CLY-124 / Cellarity - LARVOL DELTA

TARGETING DCN1 OVERCOMES DELETERIOUS EFFECTS OF BROAD NEDDYLATION INHIBITION AND ENABLES FETAL HEMOGLOBIN INDUCTION IN SICKLE CELL DISEASE (EHA 2026) - "Pan-neddylation inhibition using MLN4924 or knockout of ubiquitin conjugating enzyme E2M (UBE2M) or Cullin 3 (CUL3) induced HbF accompanied with cytotoxicity...Summary/Conclusion In summary, we identified DCN1 as a novel target for the treatment of SCD, and discovered a first-in-class inhibitor, CLY-124, that induces HbF without cytotoxicity as monotherapy and shows synergy with hydroxyurea. At pharmacologically active doses in preclinical studies, CLY-124 exhibited a favorable safety profile with no observed toxicities or cytopenias. CLY-124 is being evaluated in a first-in-human study assessing safety, pharmacokinetics, and HbF induction in healthy volunteers and participants with SCD."

First-in-human • Gene Therapies • Genetic Disorders • Sickle Cell Disease • Targeted Protein Degradation • CD34 • UBE2M

Cly-124, a first-in-class DCN1 inhibitor partially suppresses CUL3 neddylation and induces fetal hemoglobin is a new potential treatment for sickle cell disease (ASH 2025) - "Despite demonstrated efficacy, access to this therapy remains limited due tomanufacturing complexity, toxicities of busulfan conditioning, and high cost, especially for individuals inlow and middle income countries...Pan-neddylation inhibitor MLN4924 or genetic knockout ofubiquitin conjugating enzyme E2 M (UBE2M) or Cullin 3 (CUL3) induced >25 % HbF (p<0.0001), but causederythroid toxicity and lineage skewing...CLY-124, is a first-in-class DCN1inhibitor with potent HbF induction as monotherapy and in synergy with hydroxyurea, through a non-cytotoxic and non-epigenetic mechanism. Pre-clinical toxicology studies of CLY-124 demonstrated a safeprofile with no hematological toxicity, major organ dysfunction, or laboratory abnormalities at clinically-relevant exposures. CLY-124 has begun dosing in a first-in-human study that will assess safety, PK, andHbF in healthy volunteers and participants with SCD."

Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • Targeted Protein Degradation • CD34 • HBG1 • UBE2M

CLY-124: A first-in-class, oral globin-switching therapy for sickle cell disease (Cellarity Press Release) - "Preclinical evaluation of CLY-124 demonstrated superiority to hydroxyurea in both fetal hemoglobin protein and globin gene ratios (HBG1/2 over total beta-like globin transcripts), approaching levels reported for recent gene therapy programs. Further, pre-clinical combination studies demonstrated robust synergistic effects when combining CLY-124 with hydroxyurea and with no dose-limiting toxicities."

Preclinical • Sickle Cell Disease