MDA 2025: SMA gene therapy ‘transformational,’ per Novartis exec
Over 95% of diagnosed babies now treated with Zolgensma, per marketer
It’s been almost six years since the one-time gene therapy Zolgensma (onasemnogene abeparvovec-xioi) was first approved in the U.S. to treat young children with spinal muscular atrophy (SMA).
Now, more than 95% of babies diagnosed with SMA are being treated with Zolgensma, according to Daniel Grant, vice president and global program head at Novartis, the company that markets the therapy. Since its U.S. approval in May 2019, the SMA gene therapy has been approved in more than 50 countries, per Novartis.
Zolgensma is only approved for young children, but Novartis is also working to develop a gene therapy for older kids and adults with SMA.
“This is really transformational,” Grant said in an interview with SMA News Today at the Muscular Dystrophy Association‘s 2025 MDA Clinical & Scientific Conference.
SMA is chiefly caused by mutations in the gene SMN1. Zolgensma works to deliver a healthy version of this gene to the body’s cells. In the U.S., use of the gene therapy is approved for children younger than 2; specific indications vary in other regions.
“We’ve now treated over 4,000 patients around the world with Zolgensma,” Grant said.
Novartis now developing OAV101 gene therapy for older SMA patients
Data from clinical trials and real-world studies have consistently shown that Zolgensma and other disease-modifying treatments tend to have the most dramatic effects when given as early as possible. With the advent of these therapies, there’s been an increasing push to offer newborn screening, where all babies are tested for SMA soon after birth.
Newborn screening for SMA is now standard in all 50 states in the U.S. and in certain other countries. With newborn screening, it’s possible for babies to receive treatment before they start experiencing any disease symptoms.
In the clinical trial SPR1NT (NCT03505099), 29 infants who’d been diagnosed with SMA by genetic testing were treated with Zolgensma before disease symptoms developed. These children are now being followed as part of a long-term study called LT-002 (NCT04042025). According to prior reports, all of these children were able to walk and are reaching new motor milestones.
An earlier trial of Zolgensma, called START (NCT02122952), enrolled babies who had already begun to experience symptoms. Those children are now being followed in a separate long-term study, LT-001 (NCT03421977).
Motor milestone results in these children have been a bit less dramatic — 2 of 10 given a therapeutic dose of Zolgensma are able to walk unaided — but recent data showed that patients who attained motor milestones early in the START trial have maintained them for up to a decade of follow-up.
Although he noted that it’s difficult to generalize, Grant said that taking data from these two studies collectively indicates that the modern generation of SMA patients, most of whom are diagnosed by newborn screening and are getting gene therapy before symptom onset, can expect to see substantial long-term benefits from the treatment.
“As a community, we should have very high expectations for these patients,” he said.
[OAV101] is a drug that’s been developed for patients that missed out on Zolgensma because they were too old at the time Zolgensma was approved to be treated. … We want to make gene replacement therapy an option for all patients with SMA.
Novartis now is also developing OAV101, a gene therapy that contains the same agent as Zolgensma, for patients 2 and older. The company is planning to submit applications seeking approval of OAV101 in the first half of this year, Grant said.
“[OAV101] is a drug that’s been developed for patients that missed out on Zolgensma because they were too old at the time Zolgensma was approved to be treated,” Grant said. “We like to think of them [as] the last generation of patients that are having to go through early childhood without gene replacement.”
Grant added:Â “Our mission really with this program was, we want to make gene replacement therapy an option for all patients with SMA.”
Exec says OAV101 findings are ‘meaningful for the entire population’ in SMA
Zolgensma is given by infusion into the bloodstream at a dose determined by the patient’s weight. By contrast, OAV101 is administered intrathecally — via injection into the spinal canal, which is typically done under anesthesia — at a flat dose. Flat dosing is possible with OAV101, Grant said, because the amount of fluid in the spinal cord remains relatively constant in people ages 2 and older. Both Zolgensma and OAV101 mainly exert their effects by delivering a healthy copy of the SMN1 gene to cells in the spinal cord.
“There’s no patient that has to be living without a working copy of SMN1,” Grant said.
Daniel Grant, PhD, is vice president and global program head at Novartis. (Photo by Kellie Benn)
OAV101 has been tested in two Phase 3 clinical trials: STEER (NCT05089656) and STRENGTH (NCT05386680). Both studies enrolled children with SMA ages 2 to 17. This age range was chosen largely for logistical reasons, according to Grant, to minimize variability in the data and ensure that the study could be conducted at pediatric centers.
Grant, however, said he thinks the findings from these studies are “meaningful for the entire population [older than] 2.”
STEER enrolled children with SMA who had never received disease-modifying treatment. Participants were randomly assigned to treatment with OAV101 or a sham procedure and then were followed for a year. This study was designed to “accurately understand and analyze the treatment effect,” Grant said.
The study’s main goal was to assess the effect of treatment on Hammersmith Functional Motor Scale Expanded (HFMSE) scores — a standard test used to evaluate motor function in people with SMA. The HMFSE assesses whether or not patients can do a range of movements, such as raising the hand over the shoulder or standing up. If patients can do the movement completely, they get two points, while being able to do the movement partially is scored as one point.
“The reason we use these composite scores is because gain in overall function may look very different for different patients,” Grant said. “For one patient, it may be standing independently versus with support. With another patient, it may just be improvements in their strength and being able to complete tasks with their upper limbs.”
Overall, “despite all of the differences in what it looks like, we know that it’s really important for patients to preserve and gain motor function,” Grant said.
Novartis testing OAV101 in both treated and treatment-naive patients
Results from STEERÂ showed that patients given OAV101 experienced an average HFMSE improvement of 2.39 points. That compared with an improvement of 0.51 points in those given the sham procedure. According to Grant, given that one completed movement is scored as two points, the improvement seen in patients given OAV101 “is somewhere north of a full item gained” on the HFMSE.
Subgroup analyses of patients ages older than 5 — slightly less than half of all the participants in STEER — showed a similar effect on HFMSE as was seen in the overall population.
“This is really important because … these are the patients who are either untreated or dependent on chronic therapies,” Grant said, adding that, in the real world, this older population is the group “for whom gene replacement therapy is, we think, an important treatment option in the future.”
While STEER enrolled patients who’d never received SMA treatments, STRENGTH enrolled individuals previously treated with Spinraza (nusinersen) or Evrysdi (risdiplam). These treatments have also been proven to slow SMA progression. However, unlike Zolgensma and OAV101, which are one-time gene therapies, Spinraza and Evrysdi need to be taken regularly for a patient’s entire life to maintain an effect. The main goal of STRENGTH was to assess the safety of OAV101 in patients who had been on other therapies.
“If we look at patients with SMA living in the U.S. and around the world, most of these patients, many of them are already on treatment with [Spinraza or Evrysdi]. And so we know that to make the data relevant, we needed to also study the treatment in a population of patients that were previously treated,” Grant said.
In STRENGTH, scores on the HFMSE and other motor function measurements were essentially unchanged over the course of a year following OAV101 treatment. Based on these data, “we expect that patients that take the decision to switch from [Spinraza or Evrysdi] to a one-time gene replacement should be able to maintain their motor function,” Grant said.
The safety profile of OAV101 was consistent in both STEER and STRENGTH.
“We think matching the data from treatment-naive and treatment-experienced patients puts us in a good place to inform use of [OAV101] in the event of an approval,” Grant said.
Note: The SMA News Today team is providing live coverage of the 2025 MDA Clinical & Scientific Conference in Dallas. Go here to see the latest stories from the conference.
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