efficacy and safety of apitegromab in patients with later-onset spinal muscular atrophy treated with nusinersen or risdiplam

Conditions: Spinal Muscular Atrophy; Spinal Muscular Atrophy Type 3; Spinal Muscular Atrophy Type 2; SMA; Neuromuscular Diseases; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal; Neuromuscular Manifestations; Anti-myostatin

Summary: this phase 3 trial (study srk-015-003) was conducted in patients ≥2 years old at screening, who were previously diagnosed with later-onset spinal muscular atrophy (sma) (i.e., type 2 and type 3 sma) and were receiving an approved survival motor neuron (smn) upregulator therapy (i.e., either nusinersen or risdiplam), to confirm the efficacy and safety of apitegromab as an adjunctive therapy to nusinersen and evaluate the efficacy and safety of apitegromab as an adjunctive therapy to risdiplam.


Eligibility criteria:
inclusion criteria: * males and females 2 through 21 years old at screening. * documented diagnosis of 5q sma. * diagnosed with later-onset sma (i.e., type 2 and type 3 sma) before receiving an approved smn upregulator therapy (i.e., either nusinersen or risdiplam). * must be nonambulatory at screening. nonambulatory patients must be able to sit independently (sits up straight with head erect for at least 10 seconds; does not use arms or hands to balance body or support position) per world health organization (who) motor milestones definition at screening. * receiving one background therapy for sma (i.e., either nusinersen or risdiplam) for the time period specified below and anticipated to remain on that same treatment throughout the trial: 1. if receiving the smn upregulator therapy nusinersen, must have completed at least 10 months of dosing (i.e., completed the loading regimen and at least 2 maintenance doses) before screening; 2. if receiving the smn upregulator therapy risdiplam, must have completed at least 6 months of dosing before screening. * motor function score (hfmse) ≥10 and ≤45 at screening. * have no physical limitations that would prevent the patient from undergoing motor function outcome measures throughout the duration of the study. * able to receive study drug infusions and provide blood samples through the use of a peripheral intravenous (iv) or a long-term iv access device that the patient has placed for reasons independent from the study throughout the duration of the study. * able to adhere to the requirements of the protocol, including travel to the study center and completing all study procedures and study visits. * for patients who are expected to have reached reproductive maturity by the end of the study, adhere to study specific contraception requirements. exclusion criteria: * received zolgensma® (onasemnogene abeparvovec-xioi) at any time and previous treatment with apitegromab. * use of invasive ventilation and tracheostomy. * use of chronic daytime non-invasive ventilatory support for \>16 hours daily in the 2 weeks prior to dosing, or anticipated to regularly receive such daytime ventilator support chronically over the duration of the study. * any acute or co-morbid condition interfering with the well-being of the patient within 7 days of screening, including active systemic infection, the need for acute treatment or inpatient observation due to any reason. * severe scoliosis and/or contractures at screening. based on clinical judgement, any scoliosis or contractures present must be stable over the past 6 months, anticipated to be stable for the duration of the study and not prevent the patient from being evaluated on any functional outcome measures throughout the duration of the study. * pregnant or breastfeeding. * major orthopedic or other interventional procedure, including spine or hip surgery, considered to have the potential to substantially limit the ability of the patient to be evaluated on any functional outcome measures, within 6 months prior to screening, or anticipated for the duration of the study. * prior history of a hypersensitivity reaction to a monoclonal antibody (mab) or recombinant protein bearing an fc domain (such as a soluble receptor-fc fusion protein), apitegromab, or excipients of apitegromab. * treatment with investigational drugs within 3 months prior to screening. * use of therapies with potentially significant muscle effects (such as androgens, insulin-like growth factor, growth hormone, systemic beta-agonist, botulinum toxin, or muscle relaxants or muscle-enhancing supplements) or potentially significant neuromuscular effects (such as acetylcholinesterase inhibitors) within 60 days prior to screening. * nutritional status not stable over the past 6 months and not anticipated to be stable throughout the duration of the study. * patient has any other condition, which in the opinion of the investigator may compromise safety or compliance, would preclude the patient from successful completion of the study, or interfere with the interpretation of the results.