Optimizing elritercept benefit-risk profile by response-based adaptive dosing in patients with low-risk Myelodysplastic Syndromes (LR-MDS)

Abstract Background: Elritercept, an investigational, modified activin receptor type IIA/IgG1 fusion protein designed to selectively bind and block downstream signaling of select TGF-beta superfamliy ligands, including Activin A, Activin B, GDF8 and GDF11, is being investigated for treating anemia associated with LR-MDS. A comprehensive characterization of elritercept pharmacokinetics (PK), pharmacodynamics (PD) and exposure-response (E-R) relationships have been performed to inform optimal dosing strategies. Methods: A population PK (PPK) model was developed to characterize elritercept disposition. Sequential PD models described the time course of changes in hemoglobin (Hb) and platelet counts. Elritercept exposure-efficacy and -safety relationships were explored using logistic regression, especially on achieving transfusion independence for ≥8 weeks (TI ≥ 8w) within the first 24 weeks and incidence of grade 3+ treatment-emergent adverse events. Clinical trial simulations integrated these models with decision rules for individualized dose titration based on Hb count, platelet count, and efficacy/ safety response. The simulations included adaptive dosing strategies aimed at maximizing benefit-risk ratio. Results: The PPK analysis supports the weight-based dosing of elritercept. Age, sex, prior treatment, mild to moderate renal impairment and mild hepatic impairment had no clinically meaningful impact on elritercept PK. E-R analysis indicated higher elritercept exposure was associated with increased percentage of patients who achieved TI ≥ 8w. The integrated PK/PD framework accurately described the time-course of Hb and platelet responses, enabling predictions of treatment response variability in a virtual MDS population. Trial simulations demonstrated that an elritercept starting dose of 3.75 mg/kg Q4W with response-based up-titration to 5 mg/kg Q4W optimized the therapeutic window for elritercept across diverse patient-specific factors. Conclusions: The integrated analysis supports response-based adaptive dosing of elritercept in LR-MDS patients with a starting dose of 3.75 mg/kg Q4W.