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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 through 70 days. Importantly, these changes in target modulation (fMASP-3 and mCFD) all correlated with inhibition of ex vivo AP activity measured in rabbit RBC lysis and Wieslab assays in samples from HS and pts. Clinically, zaltenibart improved hematological markers in pts with PNH, including LDH, ARC, and Hb, in a dose- and exposure-related manner, with greater magnitude and duration of effects seen at the highest dose (5mg/kg) administered Q8W to patients inadequately treated with ravulizumab. Notably, change in Hb following treatment with zaltenibart correlated with a reduction in fMASP-3 levels in pts with PNH. Using a variety of modelling techniques and modelling each study separately, zaltenibart ER was best described by indirect sigmoid Emax models, which reliably predict population and individual responses of mCFD, fMASP-3, and key clinical markers (LDH, Hb, ARC) in pts with PNH. To achieve optimal fit for treatment-naïve patients, covariates of significance included were: (i) gender on the Hill parameter and history of AA/MDS on EC50 for Hb (p<0.05), (ii) gender on baseline for LDH (p<0.01), and (iii) history of AA/MDS and baseline fMASP-3 on IC50 for fMASP-3 (p<0.01). Overall, predicted values for LDH, Hb, mCFD, and fMASP-3 correlated well with observed values in ex vivo assays and clinical trials, allowing these ER models to be used to determine effective/inhibitory drug concentrations. Conclusion: PK/PD and clinical data demonstrate that zaltenibart reduces the production of mCFD through inhibition of MASP-3, with concordant reduction in fMASP-3 levels and inhibition of AP activity. The latter is directly observed to protect against both intravascular and extravascular hemolysis in PNH pts. Taken together, these data sources will enable threshold concentrations to be identified and applied to dose/dose regimen simulations to identify the optimal dose providing durable control of hemolysis in pts with PNH.