[Editor’s note: This is the first 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]]
The arrival of Zolgensma (onasemnogene abeparvovec-xioi) marks a “game-changing” period in spinal muscular atrophy (SMA) treatment and underscores the importance of newborn screening, say neurologists and researchers who aided in the development of this gene therapy.
“This treatment … will potentially change the whole landscape of SMA as we know it,” Vincent Carson, MD, a pediatric neurologist with the Clinic for Special Children in Pennsylvania said in an interview with SMA News Today. “This is a revolutionary medicine.”
The U.S. Food and Drug Administration (FDA) approved Zolgensma as an intravenous infusion to treat newborns through toddlers up to 2 years old regardless of SMA type. This label is broader than the one AveXis initially requested, which would have covered infants up to 9 months old with SMA type 1 — the most severe and common form of the disease.
Arthur Burghes, PhD, a researcher at The Ohio State University College of Medicine and professor of biological chemistry and pharmacology, was “slightly surprised that it went right away up to 2, because the best effects are obviously early on” in the disease. Still, he thought it was the “right decision.”
Burghes developed a mouse model that was crucial to early testing that made an SMA gene therapy possible and, later, a pig model.
Jerry Mendell, MD, a neurologist and clinical translational researcher at Nationwide Children’s Hospital and The Ohio State University School of Medicine — who has been a principal investigator for Zolgensma since its first clinical test opened in 2014 — largely agreed, saying that “full efficacy” in toddlers — likely with type 2 SMA — isn’t fully known because trials in older children are now underway.
“In our clinical trials, patients were only admitted if they had disease onset before six months of age, so I think we’re looking at a new picture,” Mendell said.
Still, Zolgensma is “a great advancement … really a life-saving treatment that can start at birth,” Mendell said. “I’m pretty confident that the treatment, even for type 2 by systemic [intravenous] delivery, will be helpful. But I don’t think one can truly say that right now.”
With Zolgensma — marketed by Novartis, which acquired AveXis in 2018 — this severe disease now has two disease-modifying treatments. The other is Spinraza (nusinersen, by Biogen), an intrathecal (spinal canal) infusion therapy given in three doses annually after an initial loading dose. It was approved in December 2016.
“To have two breakthroughs of this magnitude in such a short window of time puts us at the major advantage in the clinic,” said John Brandsema, MD, a pediatric neurologist at the Children’s Hospital of Philadelphia (CHOP). A few years ago, “we would be discussing losses … and now we’re talking about gains and improvements and new things that people are able to do.
“It’s been a total pivot, a game-changer,” he added of the arrival of both Zolgensma and Spinraza, “an experience that — in most people’s careers — would only come along, if they’re lucky, one time.”
“I’m so happy that this treatment, that Zolgensma, is effective in a devastating neurological condition like SMA,” Carson said, adding that published results from its earliest clinical study — the pivotal Phase 1 trial (NCT02122952) in type 1 SMA babies — were “incredibly promising.”
That trial, like those in Spinraza before it, showed muscle gains that allowed children to sit, swallow, and breathe in ways that defied SMA’s natural history.
And it did so in a single treatment.
A possible one-time therapy
Zolgensma uses a genetically engineered virus known as AAV9 to deliver a functional copy of the SMN1 gene to motor neurons, specialized nerve cells that control muscle contraction. Defects in this gene severely affect production of the SMN protein crucial to muscle health, causing symptoms like muscle atrophy.
A single dose of Zolgensma has been — and continues to be — given to all patients in its many clinical studies, with durable effectiveness now approaching five years.
Whether that effectiveness will last a lifetime is still a question waiting to be answered, these experts said — five years is not enough for scientific certainty.
“I have reasonable confidence that it will [last],” Burghes said, “because none of the patients after four or five years are showing any kind of drop-off in effect.” Still START, the long-term extension study (NCT03421977) that’s following those pivotal trials’ children for safety and efficacy, runs through 2033.” It’s a 20-year or more experiment,” he added, and five years ” is not 20 years.”
One key factor in its likely durability, these scientists said, is that motor neurons do not replicate — do not divide into new cells — and, as a result, favor sustained SMN production once the newly delivered gene is expressed and begins to produce that protein. More than tissue or other cells, “I think that the critical cell in SMA is the motor neuron,” Burghes said.
Data now out “four and a half years … is looking pretty good,” Mendell said. “We can get long-term gene expression [SMN protein production] … and we don’t know of anything that’s shutting that down.”
Repeat treatment with Zolgensma is also a research question for which there is “a lot more work” ahead regarding feasibility, Brandsema said, both in terms of safety, because of possible antibodies in reaction to the virus used, and continued effectiveness, due to treatment efficacy dropping in the presence of antibodies.
“This is why we test antibodies titers before we deliver the gene transfer therapy,” he added. “And in the context of a motor neuron disease such as SMA, [repeated doses] may not be necessary.”
Burghes agreed, noting that Zolgensma “gives us, at least in theory, a one-time treatment that can be administered and basically you don’t have to be taking drugs after that.” All clinical and preclinical study data support the likelihood that “it will last, and it will have a pronounced effect on SMA.”
That said, research into the possibility of a second treatment with this type of a gene therapy is now “extremely active” across diseases, Burghes added, with “some indications that it may be possible.”
“I think we have everything lined up for potential re-dosing,” Mendell said.
Treatment options mean choices
Interest among the SMA community at CHOP runs high, Brandsema said, with a “significant expansion” in families wanting to take part even after STR1VE, for which his hospital is a test site, was fully enrolled. A few were able to get treatment under a managed access program that opened nationwide for a limited time and “included compassionate use,” he said.
Now, with Zolgensma in the clinic, neurologists there — involved in both the Zolgensma and Spinraza trials — look forward to “open discussion” that educates “patients, families and caregivers about options available,” Brandsema said, and to make sure “you’re coming up with the right options in the current context of what’s available.”
Carson — a co-investigator in the Phase 3 SPR1NT trial (NCT03505099) in presymptomatic newborns — plans for similar conversations, also noting that each treatment has its pros and cons. “But I’m a big supporter of Zolgensma and of using Zolgensma in SMA,” he added.
SPR1NT is currently enrolling at the Clinic for Special Children in Strasburg, Pennsylvania — which serves the local Amish and Mennonite communities, both with a higher SMA prevalence than the general population — and its more than 20 other sites.
“I have very strong feelings about the efficacy and the safety of viral gene delivery using this construct … and the viral delivery systemically at these high doses. So yes, in patients … who want to have the treatment … we’re very receptive to making that available,” Mendell said.