Over the last decade, spinal muscle atrophy (SMA) has been transformed from a mostly fatal to treatable (and perhaps, even curable) disease. Treatments approved by the Food and Drug Administration (FDA) both target the genes survival of motor neurons 1 and 2 (SMN1 and SMN2), known to cause or mitigate SMA. As transformational as these treatments have been, routes of administration are challenging. Gene replacement therapy of SMN1 with onasemnogene (Zolgensma; Avexis, Bannockburn, IL) is delivered via intravenous administration of adeno-associated virus (AAV)-gene product.
Transcriptional regulation of SMN2 with nusinersen (Spinraza; Biogen, Cambridge, MA), an antisense oligonucleotide therapy (ASO) is administered with quarterly intrathecal infusions that reach only the central nervous system.
In contrast, risdiplam (RG7916; Genentech, South San Francisco, CA) is an investigational orally-available ASO that reaches all cells of the body. This is important because as the number of treated individuals increases, SMA natural history is being redefined and understood as a multisystem disease.
In results presented at the Cure SMA Researcher Meeting, 23rd International SMA Research Meeting in Anaheim, CA earlier this month, results from the JEWELFISH study (NCT03032172) showed that treatment with risdiplam rapidly increased levels of SMN protein levels and that these increases were sustained. For the 12 individuals who were exposed to risdiplam for 6 to 20 months as of December 2018, only 1 severe adverse event (limb injury) occurred. All other adverse events were mild to moderate and most frequently were abdominal discomfort, nausea, influenza, nasopharyngitis, viral infection, fever, and headache (each in 2 individuals).
Initially designed to include 24 participants from clinical trials for nusinersen or onasemnogene, this study has been broadly expanded to a target of 180 people more than age 6 months with SMA of all types, including those treated with nusinersen or onasemnogene outside of clinical trials.