Pharmacokinetic/Pharmacodynamic Modeling to Support 70 mg Sefaxersen Dose Selection for Phase 3 (IMAgINATION) in IgAN

Background: Dysregulation of the complement alternative pathway (AP) contributes to IgA nephropathy (IgAN). Elevated Factor B (FB), a key AP protein, is linked to proteinuria and renal decline. Sefaxersen is a GalNAc-conjugated antisense oligonucleotide designed for targeted hepatic delivery to suppress FB. It is the first AP mRNA-targeting therapy in late-stage IgAN development. In Phase 2, sefaxersen was well tolerated and markedly reduced systemic FB and AH50 activity. This PK/PD analysis characterized FB and AH50 kinetics to guide Phase 3 dose selection for the IMAgINATION study (NCT05797610). Methods: Data were pooled from two Phase 1 studies (ISIS 696844-CS1/-CS2) in healthy volunteers (HV) and two Phase 2 studies in IgAN (CS4) and geographic atrophy (GA; CS5). Sefaxersen was administered subcutaneously at 10-40 mg in HV. In IgAN patients, 70 mg was administered on Days 1, 15, 29, then every 4 weeks; GA patients received 40, 70 or 100 mg on the same schedule. The pharmacokinetic (PK) and pharmacodynamic (PD) dataset included 53 HV (41 active, 12 placebo) and 53 patients (IgAN: 10 active; GA: 32 active, 11 placebo). Population PK and PK/PD models were developed to characterize sefaxersen exposure, FB and AH50 responses, and assess the influence of baseline covariates. Results: Sefaxersen PK was described by a two-compartment linear model, and an indirect-response PD model best characterized the FB and AH50 time courses. Visual predictive checks confirmed good performance across the PK and PD models. For 70 mg, simulations predicted median FB reductions of 71.8% at Week 13 and 73.5% at Week 105 (5th-95th percentiles: -89.6% to -36.5% and -91.6% to -37.4%), indicating near steady-state by Week 13. Compared with 40 mg, 70 mg led to more patients achieving >75% FB reduction, while 100 mg offered minimal added benefit, indicating a plateau at ≥70 mg. AH50 followed a similar pattern. Ethnic sensitivity analyses suggested low risk of PK/PD differences between Asian and non-Asian patients, supporting global applicability of the 70 mg dose. Conclusion: These results support the 70 mg regimen (Days 1, 15, and 29, then every 4 weeks) for Phase 3 IMAgINATION in IgAN. This study has been initiated with this regimen.