vevoctadekin (ST-067) / Simcha Therap - LARVOL DELTA

Preclinical Efficacy of Decoy-Resistant IL-18 in Hematological Malignancies (ASH 2024) - P1, P1/2 | "mDR18 also showed increased survival as a single agent that was enhanced in combination with Aza+Vento...Examining the role of mDR-18 in combination with Blinatumomab, a CD3-CD19 bi-specific T-Cell engager, demonstrated greater tumor growth inhibition and a more durable response than monotherapy with either agent. Conclusion : These studies extend the efficacy of DR-18 therapy in hematologic malignancies and demonstrate the potential benefit of combining DR-18 with additional agents beyond anti-PD-1, including chemotherapy and T cell engagers. These findings strengthen the rationale for expanding the use of the Phase I human DR-18 cytokine (ST-067, NCT04787042 & NCT06492707) in combination therapies for patients with hematological tumors."

Preclinical • Acute Myelogenous Leukemia • B Cell Lymphoma • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • ABCB1 • CD4 • CD8 • IL18

Trial in Progress: ST-067 (decoy-resistant IL-18) with Teclistamab in Multiple Myeloma (ASH 2024) - "Additionally, ST-067 may be able to promote stem-like memory precursor T-cells that are likely important to long-term responses. If shown to have a favorable safety and efficacy profile in this and future studies, ST-067 has the potential to become a routine addition to bsAb therapy in MM and other malignancies."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CD8 • IL18

Trials in Progress: Decoy-Resistant Interleukin-18 (DR-18) for Relapse or Pre-Emptive Treatment of Measurable Residual Disease after Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome (DR. DREAM), a Phase I Trial (ASH 2024) - P1 | "By targeting the post-HCT population we will evaluate whether DR-18 restores T cell function and reverses exhaustion. If safety is demonstrated herein, DR-18 may be further evaluated for its ability to (1) prevent post-transplant relapse among high-risk transplant patients, (2) supplant or potentiate the efficacy of donor lymphocyte infusion (DLI) and to (3) augment engineered adoptive T cell therapeutic strategies."

Clinical • P1 data • Residual disease • Acute Graft versus Host Disease • Acute Myelogenous Leukemia • Chronic Graft versus Host Disease • Graft versus Host Disease • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • CD8 • IFNG • IL18 • IL18BP

Decoy-resistant IL-18 combination with Bi-specific T cell engager enhances anti-tumor efficacy (ESMO 2025) - "The MC38 line expressing human Claudin 18.2 in hu_CD3e mice responded to Gresonitamab alone (LOW 54% 0.05mpk; HI 78% TGI 0.5mpk) and DR-18 (84% 0.32mpk) as a single agent...Increased efficacy of DR18 combined with BITEs was not limited to solid tumor models, and DR18 in combination with Blinatumomab showed increased tumor regression and increased efficacy in the A20 huCD19 model as well...These findings strengthen the rationale for clinical combination of ST-067 with Bi-specific T-cell Engager therapeutics in patients. Legal entity responsible for the study Simcha Therapeutics, LLC."

Clinical • Melanoma • Oncology • Solid Tumor • CD3E • CLDN18 • IL18

ST-067 in Combination With CD19-Directed CAR T-Cell Therapy (Liso-cel) in Relapsed/Refractory Large B-Cell Lymphoma (clinicaltrials.gov) - P1/2 | N=33 | Recruiting | Sponsor: Fred Hutchinson Cancer Center | Not yet recruiting ➔ Recruiting

Enrollment open • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Indolent Lymphoma • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Mediastinal Large B-Cell Lymphoma

Simcha Therapeutics Presents Preclinical Data Demonstrating Potential for Decoy-Resistant IL-18 to Enhance Efficacy of Bi-specific T-cell Engagers (GlobeNewswire) - "The presentation...was delivered at the European Society for Medical Oncology (ESMO) Congress. Data presented at the conference showed that adding ST-067 to treatment with BiTEs enhanced tumor growth inhibition without observed weight loss, compared to treatment with BiTEs alone. Positive results were observed across models of solid and hematologic malignancies, including melanoma and humanized models of colorectal cancer and B-cell acute lymphoblastic leukemia."

Preclinical • B Acute Lymphoblastic Leukemia • Colorectal Cancer • Melanoma

ST-067 and Teclistamab for the Treatment of Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=1 | Terminated | Sponsor: University of Washington | N=20 ➔ 1 | Trial completion date: Dec 2026 ➔ Feb 2025 | Recruiting ➔ Terminated | Trial primary completion date: Mar 2026 ➔ Feb 2025; Study terminated due to end of funding.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

ST-067 in Combination With CD19-Directed CAR T-Cell Therapy (Liso-cel) in Relapsed/Refractory Large B-Cell Lymphoma (clinicaltrials.gov) - P1/2 | N=33 | Not yet recruiting | Sponsor: Fred Hutchinson Cancer Center

New P1/2 trial • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Indolent Lymphoma • Large B Cell Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Primary Mediastinal Large B-Cell Lymphoma

DR-18 for the Treatment of Relapsed or Persistent Acute Myeloid Leukemia or Myelodysplastic Syndrome After Hematopoietic Cell Transplantation, the DR. DREAM Trial (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: Fred Hutchinson Cancer Center | Trial completion date: May 2027 ➔ Oct 2027 | Trial primary completion date: May 2025 ➔ Oct 2026

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Transplantation

Simcha Therapeutics Announces the Opening of Two Clinical Studies Exploring ST-067 in Hematological Indications (Businesswire) - "One study (ClinicalTrials.gov ID NCT06492707) will assess ST-067 in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), while the other study (ClinicalTrials.gov ID NCT06588660) will test ST-067 in combination with teclistamab (TECVAYLI) in patients with multiple myeloma...Data to be highlighted at ASH in a poster presentation demonstrate the therapeutic activity of decoy-resistant IL-18 in multiple mouse models of hematological tumors including B-cell lymphoma, acute myeloid leukemia and plasma cell myeloma....In addition, a trials in progress poster describing the AML/MDS study will be presented at ASH."

P1 data • Preclinical • Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Multiple Myeloma • Myelodysplastic Syndrome • Oncology

ST-067 and Teclistamab for the Treatment of Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: University of Washington | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Multiple Myeloma • Oncology

KEYNOTE-E64: Phase 1a and Phase 2 Study for Safety, Preliminary Efficacy, PK and PD of ST-067 (clinicaltrials.gov) - P1/2 | N=316 | Recruiting | Sponsor: Simcha IL-18, Inc. | Active, not recruiting ➔ Recruiting | Trial completion date: Jan 2025 ➔ Dec 2025 | Trial primary completion date: Sep 2024 ➔ Jun 2025

Combination therapy • Enrollment open • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Cervical Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • ALK • MSI • TMB

ST-067 and Teclistamab for the Treatment of Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: University of Washington

New P1 trial • Hematological Malignancies • Multiple Myeloma • Oncology

DR-18 for the Treatment of Relapsed or Persistent Acute Myeloid Leukemia or Myelodysplastic Syndrome After Hematopoietic Cell Transplantation, the DR. DREAM Trial (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: Fred Hutchinson Cancer Center | Not yet recruiting ➔ Recruiting

Enrollment open • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

KEYNOTE-E64: Phase 1a and Phase 2 Study for Safety, Preliminary Efficacy, PK and PD of ST-067 (clinicaltrials.gov) - P1/2 | N=316 | Active, not recruiting | Sponsor: Simcha IL-18, Inc. | Recruiting ➔ Active, not recruiting | Phase classification: P1a ➔ P1/2 | Trial primary completion date: Jun 2024 ➔ Sep 2024

Combination therapy • Enrollment closed • Metastases • Phase classification • Trial primary completion date • Breast Cancer • Cervical Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • ALK • MSI • TMB

DR-18 for the Treatment of Relapsed or Persistent Acute Myeloid Leukemia or Myelodysplastic Syndrome After Hematopoietic Cell Transplantation, the DR. DREAM Trial (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: University of Washington

New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation

Decoy-resistant IL-18 enhances checkpoint inhibitor combinations beyond anti-PD-1 in vitro and in vivo (AACR 2024) - "These studies expand the breadth of IL-18/checkpoint synergism beyond anti-PD-1 and confirm enhanced human immune response in vitro with the clinical candidate ST-067. Taken together, these findings strengthen the rationale for clinical combination of ST-067 with ICI agents in patients with solid tumors.1.Zhou T, Damsky W, Weizman OE, et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy."

Checkpoint inhibition • Preclinical • Oncology • Solid Tumor • ABCB1 • IL18

A phase 1/2 open-label, dose-escalation study of ST-067, a decoy-resistant IL-18 cytokine, given as a monotherapy and with pembrolizumab in advanced solid tumor malignancies (SITC 2023) - P1a | "1. Recruitment is ongoing in the US."

Clinical • IO biomarker • Metastases • Monotherapy • P1/2 data • Melanoma • Oncology • Solid Tumor • IL18

Simcha Therapeutics Announces First Patient Dosed in Phase 1/2 Study Evaluating ST-067 in Combination with KEYTRUDA (Pembrolizumab) in Patients with Various Solid Tumors (Businesswire) - "Simcha Therapeutics...today announced that the first patient has been dosed in a Phase 1/2 clinical trial of ST-067, Simcha’s decoy resistant IL-18 agent, in combination with Merck's anti-PD-1 therapy, KEYTRUDA® (pembrolizumab), in patients with advanced solid tumors. The Phase 1/2 open-label, dose-escalation study is evaluating ST-067 in combination with pembrolizumab in a variety of solid tumors....The objective of the study is to determine the maximum tolerated dose (MTD), the recommended Phase 2 dose (R2PD) and preliminary activity of ST-067 in combination with pembrolizumab. Secondary endpoints include assessment of safety, pharmacokinetics, pharmacodynamics and immunogenicity."

Trial status • Breast Cancer • Genito-urinary Cancer • Head and Neck Cancer • Kidney Cancer • Lung Cancer • Melanoma • Microsatellite Instability • Non Small Cell Lung Cancer • Oncology • Renal Cell Carcinoma • Skin Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Thoracic Cancer • Triple Negative Breast Cancer

Phase 1a and Phase 2 Study for PK, PD, Safety and Preliminary Efficacy of ST-067 (clinicaltrials.gov) - P1a | N=316 | Recruiting | Sponsor: Simcha IL-18, Inc. | N=198 ➔ 316

Enrollment change • Monotherapy • Breast Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • MSI • TMB

Simcha Therapeutics Announces Clinical Trial Collaboration with Merck to Evaluate ST-067 in Combination with KEYTRUDA (Pembrolizumab) in Patients with Various Solid Tumors (Businesswire) - "Simcha Therapeutics...announced a clinical trial collaboration with Merck (known as MSD outside the US and Canada) to evaluate clinical safety and benefits of ST-067, Simcha’s decoy resistant IL-18 agent, in combination with Merck's anti-PD-1 therapy, KEYTRUDA^® (pembrolizumab), in patients with solid tumors."

Licensing / partnership • Oncology • Solid Tumor

Phase 1a and Phase 2 Study for PK, PD, Safety and Preliminary Efficacy of ST-067 (clinicaltrials.gov) - P1a | N=198 | Recruiting | Sponsor: Simcha IL-18, Inc. | Trial completion date: Jul 2023 ➔ Jan 2025 | Trial primary completion date: May 2023 ➔ Jun 2024

Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • MSI • TMB

Phase 1a and Phase 2 Study for PK, PD, Safety and Preliminary Efficacy of ST-067 (clinicaltrials.gov) - P1a; N=198; Recruiting; Sponsor: Simcha IL-18, Inc.; Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • MRI • MSI • TMB

Simcha Therapeutics Raises $40 Million Series B Financing and Initiates Phase 1/2 Study to Evaluate Novel Interleukin-18 Variant in Cancer (GlobeNewswire) - "Simcha Therapeutics...announced the closing of a $40 million Series B financing....In addition, the Company has dosed the first patient in the Phase 1 portion of a first-in human multi-center Phase 1/2 clinical trial of its first drug candidate ST-067, a first-in-class 'decoy-resistant' Interleukin-18 variant. The study is designed to evaluate the safety and bioactivity of ST-067 in a broad set of solid tumor types."

Financing • Trial status • Oncology • Solid Tumor

Phase 1a and Phase 2 Study for PK, PD, Safety and Preliminary Efficacy of ST-067 (clinicaltrials.gov) - P1a; N=198; Not yet recruiting; Sponsor: Simcha IL-18, Inc.

Clinical • Monotherapy • New P1 trial • Breast Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Hepatocellular Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer