MDA 2023: Long-term motor gains seen for SMA children on Zolgensma
Improvement after gene therapy is 'transformational,' researcher says
Children with spinal muscular atrophy (SMA) given Zolgensma (onasemnogene abeparvovec-xioi) gene therapy in clinical trials are maintaining, years later, the motor milestones they achieved in the original studies — and some have hit additional milestones even without further treatment.
That’s according to data from long-term follow-up (LTFU) studies presented at the Muscular Dystrophy Association’s MDA Clinical & Scientific Conference, held March 19-22, in Dallas. The work was funded by Zolgensma’s maker Novartis.
“I have had the privilege of observing some of the children included in the LTFU studies since they started their Zolgensma clinical trial journey, and the fact that we’re seeing them maintain and, in some cases, gain motor milestones when they are nearly eight years old is truly transformational,” Jerry R. Mendell, MD, of Nationwide Children’s Hospital, said in a Novartis press release.
“These children now have an improved quality of life, vastly different from what would have been expected for them if they had not received treatment,” Mendell said, adding, “I am excited to see the new possibilities that open up to the children, their families and others who may now be able to receive this treatment.”
The new data were presented in a poster titled, “Long-Term Follow-Up of Onasemnogene Abeparvovec Gene Therapy in Patients with Spinal Muscular Atrophy Type 1.”
A follow-up on children treated in the original clinical trials
Zolgensma is a one-time gene therapy designed to deliver a working version of SMN1, the gene that is mutated in SMA, to the body’s cells.
START (NCT02122952), the first clinical trial of Zolgensma, was launched in 2014. Conducted at Nationwide Children’s Hospital in Columbus, Ohio, it tested the therapy in babies with SMA type 1Â who had already begun to experience symptoms.
After the initial Phase 1 trial, 10 patients given the now-approved therapeutic dose of Zolgensma were enrolled in a LTFU study called LT-001 (NCT03421977), where they are being followed for up to 15 years.
At the MDA conference, scientists shared data from the trial as of May 2022, at which point the children were, on average, 7.1 years old — and the time since receiving Zolgensma was a mean of 6.9 years.
All 10 children are still alive without a need for permanent ventilation.
At the end of the START study, five of the patients had no need for respiratory support, while the other five relied on daily support from cough assist or BiPAP (bi-level positive pressure) machines. As of the latest cutoff, seven of the children have no requirements for these respiratory supports. All of the children can feed orally, and four of them don’t require any nutritional assistance.
The children have all maintained the motor milestones that they had achieved in the original START study — all of them are still able to sit unsupported, and two are able to stand and walk unsupported.
As of the latest data, five children are able to stand with support. Two of these children had reached this milestone in the earlier study. The other three only recently gained this ability, and two of them reached this new milestone without additional SMA treatment.
Six of the 10 children have begun add-on treatment with other SMA therapies, namely Spinraza (nusinersen) or Evrysdi (risdiplam). One of the children who recently gained the ability to stand with assistance did so after starting Spinraza treatment. The other children have so far reported no new motor milestone achievements since starting add-on therapy.
The LT-001 study, also done early on, enrolled three patients who were treated with Zolgensma at a lower dose than is now approved. All three of these patients are still alive; the oldest was 8.5 years old as of data cutoff. All of these patients require regular respiratory support, including one on permanent ventilation, and all require a feeding tube to meet their nutritional needs.
In the original START study, none of these three children hit any assessed motor milestones, and all three have since started add-on treatment with Evrysdi or Spinraza. As of the latest follow-up, one of them has achieved new motor milestones of head control and the ability to sit with support.
Striving for follow-up data on symptomatic babies
In a separate poster at MDA, researchers shared data from another long-term follow up study of Zolgensma, known as LT-002 (NCT04042025). That poster was titled, “Intravenous and Intrathecal Onasemnogene Abeparvovec Gene Therapy in Symptomatic and Presymptomatic Spinal Muscular Atrophy: Long-Term Follow-Up Study.”
Launched in 2020, LT-002 included patients who had participated in one of five prior clinical trials: the three STR1VE trials, SPR1NT, and STRONG. Data shared at MDA were current as of May 2022.
The STR1VE clinical trials — STR1VE-US (NCT03306277) in the U.S.,  STR1VE-EU (NCT03461289) in Europe, and STR1VE-AP (NCT03837184) in the Asia-Pacific region — tested the now-approved dose of Zolgensma in babies with SMA type 1 who had begun to experience symptoms.
By the end of the original trials, 31 of the 36 children who enrolled in long-term follow-up in LT-002 had head control. As of the data cutoff, all of the children have reached this motor milestone: two without additional treatment, and three with add-on therapy.
Almost all of the children (94.4%) are now able to sit with or without support, and two are able to walk — one was able to at the end of the original study, and one gained the ability without add-on therapy during the long-term follow-up period.
As the number of patients treated with gene therapy around the world continues to grow, our goal is that more patients, and even new SMA patient populations, will be able to experience the transformative impact of this treatment.
The SPR1NT (NCT03505099) trial tested the approved dose of the therapy in presymptomatic babies who had been diagnosed through genetic testing but had not begun to show disease manifestations.
All 25 presymptomatic babies from SPR1NT who enrolled in LT-002 are still alive and have maintained motor milestones they reached in the original study.
Four of the patients were not able to walk unsupported by the end of the original trial, but as of the data cutoff, all of them can walk under their own power. Three of the children hit this new milestone without additional treatments, the fourth after starting add-on therapy.
A few of these children also have reached new motor milestones like crawling that they hadn’t reached before, which the researchers noted reflects “the sometimes nonlinear nature of development in children with SMA.”
More than 3,000 children treated to date, per Novartis
The approved dose of Zolgensma is administered into the bloodstream (intravenously). The STRONG (NCT03381729) trial, initiated in 2017, tested the therapy administered intrathecally, or via injection through the spine into the fluid that surrounds the brain and spinal cord.
All 16 patients from STRONG who were evaluated in LT-002 have retained motor milestones achieved in the original study, and five have hit new motor milestones like crawling or standing alone. Two of the children are now able to walk.
Across all patients in the LT-002 study, most do not require feeding or respiratory support, and no new safety issues related to the gene therapy have been identified.
The researchers noted that, of the 22 total children in the LT-002 study who started any form of add-on therapy, only half achieved new motor milestones after beginning new treatment.
Collectively, the data show that Zolgensma “demonstrates consistent, substantial, and durable efficacy and no new safety signals in symptomatic and presymptomatic patients with SMA,” the researchers wrote.
According to Novartis, more than 3,000 SMA children have been treated with Zolgensma to data via trials or since the gene therapy’s approval.
“Data from the LT-001 and LT-002 studies showed that, regardless of the patient’s symptomatic status at the time of treatment, Zolgensma … is an effective and durable treatment option,” said Sitra Tauscher-Wisniewski, MD, vice president of clinical development and analytics at Novartis Gene Therapies.
“As the number of patients treated with gene therapy around the world continues to grow, our goal is that more patients, and even new SMA patient populations, will be able to experience the transformative impact of this treatment,” Tauscher-Wisniewski added.
About the Author
