Disease-modifying Therapy

Treatment for SMA has been mainly supportive, but disease-modifying therapy (DMT) with Nusinersen, Onasemnogene abeparvovec, and Risdiplam is now available.

Approach to choosing DMT: For infants and very young children (age <2 years) with SMA who are not ventilator-dependent, we recommend offering treatment with DMT using either Nusinersen, Onasemnogene abeparvovec, or Risdiplam where these are available. The efficacy of Onasemnogene abeparvovec for children two years of age and older is unknown. For older children (age ≥2 years) and adults with moderate symptoms of SMA, we suggest treatment with Nusinersen or Risdiplam. The choice among these treatments should be individualized according to drug cost, availability, adverse effect profile, burden of administration, and patient values and preferences, using a process of shared decision-making.

Short-term trials have shown modest efficacy for these treatments in a disease that, left untreated, leads to profound disability and death. However, these therapies are extraordinarily expensive. Direct comparisons between these drugs are lacking.

Children or adults who are ventilator-dependent, need enteral feeds, or have severe contractures or scoliosis may be too debilitated to derive benefit from these disease-modifying therapies. Given the uncertain benefit and unknown long-term risks for individuals with very advanced SMA (eg, those on chronic assisted ventilation) and older children and adults with mild SMA, we advise individualized treatment decisions for these patients. As an example, a patient with impending loss of ambulation may place a higher value on potential benefits and a lower value on the burden and harms of treatment, while an adult with mild symptoms may place a higher value on avoidance of burdens and harms of treatment until more is known about disease-modifying drugs in this setting.

Administration differs:

●Nusinersen is given by intrathecal injection with maintenance dosing every four months after the initial four loading doses, which are given over eight weeks.

●Onasemnogene abeparvovec is given as a one-time intravenous infusion.

●Risdiplam is given daily by mouth using a syringe.

Preliminary studies suggest that combination therapy using agents with different mechanisms of action (eg, Onasemnogene and Nusinersen) may be beneficial for SMA, but larger and longer-term studies are needed to determine the feasibility of this approach.

Nusinersen — Nusinersen is an antisense oligonucleotide that modifies splicing of the *SMN2 *gene to increase production of normal, full-length survival motor neuron protein, which is deficient in SMA.

Nusinersen is approved for marketing in several countries and regions including the United States, Canada, Brazil, Europe, Australia, and Japan.

●Effectiveness: The multicenter, double-blind, ENDEAR trial enrolled infants with SMA who were seven months of age or younger at screening, excluding those with peripheral oxygen desaturation (ie, oxygen saturation below 96 percent without ventilation support). Infants were randomly assigned to intrathecal Nusinersen treatment or sham procedure (control) in a 2 to 1 ratio. In the final analysis, improvement in motor milestones was noted in 37 of 73 (51 percent) infants treated with Nusinersen, versus 0 of 37 (0 percent) infants who received the sham procedure. In the Nusinersen treatment group, motor milestones achieved included head control (22 percent), rolling over (10 percent), sitting independently (8 percent), and standing (1 percent). In the sham procedure group, no infants achieved motor milestones. The proportion of infants who died or received permanent assisted ventilation was lower in the Nusinersen group compared with the sham group (39 versus 68 percent, hazard ratio 0.53, 95% CI 0.32-0.89).

The evidence of benefit for older children with SMA is based upon a positive interim analysis of 126 patients (84 patients assigned to Nusinersen treatment and 42 assigned to sham control) in the double-blind CHERISH trial, which enrolled children 2 to 12 years of age with SMA. Eligible children had the onset of symptoms at greater than six months of age, were able to sit independently but never walked independently, and had an estimated life expectancy of more than two years. Exclusion criteria included respiratory insufficiency (ie, need for invasive or noninvasive ventilation for more than 6 hours per 24-hour period), need for a gastric feeding tube for majority of feeds, severe contractures or severe scoliosis, or medical disability (eg, wasting or cachexia). The trial was stopped early for benefit after a prespecified interim analysis. In the final analysis, patients who received Nusinersen had a mean improvement on the Hammersmith Functional Motor Scale Expanded (HFMSE) of 3.9 points at month 15 of treatment, versus a decline of 1.0 points for those in the control group, for a mean difference of 4.9 points (95% CI 3.1-6.7), where a difference of ≥3 points was considered clinically meaningful.

Treatment benefit appears to be greater for children younger than two years of age at the start of Nusinersen treatment, as shown in a study of 143 patients from the SMArtCARE registry with early-onset SMA who were unable to sit independently prior to treatment. During the follow-up period of up to 38 months of treatment, major improvements in motor function were reported, mainly in children <2 years of age at the start of treatment. The ability to sit independently was achieved by 25 percent of children overall (33 percent in children younger than two years and 11 percent in the older cohort). Bulbar and respiratory function did not show similar improvement, and the need for tube feeding and intermittent ventilator support increased over time.

Evidence of benefit for adults with SMA comes from a prospective observational cohort study patients, ages 16 to 65 years, who received Nusinersen and had complete data available at six months (n = 124), 10 months (n = 92), and 14 months (n = 57). A clinically meaningful improvement, defined as an increase of 3 points or more in the HFMSE score compared with baseline, was observed with Nusinersen treatment at six months in 28 percent, at 10 months in 35 percent, and at 14 months in 40 percent of patients.

●Adverse effects: The most common adverse events associated with intrathecal Nusinersen treatment were respiratory tract infections and constipation. The prescribing label notes an increased risk for thrombocytopenia, coagulation abnormalities, and renal toxicity. Thus, laboratory testing for platelet count, prothrombin time, activated partial thromboplastin time, and quantitative spot urine protein is recommended at baseline and prior to each dose.

●Administration: Nusinersen is administered by intrathecal injection; each dose is 12 mg per 5 mL supplied in a single vial. Treatment is initiated with four loading doses; the first three loading doses are given at 14-day intervals, while the fourth loading dose is given 30 days after the third. Thereafter, a maintenance dose is given once every four months. The cost of each dose is listed as $125,000.

Onasemnogene abeparvovec: Another approach to treating SMA involves gene replacement of mutated SMN1 with normal SMN1. Onasemnogene abeparvovec is a recombinant adeno-associated viral vector containing complementary DNA encoding the normal human survival motor neuron protein (SMN1).

Onasemnogene abeparvovec was approved by the FDA in 2019 for the treatment of children less than two years of age with SMA who have bi-allelic mutations in SMN1.

●Efficacy: Onasemnogene abeparvovec (formerly called AVXS-101) was tested in an open-label study of 15 infants (age range 1 to 8 months) with SMA who had homozygous SMN1 deletions of exon 7. The patients were assigned to high-dose (n = 12) or low-dose (n = 3) one-time intravenous administration of Onasemnogene abeparvovec. At 20 months of age, all 15 patients were alive and did not require permanent mechanical ventilation, whereas the rate of survival without permanent ventilation in a historical control group was only 8 percent. Patients in the high-dose cohort exhibited an increase from baseline in motor function compared with a decrease in the historical controls. Unlike historical controls, a number of treated infants achieved motor milestones including sitting unassisted (n = 11), feeding orally (n = 11), rolling over (n = 9), and walking independently (n = 2). In an extension study of 13 patients, with approximately five years of follow-up since dosing, all 10 patients in the high-dose group maintained previously acquired milestones without need for permanent ventilation, while two patients reached a new milestone of standing with assistance.

Additional evidence of efficacy comes from results of the open-label STR1VE-US and STR1VE-EU studies. STR1VE-US treated 22 patients with infantile-onset SMA (mean age at enrollment 3.7 months) who were able to feed by mouth exclusively and who did not require noninvasive ventilatory support at enrollment; STR1VE-EU included 32 patients with infantile-onset SMA (mean age at enrollment 4.1 months); patients needing feeding support or noninvasive ventilatory support for less than 12 hours daily were eligible, allowing for inclusion of patients with more severe disease than STR1VE-US. At age 14 months, survival without need for permanent ventilation was achieved by 20 patients (91 percent, 95% CI 79-100) in STR1VE-US and 31 patients (97.5 percent, 95% CI 91-100) in STR1VE-EU, compared with 6 of 23 (26 percent, 95% CI 8-44) in untreated historical controls. At the 18 month-of-age study visit, the ability to sit without support was achieved by 13 patients (59 percent, 97.5% CI 36-100) in STR1VE-US and 14 patients (44 percent, 97.5% CI 26-100) in STR1VE-EU, compared with 0 of 23 untreated historical controls.

Larger and longer-term studies are needed to define the benefits and risks of this therapy.

●Adverse effects: The most common adverse effects with Onasemnogene abeparvovec are elevated aminotransferases (approximately 27 percent) and vomiting (approximately 7 percent). The label includes a boxed warning about the potential for serious liver injury; rare cases of fatal acute liver failure have been reported. Transient decreases in platelet counts, sometimes meeting criteria for thrombocytopenia, and increased serum troponin have also been observed. Several cases of severe thrombocytopenia and microangiopathic hemolysis, including one fatality, have also been reported. Increases in cardiac troponin I levels, up to 0.176 microg/L, have been observed in clinical trials, although the clinical relevance of this is unknown.

In an extension study of 13 children with approximately five years of follow-up, serious adverse events were primarily related to SMA disease, including acute respiratory failure and pneumonia.

●Administration: Onasemnogene abeparvovec is given as a one-time single dose of 1.1 × 1014 vector genomes/kg by intravenous infusion over 60 minutes to patients with clinically stable baseline health status including hydration, nutrition, and absence of infection. Administration should be postponed in patients with concurrent infection. Systemic glucocorticoids equivalent to oral prednisolone 1 mg/kg per day for 30 days should be started one day prior to Onasemnogene infusion.

There are comprehensive instructions regarding Onasemnogene abeparvovec administration, laboratory testing, and monitoring to assess safety. These include baseline platelet count, serum troponin-I level, and anti-adeno-associated virus (AAV) antibody testing, along with baseline levels and monitoring after Onasemnogene infusion for aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, albumin, prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR). Detailed information regarding treatment indication, dosing, and monitoring for Onasemnogene abeparvovec can be found at https://www.fda.gov/vaccines-blood-biologics/zolgensma.

The estimated cost of one dose of Onasemnogene abeparvovec is US $2,125,000.

Risdiplam: Risdiplam is a small molecule SMN2 splicing modifier that binds two sites in SMN2 pre-messenger RNA, thereby correcting the splicing deficit of SMN2, leading to increased levels of full-length SMN protein. Risdiplam is approved by the FDA for the treatment of SMA in pediatric and adult patients.

●Efficacy: Several small studies support the efficacy of Risdiplam.

•SMA 1: An open-label study (FIREFISH) of Risdiplam included 21 symptomatic infants with SMA type 1 who were one to seven months of age at enrollment. After 12 months of treatment at the higher dose (0.2 mg/kg per day), the number able to sit without support for at least five seconds was 7 of 17 patients (41 percent), and the number alive without permanent ventilation for both high and low dose groups was 19 of 21 patients (90 percent). At 12 months of follow-up, three infants had died, and a fourth infant died during safety follow-up at 23.8 months. These outcomes were better than those expected from the natural history of SMA disease progression.

A subsequent open-label study (FIREFISH part 2) from the same investigators treated 41 infants with SMA type 1 using the higher dose of Risdiplam (0.2 mg/kg per day). After 12 months of treatment, the proportion of patients able to sit without support for at least five seconds was 29 percent, compared with none expected based upon the natural history of SMA; the proportion who survived without permanent ventilation was 85 percent, compared with a natural history performance criterion of 42 percent, which was the upper limit of the 90 percent confidence interval for this outcome among 40 historical controls. Secondary analysis at 24 months, with 38 infants ongoing in the study, suggested continued improvement in motor function and achievement of motor milestones. As an example, the proportion of patients able to sit without support for at least 30 seconds was 44 percent, though none could stand or walk alone.

•Presymptomatic SMA: The open-label RAINBOWFISH trial enrolled 26 infants with genetically diagnosed SMA and two or more copies of SMN2 but without symptoms or signs of SMA. Treatment with once-daily oral Risdiplam was started at 16 to 41 days of age. At 12 months of treatment, 21 infants (81 percent) could sit without support for at least 30 seconds, 14 (54 percent) could stand alone, and 11 (42 percent) could walk independently. At 24 months, all 23 infants completing treatment were alive, and none needed respiratory support or assistance with feeding. These outcomes were better than those expected from the natural history of SMA disease progression, and suggest the potential benefit of treating early, before progressive symptoms develop. Infants with three or more SMN2 copies appeared to have better outcomes compared with infants with two SMN2 copies.

•SMA type 2 and nonambulatory SMA type 3: A controlled trial (SUNFISH) randomly assigned 180 patients ages 2 to 25 years with SMA type 2 or nonambulatory SMA type 3 to treatment with Risdiplam or placebo in a 2:1 ratio. Outcome (motor function) was assessed by the 32-item Motor Function Measure score (MFM36). At one year, Risdiplam treatment led to clinically meaningful improvement, with an average increase in MFM36 score of 1.36, compared with an average 0.19 decrease in MFM36 score for the placebo group (treatment difference 1.55, 95% CI 0.30-2.81).

●Adverse effects: In patients with later-onset SMA, the most common adverse effects were fever, diarrhea, and rash. In patients with infantile-onset SMA, similar adverse effects were seen, along with upper respiratory tract infection, pneumonia, constipation, and vomiting.

●Administration: Risdiplam is available as an oral solution and a tablet. The oral solution is given by mouth once a day using an oral syringe. The recommended daily dose is determined by age and body weight:

•For patients less than two months of age, the dose is 0.15 mg/kg daily.

•For patients two months to less than two years of age, the dose is 0.2 mg/kg daily.

•For patients two years of age and older weighing less than 20 kg, the dose is 0.25 mg/kg daily.

•For patients two years of age and older weighing 20 kg or more, the dose is 5 mg daily.

Risdiplam 5 mg tablet is intended only for patients prescribed the 5 mg dose. The tablet can be swallowed whole with water or dispersed in non-chlorinated drinking water.

Apitegromab: Apitegromab is an investigational monoclonal antibody that inhibits myostatin activation, thereby promoting muscle growth and function. The multicenter, double-blind SAPPHIRE trial enrolled 188 patients (156 in the age group 2 to 12 years and 32 in the age group 13 to 31 years) with nonambulatory SMA type 2 or SMA type 3. All patients had received treatment with Nusinersen for at least 10 months or Risdiplam for at least six months at screening. Exclusion criteria included prior treatment with Onasemnogene abeparvovec, or severe scoliosis or contractures. Patients ages 2 to 12 were randomly assigned in a 1:1:1 ratio to receive intravenous (IV) infusion of Apitegromab 20 mg/kg, Apitegromab 10 mg/kg, or placebo every four weeks, while patients ages 13 to 31 years were randomly assigned in a 2:1 ratio to IV Apitegromab 20 mg/kg or placebo every four weeks.

Results were assessed using a modified intention-to-treat analysis of patients aged 2 to 12 years who received at least one dose of Apitegromab or placebo and had at least one post-baseline HFMSE assessments; at 12 months, Apitegromab treatment (combined 20 mg/kg and 10 mg/kg) led to improvement on the HFMSE total score of 0.6 points compared with baseline, versus -1.2 points for placebo (least squares mean difference, 1.8 points; 95% CI 0.30-3.32). The 12-month outcome for patients 13 to 21 years showed the same least squares mean difference in HFMSE total score (1.8 points; 95% CI –1·06 to 4.57) but the difference was not statistically significant.

An important issue is whether a 1.8-point difference in the HFMSE total score is clinically meaningful. In studies evaluating Nusinersen for nonambulatory children with SMA, a difference of ≥3 points was considered clinically meaningful. However, the SAPPHIRE investigators cite other evidence suggesting that clinical stabilization is a realistic endpoint, while a 1.5 point improvement in the total HFMSE score is clinically meaningful for patients with SMA type 2 or type 3.

The most common adverse events with Apitegromab treatment were pyrexia, cough, vomiting, upper respiratory tract infection, and headache. No patients discontinued treatment due to adverse events.