It became the first therapy ever approved by the U.S. Food and Drug Administration (FDA) to treat SMA in both infants and adults in December 2016, under a priority review program for rare diseases, after it showed statistically significant improvements in both motor function and survival. Spinraza also received approval to treat infantile-onset SMA, as well as SMA types 1, 2 and 3.
The European Union approved Spinraza in June 2017 to treat SMA throughout the 28-member bloc. The European Medicines Agency (EMA) accelerated the assessment process for this treatment, and some European patients have already received Spinraza via Biogen’s pre-approval Expanded Access Programs.
How Spinraza works
Spinraza contains an antisense oligonucleotide — a molecule that works by increasing the body’s ability to produce a protein called survival motor neuron (SMN), which is essential for motor neuron health. SMA patients don’t produce enough SMN.
All people have two genes — SMN1 and SMN2 — that encode for the SMN protein. Most of this protein is made from SMN1, though SMA patients have a mutation in the SMN1 gene which renders their bodies unable to produce enough SMN protein.
The SMN2 gene can also make SMN protein, but due to a difference in the coding sequence of this gene, most of the protein that is made from this gene is shorter and gets destroyed by the cells.
Spinraza increases the ability of the SMN2 gene to produce full-length SMN protein. It does so by binding to the SMN2 messenger RNA or mRNA, which is a copy of the SMN2 gene that the cell’s protein-making machinery “reads” to produce the protein. The SMN2 gene makes a shorter-than-normal version of the SMN protein because a signal in the gene causes the mRNA to miss a piece while being processed before being sent to the cell’s protein-making machinery. Spinraza covers up this signal and allows the mRNA copied from the SMN2 gene to be full length, just like the mRNA that would normally be made from the SMN1 gene.
Spinraza in clinical trials
A randomized, double-blind, sham-procedure controlled Phase 3 clinical trial known as ENDEAR (NCT02193074) is evaluating the efficacy and safety of a 12 mg dose of Spinraza in 121 infants diagnosed with SMA. An analysis of the study published in the New England Journal of Medicine found that infants treated with Sprinraza experienced a statistically significant improvement in motor milestones compared to those not treated (51 percent versus 0 percent), as assessed by the Hammersmith Infant Neurological Examination (HINE), as well as a higher survival rate. The study also suggested that early treatment with Spinraza is necessary in order to maximize Spinraza’s benefits.
Finally, the study also showed that Spinraza had an acceptable safety profile with respiratory events and constipation being the most commonly reported adverse events. These adverse events are consistent with those expected in SMA infants.
Based on these positive results, researchers stopped the ENDEAR study and transferred participants into an open-label study (NCT02594124) called SHINE, in which all patients receive Spinraza. This ongoing study will likely conclude in August 2023.
Spinraza has also been evaluated in a series of open-label Phase 1/2 safety and tolerability studies in SMA patients ages 2-15 (NCT01494701, NCT01703988, NCT02052791, and NCT01780246). These trials have been completed, but results have not yet been published.
A randomized, 15-month long Phase 3 clinical trial (NCT02292537) called CHERISH assessed the safety and efficacy of Spinraza in 126 children with later-onset SMA, ages 2 to 12. The results have been submitted but have not yet been posted or published.
A Phase 2 double-blind trial (NCT02462759) called EMBRACE is evaluating Spinraza’s safety and pharmacokinetics in patients who didn’t qualify for the ENDEAR or CHERISH trials. This trial is still active but no longer recruiting participants, and should be finished in April 2019.
Another Phase 2 trial (NCT01839656) is assessing the efficacy, safety and pharmacokinetics of Spinraza in infants younger than 210 days. Its results appeared in The Lancet and showed that Spinraza had an acceptable safety and tolerability profile, suggesting that it may be a promising treatment for SMA.
Finally, a Phase 2 clinical trial (NCT02386553) called NURTURE is assessing Sprinraza in 25 genetically diagnosed but pre-symptomatic infants — all of whom were younger than six weeks old when given their first dose of Spinraza. The trial aims to determine whether early treatment might prevent or delay the onset of SMA symptoms. It is set to conclude in January 2022.
Spinraza is administered as an injection into the spinal canal. Treatment must, therefore, be done in hospitals or centers whose staff are trained in performing lumbar punctures. The most common side effects reported in clinical studies of Spinraza are respiratory infections and constipation.
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