Add-on Factor D Inhibitor Improves Hemoglobin Levels in PNH with Hemolysis

Add-on therapy with danicopan, an investigational oral complement factor D inhibitor, alongside C5 inhibitor therapy led to significantly improved hemoglobin concentrations in patients with paroxysmal nocturnal hemoglobinuria (PNH) and clinically significant extravascular hemolysis, based on data from the phase III ALPHA trial, published in The Lancet Haematology.

Danicopan plus ravulizumab or eculizumab “significantly improved hemoglobin concentrations at week 12 with no new safety concerns, suggesting an improved benefit-risk profile in patients with PNH and clinically significant extravascular hemolysis,” wrote the study’s lead author, Jong Wook Lee, MD, PhD, from Seoul St. Mary’s Hospital at the Catholic University of Korea in South Korea.

By the data cutoff of June 28, 2022, ALPHA researchers had randomized 73 randomized patients with PNH on eculizumab or ravulizumab for at least six months to receive either danicopan (n=49) or placebo (n=24) for 12 weeks. Danicopan was initiated at a dose of 150 mg three times a day and escalated to 200 mg three times a day based on response.

In the interim analysis of the first 63 patients, the least squares mean change from baseline hemoglobin in the danicopan group was 2.94 g/dL (95% CI, 2.52-3.36) compared with 0.50 g/dL (95% CI, -0.13 to 1.12) in the placebo group, representing a least squares mean difference of 2.44 g/dL (95% CI, 1.69-3.20; P<.0001).

Among 49 patients in the danicopan group, grade III adverse events included increased alanine aminotransferase and neutropenia in two (4%) patients each, and leukopenia, cholecystitis, COVID-19, increased aspartate aminotransferase, and increased blood pressure in one (2%) patient each. Events in the placebo group included anemia, thrombocytopenia, and asthenia in one (2%) patient each out of 24.

Overall, Dr. Lee and colleagues concluded these primary findings showed add-on therapy with danicopan was effective at controlling symptoms of anemia in patients with PNH and clinically significant extravascular hemolysis on ravulizumab or eculizumab.

Reference

Lee JW, Griffin M, Kim JS, et al. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol. 2023;10(12):e955-e965. doi:10.1016/S2352-3026(23)00315-0