dencatistat (STP938) / Step Pharma - LARVOL DELTA

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

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."

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

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

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

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

MYC-induced cytidine metabolism regulates survival and drug resistance via cGas-STING pathway in mantle cell lymphoma. (PubMed, Br J Haematol) - P1/2 | "Of these six genes, de novo CTP synthesis pathway enzyme CTPS1 whose inhibitor (STP938) is already in clinical trials for relapsed/refractory lymphomas (NCT05463263) has the highest regression coefficient. Additionally, MYC positively regulates CTPS1 expression, and TP53-aberrant and ibrutinib-resistant MCL cells also rely on cytidine metabolism. Furthermore, besides the obvious decreased CTP pool caused by CTPS1 deficiency, CTPS1 inhibition may also induce immune-related responses via activating dsDNA-cGAS-STING pathway, which plays a crucial role in impeding tumour growth in MCL patients."

Journal • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CTPS1 • TP53

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 (ASH 2022) - P1/2 | "Tumour genomics will be assessed by sequencing of circulating tumour DNA (ctDNA) prior to treatment and at disease progression using a bespoke genomic assay designed to elucidate biomarkers of response and understand mechanisms of resistance.Current statusThe study protocol has received FDA and MHRA approval. The phase 1 study (NCT05463263) will open to enrolment in the US and UK in August 2022."

Clinical • P1/2 data • Cutaneous T-cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Indolent Lymphoma • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • CXCL8 • IFNG • IL2 • TNFA

CTPS1 Is a Novel Therapeutic Target in Multiple Myeloma That Synergizes with Inhibition of ATR, CHEK1 or WEE1 (ASH 2022) - "Combining CTPS1 inhibition by STP938 with inhibitors of different components of the DDR pathway demonstrated strong synergy, with consistent results observed when combining STP938 with inhibitors of either ATR (ceralasertib, VE-821), CHEK1 (rabusertib, SRA737) or WEE1 (adavosertib) (Figure B). The ability of the homologous CTPS2 enzyme to compensate for CTPS1 loss outside the hematopoietic system suggests that inhibition of CTPS1 will not be associated with significant non-hematological toxicity. Clinical evaluation of STP938 in lymphoid malignancies will start in Q3 this year."

Hematological Malignancies • Monoclonal Gammopathy • Multiple Myeloma • ANXA5 • CHEK2

STP938, a Selective CTPS1 Inhibitor, Shows Single Agent Activity and Synergy with BCL2 Inhibition in Preclinical Models of Mantle Cell Lymphoma (ASH 2022) - "Of note, sensitivity to STP938 was independent of known indicators of poor prognosis, such as TP53 mutation, and was independent of resistance to standard of care therapies such as ibrutinib or venetoclax...Conclusions Dependence of tumor cells on elevated rates of nucleotide synthesis has been exploited by agents such as cytarabine...STP938, a highly selective CTPS1 inhibitor, demonstrates single agent activity in vitro and in vivo, and shows strong synergy with the approved BCL2 inhibitor venetoclax. STP938 will enter clinical development for relapsed refractory B and T cell lymphomas in 2022."

IO biomarker • Preclinical • Hematological Disorders • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • T Cell Non-Hodgkin Lymphoma • Transplantation • BCL2L1 • MCL1 • TP53

Step Pharma to Present Promising Data on the Therapeutic Potential of Selective Small Molecule Inhibition of CTPS1 at the 64th American Society of Hematology Annual Meeting (GlobeNewswire) - "Step Pharma, the world leader in CTPS1 inhibition for the targeted treatment of cancer, today announces that it will be presenting pre-clinical data on its lead candidate STP938 at the 64th American Society of Hematology Annual Meeting being held from the 10-13 December, 2022 in New Orleans, Louisiana and virtually. Step Pharma and collaborators will present two posters on STP938, its potent and highly selective small molecule inhibitor of CTPS1, reporting its potential as a targeted therapeutic for the treatment of Mantle Cell Lymphoma and Multiple Myeloma."

Preclinical • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Step Pharma Announces First Patient Dosed with STP938, the World’s Most Advanced CTPS1 Inhibitor, in a Phase 1/2 Trial for T cell and B cell lymphomas (GlobeNewswire) - "Step Pharma...announces today that the first patient has been successfully dosed with STP938, in a Phase 1/2 trial in adult subjects with relapsed/refractory B cell and T cell lymphomas. The dose-escalation part of the open label, non-randomised Phase 1/2 trial comprises multiple cohorts dosed with STP938, administered as an oral monotherapy, ascending in a stepwise manner. The primary objective in Phase I is to assess the safety and tolerability of STP938."

Trial status • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma

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 | Not yet recruiting ➔ Recruiting

Enrollment open • Cutaneous T-cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

Step Pharma Progresses into Oncology Clinical Trials with STP938, the World’s Most Advanced CTPS1 Inhibitor (GlobeNewswire) - "Step Pharma...announces today that its lead asset STP938 has cleared both an Investigational New Drug (IND) application by the Food and Drug Administration (FDA), and a clinical trial application (CTA) by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA), enabling Step Pharma to progress STP938, its first-in-class, selective CTPS1 inhibitor into the clinic in the US and UK. STP938 has now entered an open label, first-in-human, Phase 1/2 study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of STP938 in adult subjects with relapsed/refractory B cell and T cell lymphomas."

IND • New P1/2 trial • Hematological Malignancies • Lymphoma • Oncology