranging between €2.5 to €4 million within the first 10 years alone. Zolgensma is a transformative one-time gene therapy for a progressive genetic disease and is consistently priced worldwide under a value-based framework, however final pricing and reimbursement decisions are determined at the local level. Designed to work within existing, local pricing and reimbursement frameworks, the “Day One” access program offers ministries of health and reimbursement bodies a variety of flexible options that can be implemented immediately to support swift access and broad reimbursement.

The “Day One” access program ensures the cost of patients treated before national pricing and reimbursement agreements are in place align with the value-based prices negotiated following clinical and economic assessments. The program maintains the integrity of the local pricing and reimbursement frameworks with a variety of customizable options including:

• Retroactive rebates ensuring early access costs are aligned with negotiated prices following local clinical and economic assessment processes

• Deferred payments and installment options allowing reimbursement bodies to manage budget impact during the early access phase

• Outcomes-based rebates negotiated following clinical and economic assessments can be applied to patients treated during the early access period

• Robust training for treating institutions on administration and follow-up care

• Access to RESTORE, a global registry of patients who have been diagnosed with SMA that draws upon existing country registries

Immediate access to Zolgensma, aligned to the label, is available in France through the ATU framework and expected shortly in Germany.

“Today’s approval brings tangible progress in harnessing the transformational power of gene therapy,” said Dr. Eugenio Mercuri, Professor, Pediatric Neurology, Catholic University, Rome, Italy. “The approval of Zolgensma represents an important new way for physicians to treat patients with SMA. The results we have seen for Zolgensma to date from the STR1VE clinical trial show an impressive survival rate at the conclusion of the study, with the majority of patients achieving functional milestones, like sitting without support, that wouldn't have been reached in untreated infants.”

“SMA Europe receives with deep excitement the news on the approval by the European Commission, of a gene therapy for treating a part of our community,” said Mencía de Lemus, President of SMA Europe. “Many hopes have been put into this much awaited therapy. It will be now be up to all stakeholders involved to ensure that treating doctors, together with parents, can take the best therapeutic option based on the benefit that each of them can provide to each individual. Gathering more data on how Zolgensma impacts in the lives of patients will be extremely important to better understand the potential of this new therapy on improving lives of those living with SMA.”

The EC approval is based on the completed Phase 3 STR1VE-US and Phase 1 START trials that evaluated the efficacy and safety of a one-time IV infusion of Zolgensma in symptomatic SMA Type 1 patients <6 months of age at dosing, who had one or two copies of the SMN2 backup gene, or two copies of the SMN2 backup gene, respectively. STR1VE-EU, a comparable Phase 3 study is ongoing. Zolgensma demonstrated prolonged event-free survival; rapid motor function improvement, often within one month of dosing; and, sustained milestone achievement, including the ability to sit without support, crawl and walk independently – milestones never achieved in untreated Type 1 patients.

Additional supportive data included interim results from the ongoing SPR1NT trial, a Phase 3, open-label, single-arm study of a single, one-time IV infusion of Zolgensma in pre-symptomatic patients (<6 weeks at age of dosing) genetically defined by bi-allelic deletion of SMN1 with 2 or 3 copies of SMN2. These data demonstrate rapid, age appropriate major milestone gain, reinforcing the critical importance of early intervention in SMA patients.

The most commonly observed side effects after treatment were elevated liver enzymes and vomiting. Acute serious liver injury and elevated aminotransferases can occur. Patients with pre-existing liver impairment may be at higher risk. Prior to infusion, physicians should assess liver function of all patients by clinical examination and laboratory testing. And, they should administer systemic corticosteroid to all patients before and after treatment, and then continue to monitor liver function for at least 3 months after infusion.6 There is limited experience in patients 2 years of age and older or with body weight above 13.5 kg. The safety and efficacy of Zolgensma in these patients have not been established.

AveXis has an exclusive, worldwide license with Nationwide Children's Hospital to both the intravenous and intrathecal delivery of AAV9 gene therapy for the treatment of all types of SMA; has an exclusive, worldwide license from REGENXBIO for any recombinant AAV vector in its intellectual property portfolio for the in vivo gene therapy treatment of SMA in humans; an exclusive, worldwide licensing agreement with Généthon for in vivo delivery of AAV9 vector into the central nervous system for the treatment of SMA; and a non-exclusive, worldwide license agreement with AskBio for the use of its self-complementary DNA technology for the treatment of SMA.

SMA is the leading genetic cause of infant death. If left untreated, SMA Type 1 leads to death or the need for permanent ventilation by the age of two in more than 90% of cases. SMA is a rare, genetic neuromuscular disease caused by a lack of a functional SMN1 gene, resulting in the progressive and irreversible loss of motor neurons, affecting muscle functions, including breathing, swallowing and basic movement. It is imperative to diagnose SMA and begin treatment, including proactive supportive care, as early as possible to halt irreversible motor neuron loss and disease progression. This is especially critical in SMA Type 1, where motor neuron degeneration starts before birth and escalates quickly. Loss of motor neurons cannot be reversed, so SMA patients with symptoms at the time of treatment will likely require some supportive respiratory, nutritional and/or musculoskeletal care to maximize functional abilities. More than 30% of patients with SMA Type 2 will die by age 25.

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 IV infusion. Zolgensma represents the first approved therapeutic in the company’s proprietary platform to treat rare, monogenic diseases using gene therapy. More than 500 patients have been treated with Zolgensma, including clinical trials, commercially and through the managed access program. AveXis is pursuing registration in close to three dozen countries with regulatory decisions anticipated in Switzerland, Canada, Australia, Argentina, South Korea and Brazil in late 2020 or early 2021.

In May 2019, the U.S. Food and Drug Administration approved Zolgensma for the treatment of pediatric patients less than two years of age with SMA with bi-allelic mutations in the SMN1 gene. In the U.S. nearly all on-label patients have been approved by their payer for access to Zolgensma. On March 19, 2020, Zolgensma was approved by Japanese Ministry of Health, Labour and Welfare (MHLW) for the treatment of SMA in patients under the age of two, including those who are pre-symptomatic at diagnosis. Today’s EC approval applies to all 27 European Union member states, as well as Iceland, Norway, Liechtenstein and the United Kingdom.