Decision-Making in SMA Complicated by Insufficient Treatment Comparison

A study published in Neurotherapeutics looks at the treatment options available for spinal muscular atrophy (SMA), the treatment decisions a physician may have to make, and how lacking trial data impacts these processes.¹ SMA is a group of neurodegenerative disorders that result from the loss of spinal motor neurons. The majority of patients suffer from loss of survival motor neuron (SMN) 1 protein expression.²

The most severe form of SMA is type 0 and it has a significant symptom onset in utero, and infants require immediate respiratory support after birth.¹ Without treatment, children with SMA type 1 never achieve the ability to sit and develop feeding and respiratory failure in infancy. Individuals with type 2 achieve the ability to sit but never walk and experience a slow progressive decline. Patients with SMA type 3 all achieve the ability to walk. SMA type 4 is the mildest of all types and individuals do not experience any symptoms until adulthood. As of today, there are only 3 FDA-approved therapies for SMA.

Clinical decision-making in SMA could benefit from more comprehensive trial data comparing SMA treatments | image credit: HASAN - stock.adobe.com

Nusinersen, an antisense oligonucleotide is delivered intrathecally. It works by promoting the inclusion of exon 7 in the SMN2 transcript to increase the full-length SMN mRNA and the subsequent protein. Although the initial trial was done on patients with SMA 2 and 3, later studies showed efficacy and safety in all types. It is currently approved for all patients with SMA in over 60 countries. The currently approved dose for nusinersen is 12mg for all individuals. Although earlier recipients reported increased intracranial pressure, this complication is no longer reported today. However, there exist rare complications such as thrombocytopenia, proteinuria, and coagulation abnormalities.

Onasemogene abeparvovec (OA), a gene replacement therapy, uses an adeno-associated virus (AAV9) delivery system to introduce non-integrating SMN1 cDNA. The presence of AAV9 antibodies such as maternal antibodies in a newborn infant makes the individual unsuitable for this therapy until the antibody test is negative. OA was approved in the US for individuals under 2 years of age without end-stage disease. It is approved in 51 countries with varying approval definitions. Some of the common effects seen in patients are temporary effects of daily prednisone use, elevations in the liver ezymes ALT, AST and occasionally GGT, nausea, vomiting, asymptomatic troponin I elevations, and thrombocytopenia. Abnormal liver function before treatment seems to be related to rare complications such as liver failure and death. Two cases have reported cancers in children after months of OA therapy.

Risdiplam, is another medication with a mechanism similar to nusinersen. Unlike nusinersen, risdiplam can be taken orally and is currently approved for all age groups in over 100 countries. Dosing is age and weight-based until 20 kg and then all patients receive the same dose. As of now, no significant safety concerns have been noticed in humans.

Clinical decision-making can be quite complicated in patients with SMA. There are no clinical trials that compare all 3 treatments and each clinical trial population studied was different from others making it difficult to even compare indirectly. Treatment selection for patients is variable. The first marker for the selection of treatment is the availability considering the number of SMN copy numbers followed by safety concerns. Treatment for patients with SMN2 has been done, but these patients have significant residual weakness and the need for continued nutritional and respiratory support. In patients with 2 and 3 copies of SMN2, Risdiplam is usually the first treatment and may be switched to OA. Risdiplam may be resumed if motor development is delayed. Early combination or dual therapy may be most beneficial as SMN protein levels are the highest in utero and decrease significantly in the first few months after birth. In patients with 4 copies of SMN2, immediate treatment is now recommended with any of the approved therapies. However, drug approvals vary for copies of SMN2. As of now, the recommended treatment for patients with 5 copies of SMN2 is monitoring.

Symptomatic Infants whose diagnosis was missed in newborn screening or who were born before the newborn screening was implemented should be started on therapy as soon as possible. Risdiplam and nusinersen are the easiest to start; however, nusinersen is becoming less popular among the pediatric population due to the need for repeated lumbar punctures and possibly sedation.

Risdiplam may be the only option available for symptomatic adults. Even in adults with end-stage disease, treatment with risdiplam or nusinersen may provide benefit.

References 

1. Waldrop MA. Clinical decision making around commercial use of gene and genetic therapies for spinal muscular atrophy. Neurotherapeutics. 2024 ;21(4):e00437. doi:10.1016/j.neurot.2024.e00437.
2. Rad N, Cai H, Weiss MD. Management of spinal muscular atrophy in the adult population. Muscle Nerve. 2022;65(5):498-507. doi:10.1002/mus.27519.