Ultomiris failed to show benefit in ALS in clinical trial, per full data
While approved for other rare diseases, therapy did not slow ALS
Treatment with Ultomiris (ravulizumab-cwvz) — a therapy approved for several rare diseases that works by blocking activation of part of the immune system called the complement cascade — failed to slow the progression of amyotrophic lateral sclerosis (ALS) in a Phase 3 clinical trial that had been launched in 2020, a new study shows.
The study, which details the findings from the full 50-week trial data, supports the decision, made in 2021, to terminate that trial early.
“This trial rapidly showed that terminal complement … inhibition with [Ultomiris] did not slow functional decline in participants with ALS,” the researchers wrote.
Alexion, the therapy’s developer, ultimately stopped the trial in October 2021 after a pre-specified interim analysis failed to demonstrate any signs of efficacy from Ultomiris.
Titled “Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial,” the study was published in JAMA Neurology. The work was funded by Alexion, a subsidiary of AstraZeneca.
CHAMPION-ALS study had enrolled 382 adults
The complement cascade is composed of a group of immune proteins that can become activated to destroy threats — but in some disorders, such activation can help to drive disease-causing inflammation.
Ultomiris, which works by blocking a complement protein called C5, is approved to treat several diseases that are driven by overactivation of the complement cascade, including myasthenia gravis and paroxysmal nocturnal hemoglobinuria, known as PNH.
Although the causes of ALS aren’t well understood, abnormal inflammation is thought to play a role, and some studies had suggested that complement activity may be increased in people with ALS.
Thus, Alexion sponsored a Phase 3 clinical trial called CHAMPION-ALS (NCT04248465) to test whether Ultomiris treatment might be beneficial in ALS. The trial enrolled 382 adults with ALS, whose symptoms had started up to three years prior, and who were randomly assigned to receive Ultomiris or a placebo.
After two loading doses given two weeks apart, patients received treatment every eight weeks for up to 50 weeks, or nearly one year. All participants could then enroll in an open-label extension part and receive Ultomiris for up to 106 weeks, or a little more than two years.
The study’s main goal was to test whether Ultomiris could slow disease progression, measured by scores on the ALS Functional Rating Scale-Revised (ALSFRS-R).
Initial preterm analysis had predicted failure of Ultomiris
In large studies like this, independent data monitoring committees will regularly conduct interim analyses testing for futility. Simply put, this involves looking at the available data to calculate whether there’s a reasonable likelihood the trial might have positive results.
In an interim analysis conducted after half of participants had completed their 26-week assessment, researchers found that the average ALSFRS-R score had worsened by 14.67 points for patients on Ultomiris — in fact showing slightly more worsening than the average of 13.33 points seen in the placebo group.
Statistical analyses suggested that the odds the trial would show slower progression with Ultomiris compared with the placebo was less than 0.1%, and the trial was ultimately terminated early.
There was a clear rationale for testing [Ultomiris] as a treatment for ALS based on preclinical and clinical evidence suggesting that C5 may be involved in disease progression. … However, the CHAMPION-ALS study was terminated when the week 26 interim analysis showed that the futility criterion had been met.
The investigators now shared full analyses of all available trial data.
These results continued to show no effect of Ultomiris compared with a placebo on ALSFRS-R scores. There also was no benefit on other endpoints, including a combined assessment of survival and disease progression, changes in lung function, time to needing ventilatory support, and all-cause mortality.
Measures of muscle strength and markers of nerve damage also failed to improve with Ultomiris treatment.
A total of 80% of patients experienced side effects related to the therapy, the most common of which were headaches, falls, and constipation. Safety data showed no unexpected findings related to Ultomiris compared with what’s been seen with the therapy in people with other diseases.
“There was a clear rationale for testing [Ultomiris] as a treatment for ALS based on preclinical and clinical evidence suggesting that C5 may be involved in disease progression,” the researchers wrote.
“However,” they noted, “the CHAMPION-ALS study was terminated when the week 26 interim analysis showed that the futility criterion had been met.”
The researchers pointed that pharmacological data from the trial showed Ultomiris was blocking C5 as designed.
“It is unclear why C5 inhibition did not result in clinical benefit in patients with ALS and whether this lack of benefit might extend to other complement components,” they wrote.
The team concluded that this trial “highlights the unmet need for highly effective treatments to slow functional decline and extend survival in patients with ALS.”