dencatistat (STP938) / Step Pharma - LARVOL DELTA

CTPS1 promotes lung adenocarcinoma progression as a targetable vulnerability. (PubMed, Br J Cancer) - "CTPS1 drives LUAD progression and is linked to MX1-associated interferon signalling. Targeting CTPS1 with STP938, alone or in combination with osimertinib, represents a promising therapeutic strategy and supports CTPS1 as a targetable vulnerability in LUAD."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CTPS1 • EGFR • MX1

CTPS1 is an unexplored vulnerability in breast and ovarian cancer. (PubMed, Theranostics) - "Selective pharmacologic inhibition of CTPS1 using STP938 is a potent inhibitor of tumor cell proliferation/viability and has anti-cancer activity in patient derived ex vivo and in vivo tumor models. These findings suggest that therapeutic targeting of CTPS1 represents an alternative approach for the management of patients with advanced and aggressive forms of these diseases."

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • CTPS1 • ER • ERCC4 • RAD9A • RHOA

Step Pharma advances dencatistat into phase 2 clinical trial for essential thrombocythaemia (GlobeNewswire) - "...The phase 2 trial will evaluate the safety, tolerability and efficacy of dencatistat in up to 50 individuals with high risk ET across sites in the US, EU and UK....The Company expects to progress towards phase 3 trial initiation in ET during 2028."

New P3 trial • Trial status • Essential Thrombocythemia

A Phase 2 Study to Assess STP938 (Dencatistat) as a Monotherapy in Adults With High Risk Essential Thrombocythaemia - The VECTRA Trial (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Step Pharma, SAS | Phase classification: P1 ➔ P2 | N=20 ➔ 50 | Trial completion date: Dec 2027 ➔ Sep 2028 | Trial primary completion date: May 2026 ➔ Jun 2028

Enrollment change • Monotherapy • Phase classification • Trial completion date • Trial primary completion date

CTPS1 as a metabolic vulnerability and novel therapeutic target in breast and ovarian cancer (AACR 2026) - P1 | "Thus, a Phase 1a/b clinical trial of STP938 (NCT06297525) has been initiated, including an expansion cohort for patients with CTPS2-null ovarian tumors. These laboratory discoveries and ongoing clinical efforts aim to enable broader uptake of this novel therapeutic approach to improve long-term outcomes in patients with CTPS1-dependent disease."

Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • CTPS1 • CTPS2

Lack of CTPS2 expression exposes synthetic lethal vulnerability to selective CTPS1 inhibition: A phase 1 dose escalation study of dencatistat (STP938) with safety expansion in biomarker selected cohorts (AACR 2026) - P1 | "The study opened to enrolment in the UK, France and USA in September 2024 and is currently in dose escalation (NCT06297525). The phase 1b study is expected to commence mid-2026 and will include additional centres in Spain."

Biomarker • Clinical • Synthetic lethality • Endometrial Cancer • Hematological Malignancies • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Salivary Gland Cancer • Solid Tumor • CTPS1 • CTPS2

STP938-101: A Phase 1/2 Study of STP938 for Adult Subjects With Relapsed/Refractory B-Cell and T-Cell Lymphomas (clinicaltrials.gov) - P1/2 | N=180 | Recruiting | Sponsor: Step Pharma, SAS | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

First-in-human • Trial completion date • Trial primary completion date • B Cell Lymphoma • Cutaneous T-cell Lymphoma • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

CTPS1: An unexplored vulnerability in breast and ovarian cancer (AACR 2024) - "RNAseq analysis in aggressive cell line models following STP938 treatment or CTPS1 knockdown revealed significant regulation of genes related to DNA replication and the cell cycle pathways suggesting that combinatorial/sequential treatments of STP938 with replication stress/DNA damage response related drugs may be synergistic. STP938 is currently being developed for the treatment of lymphoma, and our findings support the repurposing of STP938 for breast and ovarian cancer, an avenue that we are currently developing."

Breast Cancer • Hematological Malignancies • Lymphoma • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • CTPS1 • ERCC4 • RAD9A • RHOA

Exploiting CTPS1 dependency for the treatment of breast and ovarian cancer (AACR 2025) - P1, P1/2 | "In partnership with Step Pharma, which has developed a first-in-class highly selective CTPS1 inhibitor (STP938), we have demonstrated that STP938 elicits potent anti-proliferative effects at nM concentrations across many cell line and patient derived models, both in 2D and 3D culture systems...In August 2024, a second phase I trial opened for advanced solid tumors, including an expansion cohort for CTPS2-null ovarian cancer (NCT06297525) at Mayo Clinic. These laboratory discoveries, and ongoing clinical studies, are expected to pave the way for a broader uptake of this novel therapeutic approach aimed at improving outcomes in patients with highly aggressive forms of these diseases."

First-in-human • Breast Cancer • Hematological Malignancies • Lymphoma • Oncology • Ovarian Cancer • Solid Tumor • T Cell Non-Hodgkin Lymphoma • Triple Negative Breast Cancer • CTPS1 • CTPS2 • ERCC4 • RAD9A • RHOA

Step Pharma secures €2.5 million EIC grant to accelerate development of dencatistat for CTPS2 null gynaecological tumours (The Manila Times) - "The funding consists of a €2.5 million grant and potentially up to €10 million in equity investment to support the advancement of Step Pharma’s first-in-class, highly selective, orally bioavailable CTPS1 inhibitor, dencatistat, in CTPS2 null ovarian and endometrial cancers...Dencatistat is currently being evaluated in a phase 1a dose escalation study in patients with solid tumours. This will be followed by safety expansion cohorts in patients with CTPS2 null cancers, including ovarian and endometrial where the prevalence of CTPS2 loss is 15-20%. These expansion cohorts are expected to start enrolling in 2026, with an additional cohort in CTPS2 null lung cancer also planned."

Financing • Trial status • Endometrial Cancer • Lung Cancer • Ovarian Cancer

Using GENIE data to drive oncology target identification and drug development (AACR-NCI-EORTC 2025) - P1, P1/2 | "Dencatistat, an orally available and highly potent inhibitor of CTPS1, is currently in clinical development for the treatment of lymphoma (NCT05463263); in a second study, dose escalation in solid tumours will be followed by safety expansion cohorts for patients with CTPS2 null cancers (NCT06297525). Together, these two use cases exemplify how high quality, clinically relevant genomic datasets can be used to accelerate drug development."

Hematological Malignancies • Lymphoma • Oncology • Ovarian Cancer • Solid Tumor • CTPS1 • CTPS2

Step Pharma to spotlight work in CTPS2-null solid tumours at 2025 EORTC-NCI-AACR International Conference on Molecular Targets and Cancer Therapeutics (GlobeNewswire) - "The presentation will focus on the use of the AACR Project GENIE data, a publicly accessible cancer registry of real-world clinico-genomic data, to identify loss of CTPS2 as a novel biomarker to select solid tumours with a synthetic lethal dependency on CTPS1...As a result of these findings, dencatistat, an orally available and highly potent inhibitor of CTPS1, which is currently being evaluated in a phase 1a dose escalation study in patients with solid tumours, will be evaluated in safety expansion cohorts in patients with CTPS2 null cancers, with the first being ovarian cancer (NCT06297525)."

Clinical data • Ovarian Cancer • Solid Tumor

Step Pharma announces completion of €38 million Series C financing (GlobeNewswire) - "The financing will enable Step Pharma to continue advancing its ‘pipeline in a product’ strategy for dencatistat, a first-in-class, highly selective, orally bioavailable CTPS1 inhibitor currently in development for the treatment of cancers and blood disorders."

Financing • Lymphoma • Solid Tumor

Dencatistat, a first in class CTPS1 inhibitor, shows early signs of efficacy in cutaneous T cell lymphoma (CTCL) (EORTC-CLTG 2025) - No abstract available

Clinical • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CTPS1

Inhibitors of pyrimidine synthesis synergize with N4-hydroxycytidine to diminish influenza virus replication. (PubMed, Antiviral Res) - "N4-hydroxycytidine (NHC), the active form of Molnupiravir, shows potent activity against influenza A viruses (IAVs) in both cell cultures and animal models, with minimal resistance observed. In a ferret model of H5N1 infection, NHC combined with the CTPS inhibitor STP938 reduced clinical symptoms and lung pathology, with NHC mostly driving antiviral activity and STP938 contributing to disease mitigation. These findings indicate that combining NHC with pyrimidine biosynthesis inhibitors enhances antiviral efficacy against IAVs, especially in rapidly replicating viruses, and may broaden the utility of nucleoside analogues in influenza therapy."

Journal • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases • CTPS1

Step Pharma announces first participant dosed in a phase 1b clinical trial of dencatistat for essential thrombocythaemia (The Manila Times)

Trial status • Essential Thrombocythemia

A Phase 1 Study to Assess STP938 as a Monotherapy in Adults With High Risk Essential Thrombocythaemia (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: Step Pharma, SAS | Not yet recruiting ➔ Recruiting

Enrollment open • Monotherapy

Synergistic interference with SARS-CoV-2 replication by molnupiravir-derived N4-hydroxycytidine and inhibitors of CTP synthetase in cell culture. (PubMed, Virology) - "While treatment with the CTPS1 inhibitor STP938 alone strongly diminished virus propagation and COVID pathology, addition of molnupiravir did not augment this effect and even counteracted the benefits of STP938 in vivo. We propose that, if further developed, CTPS inhibitors might represent candidates for antiviral therapy."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • CTPS1

A Phase 1 Study to Assess STP938 as a Monotherapy in Adults With High Risk Essential Thrombocythaemia (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: Step Pharma, SAS

Monotherapy • New P1 trial

CTPS1 is a novel therapeutic target in cutaneous T cell lymphoma (EORTC-CLTG 2024) - P1/2 | "Dencatistat (STP938) is a first in class oral CTPS1 inhibitor showing >1,300-fold selectivity over CTPS2...Conclusions Differential targeting of CTPS1, sparing the paralog CTPS2 enzyme, is a potential novel therapeutic strategy in cutaneous T cell lymphoma. Dencatistat is an orally administered selective CTPS1 inhibitor currently in clinical development in a phase 1/2 clinical trial (NCT05463263); the phase 2 study will include a dedicated cohort for individuals living with cutaneous T cell lymphoma, and is expected to commence late 2024."

Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • CTPS1 • CTPS2

Study of STP938 in Advanced Solid Tumours (clinicaltrials.gov) - P1 | N=70 | Recruiting | Sponsor: Step Pharma, SAS | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Oncology • Ovarian Cancer • Solid Tumor

A Phase 1 Study of STP938 for Adult Subjects With Advanced Solid Tumours (clinicaltrials.gov) - P1 | N=70 | Not yet recruiting | Sponsor: Step Pharma, SAS

Metastases • New P1 trial • Oncology • Ovarian Cancer • Solid Tumor

Identification of novel genetic/therapeutic vulnerabilities in breast cancer (SABCS 2023) - "Our studies have identified CTPS1 as an essential gene in TNBC. CTPS1 encodes an enzyme responsible for the catalytic conversion of UTP (uridine triphosphate) to CTP (cytidine triphosphate), an essential step in the biosynthesis of nucleic acids. These findings are timely in light of the recent and ongoing development of the first-in-class CTPS1 inhibitor, STP938, for which first-in-human studies are underway for refractory B- and T-cell lymphomas."

Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CTPS1 • ER • ERCC4 • HER-2 • PGR • RAD9A • RHOA

A PHASE 1/2 STUDY OF STP938, A FIRST IN CLASS INHIBITOR OF CTP SYNTHASE 1, IN PATIENTS WITH RELAPSED/REFRACTORY B OR T CELL LYMPHOMA (ICML 2023) - P1/2 | "The phase 1 study (NCT05463263) opened to enrolment in the US and UK in September 2022. The phase 2 study will include additional centres in France."

Clinical • P1/2 data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Mantle Cell Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CTPS1 • CTPS2 • CXCL8 • IFNG • IL2 • TNFA

A phase 1/2 study of STP938, a first-in-class inhibitor of CTP synthase 1, in patients with relapsed/refractory B or T cell lymphoma. (ASCO 2023) - P1/2 | "The phase 2 study will include additional centers in France. Clinical trial information: NCT05463263."

Clinical • P1/2 data • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Mantle Cell Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CTPS1 • CTPS2 • CXCL8 • IFNG • IL2 • TNFA