Authors' Reply: Ravulizumab in IgA Nephropathy: A Promising Step Toward Disease Modification?

We thank Gao and Huang for their Letter to the Editor1 and the questions regarding our JASN article “Efficacy and Safety of Ravulizumab in IgA Nephropathy: A Phase 2 Randomized Double-Blind Placebo-Controlled Trial.”2 Terminal complement activation contributes to inflammation and kidney damage in IgA nephropathy.3 Ravulizumab, a complement C5 inhibitor, prevents formation of C5a and C5b-9, effectors of the complement terminal pathway. As noted, ravulizumab showed a statistically significant 30.1% relative treatment effect on proteinuria reduction versus placebo at 26 weeks in the phase 2 SANCTUARY trial in IgA nephropathy.2 We agree that meningococcal B vaccination is unfortunately not accessible in all countries. However, the meningococcal ACWY vaccine is widely available and was administered to all patients, and prophylactic antibiotics were administered if randomization occurred <2 weeks after initial vaccination. This risk mitigation strategy has been effective in multiple indications with eculizumab for approximately 20 years and with ravulizumab (>37,000 patient-years of experience). No cases of meningococcal infection have been reported in the study. Prophylactic antibiotics are not expected to influence the immune response to the vaccine or the treatment effect of ravulizumab, based on the mechanism of action. The authors suggest that a reduction in BP could have contributed to the observed proteinuria reduction. However, ravulizumab did not have an effect on BP compared with placebo during the trial.4 Patients with uncontrolled hypertension at the time of screening were not eligible and were excluded; Table 1 of our article presents the percentage with a history of hypertension.2 At baseline, mean (SD) BP (mm Hg) in the ravulizumab group was 124 (11)/77 (8), and in the placebo group, it was 127 (12)/77 (9).4 In this phase 2 trial, the mean (SD) baseline eGFR was 76 (30) and 70 (30) ml/min per 1.73 m2 in the ravulizumab and placebo groups, respectively,2 a difference that should not have a clinically meaningful impact on the treatment effect of ravulizumab, given that clearance is unaffected by kidney function. Although the overall mean eGFR was 74 ml/min per 1.73 m2, the median (Q1–Q3) was 65 (48–102) (Table 1).2 The phase 3 trial (NCT06291376) will have a larger population as well as a cohort with eGFR <30 ml/min per 1.73 m2. Sodium-glucose cotransporter 2 inhibitor use in the phase 2 trial was indeed limited and was reflective of real-world practice at the time; the phase 3 trial will also provide more insight on treatment effect in the setting of background sodium-glucose cotransporter 2 inhibitors, endothelin receptor antagonists, and mineralocorticoid receptor antagonists.