Motor Function Improvements Observed Among Patients With SMA Treated With Nusinersen After Zolgensma

Improvements in motor function were observed among patients with spinal muscular atrophy (SMA) who received nusinersen (Spinraza; Biogen), a marketed antisense oligonucleotide (ASO), after being previously having been treated with onasemnogene abeparvovec (Zolgensma; Novartis), a marketed adeno-associated virus vector (AAV)-based gene therapy, in interim data from the phase 4 RESPOND clinical trial (NCT04488133).¹

Among 29 patients who were treated with nusinersen in RESPOND and evaluable for efficacy, most demonstrated an increase in mean total Hammersmith Infant Neurological Examination Section 2 (HINE-2) score from baseline. Among the subset of 24 patients who have 2 copies of the SMN2 gene and were evaluated at 6 months posttreatment, a mean improvement of more than 5 points on HINE-2 was reported. All 3 patients who have 3 copies of the SMN2 gene and were evaluated at 6 months posttreatment showed improvement on HINE-2, but because of the small number of participants no calculation of the mean change from baseline was performed. The remaining 2 patients did not undergo evaluation at the 6-month time point. RESPOND includes children and toddlers who continue to have unmet medical needs following prior treatment with onasemnogene abeparvovec.

The interim safety analysis included 38 patients who have been treated in RESPOND and have been participating in the study for a median of 230.5 days. Thirteen (34%) of these patients have experienced serious adverse events (AEs), although no serious AEs were deemed related to nusinersen and none resulted in withdrawal from participation in the trial. Furthermore, there were no new emerging safety concerns for patients receiving nusinersen after onasemnogene abeparvovec reported in the trial.

"SPINRAZA is a foundation of care for people living with spinal muscular atrophy,” C. Frank Bennett, PhD, executive vice president and chief scientific officer of Ionis Pharmaceuticals, said in a statement.¹ “The early results from RESPOND show that SPINRAZA may further improve muscle performance in patients treated with gene therapy whose outcomes have not met clinical expectations.”

Earlier safety results from RESPOND were reported in March 2023 at the 2023 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, March 19 to 22, in Dallas, Texas.² At the time, it was noted that the safety data seen in the trial were consistent with SMA and nusinersen’s safety profile. The most common AEs were upper respiratory tract infection, which was reported in 6 patients, and viral upper respiratory tract infection, which was reported in 5 patients. Mild proteinuria was observed in 2 patients; these cases were deemed related to treatment with nusinersen but resolved. No deaths or postlumbar puncture syndrome events were reported at the time.

“Animal models and limited human postmortem studies have demonstrated incomplete transduction of motor neurons by the AAV9 vector,” first author of the study presented at MDA’s conference John Brandsema, MD, a pediatric neurologist at Children's Hospital of Philadelphia, and colleagues wrote.² “Nusinersen has potential to increase SMN protein in untransduced motor neurons, which may provide additional clinical benefit to individuals with SMA.”

Nusinersen is intended to address the basis of SMA by increasing production of full-length survival motor neuron protein.¹ It was originally approved by the FDA in December 2016 and was the first drug for the treatment of children and adults with SMA to be approved by the agency.³ Onasemnogene abeparvovec was approved by the FDA a few years later, in May 2019.⁴ It was the first gene therapy for SMA to be approved by the agency; the indication includes patients less than 2 years old who have mutations in the SMN1 gene, regardless of the presence of symptoms. In June 2022, data published in Nature Medicine showed that nearly all children who were treated with onasemnogene abeparvovec in both the type 1 (2 copies of the SMN2 gene) and type 2 (3 copies of SMN2) cohorts of the phase 3 SPR1NT clinical trial (NCT03505099) achieved age-appropriate milestones including standing and walking.⁵ A new post-hoc analysis from SPR1NT reported at MDA's 2023 conference indicated that all children with presymptomatic SMA treated in the trial achieved bulbar function and motor milestones consistent with typical development.⁶ In August 2022, Novartis announced that it would update the safety labelling for Zolgensma in light of 2 patient deaths that were linked to the gene therapy outside of clinical trials.⁷

REFERENCES
1. New data highlight potential benefit of SPINRAZA® (nusinersen) in infants and toddlers with unmet medical needs after gene therapy. News release. Ionis Pharmaceuticals. June 30, 2023. Accessed July 6, 2023. https://ir.ionispharma.com/news-releases/news-release-details/new-data-highlight-potential-benefit-spinrazar-nusinersen
2. Brandsema J, Parsons J, Kuntz N, et al. Baseline characteristics and interim safety in RESPOND: A phase 4 study in children with SMA treated with nusinersen after onasemnogene abeparvovec. Presented at: 2023 MDA Conference, March 19-22; Dallas, Texas.
3. FDA approves first drug for spinal muscular atrophy. US FDA. December 23, 2016. Accessed July 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-spinal-muscular-atrophy
4. AveXis receives FDA approval for Zolgensma®, the first and only gene therapy for pediatric patients with spinal muscular atrophy (SMA). News release. Novartis. May 24, 2019. Accessed July 6, 2023. https://www.novartis.com/news/media-releases/avexis-receives-fda-approval-zolgensma-first-and-only-gene-therapy-pediatric-patients-spinal-muscular-atrophy-sma
5. Novartis announces Nature Medicine publication of Zolgensma data demonstrating age-appropriate milestones when treating children with SMA presymptomatically. News release. Novartis. June 17, 2022. https://firstwordpharma.com/story/5597735
6. McGratton KE, Shell RD, Hurst-Davis R, et al. Bulbar function in children with two or three SMN2 copies who received onasemnogene abeparvovec presymptomatically for spinal muscular atrophy. Presented at: 2023 MDA Conference, March 19-22; Dallas, Texas.
7. Silverman E. Novartis reports two children died from acute liver failure after treatment with Zolgensma gene therapy. STAT. August 11, 2022. https://www.statnews.com/pharmalot/2022/08/11/novartis-zolgensma-liver-failure-gene-therapy-death/