It was approved by the U.S. Food and Drug Administration (FDA) in December 2016 to treat children and adults with spinal muscular atrophy (SMA) type 1, 2, or 3 — the most common forms of the disease — thereby becoming the first approved therapy targeting the underlying cause of SMA.
The European Commission approved Spinraza in June 2017 for the same indication.
National health plan reimbursement for Spinraza is now available in almost 30 European countries, as well as in Australia, which extended coverage to pre-symptomatic infants in December 2020. Pre-symptomatic infants are those genetically diagnosed with SMA, but not yet showing symptoms.
According to Biogen, the therapy is available in more than 50 countries, including Canada, China, Hong Kong, Israel, Japan, South Korea, and Turkey.
How does Spinraza work?
Spinraza is a type of RNA-based molecule, called antisense oligonucleotide (ASO), designed to increase the levels of the survival motor neuron (SMN), a protein essential for motor neuron and muscle health and whose production in impaired in people with SMA. Motor neurons are the specialized nerve cells that control voluntary movement.
SMA patients produce no to low levels of SMN due to mutations in the SMN1 gene. While humans have a “backup” gene, SMN2, a slight difference in its DNA sequence results in an event called alternative splicing, which limits the amount of working SMN it produces by 10–15%.
Alternative splicing is a natural process that allows for a single gene to give rise to many different proteins. Much like in a recipe, adding or removing certain key ingredients — in this case, pieces of genetic information called exons — can change the resulting messenger RNA (mRNA) and final protein. (mRNA is a molecule derived from DNA that guides protein production.)
In SMN2, this splicing event results in the exclusion of exon 7 from most of its mRNA molecules, leading to the generation of a shorter, less stable, and poorly working SMN protein. The number of SMN2 gene copies a patient has helps to determine disease severity, as a higher number is associated with the development of milder forms of SMA.
Spinraza works by binding to SMN2’s mRNA molecule and correcting its splicing. By preventing the removal of exon 7 from the resulting mRNA molecule, the therapy has the potential to restore the production of functional SMN.
Since ASOs are too large to cross a highly selective membrane that prevents large molecules and harmful microorganisms in circulation from reaching the brain, the therapy is given directly into the spinal canal (intrathecal injection). The spinal canal is filled with the cerebrospinal fluid, the liquid that surrounds the brain and spinal cord.
Spinraza in clinical trials
Promising findings from Phase 1 and 2 trials in children with SMA type 1, a severe, infantile-onset form of the disease, prompted the launch of the Phase 3 ENDEAR trial (NCT02193074) to test the now-approved 12 mg dose of Spinraza against a sham procedure in 122 type 1 infants, up to 7 months old.
A six-month interim analysis showed that 41% of treated infants reached motor development milestones attained by none of the infants receiving the sham procedure. These findings led to the trial being stopped early, and all eligible children were transferred to an open-label extension trial — SHINE (NCT02594124) — to asses the therapy’s long-term safety and efficacy.
Another Phase 3 trial, called CHERISH (NCT02292537), evaluated the therapy’s safety and effectiveness against a sham procedure in 126 children, ages 2 to 12, with types 2 and 3 and who were able to sit, but not walk, independently.
Again, significant improvements in motor function were seen after 15 months of Spinraza treatment. Based on these positive results, this trial was also stopped early and participants moved to the SHINE study to receive the therapy over long term.
SHINE’s interim findings, released in May 2020 and concerning up to 6.5 years of treatment for some patients, showed sustained benefits — from motor skill gains to disease stabilization — across a broad range of SMA patients who now ranged from toddlers to young adults.
Ongoing clinical trials
The open-label Phase 2 NURTURE trial (NCT02386553) is evaluating Spinraza’s eight-year safety and effectiveness in 25 pre-symptomatic newborns, 6 weeks old and younger, who are likely to develop SMA type 1 or 2 based on their SMN2 copy number. The trial, running through January 2025, aims to determine whether very early treatment might prevent or delay symptom onset.
Interim results of up to 4.8 years of treatment showed that all children were alive and free from permanent ventilation, and that most were able to walk with (96%) and without (88%) assistance. In addition, 23 (92%) children maintained their ability to swallow and 84% were reported by their caregivers as being fed exclusively by mouth. All these observations highly contrasted with SMA’s natural history.
Biogen is also testing a higher Spinraza dose against its approved 12 mg dose in up to 172 SMA patients of all ages in the three-part Phase 2/3 DEVOTE trial (NCT04089566), involving 49 clinical sites across 25 countries.
RESPOND, a Phase 4 trial (NCT04488133), is evaluating the benefits of Spinraza in up to 60 infants and children, between 2 months and 3 years old, with SMA who still have unmet clinical needs following Novartis’ one-time gene therapy Zolgensma. Zolgensma is an approved therapy for young children with all or nearly all types of SMA, depending on the country. It works through a different mechanism than Spinraza.
Biogen is also launching the Phase 3b ASCEND trial (NCT05067790) to test a higher dose of Spinraza in up to 135 type 2 and 3 patients, ages 5 to 39, who were previously treated with Roche’s Evrysdi (risdiplam). Evrysdi is an oral daily therapy approved for SMA patients, ages 2 months and older. While it also targets the backup SMN2 gene, it has a different mechanism of action than Spinraza.
Spinraza is currently approved at a recommended dose of 12 mg for all patients, regardless of SMA type, age, or body weight. After an initial loading period of four doses (the first three every 14 days, and the fourth 30 days later), patients move to maintenance treatment, in which the therapy is given at the same dose once every four months (three times each year).
Since Spinraza is administered as an intrathecal injection, treatment must take place in hospitals or at centers whose staff are trained in performing lumbar punctures.
The therapy’s most common side effects include respiratory infection, fever, constipation, headache, vomiting, back pain, and post-lumbar puncture syndrome, a common complication of lumbar puncture. Post-lumbar puncture syndrome is characterized by a headache that typically starts several hours up to two days after the procedure, and that may be accompanied by vomiting, nausea, and dizziness.
Given that some ASOs have been associated with an increased risk of bleeding complications and kidney damage, patients should undergo laboratory tests to monitor for coagulation abnormalities, including severely low platelet counts, and kidney problems before initiating Spinraza and before each dose.
More information can be found on the therapy’s label.
Last updated: Dec. 20, 2021, by Marta Figueiredo PhD
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