FDA OKs First Drug to Target Muscle Loss in SMA

The FDA has approved the first therapy for spinal muscular atrophy (SMA) that directly targets muscle loss, providing a complementary approach to existing treatments that target motor neuron survival.Apitegromab-mstn (Isembyld, Scholar Rock) is approved as an add-on therapy in adults and children aged 2 years and older who are receiving a survival motor neuron 2-targeted treatment. The dosage is 10 mg/kg every 4 weeks and, depending on eligibility, infusions may be administered in a hospital, infusion center, or at home.SMA is a rare, progressive neuromuscular disease caused by mutations in the SMN1 gene, resulting in insufficient production of the SMN protein, progressive motor neuron loss, muscle weakness, and muscle wasting. Existing SMN-targeted therapies have markedly improved outcomes but do not directly address impaired muscle function."As neurologists, families consistently tell us that their top priority is gaining motor function, and we are now able to directly target the muscle, not just the motor neuron, for people living with SMA," Basil Darras, MD, director of the Neuromuscular Center and SMA program at Boston Children's Hospital and a principal investigator in SAPPHIRE, said in a company statement.SAPPHIRE Supports Approval Apitegromab is a fully human monoclonal immunoglobulin G4 antibody that binds to promyostatin and latent myostatin, preventing activation of myostatin, a negative regulator of skeletal muscle growth.The approval was based on findings from the phase 3 SAPPHIRE trial, a randomized, double-blind, placebo-controlled study involving 188 patients with nonambulatory type 2 or type 3 SMA receiving nusinersen or risdiplam. At 52 weeks, treatment with apitegromab 10 mg/kg was associated with a 2.2-point improvement in motor function as measured by Hammersmith Functional Motor Scale Expanded (HFMSE) compared to placebo (P =.0121).A clinically meaningful improvement of at least 3 points on the HFMSE occurred in 34.2% of patients treated with apitegromab compared with 13.5% receiving placebo (odds ratio, 3.8; P =.0125).The FDA noted that patients receiving apitegromab improved in motor function over 1 year, whereas those receiving placebo declined.The most common adverse reactions associated with apitegromab included upper respiratory tract infections, vomiting, cough, viral infections, headache, gastroenteritis, pharyngitis, and hypersensitivity.Fractures were reported in 9% of patients receiving the approved 10-mg/kg dose compared with 2% receiving placebo. The FDA cautioned that treatment may increase the risk for fractures, including serious fractures. The drug may also cause fetal harm and affect reproductive function.The FDA granted apitegromab fast track, orphan drug, and rare pediatric disease designations. Last year, before approval, the agency issued a complete response letter on apitegromab related solely to observations identified during a routine general site inspection of Catalent Indiana, LLC.