Dual Therapy Well-Tolerated but Presents Little Benefit to Infantile-Onset SMA

For infants at risk for developing spinal muscular atrophy (SMA) type 1, a dual therapy of onasemnogene abeparvovec (OA; Zolgensma) followed by nusinersen (Spinraza) or risdiplam (Evrysdi) did not have a protective effect against widespread muscle degeneration, according to a recent study published in Annals of Clinical and Translational Neurology.¹

SMA type 1 makes up 60% of total cases of SMA and approximately 5.5 per every 100,000 newborns.² The impact of SMA in early developmental stages contributes to the death of spinal motor neurons (SMN)—notably SMN2—as well as progressive muscle weakness, respiratory dysfunction, and more.¹

Onasemnogene abeparvovec is a gene therapy approved in the last decade for SMA | image credit: andriano_cz - stock.adobe.com

In the last decade, the approval and availability of OA, nusinersen, and risdiplam have altered the natural history of the disease and dramatically improved motor functioning when administered before the onset of weakness. With each drug’s individual treatment success, the current authors investigated the efficacy of “add-on” therapy in SMA for infants at risk for developing SMA type 1.

OA alone (monotherapy) or OA in combination with nusinersen or risdiplam (dual therapy) were preemptively given within 6 weeks of a child’s birth. Treatment groups were separated into parallel cohorts. Muscle tissue responses were additionally evaluated with a muscle ultrasound (MUS), and achievement of independent sitting and walking were also recorded.

Newborn data were collected from The Children’s Hospital of Philadelphia (CHOP, n = 12) and Clinic for Special Children (CSC, n = 11). They were split into 3 groupings depending on the number of SMN2 copies they possessed: 2 copies treated with OA only (2M, n = 11), 2 copies treated with dual therapy (2D, n = 7), and 3 copies treated with OA only (3M, n = 5). OA was administered between 7 and 43 days after birth, with infants in the 2D group receiving OA earlier vs those in 2M (median 12 vs 21 days; P = .0352). At a median time of 20 days, the 2D groups received nusinersen (n = 1) or risdiplam (n = 6). There were 6 infants from 2M who eventually transitioned to nusinersen (n = 3) or risdiplam (n = 3), constituting a 2M→D subgroup.

Infants with 3 copies of SMN2 all walked or sat independently when motor outcomes were assessed. Among infants with 2 copies, 94% (n = 17) achieved independent sitting and 83% (n = 15) hit this milestone within 9.2 months. There were 9 infants from 2M (82%) and 6 from 2D (86%) who walked.

Those in 2M achieved sitting later than both those in 2D (P = .0384) and 3M (P = .0027). Infants from 3M were able to walk significantly earlier than those in both 2M (P = .0075) and 2D (P = .0139). Those in 2D and 3M were sitting at a similar age, and 2M and 2D each began walking at a similar age.

MUS results came back normal across all points of time in 3M but tissue abnormalities were observed in 45% of 2M, 69% of 2D, and 85% of 2M→D at the time of follow-up. Additionally, sensory nerve action potential (SNAP) tests were conducted; researchers found no significant differences between any of the groups.

“Within the observed OA dosing window of 7–39 postnatal days, age of administration, age at the start of SMN2 augmentation therapy, and baseline functional measures were not predictive of motor outcomes among children with two SMN2 copies,” the authors wrote. Although, despite granting little-to-no extra benefit, their findings suggest that these forms of add-on therapy are safe and well-tolerated in those at risk for infantile-onset SMA type 1.

References

1. Matesanz SE, Brigatti KW, Young M, Yum SW, Strauss KA. Preemptive dual therapy for children at risk for infantile-onset spinal muscular atrophy. Ann Clin Transl Neurol. Published online May 31, 2024. doi:10.1002/acn3.52093

2. How common is spinal muscular atrophy? Spinalmuscularatrophy.net. Updated August, 2021. Accessed July 10, 2024. https://spinalmuscularatrophy.net/statistics