Preclinical evaluation of a next-generation, subcutaneously administered, coagulation factor IX variant, dalcinonacog alfa

• Published in: PloS one 2020-10, Vol.15 (10), p.e0240896
• Main Authors: Nichols, Timothy C, Levy, Howard, Merricks, Elizabeth P, Raymer, Robin A, Lee, Martin L
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Antigens; Bioavailability; Biological Availability; Biology and Life Sciences; Blood coagulation; Care and treatment; Clotting; Coagulation; Coagulation factor IX; Coagulation factors; Committees; Disease Models, Animal; Dogs; Dosage; Drug Design; Drug dosages; Drug Evaluation, Preclinical; Evaluation; Factor IX; Factor IX - administration & dosage; Factor IX - chemistry; Factor IX - pharmacokinetics; Factor IX deficiency; Female; Health aspects; Hemophilia; Hemophilia B - blood; Hemophilia B - drug therapy; Injections, Subcutaneous; Intravenous administration; Laboratory animals; Laboratory tests; Male; Medicine; Medicine and health sciences; Models, Molecular; Observations; Partial Thromboplastin Time; Pathology; Pharmacodynamics; Pharmacokinetics; Pharmacological research; Pharmacology; Prevention; Prophylaxis; Safety; Thromboplastin; Time measurement; Whole Blood Coagulation Time
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0240896

The rapid clearance of factor IX necessitates frequent intravenous administrations to achieve effective prophylaxis for patients with hemophilia B. Subcutaneous administration has historically been limited by low bioavailability and potency. Dalcinonacog alfa was developed using a rational design approach to be a subcutaneously administered, next-generation coagulation prophylactic factor IX therapy. This study aimed to investigate the pharmacokinetic, pharmacodynamic, and safety profile of dalcinonacog alfa administered subcutaneously in hemophilia B dogs. Two hemophilia B dogs received single-dose daily subcutaneous dalcinonacog alfa injections for six days. Factor IX antigen and activity, whole blood clotting time, and activated partial thromboplastin time were measured at various time points. Additionally, safety assessments for clinical adverse events and evaluations of laboratory test results were conducted. There was an increase in plasma factor IX antigen with daily subcutaneous dalcinonacog alfa. Bioavailability of subcutaneous dalcinonacog alfa was 10.3% in hemophilia B dogs. Daily subcutaneous dosing of dalcinonacog alfa demonstrated the effects of bioavailability, time to maximal concentration, and half-life by reaching a steady-state activity sufficient to correct severe hemophilia to normal, after four days. The increased potency of dalcinonacog alfa facilitated the initiation and completion of the Phase 1/2 subcutaneous dosing study in individuals with hemophilia B.