Trial in Progress: An Open-Label, Phase 2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of KP104 in Complement Inhibitor-Naïve Subjects with Paroxysmal Nocturnal Hemoglobinuria

Abstract

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening disease characterized by destruction of red blood cells by the complement system, leading to pathologies such as anemia and thrombosis. Currently approved complement inhibitors target C5 which addresses primarily intravascular hemolysis (IVH). However, many treated patients are still anemic and transfusion dependent since C5 inhibitors cannot treat extravascular hemolysis (EVH), which is driven by the alternative pathway (AP). C3 inhibitors need frequent administration, high dosage, and are associated with breakthrough hemolysis (BTH) (Hillmen, 2021; Rother, 2007; Stern, 2019; Rosario, 2022). Thus, the treatment of PNH still remains a challenge with significant unmet medical needs to develop more efficacious and convenient complement drugs. KP104 is a bi-functional complement inhibitor that can inhibit both C5 and C3 convertase activities and thereby achieve high potency in treating complement mediated pathologies. KP104 is an engineered anti-C5 immunoglobulin G4 monoclonal antibody (mAb) fused with the N-terminal 5 short consensus repeats of human factor H (a potent AP inhibitor) and engineered to extend serum half-life. KP104 was generally well tolerated and safe in the First-in-Human (FIH), healthy volunteer Phase 1 trial (n=66). PD data from this FIH study also support the dual mechanisms of KP104 inhibiting both AP and terminal pathway (TP). In addition, an extended half-life for KP104 has been observed in healthy volunteers, compared to other approved bispecific/fusion proteins on the market. Details of the FIH study will be published at another major conference (Wabinitz, 2022). KP104 is being developed for multiple diseases with complement cascade dysregulation, with PNH being the first indication to be investigated. Study Design and Methods: This is an open-label, 2-part, Phase 2 study to evaluate safety, tolerability, PK, PD, and efficacy of KP104 in complement inhibitor-naïve subjects with PNH (NCT05476887). Approximately 35 subjects with PNH are planned to be enrolled, including up to 18 in the dose-ranging Part 1, and up to 17 in the proof-of-concept (POC) Part 2. The primary objectives of Part 1 are to assess safety and tolerability and estimate optimal biologic dose (OBD) and regimen of KP104 in complement inhibitor-naïve subjects with PNH. Part 1 will include up to 3 cohorts of 3 to 6 subjects/cohort dosed for 12 weeks (Figure 1). When the third subject in the last cohort of Part 1 completes 4 weeks of treatment, a KP104 OBD will be estimated for evaluation in Part 2. Part 2 is to confirm POC by studying the KP104 OBD in 1 cohort of complement inhibitor-naïve subjects with PNH (Figure 1). The primary efficacy endpoint is the proportion of subjects with a ≥2 g/dL increase in hemoglobin from baseline to the end of the treatment period, with the absence of transfusion through the treatment period. The percent of subjects showing an increase from baseline in hemoglobin of ≥2 g/dL at the end of the treatment period will be compared to a 15% reference rate using an exact binomial one-sample test. The sample size was calculated to achieve approximately 90% power with 0.025 type 1 error rate (one-sided). In summary, KP104, through effective inhibition of both AP and TP complement pathways, may achieve high potency and address IVH, EVH, and BTH for treating subjects with PNH. Hillmen P, Szer J, et al. 2021. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 384:1028-1037. Rosario N, Lucio L. 2022. Breakthrough Hemolysis in PNH with Proximal or Terminal Complement Inhibition. N Engl J Med 387(2):160-166. Rother, R.P., et al. 2007. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol 25:1256-1264. Stern, R.M., and Connell, N.T. 2019. Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria. Ther Adv Hematol 10:2040620719874728. Wabinitz, P., et al. 2022. SYNERGY-1: A Phase 1, first-in-human, randomized, double-blind, placebo-controlled safety, tolerability, immunogenicity, PK and PD study of KP104 in escalating single and multiple doses. ASN abstract. Under review. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal