Despite treatment with C5 inhibitors, a subset of patients with paroxysmal nocturnal haemoglobinuria (PNH) experience continued symptoms of anaemia due to significant extravascular haemolysis (EVH). In this study, the addition of danicopan to ravulizumab or eculizumab significantly improved haemoglobin concentrations at week 12 without introducing new safety concerns. These findings suggest an improved benefit-risk profile for PNH patients experiencing clinically significant EVH when danicopan is included as an add-on therapy.
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired, potentially life-threatening haematologic disorder characterised by chronic, intravascular haemolysis caused by uncontrolled activation of the terminal complement pathway. Despite treatment with C5 inhibitors, a small subset of PNH patients experience clinically significant extravascular haemolysis (EVH), which can result in continued symptoms of anaemia and require blood transfusions. This study aimed to assess the efficacy and safety of danicopan, an investigational, first-in-class, oral complement factor D inhibitor, as an add-on therapy to the C5 inhibitors ravulizumab or eculizumab in patients with PNH and clinically significant EVH.
The phase 3 ALPHA trial enrolled adult patients (age ≥18 years) with PNH and clinically significant extravascular haemolysis (haemoglobin ≤9.5 g/dL; absolute reticulocyte count ≥120 × 109/L) receiving ravulizumab or eculizumab for at least 6 months. In total, 73 patients were randomly assigned (2:1) to receive danicopan (n=42) or placebo (n=21) added to ravulizumab or eculizumab for 12 weeks. The initial oral danicopan dose was 150 mg three times a day, although escalation to 200 mg three times a day was permitted based on clinical response. The infusion dose level of eculizumab (every 2 weeks) ranged from 900 mg to 1,500 mg, and for ravulizumab (monthly or every 8 weeks) ranged from 3,000 mg to 3,600 mg. The primary endpoint was the change in haemoglobin concentration from baseline to week 12.
A protocol-prespecified interim analysis was planned after approximately 75% of participants completed or discontinued treatment at 12 weeks.
The protocol-prespecified interim efficacy analysis set included the first 63 participants, 42 receiving danicopan and 21 receiving placebo. After 12 weeks, the addition of danicopan to ravulizumab or eculizumab resulted in a significant increase in the haemoglobin levels compared to ravulizumab or eculizumab alone (change in haemoglobin concentration from baseline: 2.94 vs. 0.50 g/dL in the danicopan and placebo arms, respectively; difference: 2.44 g/dL; p<0.0001).
Grade 3 adverse events (AEs) in the danicopan group included increased alanine aminotransferase (4%), leukopenia (2%), neutropenia (4%), cholecystitis (2%), COVID-19 (2%), increased aspartate aminotransferase (2%), and increased blood pressure (2%.) Grade 3 AEs in the placebo group included anaemia (4%), thrombocytopenia (4%) and asthenia (4%). Serious AEs reported in the danicopan group were cholecystitis (2%) and COVID-19 (2%), while anaemia and abdominal pain (both 4%) were reported in the placebo group. There were no serious AEs related to the study drug or deaths reported in the study.
These primary efficacy and safety results show that danicopan, as add-on treatment to ravulizumab or eculizumab, significantly improved haemoglobin concentrations at week 12 without introducing new safety concerns. This suggests an improved benefit–risk profile for PNH patients with clinically significant EVH when danicopan is included as an add-on therapy to ravulizumab or eculizumab.
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