Spinraza became the first therapy 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 was approval to treat infantile-onset SMA, as well as SMA type 1, type 2, and type 3.
The EU approved Spinraza in June 2017 to treat SMA throughout Europe, and the European Medicines Agency (EMA) accelerated the assessment process for this treatment.
It is now approved in numerous other countries, including Australia, Canada, Japan, Israel and Turkey.
How does Spinraza work?
Spinraza contains an antisense oligonucleotide that allows the body to produce more of a protein called survival motor neuron (SMN). SMN is essential for the health of motor neurons, nerve cells that control the movement of muscles. People with SMA do not produce enough of this protein.
Everyone has two genes — SMN1 and SMN2 — that encode for the SMN protein. Most of the SMN protein is made from the SMN1 gene. But mutations in the SMN1 gene lead to little or no SMN protein being produced from it.
Some SMN protein can also be made from the SMN2 gene, but due to a difference in the coding sequence of this gene, most of the protein produced here is shorter and quickly destroyed by cells.
Spinraza increases the ability of cells to produce functional SMN protein from the SMN2 gene. It does so by binding to the SMN2 messenger RNA (mRNA), which is a copy of the SMN2 gene that the cell’s protein-making machinery “reads” to produce the protein. The SMN2 gene naturally makes a shorter 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, allowing 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
The first one of these trials (NCT01494701) showed that Spinraza was well-tolerated and significantly increased motor function (measured by the Hammersmith functional motor scale expanded – HFMSE) three months after treatment. These improvements were further seen in its extension study (NCT01780246), in which the HFMSE score further increased after nine to 14 months of treatment.
Results from the second trial (NCT01703988) called CS2 and the third (NCT02052791), an extension study called CS12, indicated that children treated with Spinraza over three years showed improvements in motor function and stable disease activity that could not be observed in similar groups of untreated patients (SMA natural history).
A randomized and double-blind, sham-procedure controlled Phase 3 clinical trial (NCT02193074), called ENDEAR, evaluated the safety and efficacy of a 12 mg dose of Spinraza in 121 infants diagnosed with SMA. The results 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) scale, as well as a higher survival rate. The study also suggested that early treatment with Spinraza is necessary to maximize 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 infants with SMA.
Based on these positive results, researchers stopped the ENDEAR study early and transferred participants into an open-label study (NCT02594124) called SHINE, in which all were given Spinraza. The SHINE study is expected to be finish in August 2023. Interim study results found 83 children reporting adverse events, but none that were treatment-related. Children who began with Spinraza in ENDEAR and continued receiving it in SHINE showed an average HINE score of 5.8. Twenty-eight percent of these children also achieved full head control, and 15% were able to sit independently.
A randomized and sham-controlled Phase 3 clinical trial (NCT02292537), called CHERISH, assessing the safety and efficacy of Spinraza in 126 children, ages 2 to 12, with later-onset SMA finished in 2017. Children treated with Spinraza showed significant improvements in motor function. Those in CHERISH were also invited to transfer to the open-label SHINE study for long-term evaluation.
A Phase 2, double-blind clinical trial (NCT02462759), called EMBRACE, was designed to evaluate Spinraza’s safety and pharmacokinetics (movement in the body) in infants and children who did not qualify for the ENDEAR or CHERISH trials. EMBRACE was designed to be a two-part study. But early and positive results among treated patients, including 79% achieving key motor milestones, led to it being ended early in 2018. Again, all enrolled were allowed to move into SHINE and be treated with Spinraza.
Another Phase 2 trial (NCT01839656) assessing the safety, efficacy, and pharmacokinetics of Spinraza in infants younger than 210 days finished in 2018. Its results appeared in The Lancet, and showed that Spinraza had an acceptable safety and tolerability profile, further supporting its use in treating SMA.
A Phase 2 clinical trial (NCT02386553), called NURTURE , is assessing Sprinraza in 25 genetically diagnosed but pre-symptomatic infants — all younger than 6 weeks old when given their first dose. All were likely to develop either SMA type 1 or type 2. The trial aims to determine whether early treatment might prevent or delay symptom onset. Results from the ongoing trial, presented at science conferences in 2019, found that at nearly four years after the start of treatment none of these children had difficulties swallowing, all 25 were able to sit without support, and 22 of the 25 (88%) were able to walk.
A Phase 2/3 clinical trial (NCT0408956), called DEVOTE, aims to study the safety and efficacy of higher doses of Spinraza in 125 SMA patients and compare responses to these doses to those at its currently approved 12 mg dose. DEVOTE will have three parts, labeled A, B, and C. Among these, A and C will be open-label studies and B will be a double-blind randomized study with a placebo group. The trial is expected to soon begin recruiting participants; contact information is here. DEVOTE is expected to finish in December 2022.
Spinraza is currently approved at a recommended dose of 12 mg per treatment for all patients, regardless of disease type or age group. After an initial loading period of four doses, with the first three given every 14 days and the fourth 30 days later, it is administered repeatedly once every four months.
Spinraza is administered by intrathecal injection, or an injection directly into the spinal canal. Treatment must 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.
Last updated: January 22, 2020
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