Taldefgrobep Alfa and the Phase 3 RESILIENT Trial in Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA) is a rare, genetic neurodegenerative disorder caused by insufficient production of survival motor neuron (SMN) protein. Diminished SMN protein levels lead to motor neuron loss, causing muscle atrophy and weakness that impairs daily functioning and reduces quality of life. SMN upregulators offer clinical improvements and increased survival in SMA patients, although significant unmet needs remain. Myostatin, a TGF-β superfamily signaling molecule that binds to the activin II receptor, negatively regulates muscle growth; myostatin inhibition is a promising therapeutic strategy for enhancing muscle. Combining myostatin inhibition with SMN upregulation, a comprehensive therapeutic strategy targeting the whole motor unit, offers promise in SMA. Taldefgrobep alfa is a novel, fully human recombinant protein that selectively binds to myostatin and competitively inhibits other ligands that signal through the activin II receptor. Given a robust scientific and clinical rationale and the favorable safety profile of taldefgrobep in patients with neuromuscular disease, the RESILIENT phase 3, randomized, placebo-controlled trial is investigating taldefgrobep as an adjunct to SMN upregulators in SMA (NCT05337553). This manuscript reviews the role of myostatin in muscle, explores the preclinical and clinical development of taldefgrobep and introduces the phase 3 RESILIENT trial of taldefgrobep in SMA.

Keywords: RESILIENT; SMA; SMN upregulation; SMN upregulator; antimyostatin; myostatin; myostatin inhibitor; phase 3 clinical trial; spinal muscular atrophy; taldefgrobep.

Figure 1

Myostatin mechanism of action in skeletal muscle. ActRIIB, activin receptor type IIB; ALK4, activin type I receptor-like kinase type 4; ALK5, activin type I receptor-like kinase type 5; GDF11, growth differentiation factor 11.

Figure 2

Myostatin inhibitors in late-stage clinical trials in SMA. HFMSE, Hammersmith Functional Motor Scale Expanded; IV, intravenous; MFM-32, 32-item Motor Function Measure; Ph, phase; PL, placebo; RHS, Revised Hammersmith Scale; SMA, spinal muscular atrophy; SMN, survival motor neuron.

Figure 3

Taldefgrobep alfa mechanism of action [53,54].

Figure 4

(A) Plantar flexor muscle function at PND52, based on maximum torque in the RK050216 study. * p < 0.05 (using post hoc Holm–Sidak tests for pairwise comparisons) for SMA mice treated with the combination of SMN-C1 (3 mg/kg) and taldefgrobep (10 mg/kg) vs. SMA mice treated with SMN-C1. PND52, postnatal day 52. (B) Gastrocnemius muscle function in the RK100115 preclinical study. Muscle performance at PND48, based on maximal torque normalized to gastrocnemius weight in SMA mice treated with the combination of low-dose SMN-C1 (0.1 mg/kg) and taldefgrobep (10 mg/kg) vs. SMA mice treated with low-dose SMN-C1 and vehicle. * p = 0.01 at 80 Hz; p = 0.01 at 100 Hz; p = 0.02 at 150 Hz (using post hoc Holm–Sidak tests for pairwise comparisons following a 2-way repeated measures ANOVA). ANOVA, analysis of variance; PND48, postnatal day 48. (C) Ref. [5] Type IIa muscle fiber CSAs in the RK100115 preclinical study at PND48. * p < 0.05 (using a 1-way ANOVA) for SMA mice treated with the combination of low-dose SMN-C1 (0.1 mg/kg) and taldefgrobep (10 mg/kg) vs. SMA mice treated with low-dose SMN-C1 alone. CSA, cross-sectional area [5,55,56,57].

Figure 4

(A) Plantar flexor muscle function at PND52, based on maximum torque in the RK050216 study. * p < 0.05 (using post hoc Holm–Sidak tests for pairwise comparisons) for SMA mice treated with the combination of SMN-C1 (3 mg/kg) and taldefgrobep (10 mg/kg) vs. SMA mice treated with SMN-C1. PND52, postnatal day 52. (B) Gastrocnemius muscle function in the RK100115 preclinical study. Muscle performance at PND48, based on maximal torque normalized to gastrocnemius weight in SMA mice treated with the combination of low-dose SMN-C1 (0.1 mg/kg) and taldefgrobep (10 mg/kg) vs. SMA mice treated with low-dose SMN-C1 and vehicle. * p = 0.01 at 80 Hz; p = 0.01 at 100 Hz; p = 0.02 at 150 Hz (using post hoc Holm–Sidak tests for pairwise comparisons following a 2-way repeated measures ANOVA). ANOVA, analysis of variance; PND48, postnatal day 48. (C) Ref. [5] Type IIa muscle fiber CSAs in the RK100115 preclinical study at PND48. * p < 0.05 (using a 1-way ANOVA) for SMA mice treated with the combination of low-dose SMN-C1 (0.1 mg/kg) and taldefgrobep (10 mg/kg) vs. SMA mice treated with low-dose SMN-C1 alone. CSA, cross-sectional area [5,55,56,57].

Figure 5

Taldefgrobep alfa in healthy adults. (A) Free myostatin levels. (B) Ref. [41] Taldefgrobep-myostatin complex concentrations. BL, baseline; Q1W, once weekly; Q2W, twice weekly [41].

Figure 6

MAD phase of taldefgrobep study in healthy volunteers. Change in thigh muscle volume over time [41]. D57, day 57; MAD, multiple ascending dose; NS, not statistically significant [41].

Figure 7

Phase 3 RESILIENT study design. ACEND, Assessment of Caregiver Experience with Neuromuscular Disease; QOL, quality of life; RULM, Revised Upper Limb Module; SC, subcutaneous; SMAIS-ULM, SMA Independence Scale–Upper Limb Module [5,53,54,55,56,57].