Zilucoplan May Not Be Effective for Immune-Mediated 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.

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.