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CHAMPION MG

Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis

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Year of Publication: 2022

Authors: Vu T, Meisel A, Mantegazza R, ..., Howard JF Jr; CHAMPION MG Study Group

Journal: NEJM Evidence

Citation: NEJM Evidence 2022;1(5)

Link: https://doi.org/10.1056/EVIDoa2100066

PDF: https://evidence.nejm.org/doi/pdf/10.1056/EVIDoa2100066

Clinical Question

Does ravulizumab, a long-acting C5 inhibitor, improve MG-ADL and QMG scores in patients with AChR antibody-positive generalized myasthenia gravis?

Bottom Line

Intravenous ravulizumab dosed every 8 weeks significantly improved MG-ADL (-3.1 vs -1.4 with placebo; p<0.001) and QMG (-2.8 vs -0.8; p<0.001) scores at week 26 in AChR antibody-positive generalized myasthenia gravis, with benefit appearing within 1 week and sustained through 26 weeks. This established ravulizumab as an every-8-week alternative to eculizumab for complement-mediated MG.

        Major Points
        Phase 3, multinational, randomized, double-blind, placebo-controlled CHAMPION MG trial
175 adults with AChR-antibody positive generalized MG (MGFA class II-IV) on stable conventional therapy
Randomized 1:1 to intravenous ravulizumab (weight-based loading, day 1; maintenance day 15 and every 8 weeks) or placebo
26-week treatment period
Primary endpoint: change from baseline in MG-ADL at week 26
First secondary: change in QMG at week 26
Patients vaccinated against Neisseria meningitidis per protocol before dosing
MG-ADL change: -3.1 (ravulizumab) vs -1.4 (placebo); least-squares mean difference -1.6 (95% CI -2.6 to -0.7); p<0.001
QMG change: -2.8 vs -0.8; difference -2.0; p<0.001
QMG ≥5-point improvement: 30.0% (ravulizumab) vs 11.3% (placebo); p=0.005
MG-ADL ≥3-point improvement: Greater with ravulizumab
Onset of benefit within 1 week of loading dose, sustained through week 26
No meningococcal infections observed (all vaccinated)
Safety profile consistent with eculizumab class
Every-8-week maintenance dosing offers substantial convenience vs every-2-week eculizumab
Led to FDA approval of ravulizumab for generalized MG in 2022

      

Design

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

Randomization: 1

Blinding: Double-blind (participants, investigators, sponsor)

Follow-up Duration: 26 weeks (blinded treatment); open-label extension thereafter

Centers: Multinational, including US, Europe, Japan

Sample Size: 175

Analyzed: 175

Analysis: Intention-to-treat; mixed model repeated measures

Inclusion Criteria

Adults ≥18 years
AChR antibody-positive
Generalized MG, MGFA class II-IV
MG-ADL total score ≥6
Stable dose of standard MG therapies
Meningococcal vaccination per protocol

Exclusion Criteria

MuSK-antibody or seronegative MG
Purely ocular MG
Thymoma or thymectomy within last 12 months
Recent use of rituximab
History of meningococcal disease

Baseline Characteristics

Characteristic	Control	Active
N	89	86
MG-ADL baseline	Similar across arms	Similar
QMG baseline	Similar	Similar
MGFA class distribution	Balanced
AChR-Ab+ 100%		Required for eligibility

Arms

Field	Control	Ravulizumab
N	89	86
Intervention	Matching placebo IV with same schedule	IV ravulizumab (weight-based loading day 1, maintenance day 15, then every 8 weeks)
Duration	26 weeks	26 weeks

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Least-squares mean change from baseline in patient-reported MG-ADL score at week 26	Primary	-1.4 (placebo)	-3.1 (ravulizumab)		p<0.001
Change in QMG at week 26 (first secondary)	Secondary	-0.8	-2.8	Difference -2.0	p<0.001
≥5-point QMG improvement at week 26	Secondary	11.3% (10/89)	30.0% (26/86)		p=0.005
≥3-point MG-ADL improvement at week 26	Secondary	Lower proportion	Greater proportion		Favorable
Change in MG-QoL15 revised score	Secondary	Modest change	Improvement		Favorable
Change in MGC (Myasthenia Gravis Composite) score	Secondary	Modest change	Improvement		Favorable
Onset of benefit	Secondary	Gradual	Apparent within 1 week of loading dose		Fast-acting
Any adverse event	Adverse	Similar between arms	Similar between arms		No imbalance
Headache	Adverse	Common	Common		Similar
Upper respiratory tract infection	Adverse	Common	Common		Similar
Nasopharyngitis	Adverse	Common	Common		Similar
Meningococcal infection	Adverse	None	None (all vaccinated per protocol)		No cases — strict vaccination protocol
Infusion-related reactions	Adverse	Low	Low		Generally well-tolerated
Serious adverse events	Adverse	Low	Low		Similar rates
Discontinuation due to AEs	Adverse	Uncommon	Uncommon		Low rates

Subgroup Analysis

Treatment effect was consistent across prespecified subgroups by age, sex, baseline MG-ADL severity, MGFA class, disease duration, and concomitant immunosuppressive therapy. Ravulizumab's mechanism (terminal complement C5 inhibition) is specifically relevant to AChR-antibody-positive disease where complement-mediated destruction of the neuromuscular junction is central; these results do NOT extend to MuSK-antibody MG or seronegative MG.

Criticisms

26-week double-blind phase is relatively short for a chronic disease
Placebo response on patient-reported MG-ADL (-1.4) reduces absolute effect size
No head-to-head comparison with eculizumab — efficacy assumed equivalent based on mechanism
AChR-Ab+ restriction excludes MuSK-Ab+ and seronegative MG patients
Cost and meningococcal vaccination burden limit accessibility
Long-term safety (especially meningococcal infection) requires continued vigilance

Funding

Alexion, AstraZeneca Rare Disease (manufacturer of ravulizumab/Ultomiris)

Based on: CHAMPION MG (NEJM Evidence, 2022)

Authors: Vu T, Meisel A, Mantegazza R, ..., Howard JF Jr; CHAMPION MG Study Group

Citation: NEJM Evidence 2022;1(5)

Content summarized and formatted by NeuroTrials.ai.

CHAMPION MG

(2022)

Objective

Ravulizumab, a long-acting terminal complement (C5) inhibitor — to evaluate efficacy and safety in adults with AChR antibody-positive generalized myasthenia gravis.

Study Summary

• Ravulizumab significantly improved patient-reported MG-ADL by 1.7 points more than placebo at week 26 (-3.1 vs -1.4; p<0.001) and clinician-rated QMG by 2 points more (-2.8 vs -0.8; p<0.001) in AChR-antibody-positive generalized myasthenia gravis.
• Benefit was apparent within 1 week of the loading dose and sustained through 26 weeks, with 30% of ravulizumab patients achieving a ≥5-point QMG improvement vs 11.3% on placebo (p=0.005).
• Established every-8-week IV ravulizumab as a long-acting alternative to every-2-week eculizumab for complement-mediated MG — same mechanism, dramatically reduced infusion burden.

Intervention

Intravenous ravulizumab (weight-based loading dose on day 1, maintenance day 15, then every 8 weeks) vs matching placebo for 26 weeks.

Inclusion Criteria

Adults with AChR antibody-positive generalized myasthenia gravis (MGFA class II-IV), MG-ADL ≥6, on stable conventional MG therapy.

Study Design

Arms: Ravulizumab vs Placebo (1:1)

Patients per Arm: Ravulizumab 86; Placebo 89 (N=175)

Outcome

• Primary: Change in MG-ADL at week 26: -3.1 (ravulizumab) vs -1.4 (placebo); difference -1.6; p<0.001
• First secondary: Change in QMG at week 26: -2.8 vs -0.8; difference -2.0; p<0.001
• QMG ≥5-point improvement: 30.0% vs 11.3%; p=0.005
• Onset of benefit within 1 week of loading dose; sustained through week 26
• No notable safety signals; no meningococcal infections observed (all patients vaccinated per protocol)

Clinical Question

Does long-acting C5 inhibitor ravulizumab improve clinical MG-ADL and QMG outcomes in AChR antibody-positive generalized myasthenia gravis?

Bottom Line

Major Points

Phase 3, multinational, randomized, double-blind, placebo-controlled CHAMPION MG trial
175 adults with AChR-antibody positive generalized MG (MGFA class II-IV) on stable conventional therapy
Randomized 1:1 to intravenous ravulizumab (weight-based loading, day 1; maintenance day 15 and every 8 weeks) or placebo
26-week treatment period
Primary endpoint: change from baseline in MG-ADL at week 26
First secondary: change in QMG at week 26
Patients vaccinated against Neisseria meningitidis per protocol before dosing
MG-ADL change: -3.1 (ravulizumab) vs -1.4 (placebo); least-squares mean difference -1.6 (95% CI -2.6 to -0.7); p<0.001
QMG change: -2.8 vs -0.8; difference -2.0; p<0.001
QMG ≥5-point improvement: 30.0% (ravulizumab) vs 11.3% (placebo); p=0.005
MG-ADL ≥3-point improvement: Greater with ravulizumab
Onset of benefit within 1 week of loading dose, sustained through week 26
No meningococcal infections observed (all vaccinated)
Safety profile consistent with eculizumab class
Every-8-week maintenance dosing offers substantial convenience vs every-2-week eculizumab
Led to FDA approval of ravulizumab for generalized MG in 2022

Study Design

Study Type: Phase 3, multinational, randomized, double-blind, placebo-controlled, parallel-group trial
Randomization: Yes
Blinding: Double-blind (participants, investigators, sponsor)
Sample Size: 175
Follow-up: 26 weeks (blinded treatment); open-label extension thereafter
Centers: Multinational, including US, Europe, Japan

Primary Outcome

Definition: Least-squares mean change from baseline in patient-reported MG-ADL score at week 26

Control	Intervention	HR/OR	P-value
-1.4 (placebo)	-3.1 (ravulizumab)	- (-2.6 to -0.7)	p<0.001

Limitations & Criticisms

26-week double-blind phase is relatively short for a chronic disease
Placebo response on patient-reported MG-ADL (-1.4) reduces absolute effect size
No head-to-head comparison with eculizumab — efficacy assumed equivalent based on mechanism
AChR-Ab+ restriction excludes MuSK-Ab+ and seronegative MG patients
Cost and meningococcal vaccination burden limit accessibility
Long-term safety (especially meningococcal infection) requires continued vigilance

Citation

NEJM Evidence 2022;1(5)

View Original Publication →

CHAMPION MG

Terminal Complement Inhibitor Ravulizumab in Generalized Myasthenia Gravis

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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