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CHAMPION MG OLE

Long-term efficacy and safety of ravulizumab in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis: results from the phase 3 CHAMPION MG open-label extension

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Year of Publication: 2023

Authors: Meisel A, Annane D, Vu T, ..., and the CHAMPION MG Study Group

Journal: Journal of Neurology

Citation: J Neurol 2023;270:3862-3875

Link: https://doi.org/10.1007/s00415-023-11699-x

Clinical Question

Does ravulizumab provide sustained long-term efficacy and acceptable safety through 60 weeks in adults with anti-AChR antibody-positive generalized myasthenia gravis?

Bottom Line

Ravulizumab provides sustained clinical benefit through 60 weeks with maintained improvements in MG-ADL, QMG, quality of life, and fatigue scores. Patients switching from placebo achieve rapid and sustained improvement. Clinical deterioration rates are significantly reduced compared to placebo.

Major Points

  • Prespecified interim analysis of ongoing OLE (up to 4 years planned)
  • 161 patients entered OLE (78 ravulizumab-ravulizumab, 83 placebo-ravulizumab)
  • Improvements maintained through 60 weeks in continuous ravulizumab group
  • Rapid improvement (within 2 weeks) after switching from placebo to ravulizumab
  • MG-ADL responder rate (≥3-point improvement): 76.4% at week 60 vs 56.7% at week 26
  • QMG responder rate (≥5-point improvement): 49.0% at week 60 vs 30.0% at week 26
  • Clinical deterioration rate reduced 71% vs placebo (P=0.0011)
  • Several patients able to reduce or discontinue corticosteroids during OLE
  • No meningococcal infections reported
  • 4 deaths occurred (3 COVID-19, 1 cerebral hemorrhage), none treatment-related

Design

Study Type: Phase 3 open-label extension of randomized controlled trial

Randomization: 1

Blinding: OLE is open-label; Week 26 dosing designed to preserve blinding from RCP

Enrollment Period: March 2019 to November 2020 (RCP); OLE ongoing

Follow-up Duration: Up to 60 weeks (34 weeks in OLE) at interim analysis; up to 4 years planned

Centers: 85

Countries: United States, Japan, Germany, France, Italy, and 8 others

Sample Size: 161

Analysis: Mixed model for repeated measures (MMRM) adjusted for region, baseline score, and study visit; missing data assumed missing at random

Inclusion Criteria

  • Adults ≥18 years of age
  • Diagnosed with MG ≥6 months before screening
  • Anti-AChR antibody-positive
  • MGFA clinical classification II-IV
  • MG-ADL total score ≥6 at screening and randomization
  • Vaccinated against Neisseria meningitidis within 3 years
  • Completed 26-week RCP

Exclusion Criteria

  • Previous treatment with complement inhibitors (e.g., eculizumab)
  • IVIG or plasma exchange within 4 weeks before screening
  • Rituximab treatment within 6 months before screening
  • Thymectomy within 12 months before screening

Arms

FieldRavulizumab-RavulizumabControl
InterventionRavulizumab IV: loading dose 2400-3000 mg (weight-based) Day 1, maintenance 3000-3600 mg every 8 weeks starting Day 15; continued through OLEPlacebo during 26-week RCP, then switched to ravulizumab at Week 26 with loading dose 2400-3000 mg, followed by maintenance 3000-3600 mg every 8 weeks
DurationUp to 60 weeks at interim analysis26 weeks placebo + up to 34 weeks ravulizumab

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change from RCP baseline in MG-ADL total score at Week 60Primary−3.3 (95% CI −4.3, −2.2) from RCP baseline−4.0 (95% CI −4.8, −3.1) from RCP baseline<0.0001
MG-ADL change from OLE baseline to Week 60 (placebo-ravulizumab)SecondaryN/A−1.7 (95% CI −2.7, −0.8)0.0007
QMG change from RCP baseline to Week 60 (ravulizumab-ravulizumab)Secondary−3.8 (95% CI −5.1, −2.4)−4.1 (95% CI −5.4, −2.9)<0.0001
QMG change from OLE baseline to Week 60 (placebo-ravulizumab)SecondaryN/A−3.1 (95% CI −4.2, −1.9)<0.0001
MG-QOL15r change from RCP baseline to Week 60 (ravulizumab-ravulizumab)Secondary−5.4 (95% CI −7.3, −3.5)−5.0 (95% CI −6.9, −3.1)<0.0001
Neuro-QoL Fatigue change from RCP baseline to Week 60 (ravulizumab-ravulizumab)Secondary−14.0 (95% CI −18.6, −9.4)−10.2 (95% CI −15.1, −5.3)<0.0001
MG-ADL responder rate (≥3-point improvement) at Week 60Secondary43.1% (from OLE baseline)76.4% (from RCP baseline)
QMG responder rate (≥5-point improvement) at Week 60Secondary32.7% (from OLE baseline)49.0% (from RCP baseline)
Clinical deterioration event rate per 100 patient-yearsSecondary61.6 (during RCP on placebo)17.8 (on ravulizumab RCP+OLE)0.0011 (71% reduction vs placebo)
Any adverse eventAdverse86.5% (placebo RCP)88.8% (ravulizumab)
Serious adverse eventsAdverse15.7% (placebo RCP)24.3% (ravulizumab)
HeadacheAdverse25.8%16.6%
DiarrheaAdverse12.4%13.6%
NauseaAdverse10.1%9.5%
FatigueAdverse6.7%9.5%
Urinary tract infectionAdverse4.5%8.9%
DizzinessAdverse3.4%8.3%
COVID-19Adverse3.4%5.3%
DeathsAdverse04 (3 COVID-19, 1 cerebral hemorrhage)
Meningococcal infectionAdverse00

Subgroup Analysis

Response rates increased over time: MG-ADL responder rate 56.7% at week 26 vs 76.4% at week 60 in continuous ravulizumab group. Several patients reduced or discontinued corticosteroids during OLE. Placebo-ravulizumab group responder rates after 34 weeks similar to ravulizumab-ravulizumab group at 26 weeks.

Criticisms

  • Open-label extension design may contribute to overestimation of effect
  • Selection bias possible (161/162 RCP completers entered OLE)
  • High placebo response in RCP limits interpretation of switch group improvement
  • No established clinical indicators for complement inhibitor response in MG
  • Stringent responder criteria (≥3 MG-ADL, ≥5 QMG) exceed minimal clinically important difference
  • Interim analysis with limited follow-up (60 weeks of 4-year planned extension)
  • 4 deaths occurred, though assessed as unrelated to treatment
  • Unable to determine why some patients did not respond

Funding

Alexion, AstraZeneca Rare Disease

Based on: CHAMPION MG OLE (Journal of Neurology, 2023)

Authors: Meisel A, Annane D, Vu T, ..., and the CHAMPION MG Study Group

Citation: J Neurol 2023;270:3862-3875

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