Spinraza became the first therapy approved by the U.S. Food and Drug Administration (FDA) to treat SMA type 1, type 2, and type 3 — covering both infants and adults — in December 2016, under a priority review program for rare diseases. This decision was supported by trial data showing its use led to statistically significant improvements in both motor function and patient survival.
The EU approved Spinraza to treat SMA throughout Europe in June 2017, following a favorable accelerated review by the European Medicines Agency (EMA). National health plan reimbursement for Spinraza is now available in almost 30 European countries, and in countries like Australia, which also extended coverage to presymptomatic infants in December 2020.
The treatment is now widely approved in more than 50 countries, including Canada, China, Hong Kong, Japan, Israel, Turkey, and Korea.
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 that encode for the SMN protein – SMN1 and SMN2. Cells make most of the SMN protein from the SMN1 gene. But in SMA, mutations in the SMN1 gene lead to little or no SMN protein being produced from this gene.
Cells can also make some SMN protein from the SMN2 gene. However, some 90% of the protein from this gene is shorter, and cells quickly destroy it. This is because there is a signal in the gene that causes the messenger RNA (mRNA) to miss a piece while cells are processing it. (mRNA is a copy of a gene that the cell’s protein-making machinery “reads” to produce a protein.)
Spinraza increases the ability of cells to produce functional SMN protein from the SMN2 gene. It does so by binding to the SMN2 mRNA and “patching” this signal. This allows the SMN2 mRNA to be full length, just like the SMN1 mRNA.
Spinraza in clinical trials
The first of these trials (NCT01494701) showed that Spinraza was well-tolerated and significantly increased motor function three months after treatment. (Researchers used the Hammersmith functional motor scale expanded – HFMSE to assess motor function.) These improvements continued in an 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 its extension CS12 (NCT02052791) indicated that children treated with Spinraza over three years showed improvements in motor function and stable disease activity. These results were a marked departure from SMA’s known course in untreated patients (SMA’s natural history).
A Phase 2 trial (NCT01839656) assessing the safety, efficacy, and pharmacokinetics (movement in the body) of Spinraza in infants younger than 210 days finished in 2018. Its results showed that Spinraza had an acceptable safety and tolerability profile. It also led to encouraging signs of clinical efficacy, in the form of slowed progression, in infants with SMA type 1, the most severe form of the disease.
A randomized and double-blind Phase 3 clinical trial (NCT02193074), called ENDEAR, followed to evaluate the safety and efficacy of a 12 mg dose of Spinraza against a sham procedure in 121 infants with type 1 SMA. A six-month interim analysis found that 41% of treated infants reached motor development milestones, compared with 0% among babies who were not treated. They were assessed using the Hammersmith infant neurological examination (HINE) scale. These findings led to the trial being stopped early, and all children moved to Spinraza treatment.
Better survival rates and acceptable safety was also reported in ENDEAR, with respiratory events and constipation being the most common adverse events. The main trial’s final analysis showed 51% of treated babies reaching motor milestones, while those on the sham treatment remained at 0%.
A randomized and sham-controlled Phase 3 clinical trial (NCT02292537), called CHERISH, assessed the safety and efficacy of Spinraza in 126 children, ages 2 to 12, with later-onset SMA (types 2 and 3). All were able to sit, but not walk, independently. Patients were randomized to Spinraza, given as four 12 mg doses, or to a placebo over 15 months. Again, significant improvements in motor skills and muscle function — a four-point rise in the Hammersmith Functional Motor Scale-Expanded (HFMSE) scale — was seen after 15 months in the treatment group, and a 1.9-point decrease in the non-treatment group.
This trial was also stopped early and — with ENDEAR and patients in other Spinraza studies — children were moved to an open-label extension trial — SHINE (NCT02594124) — that is studying the treatment’s effectiveness and safety over years. It is due to conclude in August 2023. Interim findings released in May 2020 and reaching out for some participants to 6.5 years of treatment, showed sustained benefits — from motor skill gains to disease stabilization — across a range of SMA patients who were at ages now ranging from toddlers to young adults.
Data from CHERISH and ENDEAR, including interim data, supported Spinraza’s approval in both the U.S., Europe, and elsewhere.
A Phase 2 and double-blind trial (NCT02462759), called EMBRACE, evaluated Spinraza’s safety and pharmacokinetics in symptomatic infants and children who, for age or other reasons, did not qualify for ENDEAR or CHERISH. The first of this two-part study also showed early, positive results among treated patients, including 79% achieving key motor milestones. When the sham procedure-controlled first part ended, all moved to its open-label second part for two years of treatment. Results here showed that treatment with Spinraza led to motor milestones being reached in SMA patients, with stronger milestones evident in those treated for longer periods (starting in part one). Treatment also lowered children’s need for ventilation support.
Ongoing clinical trials
In addition to the ongoing SHINE study, the Phase 2 NURTURE trial (NCT02386553) is assessing Spinraza in 25 genetically diagnosed but pre-symptomatic infants — all no more than 6 weeks old at enrollment and likely to develop either SMA type 1 or type 2. The trial aims to determine whether very early treatment might prevent or delay symptom onset.
Researchers presented interim results at scientific conferences in 2019, showing that at nearly four years of treatment none of these now young children had difficulties swallowing. All 25 were able to sit without support, and most (22 or 88%) were able to walk without assistance. (In SMA’s natural progression, untreated type 1 and 2 infants are never able to walk.) Updated results a year later found most — 96% — of these patients able to walk with assistance, and able to breathe without assistance at an average age of almost 4. The 22 able to walk unassisted also retained that ability. NURTURE runs through February 2025.
The DEVOTE Phase 2/3 clinical trial (NCT04089566) is studying the safety and efficacy of higher doses of Spinraza in up to 152 SMA patients. It will compare responses at those higher doses to those at the treatment’s currently approved 12 mg.
This study is being conducted in three parts: A, B, and C. A and C are open-label studies. B is a double-blind randomized study testing the 12 mg approved dose (a control patient arm) against an experimental 50 mg and 28 mg dose. In Part A, now completed, type 2 and 3 patients ages 2 to 15 received three 28 mg doses of Spinraza 14 days apart, followed by another dose at around five and nine months later. Researchers noted no safety concerns.
Part B, which is now enrolling patients with types 1–3, aims to demonstrate that higher doses lead to better outcomes, as measured by the CHOP INTEND scale of motor skill ability. Patients in the experimental arm will receive two 50 mg loading doses of Spinraza at 14-day intervals, followed by two 28 mg maintenance doses about 4.5 and 9 months later, with sham dosing given to match dosing in the control group.
Part C will test adults on Spinraza for more than one year, with these patients getting a single 50 mg dose four months after their most recent treatment, followed by 28 mg maintenance doses four and eight months later. Researchers expect to finish the DEVOTE study in July 2023.
A Phase 4 clinical trial, called RESPOND (NCT04488133), is testing Spinraza in patients previously treated with the gene therapy Zolgensma. This study is currently recruiting up to 60 children, ages 3 to 36 months, reportedly at various sites worldwide. It will investigate if infants and children given Zolgensma gain additional benefits from later Spinraza treatment.
The first group will include 40 children up to nine months old, who have two copies of the SMN2 gene (likely to develop type 1 SMA) and were treated with Zolgensma before or at six months of age. The second group will include 20 children up to three years old. All will receive four initial 12 mg loading doses of Spinraza, then maintenance doses every four months for the study’s length. Benefits will be measured through changes in HINE scores, with evaluations of safety among other study goals. RESPOND is due to conclude in September 2024.
Spinraza is currently approved at a recommended dose of 12 mg per treatment 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. Here, they receive the therapy once every four months (three times each year).
Spinraza is administered as an intrathecal injection, or an injection directly into the spinal canal. Treatment must take place in hospitals or at centers whose staff are trained in performing lumbar punctures.
The most common side effects of Spinraza are respiratory infections and constipation.
Last updated: Feb. 12, 2021
SMA News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.