Background: Spinal muscular atrophy (SMA) is a debilitating, progressive, genetic condition characterized by weakness and motor neuron loss due to deficient survival of motor neuron (SMN) protein. Although SMN upregulators have been approved to treat SMA, many patients continue to experience weakness, impairing function and quality of life. In murine models of SMA, pharmacologic myostatin inhibitors have shown promise for increasing muscle mass and function when used with SMN upregulators. Taldefgrobep alfa (BHV 2000) is differentiated by both targeting the myostatin pathway to directly inhibit myostatin and blocking key downstream receptor signaling by myostatin. Extensive nonclinical studies and a well-established safety profile in patients with neuromuscular disease support continued development of taldefgrobep._x000D_
Objective: To evaluate preclinical data from murine SMA models and clinical data to establish support for conducting a phase 3 clinical trial of treatment with an approved SMN upregulator and taldefgrobep._x000D_
Methods: The combination of taldefgrobep and the SMN upregulator SMN-C1 was evaluated in 2 different studies of murine SMA models using SMN delta 7 mice. Changes in muscle structure and function and other outcomes were assessed._x000D_
Results: The addition of taldefgrobep to SMN-C1 demonstrated improved plantar flexor muscle function (P <.05), compared to SMN-C1 alone. Additionally, administration of taldefgrobep with low-dose SMN-C1 showed improvements in gastrocnemius weight and contraction and/or relaxation kinetics, as well as restoration of type IIa and IIb atrophic muscle fibers, compared to use of SMN-C1 alone (P <.05 each). _x000D_ _x000D_ Conclusions: Preclinical data suggest a potential benefit from taldefgrobep combined with SMN upregulation in SMA treatment. Along with robust safety data from clinical studies, these preclinical results support conducting the global, prospective, randomized, double-blind, placebo-controlled phase 3 RESILIENT study (NCT05337553). This study, aimed at evaluating the efficacy and safety of taldefgrobep, is now enrolling ambulatory and non-ambulatory patients with SMA who are receiving SMN-upregulating therapies.