Zolgensma Can Best Help Babies Treated Early – But Older Patients May Also Benefit, Experts Say

[Editor’s note: This is the second in a series of articles on Zolgensma and treatments for SMA, the issues they raise, and possible discoveries to come, all drawn from recent interviews with neurologists and researchers involved in this work. Others in this series can be found here.

SMA News Today is also interested in speaking with families of children treated with Zolgensma in its approved form, using intravenous injection, to share their experiences and opinions with our readers. If you or those you know are open to this interview, please contact us at [email protected]]

Newborns and infants with “minimal symptoms” are the ideal candidates for treatment with Zolgensma (onasemnogene abeparvovec-xioi) — and for Spinraza (nusinersen) as well — repeat studies show, but neurologists and researchers expect the gene therapy to also benefit toddlers, and to become available for spinal muscular atrophy (SMA) patients beyond 2 years old, its currently approved age limit for treatment.

“Our most powerful results in the AVXS-101 trials [as Zolgensma was called] were in newborns with minimal symptoms of SMA. Those are the patients that really returned basically to normal,” said Jerry Mendell, MD, a neurologist and clinical translational scientist at Nationwide Children’s Hospital and The Ohio State University College of Medicine, who has been a principal investigator for Zolgensma since its first clinical test opened in 2014.

The importance of receiving Zolgensma early in SMA’s brutal course was first suggested in animal models and confirmed in the pivotal Phase 1 study (NCT02122952) and its long-term follow-up (NCT03421977), called START. These trials, led by Mendell at Nationwide, were both crucial to approval by the U.S. Food and Drug Administration (FDA).

In the 2017 published study detailing Phase 1 results, Mendell and his team noted that “when the treatment was beyond 6 months with a low CHOP-INTEND [score], we really couldn’t reverse the disease any further. … life was saved, but the quality of life never matched patients treated at an earlier age.” 

Ultimately, decisive factors for best treatment at different ages is “a question that will only be established with clinical experience,” he said.

Likewise, data from the Phase 3 SPR1NT trial (NCT03505099), which is still enrolling, show that treating asymptomatic newborns, those likely to develop SMA types 1–3, rapidly improves muscle strength and motor function.

Only time will tell if a single dose of Zolgensma brings benefits lasting a lifetime. “I would say that it’s likely that if you treat presymptomatically … you’re going to probably correct that condition, maybe completely,” Arthur Burghes, PhD, a researcher at The Ohio State University College of Medicine, said in a separate interview with SMA News Today.

“It’s a 20-year or more experiment” now four to five years out since children were first treated as infants, added Burghes, who developed the mouse and pig models of SMA that were key to making clinical tests of Zolgensma possible.

STRONG and real-world support

Comprising about 60% of all SMA births, type 1 is the most common and severe form of this neuromuscular disease, caused by mutations in the SMN1 gene responsible for producing the SMN protein essential for muscle contraction. In the disease’s natural history, or the course it runs in a person without treatment, only 8% of type 1 babies are alive or not on permanent ventilation at 20 months.

All START children, now 4- or 5-year-olds, are “event-free” and thriving to different degrees.

Patients with types 2 or 3 have relatively milder disease forms, but without a disease-targeted treatment, they begin in childhood to lose the muscle strength needed to sit up on their own or open a soda can, much less stand and walk.

A Phase 1 study called STRONG (NCT03381729) — currently recruiting — is aimed at providing answers to questions of benefit in older patients, testing the therapy in babies and children with type 2 up to age 5, using an intrathecal (spinal cord) injection rather than the intravenous delivery approved by the FDA.

“I think there’s over 30 patients now that have been treated in the STRONG study in a multi-clinic trial” to date, Mendell said, “and the data’s looking reasonably good. The safety data’s excellent.” In terms of effectiveness, particularly, leg strength is improving in patients, and a number “can stand with support.”

Real-world experience with Biogen‘s Spinraza, the first approved SMA therapy, also showed gains in older patients with more advanced disease and to extents that “surprised several of the SMA trial leaders,” said John Brandsema, MD, a pediatric neurologist at the Children’s Hospital of Philadelphia (CHOP).

Both Zolgensma (marketed by Novartis, and first developed by AveXis) and Spinraza are designed to help specialized cells called motor neurons produce more of the critical SMN protein. Motor neurons without that protein die quickly in infancy, and although this process slows, patients whose symptoms span months and years typically have extensive loss. Reversing this damage is not yet possible.

In this way, Burghes and Mendell believe Zolgensma will benefit older patients, but to a degree that likely depends on how many motor neurons they have when treated.

“If the motor neuron is lost, then pulling the gene back into a lost cell is impossible. You can only rescue the cells that are there,” Burghes said.

Brandsema argues for research into “other ways of giving SMN back to patients” because of a gene therapy’s unknowns in older children and adults.

In the meantime, Vincent Carson, MD, a pediatric neurologist with the Clinic for Special Children in Pennyslvania, is hoping for a little “wiggle room” in treating those slightly older than the age limit given Zolegensma, like children 2 and a half years old. Doctors often use medicines they are reasonably certain will help their patients in ways “somewhat differently than what FDA approved them for,” Carson said. “Maybe that will be an option in the future.”

Combo treatments and possibilities

Zolgensma and Spinraza work in different ways to boost SMN protein levels. The gene therapy uses a modified viral vector (AAV9) to deliver a normal copy of the SMN1 gene to motor nerve cells.

Spinraza and risdiplam — an investigational oral therapy showing promise in trials — work via the SMN2 gene, by binding to its messenger RNA — derived from DNA in gene expression — and changing the way it is spliced, or edited, before it is converted into protein. This enables more full-length SMN to be produced from SMN2.

These different mechanisms make the therapies “potentially complementary to each other,” Brandsema said. “The hope is to increase the amount of SMN protein overall.”

Preclinical data also indicate that the more SMN protein that exists, the better the motor neuron repair. “I think combining a therapy that involves splicing with a gene therapy, for instance, makes sense,” Burghes said. “Obviously, I think at some point that has to be discussed.”

Such an approach would make the most sense in patients with evident symptoms, Burghes believes, as more extensive loss of motor neurons in these people likely lessens the degree of benefit they would get from a stand-alone gene therapy. “That’s, to me, where combination therapies come in.”

Future clinical trials are necessary to test combo approaches, and current experience in patients taking both Spinraza and Zolgensma is “very limited,” Brandsema said. He pointed to three children in the START trial who moved to Spinraza after gene therapy and a few patients at his hospital given Zolgensma through a managed access program.

Plans underway at Nationwide Children’s Hospital will “in a very short time” open the gene therapy to Spinraza users, Mendell said. A major consideration right now is whether a complete stop or “a holiday” in Spinraza use would be necessary.

Treatment costs, and payers’ willingness to assume multiple disease-modifying treatments, is another big unknown. Risdiplam is still in testing, but Spinraza costs $375,000 each year after an initial $750,000 loading year and Zolgensma is priced at $2.1 million for a one-time treatment.

“In the real world,” Brandsema said, “use of combination therapy is going to have to be managed very carefully” for safety and efficacy, of course, “but also whether this is going to be feasible in the current environment of coverage.”

That’s “something to navigate together as a community.”