Ravulizumab lacks treatment effect, highlights unmet need for highly effective treatment for ALS

Findings from the randomized clinical trial (RCT) of 382 adults with ALS showed that ravulizumab failed to slow functional decline and had a similar safety profile as the placebo. The researchers, therefore, emphasize the critical need for highly effective, novel treatments to extend survival and slow function decline in these patients.

Amyotrophic lateral sclerosis is a debilitating, rare, neurodegenerative disease with characteristics of extensive degeneration and death of lower and upper motor neurons, leading to progressive weakness and atrophy of skeletal muscle. Eventually, patients with ALS lose the ability to breathe, eat, speak, and move. Currently, sodium phenylbutyrate, taurursodiol (TURSO), edaravone, and riluzole are the only medications approved by the US FDA that slow ALS progression and there remains a need for more effective therapies.

Previous studies have shown that amplified neuronal C5a-C5a receptor signalling may be associated with disease progression of amyotrophic lateral sclerosis. Ravulizumab, a humanized monoclonal antibody, binds with high affinity to C5. Therefore, Angela Genge, McGill University, Montréal, Québec, Canada, and colleagues aimed to evaluate the efficacy and safety of the terminal complement C5 inhibitor ravulizumab in adults with ALS.

The researchers conducted the parallel-group, multinational, placebo-controlled, double-blind, randomized phase 3 clinical trial from 2020 to 2021 in 81 ALS speciality centres across 17 countries. An unmasked, preplanned nonbinding interim futility analysis was conducted when 33% of participants had completed week 26, wherein a conditional power below 10% would halt the trial.

Of the 478 individuals who were screened, 96 were excluded. Inclusion criteria were a weight of 40 kg or more, a minimal prestudy Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) progression score of –0.3 points per month, and fulfilment of the El Escorial diagnostic criteria.

Study treatment comprised of a placebo or a weight-based dose of IV ravulizumab every 8 weeks until week 42. Participants could continue standard-of-care treatment. A total of 382 participants were randomly assigned in the ratio 2:1 to receive ravulizumab (n = 255; mean age, 58.6 years; 63.1% male) or placebo (n = 127; mean age, 58.0 years; 54.3% male).

The study's primary endpoint was determined as the change from baseline in ALSFRS-R score at week 50 based on the Combined Assessment of Function and Survival (CAFS).

The researchers reported the following findings:

• The interim analysis showed that the observed mean change from baseline in ALSFRS-R at week 50 was −14.67 points for ravulizumab and −13.33 points for placebo, with no significant difference between the groups.
• Based on these data, the trial was terminated for futility.
• The primary analysis at week 50 showed no significant difference in CAFS between groups.
• Overall incidence rates for treatment-emergent adverse events were similar for ravulizumab (80.0% participants and placebo 85.0% participants).

"The outcomes of this RCT indicate that an unmet need remains regarding the treatment of patients with ALS, as current disease management is mainly supportive and palliative," the researchers wrote.

"There is a critical need for highly effective, novel treatments to slow functional decline and extend survival in patients with ALS," they concluded.

Reference:

Genge A, van den Berg LH, Frick G, et al. Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial. JAMA Neurol. Published online September 11, 2023. doi:10.1001/jamaneurol.2023.2851