Population Pharmacokinetics/Pharmacodynamics and Clinical Pharmacology of Zaltenibart (OMS906) in Healthy Subjects and Patients with PNH

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.4081-4081
• Main Authors: Cummings, W. Jason, Li, Yi, Hayes, Siobhan, Mills, Richard, Farrell, Colm, Griffin, Morag, Whitaker, J. Steve, Pullman, William
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-206009

Background: Mannan-binding lectin-associated serine protease-3 (MASP-3), a key activator of the alternative pathway (AP) of complement, cleaves pro-complement factor D (proCFD) into mature factor D (mCFD) and drives the amplification loop that activates C3b-mediated opsonization and terminal pathway-mediated cell lysis. Inhibition of this rate-limiting step in the AP could provide clinically meaningful benefit for diseases driven by dysregulation of the complement system, such as PNH. Zaltenibart (OMS906), a highly selective humanized mAb that binds to and inhibits MASP-3, blocking downstream AP activity, is being investigated as a novel proximal inhibitor for PNH. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles and clinical efficacy of zaltenibart have been previously reported. Here we describe PK/PD and exposure-response (ER) relationships for zaltenibart on PD measures (free MASP-3 [fMASP-3], mCFD, and AP activity) and clinical efficacy parameters (lactate dehydrogenase [LDH], hemoglobin [Hb], and absolute reticulocyte count [ARC]) to inform the optimal dosing regimen. Methods: The clinical pharmacology and population PK/PD of zaltenibart were described using data from two sources: (1) PK data from Phase 1 trials in healthy subjects (HS) and (2) PK/PD and clinical data from studies in patients (pts) with PNH. Blood samples from HS exposed to zaltenibart were analyzed for fMASP-3 and AP activity in serum and zaltenibart and mCFD in plasma. The impact of zaltenibart on downstream AP activity was evaluated ex vivo using rabbit RBC lysis and AP Wieslab assays in serum samples from participating subjects. Sparse sampling PK and PD measures were collected from pts and a series of ER models assessed the relationship between zaltenibart exposure and (i) PD biomarkers (fMASP-3, mCFD, AP activity) and (ii) clinical efficacy (LDH, Hb, ARC). The impact of potential covariates (age, weight, gender, baseline LDH/Hb/mCFD/fMASP-3 and history of aplastic anemia [AA] or myelodysplastic syndrome [MDS]) was also explored. Results: Zaltenibart exposure increased proportionally over single doses in the range of 1-8mg/kg IV (both Cmax and AUC, slopes 1.07 and 1.10 resp.) with a T1/2 of over 400 hours. In HS and pts, PK correlated with PD markers in a dose-proportional manner for all key markers, including reductions in fMASP-3 and mCFD levels. The extent and duration of effect increased with dose, and consistent with the long PK half-life, PD effects were sustained