Spinraza benefits SMA children not helped by Zolgensma: Interim data
Preclinical studies indicate gene therapy may only target motor neuron subset
Most of the infants and children with spinal muscular atrophy (SMA) in the RESPOND clinical trial who responded poorly to the gene therapy Zolgensma showed gains in motor function with Biogen’s Spinraza (nusinersen), according to early results.
Prior preclinical studies have suggested Zolgensma may target only a subset of motor neurons, the specialized nerve cells that control voluntary movement and are lost in SMA.
“We are learning that gene therapy may not be treating all motor neurons leaving the potential for disease progression,” Crystal Proud, MD, pediatric neurologist at Children’s Hospital of the King’s Daughters, said in a company press release.
RESPOND is a Phase 4 trial to assess the outcomes of infants and children treated with Spinraza after receiving Zolgensma, a regimen often used in real-world clinics. There’s been no systematic analysis of the clinical outcomes of such a combination, however.
“The RESPOND study has begun to characterize remaining unmet need in some SMA patients treated with Zolgensma whose outcomes have not met clinical expectations. These interim results provide the community with the first clinical study data evaluating Spinraza treatment following Zolgensma and suggest there may be potential for additional benefit with Spinraza treatment,” Proud said.
Biogen also presented real-world evidence that supports how Spinraza benefits motor function, showing the gains are greater or comparable to those seen in clinical trials.
Goals of RESPOND trial for infants, children with SMA
Proud shared the new interim data in the presentation, “Interim results from the ongoing respond study evaluating nusinersen in children with spinal muscular atrophy previously treated with onasemnogene abeparvovec,” at this year’s Cure SMA’s Annual SMA Research & Clinical Care Meeting, June 28-30 in Orlando, Florida.
SMA is caused by low levels of the survival motor neuron (SMN) protein due to a faulty SMN1 gene. Although SMN is in every cell type, its lack in motor neurons leads to the muscle weakness that characterizes SMA.
Spinraza was the first approved disease-modifying therapy for children and adults with all SMA types. It’s administered directly into the spinal canal every four months and works by enhancing SMN’s production by way of a backup gene, SMN2. This gene is capable of partially compensating for the loss of SMN1-derived SMN.
Novartis’ Zolgensma (onasemnogene abeparvovec-xioi) is an approved gene therapy made to correct the underlying cause of SMA. Administered one time into the bloodstream, it delivers a working copy of the SMN1 gene to cells to sustain SMN production.
The open-label RESPOND (NCT04488133) trial is evaluating the safety and effectiveness of Spinraza in infants and children between the ages of 3 months and 3 years with SMA whose clinical needs weren’t met with Zolgensma.
Its objective is to evaluate the children’s progress in reaching specific motor milestones, including head control, sitting, crawling, standing, and walking. This assessment uses the Hammersmith Infant Neurological Examination Section 2 (HINE-2) motor milestone score.
The trial’s secondary goals include determining the proportion of children achieving motor milestones defined by the World Health Organization, evaluating changes in other established measures of motor function, and tracking the time until death or the need for permanent ventilation, as well as safety measures.
The motor function measures used include the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), the Hammersmith Functional Motor Scale Expanded, and the Revised Upper Limb Module.
Gains with Spinraza
Participants were divided into two groups. One includes children nine months or younger at their first Spinraza dose with two copies of the SMN2 gene. The other group includes children who were nine months to 3 years at the time of the first Spinraza dose who have at least one copy of SMN2.
The new interim data, from up to November 15, 2022, report the outcomes of 27 of 29 patients followed for six months. According to Biogen, most saw improvements in motor function over the start of the trial (baseline).
In children with two SMN2 copies (24 children), the HINE-2 score increased by a mean of more than 5 points over the baseline. Improvements were also seen in children with three SMN2 copies. Due to the low number of children (three) in this case, no mean score change was calculated.
Also, 25 of the 27 children with investigator-reported suboptimal motor function at the trial’s start showed improvements, according to Biogen.
Younger and older participants who couldn’t sit without support showed CHOP INTEND score improvements, on average.
After a median follow-up of 230.5 days (about 7.5 months), 13 of 38 patients (34%) had serious side effects, but none were considered related to Spinraza or led to withdrawing from the study. No new emerging safety concerns were identified.
“Cure SMA’s annual conference is a unique opportunity to connect with and learn from the health care providers, patients and caregivers in attendance and share research intended to address the unmet needs of the SMA community,” said Maha Radhakrishnan, MD, chief medical Officer at Biogen. “We are pleased to present our new data, including early results from the RESPOND study evaluating the clinical benefit and safety of Spinraza treatment after gene therapy.”
Biogen is conducting a pivotal trial, called PIERRE (NCT05866419), with Alcyone Therapeutics to test ThecaFlex DRx, its implantable system for the repeat use of Spinraza. The system acts as a subcutaneous port and intrathecal catheter system — a catheter and fixation device — providing a point to administer Spinraza or collect spinal fluid to analyze.