Ravulizumab (Ultomiris) ATLAS Phase 3 — Complement Inhibition in ALS
Ravulizumab — marketed as Ultomiris by Alexion, an AstraZeneca company — is a long-acting complement C5 inhibitor already approved for several rare conditions including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Its Phase 3 trial in ALS (NCT04248465) tested the hypothesis that inhibiting complement-mediated neuroinflammation could slow motor neuron loss. The trial has completed enrollment and is no longer recruiting. Results have not been publicly announced as of April 2026. This page reviews the rationale, design, and what the outcome will mean for the neuroinflammation hypothesis in ALS.
Mechanism of action: the complement system in ALS
The complement system is a component of innate immunity that marks damaged, foreign, or abnormal cells for destruction by the immune system. In a healthy nervous system, complement activity helps clear cellular debris. In ALS, growing evidence suggests that complement activation is dysregulated — contributing to ongoing neuroinflammation and possibly accelerating motor neuron death beyond what the primary disease process alone would cause.
Complement C5 is a central node in the complement cascade. When C5 is cleaved, it generates C5a (a potent pro-inflammatory signaling molecule) and C5b (which initiates the membrane attack complex, capable of directly damaging cell membranes). Inhibiting C5 with ravulizumab blocks both downstream arms of complement-mediated injury: the inflammatory signaling through C5a and the direct cytotoxic activity through the membrane attack complex.
Ravulizumab is an updated version of eculizumab (Soliris), engineered for longer half-life to allow less frequent dosing — every 8 weeks rather than every 2 weeks. This pharmacokinetic improvement makes long-term administration more practical in chronic diseases like ALS.
What the trial involved
The Phase 3 trial (NCT04248465) was a double-blind, randomized, placebo-controlled study with an open-label extension evaluating the efficacy and safety of ravulizumab in adults with ALS. Enrollment criteria required: diagnosis of sporadic or familial ALS per El Escorial criteria (possible, laboratory-supported probable, probable, or definite); ALS disease onset within 36 months of enrollment; body weight at least 40 kg; and documented meningococcal vaccination — required because C5 inhibitors suppress immunity against encapsulated bacteria including Neisseria meningitidis, which can cause life-threatening meningococcal disease.
Ravulizumab was administered intravenously. Participants on stable riluzole therapy for at least 30 days before enrollment could continue riluzole alongside study drug.
The trial was listed as no longer recruiting as of the most recent status update. It has completed enrollment and is in follow-up or data analysis phase.
What the trial will tell us
Ravulizumab's ALS trial is one of the most rigorous tests of the neuroinflammation hypothesis in ALS. Unlike the MIROCALS trial — which tested indirect immune modulation through Treg expansion — ravulizumab directly blocks a specific, well-characterized inflammatory pathway with a drug that has proven efficacy in other complement-mediated diseases. If it shows efficacy in ALS, it would provide strong evidence that complement-mediated neuroinflammation is a meaningful contributor to ALS progression, not just a bystander finding.
If ravulizumab does not show efficacy in ALS, it would not necessarily disprove the neuroinflammation hypothesis — it would suggest that the C5 complement pathway specifically is not the dominant driver, and that other inflammatory mechanisms might be more productive targets. Either result advances the field's understanding.
PLS relevance
The ravulizumab trial enrolled ALS patients, not PLS patients. Complement activation has not been specifically studied as a pathogenic mechanism in PLS, though neuroinflammation in general is recognized as a component of PLS pathophysiology. If ravulizumab shows efficacy in ALS, the question of whether complement inhibition benefits upper motor neurons in PLS — the relevant cell type in PLS — would be a natural follow-on research question.
The meningococcal vaccination requirement reflects the known risk of complement inhibition for susceptibility to bacterial infections. This safety consideration would apply equally to any PLS application of ravulizumab.
Current status
As of April 2026, the trial has completed enrollment and is not recruiting. The clinical trial database listing is marked as not recruiting. No efficacy results have been publicly reported. The results, when announced, will be an important data point in the neuroinflammation space.
How this connects
Ravulizumab's complement approach is one of several neuroinflammation strategies being evaluated in ALS. For comparison, the MIROCALS trial tested immune modulation via Treg expansion with low-dose IL-2. Both trials target neuroinflammation but through different mechanisms. The broader context for immunotherapy in ALS and its relevance to PLS is covered in Drug Trial Research. For the foundational ALS therapy against which all trials are compared, see Riluzole Original Trials.
Citation
Alexion / AstraZeneca. A phase 3, double-blind, randomized, placebo-controlled, multicenter study with open-label extension evaluating the efficacy and safety of ravulizumab in adults with ALS. ClinicalTrials.gov NCT04248465. Enrollment completed; results pending.