Expert Views on Likely Future Work into Zolgensma, Gene Therapies and Other SMA Treatments

[Editor’s note: This is the sixth and final entry 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]]

Future work in spinal muscular atrophy could range from identifying biomarkers that allow for earlier detection, to determining if and how a gene therapy like Zolgensma might be given more than once to SMA patients, researchers involved in the gene therapy’s development say.

In interviews with SMA News Today, Jerry Mendell, MD, a neurologist and clinical translational scientist at Nationwide Children’s Hospital, and Arthur Burghes, PhD, a researcher with The Ohio State University College of Medicine, spoke in broad terms about possible avenues of study.

SMA is caused by mutations in the SMN1 gene that severely lower SMN protein levels in motor neurons, leading to rapid loss of these nerve cells in the first months of life, and continued, if slower, rates of loss with age. Zolgensma — marketed by Novartis and first developed by its subsidiary AveXis — uses a modified viral vector called AAV9 to deliver a normal copy of SMN1 to these specialized cells and restore protein production.

Both companies call Zolgensma a one-time therapy, and current data support this, showing sustained benefits almost five years after dosing in babies with SMA type 1, the disease’s most severe and common form.

A pivotal trial demonstrated “that we can get long-term gene expression” once the therapy delivers a corrected gene to the nucleus of motor neurons, said Mendell, a principal investigator of Zolgensma studies since that first trial opened in 2014. “We have data out for four and a half years, and we don’t know of anything that’s shutting that down.”

Expectations that a single dose will suffice also are supported by preclinical work, and by the rapid improvements in motor function and muscle strength seen in presymptomatic newborns in the Phase 3 SPR1NT trial (NCT03505099), which is still enrolling.

Because motor neurons don’t divide, patients treated in infancy are not expected to lose corrected SMN1 genes, or the SMN protein these genes express, as they age.

But older type 2 and 3 patients, with SMA symptoms that can stretch back years, have extensive motor neuron loss that could limit Zolgensma’s ability to raise their protein levels.

“We can save lives, clearly. We can change a type 1 to a [milder] type 2, unequivocally,” Mendell said. But early treatment is clearly the best therapy, and Zolgensma studies concentrate on newborns and infants for that reason. The FDA approved its use for all SMA types on May 24, but only for children up to age 2.

Potential effects on older children and adults are not known. Studies indicate that significant motor neuron loss cannot be reversed, experts say.

“I really feel that when you give [gene therapy] to a patient, it depends on how many motor neurons they have … at that time,” Burghes said. “You can only rescue the cells that are there.”

Research is therefore turning to ways to better stimulate existing motor neurons — getting them to “more readily fire the muscle” once a healthy gene is “back in those motor neurons” that remain, he said.

“I think that’s kind of where the next generation of therapies are going,” Burghes added, “to really recover the [limited number of] motor neurons” in older patients through a gene therapy, “and then try and ask them to do some more work” in muscles.

“That is really an area of active research at the moment,” he said.

Another means to the same end is treatments now in testing that are aimed at improving muscle strength and function, even with limited motor neurons firing.

Given the importance of early treatment, finding specific blood biomarkers for SMA that would enable more timely intervention — especially in states without newborn screening — also is under active study.

Biogen, which developed and markets Spinraza (nusinersen) — the first approved SMA treatment — recently detailed its findings into a potential biomarker called phosphorylated neurofilament heavy subunit. Blood levels of this neurofilament, a key component of motor nerve cells, are much higher in people with SMA than in those without this disease, including presymptomatic newborns.

Those levels rapidly dropped with Spinraza treatment, this research reported.

“How do you define a symptomatic patient is the first criteria” to choosing a treatment, Burghes said, and “biomarkers like neurofilaments may come into more use for determining that choice.”

Combo therapies and redosing

With two therapies approved and more possibly coming, combinations based on them may one day be possible.

But costs will weigh on decisions here, meaning benefits of dual treatment — say, Zolgensma preceding Spinraza’s use — would need to be clearly set out.

To date, the two have not been evaluated in a clinical trial, although three children in Zolgensma’s pivotal study, at their parents’ request, later also started Spinraza, which boosts SMN levels by modifying the SMN2 gene.

No side effects were evident,  said Mendell, who led that trial. “But whether there’s truly been complementary efficacy, I don’t think we can answer that.”

Rather, Mendell and Nationwide Children’s Hospital are setting procedures in place for giving Zolgensma, which he considers “a ground-breaking therapy,” to SMA patients already on Spinraza.

Only time will tell if Zolgensma is truly a one-and-done treatment, or if repeated dosing will be necessary or possible. Gene therapies are designed to be one-time treatments, Burghes said, but research into the feasibility of redosing is already underway in Pompe disease.

A big question, he added, is whether the initial dose needs to be given with an immunosuppressant to prevent subsequent immune reactions, such as antibody production against the adenovirus vector (AAV) that transports a gene therapy.

These concerns were echoed by John Brandsema, MD, a pediatric neurologist at the Children’s Hospital of Philadelphia. But Mendell spoke of results from work in primates supporting a way to remove such antibodies.

A 2013 study by Mendell and others, published in Molecular Therapy and prompted in part by the death of a teenager in a 1999 gene therapy trial due to a massive immune reaction to an AAV, detailed a blood-filtering process called plasmapheresis that can remove antibodies.

“These data support the hypothesis that removal of AAV binding antibodies by plasmapheresis permits successful and sustained gene transfer in the presence of preexisting immunity (natural infection) to AAV,” the study concluded.

“I think we have everything lined up for potential redosing,” said Mendell, whose trial into a gene therapy for limb girdle muscular dystrophy was stopped — as were all gene therapies trials across the U.S. — in late 1999 in response to the death.

Burghes also spoke of work on modifying the SMN2 gene so as to convert it to SMN1, thereby correcting the defect that causes SMA.

“In terms of gene therapy,” Burghes said, “it’s a question now of where the next advance comes from that would, for sure, give a permanent fix.”