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Ravulizumab (Ultomiris), a terminal complement C5 inhibitor, did not improve functional status and survival in patients with amyotrophic lateral sclerosis (ALS), the phase III showed.

No significant difference between ravulizumab and placebo emerged in Combined Assessment of Function and Survival (CAFS) scores at week 50 (mean difference of 5.5 points, 95% CI -15.7 to 26.6 points, P=0.61), reported James Berry, MD, MPH, of Massachusetts General Hospital in Boston, and co-authors.

The trial was terminated for futility, the researchers said in . Safety profiles of ravulizumab and placebo were similar.

Ravulizumab is designed to inhibit complement activation by binding to the C5 terminal protein. "There was a clear rationale for testing ravulizumab as a treatment for ALS based on preclinical and clinical evidence suggesting that C5 may be involved in disease progression," Berry and colleagues wrote.

Elevated plasma levels of active have been found in patients with ALS, they noted. Moreover, the expression of complement components, including C5, was dysregulated in regions surrounding motor neuron death in an .

In CHAMPION-ALS, pharmacodynamic data confirmed target engagement, the researchers observed, and it's unclear why inhibiting C5 didn't lead to clinical benefit in humans.

Ravulizumab has successfully inhibited C5 in trials of several complement-mediated diseases and recently received FDA approval to treat adults with generalized myasthenia gravis. It has two other approved indications: paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome unrelated to E. coli infection. The carries a warning for serious meningococcal infections.

CHAMPION-ALS randomized 382 people with ALS to receive ravulizumab (255 participants) or placebo (127 participants) from March 2020 to October 2021. Mean age in the ravulizumab group was 59, and 37% were women. Mean age in the placebo group was 58, and 46% were women.

Participants had a minimal pre-study ALS Functional Rating Scale-revised (ALSFRS-R) progression score of -0.3 points per month. ALSFRS-R scores range from 0 (no ability) to 48 (normal abilities).

All participants were vaccinated against Neisseria meningitidis within 3 years before the study or once treatment started. Participants could enter the trial while receiving ALS standard of care including riluzole (Rilutek) and edaravone (Radicava).

Participants received a loading dose of intravenous ravulizumab (2,400, 2,700, or 3,000 mg, based on body weight) or placebo at baseline, then maintenance doses of ravulizumab (3,000, 3,300, or 3,600 mg) or placebo on day 15 and every 8 weeks thereafter. Dose adjustments were made for participants whose weight dropped below 40 kg.

The primary outcome was the CAFS score, which was based on the change from baseline in ALSFRS-R total score on or before week 50 and time to death. A pre-planned interim futility analysis was conducted when 33% of participants had completed week 26; a conditional power of less than 10% would stop the study.

Mean change from baseline in ALSFRS-R at week 50 was -14.67 points for ravulizumab and -13.33 points for placebo (mean difference of -1.34 points, 95% CI -4.21 to 1.53 points). Secondary endpoints, including changes in serum neurofilament light concentrations, showed no differences between groups.

Incidence rates of treatment-emergent adverse events (TEAEs) were similar in the ravulizumab (80%) and placebo (85%) groups. Serious TEAEs occurred in 16.1% of the ravulizumab group and 18.9% of the placebo group. Headache, fall, and constipation were the most frequent TEAEs. Respiratory failure was the most frequent serious TEAE.

Patient advocacy groups improved the CHAMPION-ALS study design to allow participants to consider other treatment options quickly if the trial failed, Berry and colleagues pointed out.

This included the "decision to proceed directly to a properly powered phase III study with a robust interim futility analysis without first conducting a phase II study, participant selection criteria, and placebo group decline modeling," they wrote.

"The 50-week primary evaluation period ensured sufficient time to characterize effects on multiple functional and survival endpoints," they added. "This time frame allowed for a rigorous assessment of ALSFRS-R and supported survival analysis, which may take longer to demonstrate than the ALSFRS-R."

CHAMPION-ALS was conducted during the COVID-19 pandemic, which may have influenced the findings, the researchers said. The study was limited to people with a minimal pre-study ALSFRS-R progression score of -0.3 points per month; how patients with other rates of disease progression would have responded is unknown.

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