DISC-3405-102: A Phase 1b Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DISC-3405 in Participants with Sickle Cell Disease
Julie Kanter, Susanna Curtis, Amro Elshoury, Robert Ward Hagar, Abdullah Kutlar, Darla Liles, Enrico M Novelli, Charles T Quinn, Santosh L Saraf, John Strouse, Marcus Carden, Will Savage, Fuad El RassiAbstract
Background
Both intrinsic and extrinsic determinants of red blood cell (RBC) physiology, including HbF and HbS concentration, cellular hydration, whole blood viscosity, hematocrit, nitric oxide bioavailability, and cellular adhesion molecules, contribute to sickle cell disease (SCD), vaso-occlusive events (VOEs), and chronic hemolytic anemia that can drive progressive end-organ injury. There remains an unmet need for novel therapies to prevent pain and other morbidities in SCD. Emerging preclinical and clinical evidence shows that decreasing iron availability through iron restriction can reduce intracellular HbS concentration (ie, mean corpuscular hemoglobin concentration [MCHC]) and, thereby liimiting HbS polymerization and RBC sickling. Thus, iron restriction may be a safe and effective strategy to reduce hemolytic and vaso-occlusive complications and their downstream sequelae in people with SCD. DISC-3405 is an investigational, novel, humanized IgG1 monoclonal antibody (mAb) that targets transmembrane serine protease 6 (TMPRSS6, also known as matriptase 2) to stimulate endogenous production of hepcidin, a peptide hormone secreted by hepatocytes and the key regulator of iron homeostasis. In a mouse model of SCD, treatment with r4K12B (a mouse analog of DISC-3405) resulted in iron-restricted erythropoiesis and a significant decrease in hemolysis markers (Giannini, 2024). In a randomized, placebo-controlled Phase 1 study in healthy volunteers (DISC-3405-101), DISC-3405 administered subcutaneously at doses between 37.5 to 300 mg was well-tolerated, significantly increased hepcidin production with corresponding reductions in serum iron levels, and reduced MCHC (Liu, 2025; Liu, 2024). DISC-3405 is anticipated to increase hepcidin levels, restrict iron, reduce MCHC, and potentially lower intracellular HbS concentration, thereby reducing HbS polymerization and sickling and potentially leading to reduced clinical sequelae in SCD.
Methods
This is a Phase 1b, open-label, multicenter, within-participant dose-escalation study enrolling up to 24 patients with SCD in the US to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and therapeutic effect of DISC-3405 (Figure 1). After a screening period of 42 days, eligible participants will be treated and followed for 20 weeks and given up to 3 dose levels (75 mg, 150 mg, 300 mg) administered every 4 to 8 weeks. After 20 weeks, participants can continue in an optional 12-week maintenance period where additional safety and efficacy measurements will continue to be assessed. The primary endpoint of the study is to determine the safety and tolerability profile of DISC-3405. The secondary endpoints include changes in markers of hemolysis and PK. Exploratory endpoints include patient-reported outcome measures, changes and incidence of clinical measures of SCD (e.g., VOEs, transfusions, hospitalizations), changes in markers of iron homeostasis, and measures of RBC deformability and whole blood viscosity. A safety review committee will aid in the monitoring of emerging data during the study to ensure ongoing safety of study participants. Eligible participants include adults aged 18 years or older with HbSS or HbSC and normal alpha globin gene screen, hemoglobin levels ≥7 g/dL (the first 2 participants must have hemoglobin ≥9 g/dL), reticulocyte counts >1.5 x upper limit of normal, transferrin saturation 15% or higher, and ferritin between 50 to 1000 ng/mL. Participants should have evidence of SCD-related complications, including 1 to 10 vaso-occlusive pain episodes in the past 12 months or other end-organ damage. Participants taking hydroxyurea, L-glutamine, or crizanlizumab will be eligible provided they have been on a stable dose for at least 2 months prior to screening. Key exclusion criteria include the need for chronic transfusion therapy, hospitalization within 14 days of screening, hepatic dysfunction, and estimated glomerular filtration rate of < 60 mL/min/1.73 m2.
Results
This study is in progress. Enrollment has initiated. Eleven sites in the US are planned to open for enrollment.
Conclusions
DISC-3405 is an investigational, novel mAb that stimulates endogenous production of hepcidin and leads to iron restriction, which may benefit individuals living with SCD. Additional details regarding the DISC-3405-102 study can be found at https://clinicaltrials.gov/study/NCT07187973.