CLINICAL PHARMACOLOGY of OMS906, A POTENT INHIBITOR of MASP-3 and the ALTERNATIVE PATHWAY of COMPLEMENT ACTIVATION.
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All Authors
Li, Y.
Cummings, W.J.
Griffin, M.
Pullman, W.
LTHT Author
Griffin, Morag
LTHT Department
Oncology
Haematology
Haematology
Non Medic
Publication Date
2024
Item Type
Conference Abstract
Language
Subject
ADULT , HAEMATOLOGIC TESTS , COHORT STUDIES , CONTROLLED CLINICAL TRIALS AS TOPIC , DOUBLE-BLIND METHOD , ERYTHROCYTES , WOMEN , IN VITRO , MEN , HAEMOGLOBINURIA , PHARMACOLOGY , CLINICAL TRIALS AS TOPIC , PLACEBOS , ANTIBODIES, MONOCLONAL
Subject Headings
Abstract
Background: Mannan-binding lectin-associated serine protease-3 (MASP-3), an upstream activator of the alternative pathway (AP) of complement, cleaves pro-complement factor D (proCFD) to form mature CFD (mCFD), a rate-limiting enzyme in the AP. mCFD cleaves complement Factor B (CFB) to form AP C3 convertase, which drives the amplification loop of protease complexes that activates both C3b-mediated opsonization and the terminal pathway. OMS906 is a highly selective humanized mAb that binds to and inhibits MASP-3, blocking downstream AP activity. Increasing OMS906 exposure is predicted to decrease free MASP-3, mCFD, and AP activity while increasing proCFD levels. MASP-3 inhibition could provide therapeutic benefit in a variety of AP-mediated diseases, including paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare and life-threatening disorder of complement dysregulation, leading to intravascular hemolysis and thrombosis. Clinical efficacy of OMS906 in patients with PNH has been reported. Here we present findings from a study in healthy subjects and from an in vitro rabbit red blood cell (RBC) lysis assay that elucidate the effect of OMS906 on MASP-3 and downstream AP activity. Aim(s): To evaluate the effect of the pharmacokinetic (PK) profile of OMS906 on pharmacodynamic (PD) measures and the correlation between PD measures and AP activity. Method(s): In a randomized, double-blind, single-center, placebo-controlled Phase 1 study of OMS906, healthy subjects received intravenous (IV) 0.1-5 mg/kg or subcutaneous (SC) 3-8 mg/kg OMS906 or placebo in single ascending dose cohorts. Inclusion criteria included healthy males or females aged 18-64 years at screening with a BMI of 20-32 kg/m2 and weight of >=50 kg. Blood samples were collected following OMS906 administration and were analyzed for OMS906, free MASP-3, and AP activity in serum, and proCFD and mCFD in plasma. Outcomes of interest were establishment of relationships between OMS906 exposure and free MASP-3 and CFD status as determined by quantitation of mCFD and proCFD levels. The impact of OMS906 administration on downstream AP activity was assessed by measuring lysis of rabbit RBCs in diluted serum samples obtained from participating subjects. Result(s): A total of 72 healthy subjects were enrolled in the clinical study and included in this analysis. Across all doses, OMS906 administration was followed by rapid and sustained decline in mCFD levels; OMS906 concentration >5 mug/mL was associated with near-complete reduction in mCFD. In the 1-5 mg/kg IV cohorts, the decrease in free MASP-3 over time was concordant with mCFD levels, and duration of suppression increased with dose level. Decrease in mCFD was also accompanied by an increase in proCFD. Similarly, in the in vitro rabbit RBC lysis assay, samples from OMS906-administered subjects demonstrated inhibition of AP activity that correlated with decrease in mCFD (r2=0.78). In the dose groups >3 mg/kg IV, inhibition of RBC lysis was sustained with a long duration of >40 days. These effects were not observed when rabbit RBCs were exposed to serum from placebo-administered subjects. Summary/Conclusion: Reduction in free MASP-3 levels by OMS906, indicative of a selective and potent effect on the target, is concordant with MASP-3 inhibition as measured by the change in circulating CFD status with reduction in mCFD and a concomitant increase in proCFD levels and in inhibition of AP activity. OMS906 was safe and well tolerated, enabling further dose escalation with the potential for prolonging the dosing interval. Continued investigation in AP-mediated diseases is warranted.
Journal
HemaSphere