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Roche halts emugrobart development in spinal muscular atrophy after MANATEE study fails

Roche has discontinued development of emugrobart (GYM329), an investigational anti-myostatin antibody, in spinal muscular atrophy after Part 1 of the Phase...

Edited by Robert McTiernan··3 min read

Roche Halts Emugrobart Development in SMA After Phase II/III MANATEE Study Fails to Show Efficacy

Roche has discontinued development of emugrobart (GYM329), an investigational anti-myostatin antibody, in spinal muscular atrophy after Part 1 of the Phase II/III MANATEE study (NCT05115110) failed to demonstrate consistent improvements in motor function or muscle growth over treatment with risdiplam alone. The decision, disclosed in a community letter to Cure SMA, means the company will not advance emugrobart into the planned Phase III portion of the trial.

The MANATEE study was a two-part, global trial evaluating emugrobart in combination with risdiplam in individuals aged 2 to 25 years with SMA. Part 1 served as a dose-finding segment enrolling ambulant children aged 2 to 10 years and non-ambulant children aged 5 to 10 years, with the study designed to enroll up to 259 participants across both parts. Primary objectives included safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy as measured by motor function scales and MRI-assessed muscle contractile area. Part 2, the pivotal Phase III portion, was contingent on a successful Part 1 and was never initiated.

According to the company, emugrobart in combination with risdiplam "did not meaningfully improve motor function across the ambulant and non-ambulant cohorts compared to treatment with risdiplam alone." Roche stated the discontinuation was not driven by safety findings; emugrobart was well tolerated, and no serious adverse events led to withdrawals. The company said it plans to present Part 1 data at an upcoming medical conference.

Emugrobart had previously completed a Phase I study in healthy male volunteers (NCT04708847), which evaluated pharmacodynamic effects on muscle recovery following limb immobilization. A separate Phase II trial, MANOEUVRE (NCT05548556), tested emugrobart in facioscapulohumeral muscular dystrophy and was also discontinued after failing to demonstrate clinical benefit despite confirmed target engagement. Roche has pivoted emugrobart's development toward metabolic indications: a Phase I trial in obesity and overweight patients with type 2 diabetes (NCT07137585) is ongoing with primary completion expected in September 2026, and subsidiary Chugai Pharmaceutical has initiated a Phase II trial called GYMINDA evaluating the molecule in obesity, where the rationale centers on preserving lean muscle mass during GLP-1-induced weight loss.

Roche and Genentech said they remain committed to SMA care. Risdiplam (Evrysdi), the backbone therapy used in the MANATEE trial, remains an approved standard-of-care treatment for SMA across all types and age groups, having received US FDA approval in August 2020.

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Key Takeaways

  • SMA treatment has been transformed by three approved SMN-restoring therapies — risdiplam, nusinersen, and onasemnogene abeparvovec — yet many patients retain residual motor deficits, creating a rationale for SMN-independent combination approaches. Emugrobart's failure suggests that myostatin inhibition, even with confirmed target engagement, does not reliably translate into functional motor improvement in this population.

  • The anti-myostatin field has a record of clinical disappointments. Emugrobart was engineered with pH-dependent "sweeping antibody" technology designed to achieve deeper myostatin depletion than conventional neutralizing antibodies, and it selectively targeted the latent form of myostatin to avoid cross-reactivity with the structurally related protein GDF-11. Despite these design refinements, the clinical outcome mirrored earlier failures of less selective myostatin pathway inhibitors.

  • US-based Scholar Rock continues to develop apitegromab (SRK-015), another antibody that selectively inhibits latent myostatin activation, in SMA. Apitegromab remains in advanced clinical testing as an add-on to SMN-restoring therapies and represents the most direct remaining competitor in this mechanism-indication space. Whether apitegromab can succeed where emugrobart did not will be a critical test of the myostatin inhibition hypothesis in SMA.

  • A persistent scientific hurdle in SMA drug development is the gap between measurable target engagement and clinically meaningful functional outcomes. The MANOEUVRE trial in FSHD confirmed emugrobart suppressed myostatin effectively, yet this did not yield motor benefit — a pattern that raises questions about whether myostatin is a rate-limiting factor in muscle function for patients already receiving disease-modifying therapy.

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