DANICOPAN AS ADD-ON THERAPY to RAVULIZUMAB or ECULIZUMAB in PATIENTS with PAROXYSMAL NOCTURNAL HEMOGLOBINURIA and CLINICALLY SIGNIFICANT EXTRAVASCULAR HEMOLYSIS: PHASE 3 LONG-TERM DATA.
No Thumbnail Available
All Authors
Kulasekararaj, A.
Griffin, M.
Piatek, C.
Shammo, J.
Nishimura, J.-I.
Patriquin, C.
Schrezenmeier, H.
Gaya, A.
Patel, Y.
Liu, P.
LTHT Author
Griffin, Morag
LTHT Department
Oncology
Haematology
Haematology
Non Medic
Publication Date
2024
Item Type
Conference Abstract
Language
Subject
ADULT , BILIRUBIN , TREATMENT OUTCOME , COVID-19 , DOUBLE-BLIND METHOD , DRUG THERAPY , SUBSTANCE WITHDRAWAL SYNDROME , WOMEN , HEADACHE , LIVER DISEASES , MEN , MEDICATION ADHERENCE , PANCREATITIS , HAEMOGLOBINURIA , CLINICAL TRIALS AS TOPIC , RANDOMISED CONTROLLED TRIAL , BLOOD CELL COUNT , THROMBOEMBOLISM , ANTIBODIES, MONOCLONAL , HAEMOGLOBINS , ENZYMES , PLACEBOS
Subject Headings
Abstract
Background: Complement component 5 inhibitors eculizumab (Ecu) and ravulizumab (Rav) have transformed the disease course of paroxysmal nocturnal hemoglobinuria (PNH) and led to improved clinical outcomes, effective control of intravascular hemolysis, reduced thrombosis and increased patient (pt) survival. Where available, Rav is the standard of care for pts with PNH. Of pts with PNH treated with Rav/Ecu, 10-20% experience clinically significant extravascular hemolysis (cs-EVH). Efficacy and safety of danicopan (Dan; ALXN2040), a first-in-class oral factor D inhibitor, was assessed as an add-on treatment to Rav/Ecu for pts with PNH and cs-EVH in a phase 3, randomized, double-blind, placebo (Pbo)-controlled clinical trial (ALPHA, NCT04469465). Superiority of Dan vs Pbo at 12 weeks (wks) has previously been shown. Aim(s): To report open-label 24-wk and ongoing long-term extension (LTE) data from the ALPHA study. Method(s): Adult pts (>=18 years) with PNH and cs-EVH (hemoglobin [Hb] <=9.5 g/dL; absolute reticulocyte count [ARC] >=120x109/L) on Rav/Ecu for >6 months were included. Pts were randomized 2:1 to Dan or Pbo add-on therapy for 12 wks (treatment period 1 [TP1]); at wk 12, Pbo pts switched to Dan (Pbo-Dan) and Dan pts continued Dan (Dan-Dan) for another 12 wks (TP2); all pts received Dan add-on therapy in a 1-2 year LTE. Dose escalation from 150 mg 3 times daily (TID) to 200 mg was permitted. Efficacy measures included change from baseline in Hb, ARC and lactate dehydrogenase (LDH) at wks 12, 24 and 48; proportion of pts with Hb increase >=2 g/dL in the absence of transfusion at wks 12 and 24; transfusion avoidance from wks 12-24. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory abnormalities. Result(s): As of March 31, 2023, 86 pts were randomized 2:1 Dan (n=57) to Pbo (n=29). Baseline characteristics were similar between arms. At wks 24 and 48, mean Hb levels and ARC were maintained in the Dan-Dan arm and improved from wk 12 in the Pbo-Dan arm (Table). The proportion of pts with increased Hb (>=2 g/dL) without transfusion was maintained in the Dan-Dan arm and improved in the Pbo-Dan arm from wk 12 to 24 (Dan-Dan, 54.4% to 41.8%; Pbo-Dan, 0% to 33.3%). Transfusion avoidance was maintained in the Dan-Dan arm and increased in Pbo-Dan arm from wk 12 to 24 (Dan-Dan, 78.9% to 80.0%; Pbo-Dan, 30.8% to 83.3%). Mean LDH levels were maintained from wk 12 to 48 and were near normal (<1.5xULN) in both arms (Table). Transfusions decreased in the Pbo-Dan arm from wk 12 (mean [SD] 1.4 [1.4]) to wk 24 (0.3 [1.2]). During the LTE, mean (SD) study drug adherence was 97.0% (11.12) in the Dan-Dan arm and 97.4% (5.44) in the Pbo-Dan arm. Escalation to 200 mg TID occurred in 59/84 (70.2%) pts. There were no discontinuations due to hemolysis, meningococcal infections or deaths. At data cut-off, 95.2% (80/84; 644 events) of pts had >=1 TEAE after exposure to Dan (3 serious AEs related to Dan: pancreatitis and increased blood bilirubin in one pt and headache in one pt). Six breakthrough hemolysis events were reported in 5 pts; LDH was <2xULN in all events except one which was related to a complement-amplifying condition (COVID-19, resolved). Seven events (pancreatitis, hepatobiliary disorders, increased liver enzymes) in 5 pts led to Dan withdrawal. Summary/Conclusion: Dan as add-on therapy to Rav/Ecu in PNH significantly improves Hb and ARC levels and reduces the need for transfusion. The treatment effect was maintained over 48 wks. Dan demonstrated a favorable benefit-risk profile with no thromboembolic events, discontinuations due to hemolysis, meningococcal infections or deaths. (Table present).
Journal
HemaSphere