Breakthrough Hemolysis Events in Patients with Paroxysmal Nocturnal Hemoglobinuria: Data from Danicopan and Pegcetacoplan Trials
Authors: Schrezenmeier Hubert , Mahdi Mohammed , Gasteyger Christoph , De Coster Cecile 
Published: December 2024

Background
In the management of paroxysmal nocturnal hemoglobinuria (PNH), breakthrough intravascular hemolysis is indicative of insufficient disease control and may lead to significant morbidity and mortality. The terminal complement component 5 (C5) inhibitor (C5i) ravulizumab is the standard of care treatment for patients with PNH, where available. Danicopan is a first-in-class oral factor D inhibitor that targets the alternate pathway of the complement system. In the phase 3 ALPHA trial (NCT04469465), add-on danicopan therapy to background ravulizumab or eculizumab in patients with PNH and clinically significant extravascular hemolysis (csEVH) demonstrated efficacy and safety vs placebo at week 12 (Lee et al. Lancet Haematol 2023) and up to 24 weeks of the open-label extension (Kulasekararaj et al. Blood 2023).
The efficacy and safety of pegcetacoplan, an approved proximal complement C3 inhibitor, has been evaluated in patients with PNH in the phase 3 PEGASUS trial (NCT03500549). However, severe hemolysis events have been reported in 24% of patients (Hillmen et al. N Engl J Med 2021; Kulasekararaj et al. N Engl J Med 2021), requiring further investigation.
Objective
To evaluate breakthrough hemolysis (BTH) events reported in the ALPHA and PEGASUS trials.
Methods
BTH data including pre- and post-event hemoglobin (Hb) and lactate dehydrogenase (LDH) levels, and actions taken were evaluated for up to 2.5 years for add-on danicopan and 3.0 years for pegcetacoplan. The most recent data cut for ALPHA (March 22, 2024) was used and data for PEGASUS were identified from the literature (Peffault de Latour et al. Lancet Haematol 2022; de Castro et al. Blood 2023; Peffault de Latour et al. Blood Adv 2024).
Both trial designs have previously been reported (Lee et al. Lancet Haematol 2023; Hillmen et al. N Engl J Med 2021). ALPHA recruited adult patients (aged ≥ 18 years) with PNH and csEVH (Hb ≤ 9.5 g/dL, absolute reticulocyte count ≥ 120 × 109/L) who received stable doses of ravulizumab or eculizumab for ≥ 6 months before enrollment. BTH was determined by the investigator (no per-protocol definition was applied). PEGASUS recruited adult patients with PNH and Hb &lt; 10.5 g/dL who received stable doses of eculizumab for ≥ 3 months before enrollment. BTH was defined as ≥ 1 new or worsening symptom or sign of intravascular hemolysis with LDH ≥ 2 × the upper limit of normal (ULN) after a reduction of &lt; 1.5 × ULN during treatment.
Results
For up to 2.5 years of add-on danicopan therapy, 5/84 patients (6.0%) experienced ≥ 1 BTH event (7 events in total), equating to an exposure-adjusted BTH rate of 6.0 per 100 patient-years (PY). Of these events, 6/7 (85.7%) were reported to be either mild (n = 3) or moderate (n = 3) and were associated with Hb levels of 7.4-9.2 g/dL; LDH level was ≤ 2.0 × ULN in 5 events and 2.2 × ULN in 1 event. One event was considered severe and was associated with Hb of 7.3 g/dL and LDH ≤ 2.0 × ULN. All BTH events reported during add-on danicopan therapy were resolved without transfusion, dose modification or treatment withdrawal.
During the first 48 weeks of pegcetacoplan treatment, 19/80 patients (23.8%) experienced ≥ 1 BTH event (26 events in total), equating to an exposure-adjusted BTH rate of 33.5 per 100 PY. Events were either moderate (n = 14) or severe (n = 12) and were associated with increased LDH levels of up to 18.3 × ULN. Hb levels were reduced, with 5 events reporting Hb &lt; 6.5 g/dL. Of the 19 patients who experienced BTH, 11 (57.8%) required transfusions, 4 (21.1%) required rescue treatment with eculizumab and 8 (42.1%) discontinued treatment. For up to 3.0 years, 4 additional patients experienced ≥ 1 BTH event (clinical data unavailable).
Conclusions
BTH events can increase the risk of severe, potentially life-threatening complications with PNH and therefore must be minimized when possible. Evidence suggests that proximal inhibitor monotherapies can be associated with severe BTH events (Notaro et al. N Engl J Med 2022). These events have been managed by higher than label pegcetacoplan dosing (including switching to intravenous administration), C5i rescue and/or transfusions (Griffin et al. Am J Hematol 2024). Add-on danicopan therapy to background ravulizumab or eculizumab in patients with PNH and csEVH resulted in a low rate of BTH events, which were mostly mild to moderate and managed without transfusions or dosing regimen changes. Dual inhibition of C5 and factor D is a viable treatment option for this at-risk population.