REGN7257 / Regeneron - LARVOL DELTA

First-in-human evaluation of IL2RG blockade in patients with severe aplastic anemia that is refractory to or relapsed on immunosuppressive therapy (ASH 2025) - "Given that lymphocyte development, proliferation, and activity aremediated in large part by gamma chain (gc) cytokines (IL2, IL4, IL7, IL9, IL15, IL21), which share a commonreceptor subunit (interleukin 2 receptor subunit gamma; IL2RG), IL2RG blockade may provide an novelmeans to suppress pathogenic T cell responses in T cell-mediated diseases, like AA. Data from this first-in-human evaluation of REGN7257 in patients with IST-refractory or IST-relapsed SAA show that IL2RG blockade was generally well-tolerated with observed AEs being generallyconsistent with the underlying disease. Reductions in lymphocytes and changes in serum cytokines andinflammatory/effector molecules were consistent with drug activity. One patient achieved a partialhematologic response that waned as drug cleared, but returned with retreatment."

Clinical • First-in-human • P1 data • Anemia • Aplastic Anemia • Febrile Neutropenia • Immunology • Infectious Disease • Neutropenia • Thrombocytopenia • CD8 • IL15 • IL2 • IL21 • IL2RG • IL4 • IL7 • IL9

Regeneron Highlights Progress at American Society of Hematology (ASH), with Updated Data in…Paroxysmal Nocturnal Hemoglobinuria Programs (GlobeNewswire) - "Additional presentations include updated results for the novel combination of cemdisiran with pozelimab (cemdi-poze) compared to ravulizumab in paroxysmal nocturnal hemoglobinuria as well as the first-in-human evaluation of REGN7257 in severe aplastic anemia."

Clinical data • First-in-human • Aplastic Anemia • Paroxysmal Nocturnal Hemoglobinuria

Blockade of Common Gamma Chain Cytokine Signaling with REGN7257, an Interleukin 2 Receptor Gamma (IL2RG) Monoclonal Antibody, in Combination with Costimulatory Blockers Delayed Skin Graft Rejection in Mice (ASH 2023) - "To understand the role of γc cytokines in driving transplant rejection, we generated REGN7257, a fully human IL2RG monoclonal antibody that inhibits γc cytokine-induced signaling, and we tested its ability to suppress allogeneic immune cell responses in a mouse model of skin graft rejection when delivered as a monotherapy and in combination with mycophenolate mofetil (MMF) or T cell costimulatory pathway blockers...Similarly, induction therapy consisting of γc cytokine signaling blockade followed by maintenance immunosuppression using the CTLA4-Ig fusion protein abatacept, significantly improved overall skin graft survival (MSTIL2RG+CTLA4=19.5 [****vs control]) compared to REGN7257 induction only (MSTIL2RG=11 [****vs control and combo]) or abatacept maintenance only (MSTCTLA4=10 [*vs control, ****vs combo])...Our data also highlighted the inherent complexity of effector mechanisms and pathways involved in allograft rejection and showed that prolonged allograft survival..."

Combination therapy • Preclinical • Immunology • Solid Organ Transplantation • Transplant Rejection • Transplantation • CD40LG • CD8 • IL15 • IL2 • IL21 • IL2RG • IL4 • IL7 • IL9

REGN7257 in Adult Patients With Severe Aplastic Anemia That Is Refractory to or Relapsed on Immunosuppressive Therapy (clinicaltrials.gov) - P1 | N=17 | Terminated | Sponsor: Regeneron Pharmaceuticals | Phase classification: P1/2 ➔ P1

Phase classification • Anemia • Aplastic Anemia • Hematological Disorders

REGN7257 in Adult Patients With Severe Aplastic Anemia That Is Refractory to or Relapsed on Immunosuppressive Therapy (clinicaltrials.gov) - P1/2 | N=17 | Terminated | Sponsor: Regeneron Pharmaceuticals | N=33 ➔ 17 | Trial completion date: Jul 2026 ➔ Oct 2024 | Suspended ➔ Terminated | Trial primary completion date: Jan 2026 ➔ Oct 2024; Sponsor Decision

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Anemia • Aplastic Anemia • Hematological Disorders

REGN7257 in Adult Patients With Severe Aplastic Anemia That Is Refractory to or Relapsed on Immunosuppressive Therapy (clinicaltrials.gov) - P1/2 | N=33 | Suspended | Sponsor: Regeneron Pharmaceuticals | Recruiting ➔ Suspended

Trial suspension • Anemia • Aplastic Anemia • Hematological Disorders

REGN7257 in Adult Patients With Severe Aplastic Anemia That Is Refractory to or Relapsed on Immunosuppressive Therapy (clinicaltrials.gov) - P1/2 | N=33 | Recruiting | Sponsor: Regeneron Pharmaceuticals | N=57 ➔ 33 | Trial completion date: Jan 2026 ➔ May 2026

Enrollment change • Trial completion date • Anemia • Aplastic Anemia • Hematological Disorders

REGN7257 in Adult Patients With Severe Aplastic Anemia That Is Refractory to or Relapsed on Immunosuppressive Therapy (clinicaltrials.gov) - P1/2 | N=57 | Recruiting | Sponsor: Regeneron Pharmaceuticals | Trial completion date: Aug 2024 ➔ Jan 2026 | Trial primary completion date: Aug 2024 ➔ Jan 2026

Trial completion date • Trial primary completion date • Anemia • Aplastic Anemia • Hematological Disorders

Blocking common γ chain cytokine signaling ameliorates T cell-mediated pathogenesis in disease models. (PubMed, Sci Transl Med) - "Our findings indicate that γc cytokines contribute to GVHD and aplastic anemia pathology by promoting these characteristic features. By demonstrating that broad inhibition of γc cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of γc cytokines as key drivers of pathogenic T cell responses, offering a potential strategy for the management of T cell-mediated diseases."

Journal • Acute Graft versus Host Disease • Aplastic Anemia • Chronic Graft versus Host Disease • CNS Disorders • Fibrosis • Graft versus Host Disease • Hematological Disorders • Hepatology • Immunology • Liver Cirrhosis • Multiple Sclerosis • IL15 • IL2 • IL21 • IL4 • IL7 • IL9

Evaluation of Common Gamma Chain Cytokine Signaling Blockade with REGN7257, an Interleukin 2 Receptor Gamma (IL2RG) Monoclonal Antibody, on Immune Cell Populations in Monkey and Human (ASH 2022) - "Taken together, these pharmacological observations highlight the major role for γc cytokine signaling in maintenance of lymphocyte populations (i.e. NK-cells and T-cells), but not other immune cell populations, such as granulocytes, platelets and red blood cells. Furthermore, our data highlight the importance of γc cytokines in driving functions of cynomolgus monkeys and human effector NK and T-cells, opening a potential new route for the management of immune-mediated diseases."

Clinical • Preclinical • Genetic Disorders • Immunology • Inflammation • Primary Immunodeficiency • CD4 • CD8 • IFNG • IL15 • IL2 • IL21 • IL4 • IL7 • IL9

Blockade of Common Gamma Chain Cytokine Signaling with REGN7257, an Interleukin 2 Receptor Gamma (IL2RG) Monoclonal Antibody, Protected Mice from Inflammatory and Autoimmune Diseases (ASH 2022) - "Blockade of γc cytokine signaling with REGN7257 protected mice against immune cell-mediated pathology in multiple disease models: an EAE model of MS, an allogeneic GVHD model, and a xenogeneic GVHD model that uniquely presents hallmarks of both acute and chronic GVHD as well as immune aplastic anemia. These data provide evidence of γc cytokines as key drivers of pathogenic immune cell responses, offering a potentially novel strategy for the management of inflammatory and autoimmune diseases, such as GVHD, immune aplastic anemia and MS."

Preclinical • Acute Graft versus Host Disease • Anemia • Aplastic Anemia • Chronic Graft versus Host Disease • CNS Disorders • Fibrosis • Graft versus Host Disease • Hematological Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Multiple Sclerosis • Solid Tumor • Thrombocytopenia • CD4 • CD8 • IL15 • IL2 • IL21 • IL4 • IL7 • IL9

EVALUATION OF COMMON GAMMA CHAIN CYTOKINE SIGNALING BLOCKADE WITH REGN7257, AN INTERLEUKIN 2 RECEPTOR GAMMA (IL2RG) MONOCLONAL ANTIBODY, ON IMMUNE CELL POPULATIONS ACROSS SPECIES (EHA 2022) - "Conclusion Taken together, these pharmacological observations highlight the major role for γc cytokine signaling in maintenance of lymphocyte populations (i.e. NK cells and T cells) in mouse and CM, but not other immune cell populations (i.e. granulocytes, platelets and red blood cells). Furthermore, our data highlight the importance of γc cytokines in driving functions of CM and human T cells, opening a potential new route for the management of T cell-mediated diseases."

Clinical • Genetic Disorders • Immunology • Inflammation • Primary Immunodeficiency • CD4 • CD8 • IL15 • IL2 • IL21 • IL4 • IL7 • IL9

BLOCKADE OF COMMON GAMMA CHAIN CYTOKINE SIGNALING WITH REGN7257, AN INTERLEUKIN 2 RECEPTOR GAMMA (IL2RG) MONOCLONAL ANTIBODY, PROTECTED MICE FROM GRAFT-VERSUS-HOST DISEASE AND IMMUNE APLASTIC ANEMIA (EHA 2022) - "Conclusion Blockade of γc cytokine signaling with REGN7257 protected against T cell-mediated pathology in a xenogeneic GVHD mouse model that uniquely presents hallmarks of both acute and chronic GVHD, with T-cell expansion/infiltration into tissues and liver fibrosis, as well as hallmarks of immune aplastic anemia, with bone marrow aplasia and peripheral cytopenia. These data provide evidence of γc cytokines as key drivers of T cell-mediated responses, offering a potentially novel strategy for the management of T cell-mediated diseases, such as GVHD and immune AA."

Preclinical • Acute Graft versus Host Disease • Anemia • Aplastic Anemia • Chronic Graft versus Host Disease • Fibrosis • Graft versus Host Disease • Hematological Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Thrombocytopenia • IL15 • IL2 • IL21 • IL4 • IL7 • IL9

REGN7257 in Adult Patients With Severe Aplastic Anemia That Is Refractory to or Relapsed on Immunosuppressive Therapy (clinicaltrials.gov) - P1/2; N=48; Recruiting; Sponsor: Regeneron Pharmaceuticals; Trial completion date: Aug 2023 ➔ Aug 2024; Trial primary completion date: Aug 2023 ➔ Aug 2024

Clinical • Trial completion date • Trial primary completion date • Anemia • Aplastic Anemia • Hematological Disorders

[VIRTUAL] Blockade of Common Gamma Chain Cytokines with REGN7257, an Interleukin 2 Receptor Gamma (IL2RG) Monoclonal Antibody, Protected Mice from Graft-Versus-Host Disease (TCT-ASTCT-CIBMTR 2021) - "IL2RG blockade with REGN7257 protected mice from human T cell-mediated disease by impacting multiple features of the pathogenic response, including T-cell expansion and infiltration into tissues as well as pro-inflammatory cytokine release, resulting in improved survival. These data provide evidence of γc cytokines as key drivers of T cell-mediated responses, offering a potentially novel strategy for the management of T cell-mediated diseases, such as GVHD and acquired aplastic anemia."

Aplastic Anemia • Graft versus Host Disease • Hematological Disorders • Immunology • CD8 • IL15 • IL2 • IL21 • IL4 • IL7 • IL9

[VIRTUAL] Blockade of Common Gamma Chain Cytokines with REGN7257, an Interleukin 2 Receptor Gamma (IL2RG) Monoclonal Antibody, Protected Mice from Graft-Versus-Host Disease (TCT-ASTCT-CIBMTR 2021) - "IL2RG blockade with REGN7257 protected mice from human T cell-mediated disease by impacting multiple features of the pathogenic response, including T-cell expansion and infiltration into tissues as well as pro-inflammatory cytokine release, resulting in improved survival. These data provide evidence of γc cytokines as key drivers of T cell-mediated responses, offering a potentially novel strategy for the management of T cell-mediated diseases, such as GVHD and acquired aplastic anemia."

Aplastic Anemia • Graft versus Host Disease • Hematological Disorders • Immunology • CD8 • IL15 • IL2 • IL21 • IL4 • IL7 • IL9

[VIRTUAL] Blockade of Common Gamma Chain Cytokines with REGN7257, an Interleukin 2 Receptor Gamma (IL2RG) Monoclonal Antibody, Protected Mice from Graft-Versus-Host Disease (TCT-ASTCT-CIBMTR 2021) - "IL2RG blockade with REGN7257 protected mice from human T cell-mediated disease by impacting multiple features of the pathogenic response, including T-cell expansion and infiltration into tissues as well as pro-inflammatory cytokine release, resulting in improved survival. These data provide evidence of γc cytokines as key drivers of T cell-mediated responses, offering a potentially novel strategy for the management of T cell-mediated diseases, such as GVHD and acquired aplastic anemia."

Aplastic Anemia • Graft versus Host Disease • Hematological Disorders • Immunology • CD8 • IL15 • IL2 • IL21 • IL4 • IL7 • IL9

[VIRTUAL] Blockade of Common Gamma Chain Cytokines with REGN7257, an Interleukin 2 Receptor Gamma (IL2RG) Monoclonal Antibody, Protected Mice from Graft-Versus-Host Disease (TCT-ASTCT-CIBMTR 2021) - "IL2RG blockade with REGN7257 protected mice from human T cell-mediated disease by impacting multiple features of the pathogenic response, including T-cell expansion and infiltration into tissues as well as pro-inflammatory cytokine release, resulting in improved survival. These data provide evidence of γc cytokines as key drivers of T cell-mediated responses, offering a potentially novel strategy for the management of T cell-mediated diseases, such as GVHD and acquired aplastic anemia."

Aplastic Anemia • Graft versus Host Disease • Hematological Disorders • Immunology • CD8 • IL15 • IL2 • IL21 • IL4 • IL7 • IL9

[VIRTUAL] Blockade of Common Gamma Chain Cytokines with REGN7257, an Interleukin 2 Receptor Gamma (IL2RG) Monoclonal Antibody, Protected Mice from Graft-Versus-Host Disease (TCT-ASTCT-CIBMTR 2021) - "IL2RG blockade with REGN7257 protected mice from human T cell-mediated disease by impacting multiple features of the pathogenic response, including T-cell expansion and infiltration into tissues as well as pro-inflammatory cytokine release, resulting in improved survival. These data provide evidence of γc cytokines as key drivers of T cell-mediated responses, offering a potentially novel strategy for the management of T cell-mediated diseases, such as GVHD and acquired aplastic anemia."

Aplastic Anemia • Graft versus Host Disease • Hematological Disorders • Immunology • CD8 • IL15 • IL2 • IL21 • IL4 • IL7 • IL9

REGN7257 in Adult Patients With Severe Aplastic Anemia That Is Refractory to or Relapsed on Immunosuppressive Therapy (clinicaltrials.gov) - P1/2; N=48; Recruiting; Sponsor: Regeneron Pharmaceuticals; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Anemia • Aplastic Anemia • Hematological Disorders

REGN7257 in Adult Patients With Severe Aplastic Anemia That Is Refractory to or Relapsed on Immunosuppressive Therapy (clinicaltrials.gov) - P1/2; N=48; Not yet recruiting; Sponsor: Regeneron Pharmaceuticals

Clinical • New P1/2 trial • Anemia • Aplastic Anemia • Hematological Disorders