Danicopan a Safe Option for Breakthrough Bleeds in PNH

Hubert Schrezenmeier, MD

Credit: Ulm University

Add-on danicopan therapy to eculizumab or ravulizumab reduced breakthrough hemolysis (BTH) events and reduced the need for potentially unsafe higher than label pegcetacoplan dosing in people with paroxysmal nocturnal hemoglobinuria (PNH).¹

These findings, from an analysis of the phase 3 ALPHA and PEGASUS trials evaluating danicopan and pegcetacoplan in people with PNH, respectively, were presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7-10, 2024, in San Diego, California, by Hubert Schrezenmeier, MD, professor, Institute of Transfusion Medicine, Ulm University, Germany.

“In the management of 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,” Schrezenmeier said during his presentation.¹

Danicopan is a first-in-class oral factor D inhibitor that was evaluated in the ALPHA trial in addition to ravulizumab or eculizumab in patients with PNH and clinically significant extravascular hemolysis. Pegcetacoplan is an approved complement component 3 inhibitor that was evaluated in the PEGASUS trial, during which severe hemolysis events were evaluated in 24% of patients.²

Schrezenmeier and colleagues found that during 2.5 years of add-on danicopan therapy 5 of 84 participants (6.0%) experienced at least 1 BTH event (n = 7) for an exposure-adjusted BTH rate of 6.0 per 100 patient-years (PY). Six of 7 evnets (85.7%) were either mild (n = 3) or moderate (n = 3) and associated with hemoglobin (Hb) levels between 7.4 and 9.2 g/dL. Lactate dehydrogenase (LDH) levels were at most 2.0 times the upper limit of normal (ULN) in 5 events and 2.2 times the ULN in 1 event. One event was considered severe and was associated with Hb of 7.3 g/dL and LDH of at most 2.0 times ULN. The BTH events reported without transfusion, dose modification or treatment withdrawal.¹

In contrast, during the first 48 weeks of pegcetacoplan treatment, 19 of 80 patients (23.8%) experienced at least 1 BTH event (n = 26), for an exposure-adjusted BTH rate of 33.5 per 100 PY. These events were moderate (n = 14) or severe (n = 12) and associated with increased LDH levels of up to 18.3 times ULN. Hb levels were reduced, with 5 events reporting Hb levels of less than 6.5 g/dL. Of the patients who experienced BTH, 11 (57.8%) required transfusions, 4 (21.1%) required rescue treatment with eculizumab and 8 (42.1%) discontinued treatment. With follow-up for up to 3.0 years, 4 additional patients experienced at least 1 BTH event, although clinical data were not available.¹

“Evidence suggests that proximal inhibitor monotherapies (such as pegcetacoplan) can be associated with severe BTH events. Add-on danicopan therapy to background ravulizumabor eculizumab resulted in a low rate of BTH events, which were mostly mild-to-moderate and managed without transfusions or dosing regimen changes,” Schrezenmeier said.¹ “Therefore, dual inhibition of C5 and factor D is an effective treatment option for this at-risk population.”

REFERENCES

1. Schrezenmeier H, Mahdi M, Gasteyger C, De Coster C. Breakthrough Hemolysis Events in Patients with Paroxysmal Nocturnal Hemoglobinuria: Data from Danicopan and Pegcetacoplan Trials. Presented at: ASH Annual meeting; December 7-10; San Diego, California. Abstract 2694.

2. Hillmen P, Szer J, Weitz I, et al. Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Eng J Med. 2021;384(11):1028-1037. doi: 10.1056/NEJMoa2029073