talabostat (BXCL701) / BioXcel - LARVOL DELTA

First-in-class oral innate immune activator BXCL701 combined with pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC) of small cell neuroendocrine (SCNC) phenotype: Phase 2a final results. (ASCO-GU 2023) - P1b/2 | "Oral BXCL701 in combination with pembrolizumab demonstrates encouraging anti-tumor activity with durability of response in late-line, refractory mCRPC SCNC for which there is currently no standard of care. BXCL701 BID dosing continues to demonstrate an acceptable safety profile. Clinical trial information: NCT03910660."

Clinical • Metastases • P2a data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • IL18 • TMB

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

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

Boron-Containing Drug Candidates in Clinical Trials. (PubMed, Handb Exp Pharmacol) - "The agents reviewed include borofalan, delanzomib, flovagatran, dutogliptin, talabostat, numidargistat, OATD-02, AN0128, epetraborole, ganfeborole, acoziborole, taniborbactam, xeruborbactam, and sodium borocaptate, as well as the five FDA-approved boroncontaining drugs (bortezomib, ixazomib, crisaborole, tavaborole, vaborbactam). The review also highlights how clinical success depends on matching pharmacology with unmet need, feasible administration, competitive differentiation, and durable development partnerships. Ongoing advances in scaffold design, delivery, combination therapy, and indication selection are expected to broaden the therapeutic impact of boron-containing medicines."

Journal • Cardiovascular • Head and Neck Cancer • Hematological Disorders • Infectious Disease • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • Thrombosis • Tuberculosis

Induced pluripotent stem cell-derived macrophages enable broad modeling of human inflammasome signaling. (PubMed, Cell Rep Methods) - "Finally, unlike human monocyte-derived macrophages (HMDMs), talabostat activates NLRP1 in iMacs. Therefore, we demonstrate that iMacs are a physiologically relevant and attractive model to study inflammasome signaling."

Journal • Inflammation • NLRP1 • NLRP3

BXCL701 plus pembrolizumab in second-line advanced pancreatic ductal adenocarcinoma: Final outcomes of the EXPEL PANC trial. (ASCO 2026) - P2 | "'701 plus pembrolizumab in second-line advanced PDAC did not reach the preliminary efficacy endpoint to trigger the second stage. However, there were encouraging signs as this combination induced objective responses in 2 MSS pts, and PFS exceeded 6 months in 3 pts. Ongoing correlative studies should elucidate predictive markers of efficacy and resistance to this novel immunotherapy combination."

Clinical • IO biomarker • Metastases • Fibrosis • Gastrointestinal Cancer • Immunology • Microsatellite Instability • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD8 • CXCL9 • CXCR3 • MSI

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 | Trial completion date: Dec 2024 ➔ Aug 2025

Trial completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Genitourinary Neuroendocrine Carcinoma • Neuroendocrine Tumor • Oncology • Prostate Cancer • Solid Tumor

Phase 2 study of talabostat, a small molecule inhibitor of dipeptidyl peptidases (DPP), administered in combination with pembrolizumab in patients with small cell neuroendocrine prostate cancer. (PubMed, J Immunother Cancer) - P1/2 | "Talabostat plus pembrolizumab demonstrates preliminary anti-tumor activity in patients with relapsed SCNC. Further evaluation in a randomized study is warranted to assess the contribution of talabostat in this high-risk disease subset."

Journal • P2 data • Tumor mutational burden • Dermatology • Fatigue • Genito-urinary Cancer • Genitourinary Neuroendocrine Carcinoma • Hypotension • Oncology • Prostate Cancer • Pruritus • Solid Tumor • DPP9 • TMB

Mechanistic studies of fibroblast activation protein activated prodrug AVA6000 in pancreatic and liposarcoma models (AACR 2026) - P1 | "In addition, we studied the effects of the FAP inhibitor Talabostat (PT100) in reversing the effects of AVA6000 in co-culture conditions. Further, we tested the effects of the combination of an ATR inhibitor BAY1895344 in combination with AVA6000 in the coculture system. The GI50 of AVA6000 in two pancreatic cancer cell lines ASPC-1 and Mia-Paca-2 in the co-culture system with PSCs was 58±21.4nM, (Stdev,n=3) and 66.5±16.3nM (Stdev, n=3)... AVA6000, is selectively activated by FAP expressing PSCs and is active in pancreatic and liposarcoma co-culture models. It also exhibits synergistic growth inhibition activity with ATR inhibitors in liposarcoma co-culture models. Clinical trials of AVA6000 are ongoing (NCT04969835)."

Liposarcoma • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • CAFs • FAP

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 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

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