talabostat (BXCL701) / BioXcel - LARVOL DELTA

Phase 1 Study of BXCL701, a Dipeptidyl Peptidase Inhibitor, in Relapsed/Refractory Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome (ASH 2023) - P1 | "Major eligibility criteria include: ≥18 years of age, relapsed or refractory AML or relapsed or refractory MDS with ≥10%.refractory to at least 4 cycles of hypomethylating agent, ECOG performance status ≤2, adequate renal function (CrCl ≥30 mL/min), adequate liver function (total bilirubin ≤1.5 x ULN, ALT and AST ≤3 x ULN), WBC 100 days from allogeneic bone marrow transplant with no active graft versus host disease...There will be a second phase of the study that will evaluate BXCL701 in combination with a hypomethylating agent (decitabine or azacytidine) and venetoclax. The trial is currently open and continuing to enroll."

P1 data • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Cardiovascular • CNS Disorders • Gastrointestinal Cancer • Genito-urinary Cancer • Graft versus Host Disease • Hematological Malignancies • Hypertension • Hypotension • Immunology • Infectious Disease • Leukemia • Lung Cancer • Lymphoma • Melanoma • Myelodysplastic Syndrome • Neuroendocrine Carcinoma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor • Transplantation • CASP1 • IL18 • NLRP1

Localized hydrogel delivery of a small molecule inhibitor of fibroblast activation protein alters the trajectory of post-myocardial infarction remodeling (AHA 2025) - "While small molecule FAP inhibitors, such as talabostat have been developed, systemic delivery has been problematic... This is the first study to demonstrate the feasibility and efficacy of targeted delivery of a self-assembling hydrogel containing a small molecule FAP inhibitor, using a minimally invasive cardiothoracic surgical approach at a relevant post-MI time point. This strategy may provide a platform for repurposing small molecule inhibitors for localized delivery to the LV myocardium."

Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Infarction • Reperfusion Injury

BXCL701-201: A Trial of BXCL701 and Pembrolizumab in Patients With mCRPC Either Small Cell Neuroendocrine Prostate Cancer or Adenocarcinoma Phenotype. (clinicaltrials.gov) - P1/2 | N=98 | Completed | Sponsor: BioXcel Therapeutics Inc | Active, not recruiting ➔ Completed | Phase classification: P1b/2 ➔ P1/2 | Trial completion date: Dec 2025 ➔ Dec 2024

Phase classification • Trial completion • Trial completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor

CARD8 INFLAMMASOME ACTIVATION INDUCES PYROPTOSIS AND INTERLEUKIN-16 RELEASE IN HUMAN T CELLS (UEGW 2025) - "- Dipeptidyl-peptidase (DPP) inhibition triggers a lytic form of cell death in primary human T cells- Biochemical and morphological analyses reveal that the cell death triggerd by the DPP-inhibitor Val-boroPro recapitulates features of pyroptosis in human T cells- CRISPR-Cas9 editing reveals a functional CARD8 inflammasome in human T cells- Pyroptotic human T cells and macrophages release an as to yet uncharacterized fragment of the cytoplasmic cytokine Interleukin-16- Future studies will elucidate whether genetic CARD8 variants with a described role in IBD susceptibility are in fact gain-of-function variants causing excessive CARD8 inflammasome activation in T cells"

Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Immunology • Inflammatory Bowel Disease • Leukemia • CD4 • IL16

EXPEL PANC: BXCL701 and Pembrolizumab in Patients With Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov) - P2 | N=22 | Active, not recruiting | Sponsor: Georgetown University | Recruiting ➔ Active, not recruiting | N=43 ➔ 22 | Trial primary completion date: Nov 2026 ➔ Jan 2026

Enrollment change • Enrollment closed • Trial primary completion date • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CA 19-9

Senolytic therapy increases replicative capacity by eliminating senescent endothelial cells. (PubMed, Exp Gerontol) - "In this study, we treated replicative senescent human umbilical vein endothelial cells (HUVECs), used as a model of aged ECs, with Talabostat (10 μM), a novel senolytic, and Navitoclax, 1.0 μM). Talabostat appears more effective, as it is associated with lower oxidative stress and improved genomic integrity. These results provide insight into how distinct senolytics differentially influence aging-related phenotypes in endothelial cells."

Journal • Cardiovascular • Inflammation • TP53BP1

FAP deficiency attenuates T2DM-associated HFpEF by suppressing the CaMKIIδ-Calcineurin A-NFATc2 signaling pathway. (PubMed, Clin Sci (Lond)) - "Additionally, FAP KO and FAP inhibitor Talabostat alleviated myocardial inflammation, fibrosis, cardiomyocyte apoptosis, oxidative stress and energy metabolism dysfunction...In contrast, FAP KO suppressed the CaMKIIδ-Calcineurin A-NFATc2 signaling pathway and attenuated these pathological changes. Overall, these findings suggest that FAP may serve as a critical therapeutic target for T2DM-induced HFpEF."

Journal • Cardiovascular • Congestive Heart Failure • Diabetes • Fibrosis • Heart Failure • Immunology • Inflammation • Metabolic Disorders • Myocardial Infarction • Type 2 Diabetes Mellitus • CAMK2D

BXCL701 plus pembrolizumab in second-line advanced pancreatic ductal adenocarcinoma (ESMO-GI 2025) - P2 | "This study will determine the efficacy of '701 + pembrolizumab in second-line advanced PDAC. Preliminary findings suggest efficacy in a historically immunotherapy-resistant population."

Clinical • IO biomarker • Metastases • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD8 • CXCL9 • CXCR3 • MSI

BXCL701 Phase 1 R/R Acute Myeloid Leukemia or Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Eric Stephen Winer, MD | Trial completion date: Jul 2025 ➔ Jul 2026 | Trial primary completion date: Feb 2025 ➔ Mar 2026

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

ESMO GI 2025 Highlights: BXCL701 + Pembrolizumab in Second-Line Advanced PDAC (OncoDaily) - P2 | N=95 | EXPEL PANC (NCT05558982) | "The EXPEL PANC Phase II trial (NCT05558982), presented by Dr. Benjamin A. Weinberg from Georgetown University Medical Center at the ESMO Gastrointestinal (GI) Cancers Congress 2025 in Barcelona, investigates the combination of BXCL701 and pembrolizumab in patients with second-line advanced pancreatic ductal adenocarcinoma (PDAC)...Response Rates: Three patients (17%) achieved partial responses (PR); Four patients (22%) had stable disease (SD); The overall disease control rate (DCR) was 39%; Median Progression-Free Survival (PFS): The median PFS for evaluable patients was 2.3 months (95% CI 1.58–5.29 months); Median Overall Survival (OS): The median OS has not yet been reached, suggesting that a significant proportion of patients remain alive at the time of the analysis; Safety: No new safety signals were identified."

P2 data • Pancreatic Ductal Adenocarcinoma

Dipeptidyl peptidase 9 (DPP9) depletion from hepatocytes in mice to retard tumour growth, increase intrahepatic caspase-1 activation, and alter metabolic markers. (ASCO 2025) - "Funded by Deutsche Forschungsgemeinschaft, The University of Sydney Background: Dipeptidyl peptidase 9 (DPP9) is one of four enzymes targeted by a novel compound class that includes talabostat and BXCL701, which have reached clinical oncology trials... Lifelong intrahepatic DPP9 depletion reduced tumour sizes at 28 weeks of age in this DEN/TAA/HFD experimental model. Mechanisms might include increased caspase-1 activation following NLRP1 activation, increased autophagy and p53 and improved energy metabolism in epithelial cells. DPP9 inhibition may contribute to efficacy in therapies that target DPP4 protease family."

Preclinical • Fibrosis • Hepatocellular Cancer • Immunology • Liver Cancer • Oncology • Solid Tumor • BECN1 • BRCA2 • CXCL10 • DPP9 • NLRP1

HSPB1 suppresses oxLDL-induced vascular smooth muscle cell ferroptosis by inhibiting DPP4. (PubMed, Arch Biochem Biophys) - "This study reveals for the first time that HSPB1 suppresses oxLDL-induced VSMC ferroptosis by inhibiting DPP4 through NF-κB, which provides new strategies for prevention and treatment of atherosclerosis."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • ANXA2 • GPX4 • HSPB1

Talabostat and Pembrolizumab for the Treatment of Advanced Solid Cancers (clinicaltrials.gov) - P2 | N=31 | Terminated | Sponsor: M.D. Anderson Cancer Center | N=15 ➔ 31 | Trial completion date: Dec 2025 ➔ Mar 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Dec 2025 ➔ Mar 2025; There is no PR/CR observed in the first stage, so study stopped without proceeding to the stage 2 of efficacy stage.

Enrollment change • Pan tumor • Trial completion date • Trial primary completion date • Trial termination • Tumor mutational burden • Oncology • Solid Tumor • PD-L1

Talabostat and Pembrolizumab for the Treatment of Advanced Solid Cancers (clinicaltrials.gov) - P2 | N=15 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Apr 2025 ➔ Dec 2025 | Trial primary completion date: Apr 2025 ➔ Dec 2025

Pan tumor • Trial completion date • Trial primary completion date • Tumor mutational burden • Oncology • Solid Tumor • PD-L1

A phase 2 basket study of talabostat, a small-molecule inhibitor of dipeptidyl peptidases, administered in combination with pembrolizumab in patients with advanced solid cancers. (PubMed, Cancer) - "This study of the combination of talabostat and pembrolizumab in patients with advanced solid tumors demonstrated predictable adverse events and limited activity. The combination was shown to be safe. Efficacy data shows immune stable disease in nine of 19 evaluable patients, and an unconfirmed immune partial response in a patient with endometrial cancer."

Journal • P2 data • Endometrial Cancer • Fatigue • Hematological Disorders • Hypotension • Oncology • Solid Tumor • Thrombocytopenia

Comparison of Different Keratinocyte Cell Line Models for Analysis of NLRP1 Inflammasome Activation. (PubMed, Biomolecules) - "Moreover, our data showed that both UVB and talabostat triggered cell death, and NLRP1 inflammasome activation was readily detected in primary keratinocytes but not in the analyzed immortalized keratinocyte cell lines. Therefore, we do not recommend the use of the immortalized keratinocyte cell lines HaCaT, HaSKpw, and SVTERT for analyzing inflammasome activation in keratinocytes; we strongly recommend the use of primary keratinocytes for these studies."

Clinical • Journal • Preclinical • NLRP1

BXCL701 Phase 1 R/R Acute Myeloid Leukemia or Myelodysplastic Syndrome (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: Eric Stephen Winer, MD | Trial primary completion date: Jul 2024 ➔ Feb 2025

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

Integrated Genetic and Cellular Analysis Reveals NLRP1 Activation in CD4+ T Lymphocytes During Chronic HIV Infection. (PubMed, Immunol Invest) - "The activation of NLRP1 in CD4+ T cells was assessed ex-vivo and in-vitro by the meaning of anti-CD3/anti-CD28 and Talabostat/Val-boroPro (VbP) response...Functional variants in NLRP1 significantly affected the level of inflammatory dysregulation of CD4+ T cells, therefore explaining at least in part the association with CD4+ T-mediated diseases. PLWH CD4+ T cells are more prone to IL-1β release and pyroptosis, therefore contributing to chronic inflammation."

Journal • Infectious Disease • Inflammation • CD4 • IL1B • NLRP1 • NLRP3

Size exclusion chromatography based proteomic and degradomic profiling of inflammasome-activated, murine bone marrow-derived dendritic cells highlights complex retention and release of cleavage products. (PubMed, Mol Omics) - "Cultured BMDCs were primed with LPS and subsequently treated with nigericin or Val-boroPro (VbP)...VbP treatment led to the accumulation of ISG15 in low MW fractions while RNA polymerase II coactivator p15 shifted to higher MW fractions. This study demonstrates that SEC-coupled proteomics and degradomic profiling offer unique insights into protein complex dynamics and proteolytic processes upon inflammasome activation."

Journal • Preclinical • GSN • IL1B • MMP14 • TFAP2A

A phase II study of the first-in-class oral innate immune activator BXCL701 with pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC): Long-term follow-up (ESMO 2024) - P1b/2 | "Combination of BXCL701 + pembrolizumab demonstrates encouraging response rates and median survival times in a genomically unselected, late-line mCRPC patient population with limited standard of care treatment options, coupled with an acceptable safety profile. Results appear favorable to those expected with pembrolizumab monotherapy; further evaluation in a randomized trial is warranted."

Clinical • Metastases • P2 data • Tumor mutational burden • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor

Retention of ES cell-derived 129S genome drives NLRP1 hypersensitivity and transcriptional deregulation in Nlrp3tm1Flv mice. (PubMed, Cell Death Differ) - "Using alternative models of NLRP3 deficiency, including a previously undescribed conditional Nlrp3 allele enabling precise temporal and cell-type specific control over Nlrp3 deletion, we further show that NLRP3 contributes to Talabostat-driven IL-1β release. Our study also establishes a generic framework to identify functionally relevant SNPs and assess genomic contamination in transgenic mice using RNAseq data. This allows for unambiguous attribution of phenotypes to the target gene and advances the precision and reliability of research in the field of host defence responses."

Journal • Preclinical • Immunology • IL1B • NLRP1 • NLRP3

Talabostat, fibroblast activation protein inhibitor, attenuates inflammation and fibrosis in systemic sclerosis. (PubMed, Inflammopharmacology) - "In summary, Talabostat modulates fibrotic genes in SSc, thereby inhibiting myofibroblast differentiation, activation, and migration. These findings suggest promising therapeutic avenues for targeting fibrosis in SSc."

Journal • Fibrosis • Immunology • Inflammation • Rheumatology • Scleroderma • Systemic Sclerosis • ANXA5 • COL1A1 • COL1A2 • IL6 • MMP1 • MMP2 • MMP9 • TGFB1

NLRP1B expressed in intestinal epithelial cells is refractory to activation with Val-boro-Pro. (PubMed, Microbes Infect) - "We furthermore did not detect Nlrp1b in organoids derived from Balb/cJ mice, which express a different allele than the one expressed in C57BL/6J mice. Together, our results suggest that NLRP1B may have an allele-dependent function in murine IECs whose regulation is distinct from that of macrophages."

Journal • Infectious Disease • CASP1 • IL13 • NLRP1

REPURPOSING OF SPIRONOLACTONE AS NLRP1 INHIBITOR FOR THE TREATMENT OF DIAMOND-BLACKFAN ANEMIA (EHA 2024) - "Notably, Talabostat, acting on its broadly identified inhibitor dipeptidyl peptidase 9, and tyrosinekinase inhibitors, acting on ZAKα, are the only known drugs modulating NLRP1 activity. Our findings provide novel insights into NLRP1 pharmacological modulation,opening avenues for therapeutic interventions in congenital anemias and chronic inflammatorydiseases."

Anemia • Dermatology • Genetic Disorders • Hematological Disorders • Oncology • NLRP1

Phase II trial of BXCL701 and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (EXPEL-PANC): Preliminary findings. (ASCO 2024) - P2 | "BXCL701 plus pembrolizumab is well-tolerated and shows early signs of potential clinical activity in patients with mPDAC refractory to chemotherapy."

Clinical • IO biomarker • Late-breaking abstract • Metastases • P2 data • Fibrosis • Gastrointestinal Cancer • Immunology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CA 19-9 • CD4 • CD8 • IL6 • KRAS