What were the key findings of the SAPPHIRE trial?

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SAPPHIRE

Year of Publication: 2025

Bottom Line

SAPPHIRE is the first phase 3 trial to demonstrate that a myostatin-targeting agent can improve motor function in any disease. Combined-dose apitegromab (20 + 10 mg/kg) significantly improved HFMSE scores by 1.8 points vs placebo at 12 months in nonambulatory SMA patients aged 2-12 already on nusinersen or risdiplam. The placebo group declined while the apitegromab group improved, with separation visible by week 8. The individual 20 mg/kg dose did not reach significance alone (p=0.11), likely reflecting population heterogeneity rather than a true dose-response, as pharmacodynamic effects were indistinguishable between doses. Safety was favorable with no treatment-related serious adverse events. Results support muscle-targeted therapy as a complement to SMN-targeted treatments.

        Major Points
        First placebo-controlled phase 3 trial to show functional benefit of selective myostatin inhibition in any disease — a milestone after decades of failed myostatin-targeting approaches.
Combined apitegromab met the primary endpoint with HFMSE improvement of +1.8 points vs placebo (p=0.019) in ages 2-12, exceeding the 1.5-point clinically meaningful threshold for SMA type 2/3.
Placebo patients declined by -1.2 points over 12 months despite ongoing SMN-targeted therapy, confirming the unmet need for muscle-directed therapies that address accumulated atrophy.
The 20 mg/kg dose alone did not reach significance (p=0.11), but pharmacokinetic data showed both doses achieved target saturation with superimposable latent myostatin levels, suggesting pharmacological equivalence.
Efficacy was consistent across subgroups of age, SMN-targeted therapy type, age at therapy initiation, and region — supporting broad applicability across the SMA population.
Effect size appeared smaller in risdiplam-treated patients, partly attributed to higher proportion with two prior SMN-targeted therapies (54% of risdiplam patients vs 2% of nusinersen patients).
RULM and WHO motor milestones showed positive trends favoring apitegromab but did not reach significance, consistent with prior SMA trials where upper limb effects take longer to manifest.
Safety profile was favorable: no treatment-related serious AEs, no deaths, no discontinuations due to AEs, and no infusion/hypersensitivity reactions — consistent with the phase 2 TOPAZ trial.
98% of participants (185/188) enrolled in the long-term ONYX extension study, reflecting both high completion rates and patient/family engagement.
Apitegromab's selective targeting of myostatin precursors avoids off-target effects seen with prior anti-myostatin approaches (e.g., blocking growth differentiation factor 11), explaining its clean safety profile.

      

Design

Study Type: Phase 3, double-blind, randomized, placebo-controlled trial

Randomization: 1

Blinding: Double-blind

Follow-up Duration: 52 weeks

Centers: 48

Countries: Belgium, France, Germany, Italy, Poland, Spain, Netherlands, UK, USA

Sample Size: 188

Inclusion Criteria

Age 2-21 years; genetically documented SMN-deficient nonambulatory SMA type 2 or 3; estimated life expectancy >2 years; HFMSE scores 10-45; on nusinersen ≥10 months or risdiplam ≥6 months at screening.

Exclusion Criteria

Previous treatment with onasemnogene abeparvovec-xioi or apitegromab; history of severe hypersensitivity reactions to nusinersen or risdiplam; severe scoliosis or contractures (CTCAE grade 3); conditions anticipated to be unstable or likely to impact motor function assessment.

Arms

Field	Apitegromab 20 mg/kg (ages 2-12)	Apitegromab 10 mg/kg (ages 2-12)	Control	Apitegromab 20 mg/kg (ages 13-21)	Control
Intervention	Apitegromab 20 mg/kg IV every 4 weeks for 12 months, added to background nusinersen or risdiplam	Apitegromab 10 mg/kg IV every 4 weeks for 12 months, added to background nusinersen or risdiplam	Placebo IV every 4 weeks for 12 months, with background nusinersen or risdiplam	Apitegromab 20 mg/kg IV every 4 weeks for 12 months, added to background nusinersen or risdiplam	Placebo IV every 4 weeks for 12 months, with background nusinersen or risdiplam
Duration

Outcomes

Outcome	Type	Intervention	HR / OR / RR	P-value
Change from baseline in HFMSE at 12 months — combined apitegromab (20 + 10 mg/kg) vs placebo (ages 2-12) \| Change from baseline in HFMSE at 12 months — apitegromab 20 mg/kg vs placebo (ages 2-12): LS mean difference +1.4 points (95% CI -0.34 to 3.13; p=0.11). Did not reach statistical significance.	Primary	LS mean difference +1.8 points (95% CI 0.30-3.32; p=0.019). Apitegromab LS mean +0.6 vs placebo -1.2.		p=0.019
Change from baseline in RULM at 12 months — apitegromab 20 mg/kg vs placebo (ages 2-12)	Secondary	LS mean difference +0.7 (95% CI -0.31 to 1.71); not significant (exploratory due to hierarchical testing).
Proportion achieving ≥3-point HFMSE improvement — apitegromab 20 mg/kg vs placebo (ages 2-12)	Secondary	OR 2.4 (95% CI 0.82-7.07); not significant.	2.4
Change in WHO motor milestones — apitegromab 20 mg/kg vs placebo (ages 2-12)	Secondary	LS mean difference +0.2 (95% CI -0.10 to 0.40); not significant.
Change from baseline in HFMSE at 12 months — apitegromab 10 mg/kg vs placebo (ages 2-12)	Secondary	LS mean difference +2.2 (95% CI 0.49-3.95); exploratory.
Change from baseline in RULM — apitegromab 10 mg/kg vs placebo (ages 2-12)	Secondary	LS mean difference +0.6 (95% CI -0.42 to 1.61); exploratory.
Proportion achieving ≥3-point HFMSE improvement — apitegromab 10 mg/kg vs placebo (ages 2-12)	Secondary	OR 3.8 (95% CI 1.23-10.90); exploratory.	3.8
Change from baseline in HFMSE at 12 months — pooled population ages 2-21	Secondary	LS mean difference +1.8 points (95% CI 0.46-3.16).
Change from baseline in HFMSE at 12 months — ages 13-21	Secondary	LS mean difference +1.8 points (95% CI -1.06 to 4.57); exploratory.
Odds ratio of achieving ≥3-point HFMSE improvement — apitegromab vs placebo	Secondary	OR 3.0 (95% CI 1.15-8.0).	3
Any adverse event	Adverse	Apitegromab 91% vs placebo 87% (pooled ages 2-21)
Serious adverse events	Adverse	Apitegromab 16% (21/128) vs placebo 10% (6/60); driven by infections and respiratory events, none assessed as treatment-related
Treatment-related adverse events	Adverse	Apitegromab 19% (24/128) vs placebo 18% (11/60); similarly balanced
Pyrexia	Adverse	Apitegromab 33 (26%) vs placebo 17 (28%)
Nasopharyngitis	Adverse	Apitegromab 32 (25%) vs placebo 14 (23%)
Cough	Adverse	Apitegromab 30 (23%) vs placebo 12 (20%)
Vomiting	Adverse	Apitegromab 29 (23%) vs placebo 10 (17%); ≥5% higher in apitegromab group
Upper respiratory tract infection	Adverse	Apitegromab 28 (22%) vs placebo 18 (30%)
Headache	Adverse	Apitegromab 27 (21%) vs placebo 12 (20%)
Serum creatine kinase elevation	Adverse	Apitegromab 32 (25%) vs placebo 7 (12%) experienced severity grade increase from baseline; considered possible downstream effect of increased muscle activity
Pneumonia (serious AE)	Adverse	Apitegromab 7 (5%) vs placebo 0
Discontinuation due to AEs	Adverse	None in any group
Deaths	Adverse	None

Based on: SAPPHIRE (2025)

Content summarized and formatted by NeuroTrials.ai.

SAPPHIRE

Objective

To assess the safety and efficacy of apitegromab, a selective myostatin inhibitor, as add-on to nusinersen or risdiplam in nonambulatory patients with type 2 or type 3 spinal muscular atrophy.

Study Summary

• Combined apitegromab (20 mg/kg + 10 mg/kg) improved HFMSE by +1.8 points vs placebo at 12 months (95% CI 0.30-3.32; p=0.019) in ages 2-12 years
• Apitegromab 20 mg/kg alone showed +1.4-point HFMSE difference vs placebo (p=0.11), not reaching significance individually
• Placebo group declined by -1.2 points (SE 0.66) while apitegromab group improved by +0.6 points (SE 0.48) from baseline
• Separation from placebo observed as early as 8 weeks
• Similar trend in ages 13-21 years (+1.8 points, 95% CI -1.06 to 4.57) and pooled population (+1.8 points, 95% CI 0.46-3.16)
• RULM and WHO milestones showed positive trends but did not reach significance
• AE rates similar between groups (91% apitegromab vs 87% placebo); no treatment-related serious AEs or deaths
• Moderate serum creatine kinase elevations observed (25% apitegromab vs 12% placebo)

Intervention

Apitegromab 20 mg/kg IV every 4 weeks for 12 months, added to background nusinersen or risdiplam vs Apitegromab 10 mg/kg IV every 4 weeks for 12 months, added to background nusinersen or risdiplam vs Placebo IV every 4 weeks for 12 months, with background nusinersen or risdiplam vs Apitegromab 20 mg/kg IV every 4 weeks for 12 months, added to background nusinersen or risdiplam vs Placebo IV every 4 weeks for 12 months, with background nusinersen or risdiplam

Inclusion Criteria

Age 2-21 years; genetically documented SMN-deficient nonambulatory SMA type 2 or 3; estimated life expectancy >2 years; HFMSE scores 10-45; on nusinersen ≥10 months or risdiplam ≥6 months at screening.

Study Design

Arms: Array

Outcome

Combined apitegromab significantly improved HFMSE vs placebo (+1.8 points; p=0.019) in ages 2-12; individual 20 mg/kg dose did not reach significance (p=0.11); well tolerated with favorable safety profile

Bottom Line

Major Points

First placebo-controlled phase 3 trial to show functional benefit of selective myostatin inhibition in any disease — a milestone after decades of failed myostatin-targeting approaches.
Combined apitegromab met the primary endpoint with HFMSE improvement of +1.8 points vs placebo (p=0.019) in ages 2-12, exceeding the 1.5-point clinically meaningful threshold for SMA type 2/3.
Placebo patients declined by -1.2 points over 12 months despite ongoing SMN-targeted therapy, confirming the unmet need for muscle-directed therapies that address accumulated atrophy.
The 20 mg/kg dose alone did not reach significance (p=0.11), but pharmacokinetic data showed both doses achieved target saturation with superimposable latent myostatin levels, suggesting pharmacological equivalence.
Efficacy was consistent across subgroups of age, SMN-targeted therapy type, age at therapy initiation, and region — supporting broad applicability across the SMA population.
Effect size appeared smaller in risdiplam-treated patients, partly attributed to higher proportion with two prior SMN-targeted therapies (54% of risdiplam patients vs 2% of nusinersen patients).
RULM and WHO motor milestones showed positive trends favoring apitegromab but did not reach significance, consistent with prior SMA trials where upper limb effects take longer to manifest.
Safety profile was favorable: no treatment-related serious AEs, no deaths, no discontinuations due to AEs, and no infusion/hypersensitivity reactions — consistent with the phase 2 TOPAZ trial.
98% of participants (185/188) enrolled in the long-term ONYX extension study, reflecting both high completion rates and patient/family engagement.
Apitegromab's selective targeting of myostatin precursors avoids off-target effects seen with prior anti-myostatin approaches (e.g., blocking growth differentiation factor 11), explaining its clean safety profile.

Study Design

Study Type: Phase 3, double-blind, randomized, placebo-controlled trial
Randomization: Yes
Blinding: Double-blind
Sample Size: 188
Follow-up: 52 weeks
Centers: 48
Countries: Belgium, France, Germany, Italy, Poland, Spain, Netherlands, UK, USA

Primary Outcome

Definition: Change from baseline in HFMSE at 12 months — combined apitegromab (20 + 10 mg/kg) vs placebo (ages 2-12) | Change from baseline in HFMSE at 12 months — apitegromab 20 mg/kg vs placebo (ages 2-12): LS mean difference +1.4 points (95% CI -0.34 to 3.13; p=0.11). Did not reach statistical significance.

Control	Intervention	HR/OR	P-value
	LS mean difference +1.8 points (95% CI 0.30-3.32; p=0.019). Apitegromab LS mean +0.6 vs placebo -1.2.	- (0.30-3.32)	p=0.019

SAPPHIRE

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Ask about SAPPHIRE