Ravulizumab Does Not Improve Functional Status, Survival in Patients with ALS

Ravulizumab does not slow functional decline in patients with amyotrophic lateral sclerosis (ALS) and shares a similar safety profile with placebo, according to study findings published in JAMA Neurology.

Researchers conducted the randomized, double-blind, placebo-controlled, parallel-group, phase 3 Changing Paradigms in Complement Inhibition-ALS (CHAMPION-ALS; ClinicalTrials.gov Identifier: NCT04248465) clinical trial to assess the safety and efficacy of ravulizumab in adults with ALS. Across 17 countries, 81 ALS specialist centers participated in the study.  

The researchers included patients who:

• Were aged 18 years or older;
• Weighed 40 kg or more;
• Fulfilled the El Escorial diagnostic criteria for ALS;
• Experienced first onset of muscle weakness within the past 36 months;
• Showed a slow vital capacity of 65% predicted or higher;
• Were not dependent on mechanical ventilation; and,
• Demonstrated a minimum Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score of -0.3 points per month.

 The researchers excluded patients with ALS who were taking sodium phenylbutyrate or taurursodiol or previously not vaccinated against Neisseria meningitidis.

In a 2:1 ratio, the researchers assigned patients to a treatment or placebo group. The patients received a weight-based loading dose of ravulizumab (2400 mg, 2700 mg, or 3000 mg) or placebo on day 1, followed by maintenance doses (3000 mg, 3300 mg, or 3600 mg) on day 15 and every following 8 weeks until week 42. Patients who entered the open-label extension period continued the same maintenance dose of ravulizumab for up to 106 weeks.

The primary endpoint was the patient’s change from baseline ALSFRS-R score at week 50 according to the Combined Assessment of Function and Survival (CAFS). The secondary endpoints included duration of patient survival without ventilation assistance.

Following exclusions, a total of 382 patients participated in the study, of whom 255 (mean age, 58.6; women, 36.9%; White, 79.2%) were in the ravulizumab group and 127 (mean age, 58.0; women, 45.7%; White, 81.1%) were in the placebo group.

According to the interim analysis, the mean baseline ALSFRS-R score changes at week 50 for the ravulizumab and placebo groups were -14.67 points (mean difference [SE], 0.89; 95% CI, -16.42 to -12.91) and -13.33 points (SE, 1.22; 95% CI, -15.72 to -10.93), respectively. Based on the least squared mean (LSM) of the difference between score changes for the 2 groups, the treatment effect was -1.34 points (SE, 1.46; 95% CI, -4.21 to 1.53).

The conditional power of the study was less than 0.1% and below the 10% futility threshold, which resulted in trial termination.

The primary analysis confirmed the insignificant interim analysis findings, as the LSM CAFS rank difference estimate showed a treatment effect of 5.5 points (SE, 10.8; 95% CI, -15.7 to 26.6; P =.61). The ALSFRS-R score changes from baseline at week 50 for the ravulizumab and placebo groups were -14.41 points and-13.21 points, respectively.

The researchers noted no significant differences in the adverse event profiles between patients in the ravulizumab and placebo groups. The most common treatment-emergent adverse events were headaches, falls, and constipation. Death related to ALS occurred in 5.5% of the ravulizumab group and 3.9% of the placebo group.

Study limitations include its restriction to patients with a minimal ALSFRS-R progression score of -0.3 per month, the lack of non-White patients, and it taking place during the COVID-19 pandemic.

“The outcomes of this randomized clinical trial indicate that unmet need remains regarding the treatment of people with ALS, as current disease management is mainly supportive and palliative,” the researchers wrote. “Highly effective, novel treatments are critically needed to slow functional decline and extend survival in patients with ALS.”

Disclosures: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.