Screening Tests and Other Steps for Zolgensma’s Use – Here’s Why They’re Necessary

Monitoring liver function and immune reactions, being alert to signs of a respiratory infection, and making sure that a child’s vaccination schedule does not interfere with necessary corticosteroid use are among the key health and safety requirements for families and doctors interested in using Zolgensma to treat a young spinal muscular atrophy (SMA) patient.

Noted in documents created and posted online by AveXis, the gene therapy’s developer, they cover the five steps to Zolgensma treatment. The second of these steps is contacting a patients’ assistance program, OneGene, also explained in an article available here.

Zolgensma (onasemnogene abeparvovec-xioi), the first gene therapy for SMA and its second disease-modifying treatment after Spinraza, was recently approved in the U.S. for children up to age 2 regardless of disease type or body weight. A trial in type 2 patients up to age 5 is underway, and its findings may lead to broader use.

Treatment with Zolgensma for infants and toddlers is now available at 36 sites in 23 states and Washington, D.C., with an ultimate goal of 50 to 100 locations. Updates can be checked here; a suitable treatment center may also be found by emailing [email protected].

Children’s Hospital of Philadelphia is among these sites, and told SMA News Today that “commercial,” or post-approval, dosing of new patients is expected to get underway in a matter of days.

In a recent webinar, AveXis — now part of Novartis — and Cure SMA went over these five steps, covering aspects related to safety, requirements for eligibility, and actions to take before and after treatment.

Zolgensma is reported to be a one-time therapy, one “that targets the genetic root cause of SMA,” Doug Sproule, MD, AveXis’ vice president of clinical development and SMA therapeutic area head, said in the webinar.

Given as a 60-minute intravenous infusion into a vein in an arm or leg, it uses a genetically engineered subtype of an adeno-associated virus called AAV9 to deliver a healthy copy of the SMN1 gene to motor nerve cells. Mutations in SMN1 cause SMA by greatly lowering levels of the SMN protein the gene works to produce, and which are necessary for these specialized neurons to survive, much less thrive. The protein’s loss, and subsequent motor neuron damage and death, leads to disease symptoms marked by widespread and progressive muscle weakness.

Eligibility steps begin with confirmation of an SMA diagnosis by genetic screening. If confirmed, a small blood sample will then be tested for the presence and degree of anti-AAV9 antibodies. These antibodies provoke a defensive immune reaction by targeting the vector, and as such pose a serious safety concern. If treatment is given, which appears unlikely if levels are thought too high, the antibodies would also reduce Zolgensma’s effectiveness.

This test may be required by insurance providers, and can be retaken if antibody levels are initially too high, said Izzy Tyszler, AveXis’ senior director of marketing, whose department produced the Zolgensma explainers.

Vaccination against the respiratory syncytial virus “is recommended,” Sproule said, as this could cause severe lung and respiratory infection in infants with SMA. Being alert to signs of a respiratory infection before or after infusion is crucial, like “coughing, wheezing, sneezing, runny nose, sore throat, or fever,” said Sproule, a pediatric neurologist by training.

Before and at regular periods after treatment, patients’ liver function and platelet counts are assessed, as Zolgensma could raise the levels of liver enzymes such as aminotransferase — an indicator of liver damage — and drop those of platelets. These reactions were observed in infants in the ongoing STR1VE Phase 3 trial (NCT03306277), although the changes were temporary.

Of note, raised levels of liver enzymes and vomiting were the most common side effects reported in both STR1VE and the completed START Phase 1 long-term study (NCT03421977).

Other markers checked pre- and post-treatment include levels of troponin-I, a protein indicator of cardiac muscle injury. Cardiac toxicity was found in preclinical studies, and temporary increases in cardiac troponin-I levels were seen in clinical trials.

These clinical exams and blood tests will be given weekly over the first month, and every other week for the second and third months. Some may continue for a longer period.

Patients will also receive the corticosteroid prednisolone, at 1 mg/kg, daily for about 30 days starting on the day prior to a Zolgensma infusion. This helps to manage potential immune reactions against the AAV9 vector and changes in liver enzyme levels. The dose will then be tapered until stopped, although corticosteroid use could continue unless liver tests “are reassuring,” said Dave Lennon, AveXis’ president. Keeping to a corticosteroid regimen is “critical,” he added.

Following an age-relevant schedule of vaccinations, including those against the syncytial virus, is essential, but adjustments should be made — in conjunction with the prescribing doctor — if necessary due to corticosteroid use. Its use is not recommended in premature infants, given the impact corticosteroids can have on their neurologic development.

Sproule urged families to contact their prescribing physician immediately if a treated child’s skin and/or the whites of the eyes appear yellowish, which may indicate jaundice — a complication often signaling liver problems. Caregivers should also inform that doctor at any signs of difficulty swallowing or breathing, respiratory infection, muscle weakness, or a child vomiting. Missing a dose of prednisolone, and easy bruising or bleeding that may indicate fewer platelets, should also be reported quickly.

Small amounts of the therapy may be carried in stool for the first month post-treatment, and caregivers are advised to use good hand hygiene when in direct contact with a child’s waste. Disposable diapers should be sealed in trash bags and thrown out with other household trash.

Questions related to Zolgensma’s use could be answered by a family’s care team, or the resource manager in the patients’ assistance OneGene Program. But while OneGene team members will be sources of support and aid throughout a family’s “Zolgensma journey,” they cannot give medical advice — that must come from the treating physician.

That prescribing doctor will also need to file a signed patient consent form for acceptance into the OneGene Program, along with results of required tests.

Zolgensma is shipped once an insurer has approved the prescription. Those in charge of providing it will work with the doctor in informing a family of approval, and in setting an infusion date. A child’s physician and health care team are always a “good point of contact,” repeat webinar speakers said.

“Please follow up with your neuromuscular specialist … work with a nutritionist, and meet with a pulmonologist to determine what kind of supportive care may be best for your child,” Sproule said.

Bringing Zolgensma to the children it’s now approved to treat is a chief goal of AveXis and Novartis. But both continue to work toward a possible revised label, one that might allow treatment well beyond age 2 and using a different administration route — intrathecal (spinal cord) injection.

Treating older patients is “a hot topic … for an obvious and good reason,” Sproule said in concluding AveXis’ part of the webinar. A planned study that will include all SMA types through age 18, to be called REACH, is “envisioned,” he added, should next year’s conclusion of the STRONG trial support such a study.