Phase 1 Healthy Volunteer Study of DISC-3405, a Recombinant Humanized Antibody Targeting TMPRSS6
Authors: Liu Guowen , Howell Haley , Rudin Dan , Arumugam Nanthini , Jadia Janel , Yang Hua , Savage Will 
Published: December 2024

Background: Hepcidin is a small peptide hormone secreted by hepatocytes and a key regulator of iron homeostasis. Dysregulated iron metabolism due to low hepcidin has been implicated in diseases associated with iron overload, such as beta-thalassemia, hereditary hemochromatosis, and polycythemia vera (PV). Transmembrane serine protease 6 (TMPRSS6, also referred to as matriptase-2) downregulates hepcidin expression. DISC-3405 is a novel humanized, monoclonal antibody that targets TMPRSS6 to stimulate endogenous production of hepcidin, representing a strategy for the treatment of these diseases. In preclinical studies, DISC-3405 significantly increased hepcidin production, suppressed iron levels, and demonstrated efficacy in disease models of PV and beta-thalassemia. DISC-3405 is being developed as a treatment for PV and other diseases where iron restriction may be therapeutic.

Methods: This was a Phase 1, randomized, double-blind, placebo-controlled singleascending dose (SAD) and multipleascending dose (MAD) study. Eligible participants included healthy females and males aged 18 to 65 years with no clinically significant medical history. Subjects were randomized in a 6:2 ratio per cohort (n=8) to receive DISC-3405 or placebo. In the SAD portion of the study, DISC3405 was administered intravenously (IV) at 75 mg or subcutaneously (SC) at 37.5, 75, 150, or 300 mg. In the MAD portion, DISC-3405 was administered SC at 75 and 150 mg every 4 weeks for a total of 2 doses. The primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetic (PK) and pharmacodynamic (PD) responses (ie, serum hepcidin-25 and iron).

Results: Dosing has been completed and data analysis is ongoing. The active treatment group median age was 42.5 years (range: 22-64), and 45% of participants were female. The pooled placebo group had a median age of 45 years (range: 39-62), and 29% of participants were female. Baseline serum iron, hepcidin, and hemoglobin were generally in the normal range for DISC-3405 and placebo groups in both SAD and MAD cohorts. There was no clinically significant abnormality. DISC-3405 was well tolerated, with no serious adverse events (AEs), Grade &gt;2 AEs, or AEs leading to study withdrawal. No individual or study stopping rules were met.

Preliminary analysis showed PK profiles with the anticipated patterns, ie, lower Cmax and longer Tmax in SC compared to those parameters in IV; some accumulation was observed following repeat dosing due to the long half-life. Marked drug exposure-related increases in hepcidin were observed. Meaningful and sustained serum iron reductions (&gt;50%) and expected hematological parameter modulations (eg, reticulocyte hemoglobin, hemoglobin, and hematocrit reductions) were observed following DISC-3405 treatment. Data analysis is ongoing, and the full PK/PD dataset from both SAD and MAD cohorts will be presented.

Conclusion: Preliminary findings of both SAD and MAD cohorts of DISC-3405 in healthy volunteers suggest an acceptable safety and tolerability profile, with consistent evidence of target engagement. The dosing phase of this study was completed, and detailed results across all cohorts will be presented.