OBI-3424 / OBI Pharma, Ascentawits Pharma - LARVOL DELTA

OBI Pharma Announces Poster Presentations at the AACR 2025 Annual Meeting for OBI-992 and OBI-902 Antibody-Drug Conjugates (ADCs), GlycOBI and ThiOBI ADC enabling technologies, the OBI-3424 prodrug, and Globo H (GH) science (GlobeNewswire) - "OBI Pharma, Inc...today announced nonclinical data for OBI-902, a potential best-in-class anti-TROP2 ADC developed using the next generation proprietary GlycOBI technologies. OBI-902 demonstrated superior antitumor activity and favorable PK/PD properties compared to benchmark TROP2 ADCs across various animal models. OBI-992...demonstrated a differentiated resistance profile compared to benchmark ADCs. Additionally, characterization and non-clinical in vivo data will be presented for the glycan-specific GlycOBI and cysteine-based ThiOBI proprietary ADC platforms, highlighting enhanced antitumor activity and stability in animal model studies. ThiOBI is a new next-generation platform and adds to OBI’s armamentarium of ADC enabling technologies. Additionally, the non-clinical and antitumor activity of OBI-3424, a novel AKR1C3 targeted prodrug, will be presented."

Preclinical • Solid Tumor

Exploring site-specific activation of kinase inhibitors via AKR1C3-mediated prodrug strategy (AACR 2025) - "In this study, we designed prodrugs of the kinase inhibitor OTS964, a potent inhibitor of the pan-essential kinase CDK11, modeled after the AKR1C3-activated prodrug OBI3424. Subsequent in vitro assays demonstrated that these prodrugs retained comparable activity to the parent compound in cell viability, immunoblotting, and NanoBRET assays. This study introduces a promising strategy to enhance the therapeutic window of pan-essential kinase inhibitors by concentrating their effects in affected tissues while sparing normal cells."

Oncology • AKR1C3 • CDK1

Preclinical evaluation of the AKR1C3-activated alkylator OBI-3424 in hepatoblastoma: A report from the Pediatric Preclinical In Vivo Testing Consortium (PIVOT) (AACR 2025) - "OBI-3424 shows promising preclinical activity in hepatoblastoma PDX models inducing objective responses. The role of AKR1C3 expression as a response biomarker for hepatoblastoma requires further investigation. Results from this study along with encouraging interim Phase 2 clinical data for advanced HCC patients may provide rationale for future clinical development of OBI-3424 in hepatoblastoma."

Preclinical • Acute Lymphocytic Leukemia • Genito-urinary Cancer • Hematological Malignancies • Hepatoblastoma • Hepatocellular Cancer • Leukemia • Oncology • Prostate Cancer • Solid Tumor • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • AKR1C3

Potentiation of AKR1C3- and P53-dependent AST-3424 activity via PUMA-mediated degradation of Rad51 (AACR 2025) - "Co-treatment with AST-3424 and the P53 activator nutlin-3 significantly potentiated AST-3424's pharmacological activities, including in vitro cytotoxicity, reduced colony formation, apoptosis induction, DNA damage (γH2AX), and G2/M phase cell cycle arrest. We elucidate the mechanism of tumor-specific enhancement associated with P53-dependent RAD51 degradation, leading to decreased homology-directed DNA repair and synthetic lethality. These insights have significant implications for optimizing AST-3424's antitumor efficacy and potentially improving survival rates in patients with functional P53."

IO biomarker • Hematological Malignancies • Liver Cancer • Oncology • AKR1C3 • HRD • RAD51

AST-3424-001: A Phase I/II Study of AST-3424 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=51 | Active, not recruiting | Sponsor: Ascentawits Pharmaceuticals, Ltd | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor

S1905: Study to Test AKR1C3-Activated Prodrug OBI-3424 (OBI-3424) in Patients With Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia (T-ALL) (clinicaltrials.gov) - P2 | N=39 | Recruiting | Sponsor: SWOG Cancer Research Network | Trial completion date: Aug 2027 ➔ Aug 2032 | Trial primary completion date: Aug 2026 ➔ Aug 2028

Trial completion date • Trial primary completion date • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • AKR1C3

A Phase I/II Study of AKR1C3-Activated Prodrug OBI-3424 (OBI-3424) in Patients with Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia (TALL)/ T-Cell Lymphoblastic Lymphoma (T-LBL) (SWOG-Fall 2024) - "Prior nelarabine therapy is not required...Patients must not have had chemotherapy within 14 days prior to registration except for steroids, oral 6-mercaptopurine, oral methotrexate, vincristine, intrathecal chemotherapy, or hydroxyurea...The study is currently open to accrual at dose level 3. One more patient must be evaluated for DLTs at this dose level before the Phase 1 portion of the trial is complete."

Clinical • P1/2 data • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • Chronic Graft versus Host Disease • CNS Disorders • Graft versus Host Disease • Human Immunodeficiency Virus • Immunology • Infectious Disease • Lymphoma • Septic Shock • T Acute Lymphoblastic Leukemia • AKR1C3

A prospective, open-label, multicenter phase II clinical study on the efficacy and safety of AST-3424 monotherapy in the treatment of advanced hepatocellular carcinoma (CSCO 2024) - "Study group: [Organizing Committee]"

Clinical • Metastases • Monotherapy • P2 data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Enhanced pharmacological activities of AKR1C3-activated prodrug AST-3424 in cancer cells with defective DNA repair. (PubMed, Int J Cancer) - "The results showed that AST-3424 exhibited enhanced in vitro cytotoxicity and superior and durable in vivo anti-tumor effects in cells deficient of DNA repair protein BRCA2. In summary, we report here that when DNA repair capacity is reduced, the in vitro and in vivo activity of AST-3424 can be further enhanced, thus providing supporting evidence for the further evaluation of AST-3424 in the clinic."

Journal • Oncology • BRCA • BRCA2 • RAD51

Safety, tolerability, pharmacokinetics and clinical activity of AST-3424, an AKR1C3-activated bis-alkylating moiety prodrug, in subjects with advanced solid tumors in China: A phase I dose-escalation study. (ASCO 2024) - P1/2 | "AST-3424 showed a tolerable safety profile and preliminary anti-tumor activity in advanced solid tumors. The phase II dose expansion phase of AST-3424 monotherapy is ongoing in subjects diagnosed as advanced HCC and with high AKR1C3 expression."

Clinical • Metastases • P1 data • PK/PD data • Anemia • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hematological Disorders • Hepatocellular Cancer • Hepatology • Oncology • Pancreatic Cancer • Prostate Cancer • Salivary Gland Cancer • Solid Tumor • AKR1C3

A Phase I/II Study of OBI-3424 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=68 | Terminated | Sponsor: OBI Pharma, Inc | N=104 ➔ 68 | Trial completion date: Dec 2024 ➔ Mar 2024 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2024 ➔ Feb 2024; Little evidence of clinical activity in tumor types enrolled

Enrollment change • Metastases • Trial completion date • Trial primary completion date • Trial termination • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

A Phase I/II Study of AKR1C3-Activated Prodrug OBI-3424 (OBI-3424) in Patients with Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia (TALL)/ T-Cell Lymphoblastic Lymphoma (T-LBL) (SWOG-Spring 2024) - "Patients who receive nelarabine during initial induction or post remission treatment are eligible only if the physician does not feel they would benefit from other, multi agent chemotherapy. Patients must not have had chemotherapy within 14 days prior to registration except for steroids, oral 6-mercaptopurine, oral methotrexate, vincristine, intrathecal chemotherapy, or hydroxyurea...No other Grade 2 or higher treatment related non-hematologic events were reported. One patient had a DLT: Grade 4 platelet count decrease deemed probably related to OBI-3424 and resulting in permanent discontinuation of the study drug."

Clinical • P1/2 data • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • Chronic Graft versus Host Disease • CNS Disorders • Graft versus Host Disease • Human Immunodeficiency Virus • Immunology • Infectious Disease • Lymphoma • Septic Shock • T Acute Lymphoblastic Leukemia • Transplantation • AKR1C3

OBI ANNOUNCES THE TERMINATION OF OBI-3424 PHASE II TRIAL (OBI Pharma Press Release) - P2 | N=104 | NCT03592264 | Sponsor: OBI Pharma, Inc | "Following a strategic portfolio review, the Board of Directors of OBI Pharma, Inc...has decided to terminate the OBI-3424-001 trial today (March 11, 2024), while continuing the collaboration of OBI-3424 with partners, given that the OBI-3424 development is still ongoing...Dr. Heidi Wang...emphasized that this decision was made to allocate limited resources to other priority projects...OBI-3424 has not demonstrated therapeutic potentials in these cancer patients. After careful assessment, the Company decided to terminate OBI-3424-001 trial. An estimated NT$300 million (or US~$10 million) will be shifted to support other priority projects after OBI-3424-001 trial is terminated...The Company will continue to provide medical care to patients still on study in accordance with the clinical study protocol....The Company also continues the collaboration with Ascentawits Pharmaceuticals, Ltd., who owns the OBI-3424..."

Licensing / partnership • P2 data • Trial termination • Oncology • Solid Tumor

A Phase I/II Study of AST-3424 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=51 | Recruiting | Sponsor: Ascentawits Pharmaceuticals, Ltd

New P1/2 trial • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor

Study to Test AKR1C3-Activated Prodrug OBI-3424 (OBI-3424) in Patients With Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia (T-ALL) (clinicaltrials.gov) - P2 | N=39 | Recruiting | Sponsor: SWOG Cancer Research Network | Active, not recruiting ➔ Recruiting

Enrollment open • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • AKR1C3

A Phase I/II Study of AKR1C3-Activated Prodrug OBI-3424 (OBI3424) in Patients with Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia (T-ALL) / T-Cell Lymphoblastic Lymphoma (T-LBL). (SWOG-Fall 2023) - "Prior nelarabine therapy is not required, but patients who do not receive nelarabine during initial induction or post-remission treatment are eligible only if the physician does not feel they would benefit from other, multi-agent chemotherapy. Patients must not have had chemotherapy within 14 days prior to registration except for steroids, oral 6-mercaptopurine, oral methotrexate, vincristine, intrathecal chemotherapy, or hydroxyurea...This dose level temporarily closed on December 22, 2022, to fully assess the safety profile of the cohort. Three additional patients will be enrolled at dose level 3 after the study is reopened with a protocol amendment to relocate the MRD testing lab."

Clinical • P1/2 data • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • Chronic Graft versus Host Disease • CNS Disorders • Febrile Neutropenia • Graft versus Host Disease • Hematological Malignancies • Human Immunodeficiency Virus • Immunology • Infectious Disease • Lymphoma • Neutropenia • Septic Shock • T Acute Lymphoblastic Leukemia • Transplantation • AKR1C3

A Phase I/II Study of AKR1C3-Activated Prodrug OBI-3424 (OBI3424) in Patients with Re-lapsed/Refractory T-Cell Acute Lymphoblastic Leukemia (T-ALL)/T-Cell Lymphoblastic Lymphoma (T-LBL). (SWOG-Fall 2023) - "Prior nelarabine therapy is not required, but patients who do not receive nelarabine during initial induction or post-remission treatment are eligible only if the physician does not feel they would benefit from other, multi-agent chemotherapy. Patients must not have had chemotherapy within 14 days prior to registration except for steroids, oral 6-mercaptopurine, oral methotrexate, vincristine, intrathecal chemotherapy, or hydroxyurea...This dose level temporarily closed on December 22, 2022, to fully assess the safety profile of the cohort. Three additional patients will be enrolled at dose level 3 after the study is reopened with a protocol amendment to relocate the MRD testing lab."

Clinical • P1/2 data • Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • Chronic Graft versus Host Disease • CNS Disorders • Febrile Neutropenia • Graft versus Host Disease • Hematological Malignancies • Human Immunodeficiency Virus • Immunology • Infectious Disease • Lymphoma • Neutropenia • Septic Shock • T Acute Lymphoblastic Leukemia • Transplantation • AKR1C3

The essential role of DNA repair in the pharmacological activities of AST-3424 (ESMO 2023) - "However, enhancement of AST-3424 cytotoxicity by G2 arrest inhibitors, including adavosertib, AZD7762 and ceralasertib was only observed in HT29 but not in H460 cells. Conclusions DNA repair plays an essential role in AST-3424-mediated in vitro biological activities and in vivo anti-tumor activity. The preclinical data presented in this study support a new approach for cancer treatment."

Oncology • Pancreatic Cancer • AKR1C3 • BRCA • CDK1 • RAD51

A Phase I/II Study of AKR1C3-Activated Prodrug OBI-3424 (OBI3424) in Patients with Relapsed/Refractory T-Cell Acute LymphoblasticLeukemia (T-ALL) / T-Cell Lymphoblastic Lymphoma (T-LBL). (SWOG-Spring 2023) - No abstract available

Clinical • P1/2 data • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • AKR1C3

A novel AKR1C3 specific prodrug AST-3424 and its combination therapy in hepatocellular carcinoma. (PubMed, J Pharmacol Sci) - "AST-3424 had a promising effect against HCC in PDTX model and orthotopic model with good safety. It could promote the sensitivity of other drugs without increasing toxicity. Clinical trials are warranted to further certify its antitumor effect and safety."

Combination therapy • Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Transplantation • AKR1C3

Phase 1 dose-escalation study evaluating the safety, pharmacokinetics, and clinical activity of OBI-3424 in patients with advanced or metastatic solid tumors. (PubMed, Br J Cancer) - P1/2 | "The RP2D is 12 mg/m once every 3 weeks. OBI-3424 was well tolerated; dose-dependent, noncumulative thrombocytopenia and anemia were dose-limiting."

Journal • Metastases • P1 data • PK/PD data • Hematological Disorders • Oncology • Solid Tumor • Thrombocytopenia

A Phase I/II Study of OBI-3424 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=104 | Recruiting | Sponsor: OBI Pharma, Inc | Trial completion date: Apr 2024 ➔ Dec 2024 | Trial primary completion date: Feb 2024 ➔ Dec 2024

Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • AKR1C3

A Phase I/II Study of AKR1C3-Activated Prodrug OBI-3424 (OBI3424) in Patients with Re-lapsed/Refractory T-Cell Acute Lymphoblastic Leukemia (T-ALL)/T-Cell Lymphoblastic Lymphoma (T-LBL) (SWOG-Fall 2022) - No abstract available

Clinical • P1/2 data • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • AKR1C3

OBI-3424, an AKR1C3-activated prodrug, exhibits in vivo synergistic anti-tumor effect in combination with pembrolizumab by induction of immunogenic cell death (AACR 2022) - P1/2, P2 | "The results suggest that a combination therapy of OBI-3424 and anti-PD-1 in human clinical study is warranted. OBI-3424 is currently in Phase 1/2 clinical trials for solid tumor and acute lymphoblastic leukemia (NCT03592264 and NCT04315324)."

Combination therapy • Immunogenic cell death • IO biomarker • Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • AKR1C3 • CALR • CD69 • CD8 • CD86 • HMGB1 • ITGAM • PTPRC

Haoding’s new precursor chemotherapy drug OBI-3424 has been approved by TFDA for phase II clinical trial (udn.com) - "Haoding (4174) announced...that the new precursor chemotherapy drug OBI-3424 developed by the company has been approved by the Food and Drug Administration (TFDA) of the Ministry of Health and Welfare for the second phase human clinical trials....OBI-3424 has been approved by the TFDA for the second phase of human clinical trials, and it is expected that the second phase of clinical trials will be completed in 2024."

New P2 trial • Oncology