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Gene Therapy Improves Motor Function In Spinal Muscular Atrophy At 52 Weeks
April 01, 2025
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Intrathecal treatment with a vector-based gene therapy was associated with a greater improvement in motor function at 52 weeks compared with sham in patients aged 2 to 18 years with spinal muscular atrophy, data show.
The findings were presented at the Muscular Dystrophy Association Clinical & Scientific Conference.
Data from the phase 3 STEER clinical trial found intrathecal onasemnogene abeparvovec led to greater motor function improvement compared to sham at 52 weeks. Image: Adobe Stock"While many children and young adults with SMA receive chronic SMA therapies, there is still a critical unmet need for a single-administration therapy that helps halt functional decline and addresses the genetic root cause of the disease by providing a functional copy of the SMN1 gene," Daniel Grant, vice president and global program head at Novartis, which funded the study, told Healio.
Crystal Proud, MD, a board-certified neurologist at the Children's Hospital of the King's Daughters, and colleagues assessed the safety and efficacy of intrathecal onasemnogene abeparvovec (OA; Zolgensma, Novartis), an adeno-associated vector-based gene therapy for SMA, in the STEER clinical trial, a phase 3, multicenter, randomized, sham-controlled, double-blind study.
The study included 126 treatment-naïve, nonambulatory patients with SMA aged 2 to 18 years who were randomly assigned on a 3:2 basis to receive either OA (n = 75; mean age, 5.89 years; 54.7% girls) or sham (n = 51; mean age 5.87 years; 54.9% boys).
The primary outcome was comparative efficacy measured as change from baseline in Hammersmith Functional Motor Scale – Expanded (HFMSE) total score over 52 weeks. Secondary outcomes included improvement of at least three points in HFMSE score and change from baseline in the Revised Upper Limb Module (RULM) at 52 weeks for the total study population, as well as total change from baseline in HFSME and RULM and improvement of at least three points in HFMSE at week 52 for those aged 2 to younger than 5 years.
Proud and colleagues also conducted safety assessments to evaluate adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESI), along with liver function evaluations.
According to the results, patients treated with OA registered an improvement of 2.39 points in the HFMSE at 52 weeks, compared with 0.51 points for patients given sham treatment.
In the overall study population, data showed the treatment cohort logged an improvement of 2.44 points in the RULM vs. 0.92 points for the sham cohort, while 29 of 74 patients given OA (39.2%) posted a 3-point increase in the HFMSE against 13 of 50 (26%) given sham treatment.
Patients aged 2 to 4 years who received OA had an improvement of three points vs. 1.56 for the sham cohort in HFSME, with an improvement of 3.27 vs. 1.82 in RULM. Nine of 33 (27.3%) patients in this cohort recorded a three-point HFSME improvement in the OA group vs. Two of 21 (9.5%) for sham.
Proud and colleague reported that the overall incidence of adverse events, serious adverse events and adverse events of special interest were similar between both groups. The most common reported adverse events were upper respiratory tract infection and pyrexia, while the most frequent serious adverse events were pneumonia and vomiting for the treatment group and pneumonia and lower respiratory tract infection for sham.
"Results from both trials support the potential of this therapy to provide patients the opportunity to avoid repeated treatment administration while maintaining or improving motor function among patients," Grant said.
Sources/DisclosuresCollapse Source: Proud C, et al. Intrathecal onasemnogene abeparvovec for patients with spinal muscular atrophy: Phase 3 randomized, sham-controlled, double-blind STEER study. Presented at: Muscular Dystrophy Association Clinical & Scientific Conference; March 16-19, 2025; Dallas.Disclosures: Grant is employed by Novartis.
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Amino Acid Balance Could Play Role In SMA, Study Finds
The balance of amino acids capable of influencing neurological function is disrupted in patients with spinal muscular atrophy (SMA) and in mouse models, a study found.
Observed changes in patients were partially normalized after treatment with the disease-modifying therapy Spinraza (nusinersen). Treatment with one of the amino acids, D-serine, improved motor function in a mouse model.
Taken together, the findings offer "direct evidence" of amino acid dysregulation in SMA, and "have potential implications for treating this neurological disorder," the researchers wrote. The study, "Dysregulated balance of D- and L-amino acids modulating glutamatergic neurotransmission in severe spinal muscular atrophy," was published in Neurobiology of Disease.
In SMA, genetic mutations lead to a lack of the SMN protein, which causes progressive degeneration of the specialized nerve cells that control voluntary movements, or motor neurons. Patients experience muscle weakness, among other SMA symptoms.
Problems within individual motor neurons can't fully explain how SMA manifests, according to the authors. Rather, they said, research suggests that impaired communication between nerve cells may disrupt larger neuronal circuits involved in motor control.
Amino acid balanceOne thing that's observed in SMA is a loss of excitatory input (activating signals) to motor neurons from the sensory nerve cells that communicate with them.
Normally, these sensory cells release a signaling chemical called glutamate at synapses, the sites through which nerve cells communicate, which in turn activates motor neurons. Without this input, motor neurons don't fire as they should, and the ability for muscles to contract is impaired.
Glutamate is an amino acid, one of the building blocks of proteins. While it is a key player, there are other neuroactive amino acids that can directly or indirectly influence function of the same synapses. These include serine and aspartate, as well as the glutamate precursor glutamine.
Whether these amino acids contribute to neuronal dysfunction in SMA hasn't been explored. In the study, researchers measured their levels in the cerebrospinal fluid (the fluid surrounding spinal cord and brain) of untreated SMA patients — 34 with SMA type 1, 22 with SMA type 2, and 17 with SMA type 3 — and in seven healthy people, who served as a control group.
Results showed a variety of amino acid alterations in the SMA patients. Among the observed changes was a glutamate deficiency in people with SMA type 1, as well as an elevated glutamine-to-glutamate ratio in SMA types 1 and 2 relative to healthy people, reflective of impaired glutamine to glutamate conversion.
Amino acid alterations in SMA type 1 patients were found to be partially corrected 302 days (about 10 months) after starting treatment with Spinraza for a subgroup of patients with available samples. In people with SMA type 3, Spinraza was associated with decreases in levels of a number of amino acids, with no effects in SMA type 2.
"Disease severity and the stage of SMA progression appear to be critical factors guiding specific metabolic responses to [Spinraza] treatment," the researchers wrote.
The scientists also looked at levels of amino acids in a mouse model of SMA. Results showed altered metabolism of neuroactive amino acids during symptomatic stages, particularly an increased glutamine-to-glutamate ratio, relative to healthy mice.
This altered glutamine-to-glutamate conversion "emerges as a conserved signature of neurochemical dysregulation in … severe SMA patients and … mouse models," the researchers wrote.
Certain serine alterations were observed in SMA type 1 patients. In these patients, serine measures correlated with motor function both before and after treatment, though the relationship appeared dependent on age. In those with SMA type 2, serine levels positively correlated with motor function after Spinraza initiation.
Given the potential relationship between serine and motor function, the researchers treated the SMA mouse model with D-serine supplements. This led to a moderate improvement in motor function, but did not influence weight, survival, or SMN levels.
Although it isn't exactly clear how D-serine influences neurological function, the findings "highlight the potential of this atypical amino acid as a therapeutic target and encourage exploration of combinatory therapeutic strategies in future clinical trials," the researchers wrote.
Overall, the study demonstrated "prominent dysregulation" of amino acids that influence glutamatergic synapses, and "supports further investigation into pharmacological approaches … aimed at improving glutamatergic neurotransmission [chemical communication] deficits for use in combination therapies," the team concluded.
MDA 2025: SMA Gene Therapy 'transformational,' Per Novartis Exec
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 patientsData 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: "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 SMAZolgensma 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 patientsResults from STEER 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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