A Phase 1b, Double-Blind, Placebo-Controlled Study of DISC-0974, an Anti-Hemojuvelin Antibody, in Patients with Nondialysis-Dependent CKD and Anemia

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Background: Hepcidin is pathologically elevated in patients with NDD-CKD and anemia. DISC-0974, an investigational, monoclonal antibody directed against hemojuvelin, suppresses hepcidin. In healthy volunteers, treatment with DISC-0974 showed dose-dependent reductions in serum hepcidin, increases in serum iron, increasing trends in hemoglobin (Hgb), and a favorable safety profile. DISC-0974-103 is a Phase 1b, double-blind, placebo-controlled study (NCT05745883) to assess safety, PK, PD, and efficacy of single (dose-escalation) and multiple doses of DISC-0974 SC in participants with NDD-CKD and anemia. Methods: The single-ascending dose (SAD) portion consisted of 4 cohorts (n=8-12) randomized 3:1 to DISC-0974 (28, 40, 60, 90 mg) or placebo with evaluations through Day 57. The multiple-dose portion of the study includes 2 cohorts randomized 2:1 to DISC-0974 (60 or 90 mg) or placebo administered every 4 weeks for 3 doses. Participants are CKD Stages 2-5, Hgb <11 g/dL, serum ferritin ≥50 μg/L, and TSAT ≤35%. Exclusionary criteria: concomitant treatment with IV iron or ESAs. Results: At data cut, 21 participants had enrolled at 3 dose levels for the SAD portion: 28 mg (n=9), 40 mg (n=6), 60 mg (n=6). DISC-0974 led to sustained reductions in serum hepcidin, median reduction >75% from baseline at 60 mg, with sustained increase in TSAT vs placebo across dose levels. An early sustained increase in mean reticulocyte Hgb across all dose groups was noted through Day 22. Most AEs were not related to DISC-0974, and treatment-related AEs were Grade 1/2. DISC-0974 has acceptable safety and tolerability at the dose levels evaluated. Conclusion: DISC-0974 resulted in decreased hepcidin and increased serum TSAT, along with increased mean reticulocyte Hgb compared to placebo. These data provide initial proof that in CKD, hemojuvelin-targeting therapy with DISC-0974 can suppress hepcidin, mobilize iron into circulation, and improve hematologic parameters. Multiple-dose cohort enrollment is ongoing to evaluate optimal regimen for sustained Hgb increase. Complete SAD and available multiple-dose cohort data are forthcoming. Funding: Commercial Support - Disc Medicine

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