Pharmacokinetics and pharmacodynamics of pozelimab alone or in combination with cemdisiran in non-human primates

• Published in: PloS one Vol. 17; no. 6; p. e0269749
• Main Authors: Devalaraja-Narashimha, Kishor, Huang, Cong, Cao, Marc, Chen, Ya Ping, Borodovsky, Anna, Olson, William C., Morton, Lori G., Retter, Marc W.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.06.2022; Public Library of Science (PLoS)
• Subjects: Animal protection; Animal welfare; Antibodies; Biological response modifiers; Biology and Life Sciences; Chemical properties; Chromatography; Classical pathway; Complement; Complement activation; Complement component C5; Complement system; Dosage; Dosage and administration; Drug interactions; Drug therapy; FDA approval; Health care; Hemoglobinuria, Paroxysmal; Laboratory animals; Mass spectrometry; Medicine and Health Sciences; Monoclonal antibodies; N-Acetylgalactosamine; Paroxysmal nocturnal hemoglobinuria; Pharmacodynamics; Pharmacokinetics; Pharmacology; Primates; Proteins; Rare diseases; RNA-mediated interference; Scientific imaging; Sheep; Testing; Veterinarians; United States
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0269749

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease caused by uncontrolled complement activation; effective and approved treatments include terminal complement inhibition. This study assessed whether combination cemdisiran (an investigational N-acetylgalactosamine-conjugated RNAi therapeutic that suppresses liver production of complement component C5) and pozelimab (an investigational fully human monoclonal antibody against C5) results in more effective and durable complement activity inhibition than the individual agents alone in non-human primates. Cynomolgus monkeys received a single subcutaneous injection of cemdisiran (5 or 25 mg/kg), pozelimab (5 or 10 mg/kg), or combination cemdisiran and pozelimab (5+5 mg/kg, 5+10 mg/kg, or 25+10 mg/kg, respectively). When given in combination, pozelimab was administered 2 weeks after cemdisiran dosing. Pharmacokinetics and ex vivo pharmacodynamic properties were assessed. The half-life of pozelimab alone was 12.9–13.3 days; this increased to 19.6–21.1 days for pozelimab administered in combination with cemdisiran. In ex vivo classical pathway hemolysis assays (CH 50 ), pozelimab + cemdisiran combinations achieved durable and more complete suppression of complement activity (8–13 weeks) vs monotherapy of either agent. Cemdisiran monotherapy demonstrated dose-dependent suppression of total C5 concentrations, with the higher dose (25 mg/kg) achieving >90% maximum suppression. Total C5 concentrations after administration of pozelimab + cemdisiran combinations were similar compared with administration of cemdisiran alone. The combination of pozelimab + cemdisiran mediates complement activity inhibition more efficiently than either pozelimab or cemdisiran administered alone. The pharmacokinetic/pharmacodynamic profile of combination pozelimab + cemdisiran in non-human primates appears suitable for further clinical investigation as a potential long-acting treatment for PNH and other complement-mediated diseases.