P04 Taldefgrobep alfa: preclinical and clinical data supporting the phase 3 RESILIENT study in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a progressive, debilitating, genetic condition resulting from a homozygous deletion or mutation in the survival of motor neuron (SMN1) gene and diminished levels of survival motor neuron (SMN) protein. Patients experience muscular atrophy and motor neuron loss. Despite the use of SMN upregulators, many experience muscle weakness that impairs function and quality of life. Combining a myostatin inhibitor with SMN upregulators may increase muscle mass and function in SMA. Taldefgrobep alfa (BHV-2000) targets the myostatin pathway both to directly inhibit active myostatin and block key downstream receptor signaling. Extensive nonclinical studies, including delta 7 mouse models, and a well-established safety profile in patients with neuromuscular disease support taldefgrobep development for SMA. Here, we review taldefgrobep preclinical and clinical data and provide an overview of the phase 3 global, randomized, double-blind, placebo-controlled RESILIENT trial in SMA. Two studies of murine SMA models evaluated the combination of taldefgrobep and SMN upregulator SMN-C1 in SMN delta 7 mice and assessed changes in muscle structure, muscle function and other outcomes. Adding taldefgrobep to SMN-C1 improved plantar flexor muscle function (P <.05), compared to SMN-C1 alone. Taldefgrobep and low-dose SMN-C1 improved gastrocnemius weight and contraction and/or relaxation kinetics, as well as restored type IIa and IIb atrophic muscle fibers, compared to use of SMN-C1 alone (P <.05 each). Preclinical data suggest a potential benefit from taldefgrobep plus SMN upregulation in SMA. Along with robust safety data from clinical studies, these results support phase 3 RESILIENT (NCT05337553). Aimed at evaluating the efficacy and safety of taldefgrobep, RESILIENT is now enrolling ambulatory and non-ambulatory participants, ages 4-21, who are receiving SMN-upregulating therapies, regardless of SMA type. Spinal muscular atrophy (SMA) is a progressive, debilitating, genetic condition resulting from a homozygous deletion or mutation in the survival of motor neuron (SMN1) gene and diminished levels of survival motor neuron (SMN) protein. Patients experience muscular atrophy and motor neuron loss. Despite the use of SMN upregulators, many experience muscle weakness that impairs function and quality of life. Combining a myostatin inhibitor with SMN upregulators may increase muscle mass and function in SMA. Taldefgrobep alfa (BHV-2000) targets the myostatin pathway both to directly inhibit active myostatin and block key downstream receptor signaling. Extensive nonclinical studies, including delta 7 mouse models, and a well-established safety profile in patients with neuromuscular disease support taldefgrobep development for SMA. Here, we review taldefgrobep preclinical and clinical data and provide an overview of the phase 3 global, randomized, double-blind, placebo-controlled RESILIENT trial in SMA. Two studies of murine SMA models evaluated the combination of taldefgrobep and SMN upregulator SMN-C1 in SMN delta 7 mice and assessed changes in muscle structure, muscle function and other outcomes. Adding taldefgrobep to SMN-C1 improved plantar flexor muscle function (P <.05), compared to SMN-C1 alone. Taldefgrobep and low-dose SMN-C1 improved gastrocnemius weight and contraction and/or relaxation kinetics, as well as restored type IIa and IIb atrophic muscle fibers, compared to use of SMN-C1 alone (P <.05 each). Preclinical data suggest a potential benefit from taldefgrobep plus SMN upregulation in SMA. Along with robust safety data from clinical studies, these results support phase 3 RESILIENT (NCT05337553). Aimed at evaluating the efficacy and safety of taldefgrobep, RESILIENT is now enrolling ambulatory and non-ambulatory participants, ages 4-21, who are receiving SMN-upregulating therapies, regardless of SMA type.