Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria

• DOI: 10.1007/s00277-022-04903-x
• Publication Date: 2022-07-22T18:04:49Z
• Authors: Raymond S. M. Wong; Humphrey W. H. Pu...; Ismail Amine; Andrija Bogdanovic; Pascal Deschatelets; Cedric G. Francois; Kalina Ignatova; Surapol Issaragrisil; Pimjai Niparuck; Tontanai Numbenjapon; Eloy Roman; Jameela Sathar; Raymond Xu; Mohammed Al-Adhami; Lisa Tan; Eric Tse; Federico V. Grossi
• Keywords: Adult; 0301 basic medicine; Immunology; Hemoglobinuria, Paroxysmal; Complement; Hemoglobinuria; Discontinuation; Pathophysiology of Glomerular Diseases and Nephrotic Syndromes; Adverse effect; Peptides, Cyclic; Hemolysis; Hemoglobins; 03 medical and health sciences; Clinical Trials, Phase II as Topic; Role of Complement System in Immune Response; Health Sciences; Genetics; Humans; Paroxysmal nocturnal hemoglobinuria; Genetic and Clinical Aspects of Hemoglobin Disorders; Internal medicine; Immunology and Microbiology; Clinical Trials, Phase I as Topic; FOS: Clinical medicine; Gastroenterology; Cohort; Life Sciences; 3. Good health; Complement Inactivating Agents; Nephrology; FOS: Biological sciences; Medicine; Original Article; Biomarkers

AbstractParoxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270–360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90–18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200).