Zolgensma (onasemnogene abeparvovec-xioi), previously known as AVXS-101, is a gene therapy originally developed by AveXis, now known as Novartis Gene Therapies after being acquired by Novartis, which is further developing and marketing the treatment.
It was approved by the U.S. Food and Drug Administration (FDA) in May 2019 to treat newborns and toddlers up to age 2 with all types of spinal muscular atrophy (SMA) — making it the second disease-modifying treatment for the disease, and its first gene therapy.
Zolgensma was also granted conditional approval by the European Commission in May 2020 for children weighing up to 21 kilograms (kg, or about 46 pounds, or lbs) with SMA type 1 or those still without symptoms but carrying up to three copies of the “backup” SMN2 gene, meaning they are expected to develop type 1 or 2 disease. A weight of 21 kg likely includes children up to 5 years old. The therapy is available at low or no cost to eligible SMA patients in England and Scotland through the countries’ national health services.
Health Canada approved Zolgensma in December 2020 for a similar indication as in Europe. The therapy was recommended for reimbursement in the country only for eligible children younger than 6 months. Those older than that may receive the therapy at low or no cost in Quebec on a case-by-case basis.
Zolgensma is considered the most expensive therapy in the world, with a U.S. list price of $2.1 million for a single dose. Novartis allows for installment payments of $425,000 over five years.
How does Zolgensma work?
SMA is caused by low to no levels of SMN, a protein essential for the health of motor neurons and muscle, due to mutations in the SMN1 gene. Motor neurons are the specialized nerve cells that control voluntary movement.
Administered directly into the bloodstream through a single infusion at a dose proportional to a patient’s body weight, Zolgensma uses a genetically engineered and harmless adeno-associated virus serotype 9 (AAV9) to deliver a working copy of SMN1 to cells.
The delivered gene consists of double-stranded DNA, meaning that it takes the same form as natural genes and can be activated more quickly to be a faster and more efficient therapy. Zolgensma also includes genetic instructions to activate the gene, so that SMN production is continuous and sustainable.
That delivered gene is not inserted into a person’s DNA and remains outside the nucleus, where all the genetic information is stored. However, given that cells that do not divide into new cells (like motor neurons) are less likely to lose the delivered gene over time, a single dose of Zolgensma is expected to promote sustained SMN levels in these highly susceptible cells.
Zolgensma in clinical trials
Promising findings from a Phase 1 clinical trial, called START (NCT02122952), led to the initiation of three Phase 3 trials taking place in different regions of the globe and involving a total of 57 type 1 infants up to 6 months of age. These completed studies included STR1VE (NCT03306277) in the U.S., STR1VE-EU (NCT03461289) in Europe, and STR1VE-AP (NCT03837184) in the Asia-Pacific region.
Novartis also launched the Phase 3 SPR1NT trial (NCT03505099) to test Zolgensma in 30 pre-symptomatic babies (up to 6 weeks old) with SMA and carrying two or three copies of the backup SMN2 gene. A higher number of SMN2 copies is associated with less severe disease, and patients with two copies are likely to have SMA type 1 while those carrying three copies are expected to develop type 2, a milder form of the disease.
Interim results showed that all of the now-toddlers, with ages up to 2, were alive and free of ventilatory or feeding tube support, and most also achieved motor milestones within the window of normal development and similar to healthy, typically developing children.
Novartis is also evaluating the safety and effectiveness of a more targeted route of administration, directly into the spinal canal (intrathecal injections), in the Phase 1/2 STRONG trial (NCT03381729). The study was designed to treat up to 51 SMA type 2 and 3 children, ages 6 months to 5 years, with one of three doses of OAV-101 — by which Zolgensma is currently known when delivered through this route.
STRONG was put on a partial clinical hold by the FDA in October 2019 after troubling safety findings in nonhuman primates given OAV-101. Such safety concerns have not been detected in children treated in the trial, and comprehensive toxicology studies addressed all issues identified by the agency, prompting the lift of the trial’s hold in August 2021.
Interim results before the clinical hold showed that treated children continued to show gains in motor function and that no new safety concerns were identified relative to those previously reported with into-the-vein Zolgensma.
Novartis is also launching a Phase 3 trial, called STEER (NCT05089656), to test OAV-101 in up to 125 children and adolescents, ages 2 to 17, with SMA type 2 and who are able to sit but have never walked. The new trial was requested by the FDA to aid in the potential approval of this new administration route for older patients.
Participants, who must have not received any prior disease-modifying treatment, will be given either OAV-101 or a sham procedure and monitored for about a year. After that period, those given the sham procedure will receive the therapy, and vice versa.
The Phase 3b SMART trial (NCT04851873) is evaluating Zolgensma’s one-year safety and effectiveness in young children with SMA who weigh 8.5 to 21 kgs (about 18 to 46 lbs). More than half of children in Europe given the therapy are within this weight range, which can correspond to ages of 5 up to 8 — considerably older than the 2-year-old threshold in the U.S.
While Zolgensma is expected to be a one-time, lifelong treatment, not enough time has passed from its first clinical trials to know that with certainty. Nevertheless, the therapy can be given only once due to the body’s natural production of immune antibodies against the viral carrier.
However, patients still may develop immune reactions after the single dose, which can increase the levels of liver enzymes — an indicator of liver damage — and drop those of platelets, tiny blood cells responsible for blood clotting. This is a problem shared by virus-based gene therapies in development for other diseases.
For that reason, an immunosuppressive regimen should be started on the day before Zolgensma treatment, with liver health and platelet counts monitored before treatment and at regular periods thereafter for at least three months.
The therapy’s label contains a boxed warning highlighting the risk of higher-than-normal levels of liver enzymes, acute liver damage, and acute liver failure. Rises in liver enzymes, as well as vomiting, are Zolgensma’s most common side effects.
Given that children with pre-existing liver impairment or viral infection in the liver may be at higher risk of these serious adverse events, it is recommended that Zolgensma’s risks and benefits be carefully weighed in these patients. It also is recommended that Zolgensma not be given to children with clinical signs or symptoms of infection and be postponed until any occurring infection is resolved.
Thrombotic microangiopathy (TMA), a rare condition characterized by red blood cell destruction, low platelet counts, and blood clots in small blood vessels throughout the body, was also added to the list of safety concerns with Zolgensma use. This decision was based on reports of six confirmed cases within one to two weeks post-treatment. All cases of TMA, which can also be triggered by abnormal immune reactions, were resolved with specific treatment.
Parents and caregivers are recommended to seek urgent medical care if a child shows any signs or symptoms of TMA, such as unexpected bruising or bleeding, high blood pressure, seizures, or reduced urination after receiving Zolgensma.
Last updated: Dec. 22, 2021, by Marta Figueiredo PhD
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