Clinical deep dive 

SMA is a rare, debilitating, hereditary disease characterized by progressive motor function decline and muscular atrophy. Most commonly, SMA results from a deletion or variant in the survival motor neuron 1 (SMN1) gene located on chromosome 5, resulting in little to no function in the SMN protein. The lack of SMN protein causes nerve cells to degenerate, which leads to severe and sometimes fatal muscle weakness. The SMN2 gene can partially compensate for nonfunctional SMN1 genes; however, most SMN protein produced by SMN2 is not functional. Although it is estimated that approximately 10% of the protein produced by each SMN2 copy is functional, SMA patients with more copies of the SMN2 gene may be able to better compensate for the loss of the SMN1 gene, resulting in less severe disease.  

Several types of SMA have been identified and vary by age of onset, severity and prognosis. Complications depend on the degree of muscle weakness and include respiratory infections, scoliosis and joint contractures. SMA type 0 is an extremely rare and severe form of the disease, which develops before birth. These patients typically progress rapidly into respiratory failure and often survive only the first few months of life. Onset of SMA type 1 occurs soon after birth to 6 months of age. Patients with type 1 typically do not achieve motor milestones and require nutritional support and possibly respiratory support by 12 months of age. Symptoms of type 2 present between 6 to 18 months of age and lead to an inability to stand or walk without assistance. The onset of type 3 symptoms occurs after 18 months of age. Affected individuals achieve independent mobility but lose the ability to stand and walk over time. Lastly, SMA type 4 is a milder form with onset in adulthood.

The incidence of SMA in the United States is approximately 1 in 15,000 births. SMA type 1 is the most common phenotype, accounting for about 60% of cases. SMA types 2, 3 and 4 account for about 20%, 20% to 30% and < 5% of SMA cases, respectively. A report from Cure SMA estimates that there are about 9,000 to 9,500 individuals with SMA living in the United States. 

There is no cure for SMA at the present time. Disease modifying pharmacological agents include intrathecal Spinraza, which is administered every four months in maintenance dosing and oral Evrysdi, which is administered daily. Both agents increase the production of the SMN protein. Additionally, the single-dose, IV gene therapy Zolgensma delivers a functional copy of the SMN1 gene and is indicated for patients under 2 years of age. Supportive therapy may include physical therapy, occupational therapy, use of orthotics and adaptive equipment and monitoring and intervention as indicated for respiratory function, nutritional status and spinal curvature. 

Drug and clinical trial overview 

The double-blind, placebo-controlled, Phase 3 SAPPHIRE (NCT05156320) trial evaluated apitegromab for the treatment of non-ambulatory patients with SMA type 2 or type 3 who were receiving current SOC (nusinersen or risdiplam). The study enrolled 156 patients 2 through 12 years of age. Patients were randomized 1:1:1 to receive apitegromab 10 mg/kg, apitegromab 20 mg/kg or placebo added to SOC therapy. Apitegromab and placebo were administered via IV infusion every 4 weeks for 12 months. The trial reported that apitegromab achieved the primary endpoint of statistically significant improvement in motor function from baseline to month 12 compared to placebo, as measured by the Hammersmith Functional Motor Scale Expanded (HFMSE) (least squares mean [LSM] difference: 1.8 points [p=0.0192] with both doses combined, 1.4 points nonsignificant [p=0.1149] with apitegromab 20 mg/kg and 2.2 points [nominal p=0.0121] with apitegromab 10 mg/kg). Approximately 30.4% of patients in the apitegromab groups achieved a ≥ 3-point improvement in HFMSE score compared to 12.5% in the placebo group. Apitegromab was well tolerated. Adverse events with the highest incidence included pyrexia, nasopharyngitis and cough, while serious adverse events with the highest incidence included pneumonia and dehydration. No serious adverse events were determined to be related to apitegromab treatment. Similar efficacy and safety results were reported in an exploratory population of patients 13 to 21 years of age with SMA type 2 or type 3 who received apitegromab 20 mg/kg (LSM difference compared to placebo in change in HFMSE, 1.8 points).  

The Phase 2 TOPAZ (NCT03921528) trial evaluated apitegromab in 58 patients with SMA type 2 or type 3  in three study cohorts. Apitegromab was administered via IV infusion every 4 weeks for 12 months. Cohort 1 stratified ambulatory patients 5 through 21 years of age into two arms (apitegromab 20 mg/kg alone or in combination with nusinersen). Cohort 2 evaluated apitegromab 20 mg/kg combined with nusinersen in non-ambulatory patients 5 to 21 years of age. Lastly, cohort 3 randomized patients ≥ 2 years of age to apitegromab 2 mg/kg or 20 mg/kg in combination with nusinersen in a blinded manner. At month 12, the mean change from baseline in the primary endpoint of HFMSE score in cohort 1 was -0.3 points in patients who received apitegromab plus nusinersen and -0.4 points in patients who received apitegromab alone. The mean change in HFMSE in cohort 2 was +0.6 points. In cohort 3, the mean change in HFMSE was +5.3 and +7.1 points for the 2 mg/kg and 20 mg/kg arms, respectively. The five most commonly reported treatment-emergent adverse events were headache, pyrexia, upper respiratory tract infection, cough and nasopharyngitis.