Pharmacokinetics of recombinant factor VIII in adults with severe hemophilia A: fixed-sequence single-dose study of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa.

Background: Efanesoctocog alfa is a new class of factor (F) VIII replacement therapy designed to provide high sustained factor levels for longer by overcoming the von Willebrand factor half-life ceiling. Objectives: To assess the pharmacokinetics and safety of standard half-life (octocog alfa) and extended half-life (rurioctocog alfa pegol) FVIIIs and efanesoctocog alfa. Methods: This phase 1 study (NCT05042440; EudraCT 2021-000228-37) enrolled previously treated adult men with severe hemophilia A. Patients received sequential single 50-IU/kg doses of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa after appropriate washout periods between each dose. Results: Thirteen participants were enrolled. Geometric mean elimination half-life of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa was 11.0, 15.4, and 43.3 hours, respectively, and area under the FVIII activity-time curve was 1670, 2820, and 10,100 IU × h/dL, respectively. Efanesoctocog alfa maintained mean FVIII activity levels of >40 IU/dL for up to 4 days and at ∼10 IU/dL on day 7. Corresponding times for >40 IU/dL and >10 IU/dL were <1 and <2 days, respectively, for octocog alfa and 1 day and <3 days, respectively, for rurioctocog alfa pegol. No serious treatment-emergent adverse events were reported for efanesoctocog alfa, and no inhibitor development to FVIII was detected. Conclusion: Efanesoctocog alfa had 3- to 4-fold longer elimination half-life and 3- to 6-fold greater exposure (area under the FVIII activity-time curve, 6.03 and 3.57 folds) than octocog alfa and rurioctocog alfa pegol. Efanesoctocog alfa provided high sustained FVIII activity in the normal-to-near-normal range (>40 IU/dL) for up to 4 days after the dose and at ∼10 IU/dL on day 7.

Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist.

Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism.