TY - JOUR
T1 - Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA)
T2 - a double-blind, randomised, phase 3 trial
AU - ALXN2040-PNH-301 Investigators
AU - Lee, Jong Wook
AU - Griffin, Morag
AU - Kim, Jin Seok
AU - Lee Lee, Lily Wong
AU - Piatek, Caroline
AU - Nishimura, Jun ichi
AU - Carrillo Infante, Cynthia
AU - Jain, Deepak
AU - Liu, Peng
AU - Filippov, Gleb
AU - Sicre de Fontbrune, Flore
AU - Risitano, Antonio
AU - Risitano, Antonio
AU - Kulasekararaj, Austin G.
AU - Kulasekararaj, Austin G.
AU - Barcellini, Wilma
AU - Barraco, Fiorenza
AU - Beneitez Pastor, David
AU - Capra, Marcelo
AU - Chew, Lee Ping
AU - Chrysavgi, Lalayanni
AU - De Castro, Carlos
AU - de la Tour, Régis Peffault
AU - De Oliveira, Michel Michels
AU - Di Bona, Eros
AU - Forcade, Edouard
AU - Fu, Chieh Lin
AU - Furha, Cossor
AU - Gaya Valls, Anna
AU - Giannouli, Stavroula
AU - Gonzalez-Fernandez, Ataulfo
AU - Griffin, Morag
AU - Gural, Alexander
AU - Gutierrez, Emilio Ojeda
AU - Hernández-Rodríguez, Inés
AU - Ibrahim, Ibrahim
AU - Iori, Anna Paola
AU - Ishida, Tadao
AU - Jang, Jun Ho
AU - Kim, Jeong A.
AU - Kim, Jin Seok
AU - Kitano, Toshiyuki
AU - Kosugi, Hiroshi
AU - Kreiniz, Natalia
AU - Kulasekararaj, Austin
AU - Lee, Jong Wook
AU - Lee Lee, Lily Wong
AU - Mayer, Jiri
AU - Mitchell, Lindsay
AU - Mori, Yasuo
N1 - Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/12
Y1 - 2023/12
N2 - 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 × 109/L) on ravulizumab or eculizumab for at least 6 months. Patients were randomly assigned (2:1) to danicopan or placebo added to ravulizumab or eculizumab for 12 weeks using an interactive response technology system. Randomisation was stratified based on transfusion history, haemoglobin, and patients enrolled from Japan. The initial oral danicopan dose was 150 mg three times a day; 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 1500 mg, and for ravulizumab (monthly or every 8 weeks) ranged from 3000 mg to 3600 mg. The primary endpoint was change in haemoglobin concentration from baseline to week 12. Here we present the protocol-prespecified interim analysis, planned when approximately 75% of participants were randomly assigned to treatment and completed or discontinued at 12 weeks. This trial is registered with ClinicalTrials.gov (NCT04469465). 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.
AB - 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 × 109/L) on ravulizumab or eculizumab for at least 6 months. Patients were randomly assigned (2:1) to danicopan or placebo added to ravulizumab or eculizumab for 12 weeks using an interactive response technology system. Randomisation was stratified based on transfusion history, haemoglobin, and patients enrolled from Japan. The initial oral danicopan dose was 150 mg three times a day; 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 1500 mg, and for ravulizumab (monthly or every 8 weeks) ranged from 3000 mg to 3600 mg. The primary endpoint was change in haemoglobin concentration from baseline to week 12. Here we present the protocol-prespecified interim analysis, planned when approximately 75% of participants were randomly assigned to treatment and completed or discontinued at 12 weeks. This trial is registered with ClinicalTrials.gov (NCT04469465). 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.
UR - http://www.scopus.com/inward/record.url?scp=85178650591&partnerID=8YFLogxK
U2 - 10.1016/s2352-3026(23)00315-0
DO - 10.1016/s2352-3026(23)00315-0
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C2 - 38030318
AN - SCOPUS:85178650591
SN - 2352-3026
VL - 10
SP - e955-e965
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 12
ER -