Zilucoplan May Not Be Effective for Immune-Mediated Necrotizing Myopathy

Complement activation may be secondary to muscle injury as opposed to being a primary driver of disease activity in necrotizing myopathy.

Complement 5 (C5) inhibitors may not be an effective treatment for immune-mediated necrotizing myopathy, according to study results published in Lancet Rheumatology.

Previous studies have found that complement activation may be pathogenic in immune-mediated necrotizing myopathy, suggesting C5 blockade may have clinical utility in the disease.

The IMNM-01 study (ClinicalTrials.gov Identifier: NCT04025632) was a multicenter, randomized, double-blind, placebo-controlled, phase 2 trial conducted at 15 sites in the US, UK, Netherlands, and France between November 2019 and January 2021.

Adults with immune-mediated necrotizing myopathy positive for anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase or anti-signal recognition particle autoantibodies were randomly assigned 1:1 to receive 0.3 mg/kg subcutaneous zilucoplan or placebo daily for 8 weeks.

The primary efficacy endpoint was the change from baseline in creatine kinase concentration.

Although the results are disappointing from the clinical perspective, our study provides valuable insight into the pathophysiology of immune-mediated necrotizing myopathy…

The study participants (N=27) were aged a mean of 54.6 (SD, 11.8) years; 52% were men; 63% were White; and 93% received previous treatment for necrotizing myopathy. A total of 12 patients received zilucoplan and 15 received placebo.

Among study participants who received zilucoplan, complement activity decreased from 84.65% at baseline to 3.67% after 8 weeks of zilucoplan.

The median change from baseline in creatine kinase at week 8 was -15.1% for those who received zilucoplan compared with -16.3% for those who received placebo (odds ratio, 0.55; 95% CI, 0.2-1.6; P =.46).

The rate of any treatment-emergent adverse event was 75% among those who received zilucoplan and 87% among those who received placebo. No serious events occurred among patients who received zilucoplan. The most common zilucoplan-related adverse events included headache (17%) and nausea (17%).

Study limitations included the small sample size and short duration. Moreover, the findings of this study may be biased, as this was a heavily pretreated patient population and the participants may have had advanced disease that did not respond to C5 inhibition.

“Unexpectedly, terminal complement pathway inhibition did not show a significant effect on either creatine kinase concentrations or clinical symptoms in this study,” the study authors concluded. […] Although the results are disappointing from the clinical perspective, our study provides valuable insight into the pathophysiology of immune-mediated necrotizing myopathy, might support evidence-based treatment decisions in the future, and makes future clinical trials with an efficient study design possible in people with immune-mediated necrotizing myopathy.”

Disclosure: This research was supported by Ra Pharmaceuticals (now a part of UCB Pharma). Please see the original reference for a full list of authors’ disclosures.

This article originally appeared on Rheumatology Advisor


Mammen AL, Amato AA, Dimachkie MM, et al. Zilucoplan in immune-mediated necrotising myopathy: a phase 2, randomised, double-blind, placebo-controlled, multicentre trial. Lancet Rheumatol. 2023;5:e67-76. doi:10.1016/S2665-9913(23)00003-6