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.

BACKGROUND

Symptoms of anaemia due to clinically significant extravascular haemolysis can affect patients with paroxysmal nocturnal haemoglobinuria (PNH) treated with C5 inhibitors (ravulizumab or eculizumab). The aim of this study was to assess the efficacy and safety of danicopan (ALXN2040), an investigational, first-in-class, oral complement factor D inhibitor, as add-on therapy to ravulizumab or eculizumab in patients with PNH and clinically significant extravascular haemolysis.

METHODS

ALPHA is an ongoing, international, phase 3, randomised, double-blind, placebo-controlled trial evaluating danicopan as add-on therapy to ravulizumab or eculizumab. Eligible patients were adults (age ≥18 years) with PNH and clinically significant extravascular haemolysis (haemoglobin ≤9·5 g/dL; absolute reticulocyte count ≥120 × 10

FINDINGS

Individuals were randomly assigned between Dec 16, 2020, and Aug 29, 2022. At data cutoff (June 28, 2022), 73 individuals were randomly assigned, received treatment, and were analysed for safety (danicopan, n=49; placebo, n=24). The protocol-prespecified interim efficacy analysis set included the first 63 participants (danicopan, n=42; placebo, n=21). At week 12, danicopan plus ravulizumab or eculizumab increased haemoglobin versus placebo plus ravulizumab or eculizumab (least squares mean [LSM] change from baseline: danicopan, 2·94 g/dL [95% CI 2·52 to 3·36]; placebo, 0·50 g/dL [-0·13 to 1·12]; LSM difference, 2·44 g/dL [1·69 to 3·20]; p<0·0001). Grade 3 adverse events in the danicopan group were increased alanine aminotransferase (two [4%] of 49 patients), leukopenia (one [2%]), neutropenia (two [4%]), cholecystitis (one [2%]), COVID-19 (one [2%]), increased aspartate aminotransferase (one [2%]), and increased blood pressure (one [2%]), and in the placebo group were anaemia (one [4%] of 24 patients), thrombocytopenia (one [4%]), and asthenia (one [4%]). The serious adverse events reported in the danicopan group were cholecystitis (one [2%] patient) and COVID-19 (one [2%]) and in the placebo group were anaemia and abdominal pain, both in one (4%) patient. There were no serious adverse events related to study drug or deaths reported in the study.

INTERPRETATION

These primary efficacy and safety results show that danicopan as add-on treatment to ravulizumab or eculizumab significantly improved haemoglobin concentrations at week 12 with no new safety concerns, suggesting an improved benefit-risk profile in patients with PNH and clinically significant extravascular haemolysis.

FUNDING

Alexion, AstraZeneca Rare Disease.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests JWL has received honoraria from Alexion, AstraZeneca Rare Disease; and is a consultant to Alexion, AstraZeneca Rare Disease; AlloVir; Arrowhead; Kira; and Samsung. MG has received honoraria from Alexion, AstraZeneca Rare Disease and Sobi; has served as an advisory board member for Alexion, AstraZeneca Rare Disease; Amgen; Novartis; Biocryst; and Sobi; has served as a consultant for Biocryst and Regeneron Pharmaceuticals; and has received educational grant support from Apellis. JSK has received consulting fees from Alexion, AstraZeneca Rare Disease. CP has served as a consultant to Alexion, AstraZeneca Rare Disease; has served on board or advisory committees for Annexon Biosciences; Apellis; Alexion, AstraZeneca Rare Disease; Rigel; Sanofi; and Sobi; has served on a speakers bureau for Sobi; and has received research funding from Argenx; Alexion, AstraZeneca Rare Disease; Celgene; Oscotec; Rigel; Sanofi; and Incyte. JN has received grants from Alexion, AstraZeneca Rare Disease; is an advisory board member for Alexion, AstraZeneca Rare Disease; Chugai; and Roche; and has received honoraria from Alexion, AstraZeneca Rare Disease. CCI, DJ, PL, and GF are employees of Alexion, AstraZeneca Rare Disease. FSdF has received honoraria and research support (to Saint-Louis Hospital, Paris) from Alexion, AstraZeneca Rare Disease; Novartis; and Sobi. AR has received consulting fees and honoraria from Alexion, AstraZeneca Rare Disease; Roche; and Novartis; and research funding from Alexion, AstraZeneca Rare Disease and Roche. AGK has received honoraria from Alexion, AstraZeneca Rare Disease; Amgen; Celgene/BMS; Novartis; and Ra Pharma; is on the board of directors or is an advisory board member for Alexion, AstraZeneca Rare Disease; Amgen; Celgene/BMS; Novartis; Roche; and Ra Pharma; and has received consulting fees from Achillion; Agios Pharmaceuticals; Akari Therapeutics; Alexion, AstraZeneca Rare Disease; Biocryst; Celgene/BMS; Novo Nordisk; Janssen Pharmaceuticals; Roche; Samsung; and Novartis. LWLL declares no competing interests.