HRO761 / Novartis - LARVOL DELTA

First-in-human phase I/Ib study of the oral Werner (WRN) helicase inhibitor HRO761 in patients (pts) with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors: Interim safety and efficacy analysis from HRO761 single agent dose escalation (ESMO 2025) - P1 | "Of pts with detectable BL circulating tumor DNA (ctDNA), ctDNA cleared by ∼1 mo in 1/1 pt with partial response, 5/8 pts with stable disease, and 0/5 pts with progressive disease; median treatment duration was 9.3 mos in the 6 pts (5 ongoing) with ctDNA clearance. Table: 925MO Response CRC N=19 Non-CRC N=16 All N=35 Best overall response Partial response Stable disease Progressive disease Not evaluable (NE) 2 (10.5%) 14 (73.7%) 3 (15.8%) 0 1 (6.3%) 7 (43.8%) 7 (43.8%) 1 (6.3%) 3 (8.6%) 21 (60.0%) 10 (28.6%) 1 (2.9%) Overall response rate (95% CI) 2 (10.5%) (1.3, 33.1) 1 (6.3%) (0.2, 30.2) 3 (8.6%) (1.8, 23.1) Disease control rate (95% CI) 16 (84.2%) (60.4, 96.6) 8 (50.0%) (24.7, 75.3) 24 (68.6%) (50.7, 83.1) Median progression-free survival, months (95% CI) NE (3.3, NE) 2.1 (1.8, NE) 5.6 (2.1, NE) Conclusions HRO761 showed an acceptable safety profile and durable antitumor activity with ctDNA clearance in heavily treated post-ICI pts with advanced MSI-H/dMMR cancers."

Clinical • dMMR • First-in-human • Metastases • Mismatch repair • MSI-H • P1 data • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

CRISPR Screening Identifies SMARCAL1 and MRN as Modulators of WRN Dependency in MSI-H Colorectal Cancer. (PubMed, Cancer Res) - "Loss of WRN induces replication stress and double-strand breaks (DSBs), a vulnerability that can be recapitulated by the selective WRN inhibitor HRO761 in MSI cancer cells. Importantly, the key resistance mechanisms identified in this study were independently validated using a structurally distinct clinical-stage WRN inhibitor VVD-214. Collectively, these findings identify the SMARCAL1-MRN-ATM axis as a critical regulator of WRN dependency and provide mechanistic insight into resistance to WRN-targeted therapy."

Journal • MSI-H • Colorectal Cancer • Metabolic Disorders • Microsatellite Instability • Oncology • Solid Tumor • ERCC1 • MSI • MUS81 • RAD50 • WRN

eIF4E2 deficiency translationally unleashes WRN to sustain DNA repair-mediated chemoresistance. (PubMed, Cell Rep) - "Furthermore, combining the WRN inhibitor HRO761 with cisplatin enhances cytotoxicity in cisplatin-resistant cells. Collectively, these results establish that low eIF4E2 and high WRN levels predict chemoresistance, and that targeting WRN is a promising strategy to overcome cisplatin resistance in NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCR4 • MIR130B • WRN

Structure-Guided Discovery of Potent, Selective, and Orally Bioavailable Werner Syndrome RecQ Helicase Inhibitors for the Treatment of Microsatellite Instability-High Tumors. (PubMed, J Med Chem) - "Guided by the key structural features of the WRN-HRO761 complex, we rationally designed two classes of WRN inhibitors─spirocyclic compounds and benzo-fused heterocyclic analogs─by targeting the solvent-exposed region...Preliminary safety evaluation further indicated that Q15 possesses a favorable safety profile. These findings support Q15 as a promising WRN inhibitor candidate for the treatment of MSI-H tumors."

Journal • MSI-H • Metabolic Disorders • Microsatellite Instability • Oncology • MSI • WRN

WRN under the scalpel: Helicase-domain hotspot & splice-site knock-ins in HCT116 and RKO (AACR 2026) - "Dose-response viability assays (72-96 h, 10-point curves) were fit with four-parameter logistic models to derive IC₅₀; each clone included n≥2-3 biological replicates. This WRN allele panel is immediately deployable to (1) build allele-resolved resistance maps, (2) prioritize chemotype backups based on the C727/I852 complementarity, (3) generate patient-selection/biomarker hypotheses for MSI-H settings, and (4) accelerate SAR and combination strategies—thereby front-loading chemical and clinical derisking for VVD-214- and HRO761-class WRN inhibitors."

Microsatellite Instability • Oncology • MSI • WRN

Characterization of ARTS-051, a potent and selective Werner helicase inhibitor effective against a broad range of MSI-H colorectal cancer models (AACR 2026) - "In contrast, ARTS-051 is effective in WRN C727S and C727A mutant HCT116 cells, outperforming the clinical stage WRN inhibitor HRO761 by nearly 10-fold. Additionally, ARTS-051 displays good drug-like properties including solubility, permeability, and liver microsome stability, as well as a positive PK profile with low clearance and good oral exposure across species, supporting favorable clinical dose projections. Taken together, these data show that ARTS-051 is a promising WRN inhibitor with best-in-class potential to treat MSI-H colorectal cancers."

Late-breaking abstract • MSI-H • Preclinical • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

CRISPR screening identifies SMARCAL1 and MRN as modulators of WRN dependency in MSI-H colorectal cancer (AACR 2026) - "Pharmacologic inhibition of WRN with the selective small molecule HRO761 recapitulates WRN loss, causing replication stress and double-strand breaks (DSBs)...Our results identify SMARCAL1 and the MRN-ATM axis as critical regulators of WRN dependency in MSI-H CRC. These findings redefine the mechanism of WRN synthetic lethality and provide a framework for predicting and overcoming resistance to emerging WRN-targeted therapies."

MSI-H • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • ERCC1 • MRE11A • MSI • MUS81 • RAD50 • WRN

ETX-880, a potential best-in-class, oral, highly potent and selective covalent inhibitor of Werner helicase for the treatment of microsatellite instability-high (MSI-H) cancers (AACR 2026) - "The preclinical activity of ETX-880 was characterized and compared to clinical stage WRN inhibitors, including RO7589831, HRO761, and GSK4418959 (non-covalent). Importantly, human PK predictions reveal low clearance, high oral bioavailability and long half-life, supporting a low once daily oral efficacious dose. Overall, ETX-880 is a potent, selective, covalent WRN inhibitor with excellent ADMET properties leading to deep and sustained target coverage, highlighting its best-in-class potential in MSI-H cancers."

IO biomarker • MSI-H • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

ZMS-4084, a potent and selective WRN inhibitor induces significant tumor regression and sustained complete responses in MSI-H tumor models (AACR 2026) - "The two clinical-stage WRN inhibitors, HRO761 and RO7589831, have demonstrated the clinical efficacy in phase I trials. In conclusion, we have developed a novel WRN inhibitor, ZMS-4084, which demonstrates robust antitumor activity in both xenograft models and patient-derived organoids representing diverse MSI-H tumor types. Given the synthetic lethality between WRN inhibition and MSI-H status, along with its broad antitumor activity across multiple tumor lineages, ZMS-4084 holds strong potential as a tissue-agnostic therapeutic agent for patients with MSI-H tumors."

IO biomarker • MSI-H • Preclinical • Colorectal Cancer • Microsatellite Instability • Oncology • Ovarian Cancer • Solid Tumor • CDKN1A • MSI • WRN

On-target WRN mutations drive resistance to WRN inhibitors in TA-repeat-expanded MSI cancers (AACR 2026) - "Some WRN mutations conferred broad cross-resistance, whereas others preserved sensitivity to alternative WRNi; for example, I852F retained sensitivity to VVD-133214 but not to HRO761, whereas F730L conferred pan-resistance to both yet remained vulnerable to GSK4418959...Finally, resistant clones remained vulnerable to rational strategies: combining WRNi with irinotecan suppressed resistant outgrowth, while ATR inhibitors and orthogonal WRNi offer additional routes to extend response. These findings establish on-target WRN mutation as the dominant mechanism of resistance to WRN inhibitors and define a framework for resistance-informed clinical trial design. They also outline actionable strategies to detect and overcome resistance, including ctDNA-based molecular monitoring and rational combination therapies to extend clinical benefit."

IO biomarker • Oncology • WRN

Cellular comparison of a covalent and non-covalent WRN inhibitor reveals shared and unique response biomarkers (AACR 2026) - "The WRN inhibitors HRO761 and VVD-214 showed similar response profiles in the tested cancer cell lines, although some differences were observed. This study highlights potential shared and unique response biomarkers for the WRN inhibitors HRO761 and VVD-214."

Biomarker • Microsatellite Instability • Oncology • MLH1 • MSI • WRN

Identifying synthetic lethality targets in DDX41-mutated MDS/AML (AACR 2025) - "In DDX41-knockout HeLa cells, treatment with WRN inhibitors NSC 617145 and HRO761 significantly reduced cell growth compared to WT controls...Future studies aim to elucidate the molecular mechanisms underlying SL interactions between DDX41 and its partners, providing insights into the therapeutic potential of targeting these vulnerabilities. This work offers a promising avenue for developing novel treatments for MDS/AML patients harboring DDX41 mutations, ultimately improving clinical outcomes."

Synthetic lethality • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • DDX23 • DDX41 • WRN

Biochemical tools to characterize specific Werner syndrome helicase inhibitors and accelerate drug discovery (AACR 2025) - "Using clinical-stage WRN helicase inhibitor HRO761 and VVD214, we present a complete MOA study demonstrating that the assays generated by Eurofins Discovery teams are well suited for WRN drug discovery project. This demonstration provides strong evidence that the developed assays are well suited for helicase drug candidate discovery, development and characterization. These will help providing innovative solution to fight against cancer an especially the one involving WRN over expression."

Oncology • WRN

Discovery of WRN helicase inhibitors that covalently engage a novel, induced allosteric site (AACR 2025) - "The two clinical-stage WRN inhibitors, HRO761 and RO7589831, both bind in an allosteric pocket near the interface of the two helicase domains (D1 and D2). Whole-genome CRISPR modifier screens with Compound C and a close analog of HRO761 in HCT116 and KM12 cells showed generally concordant functional genomic profiles, with perturbations in SMARCAL1, HELLS, and WDR76 enriched and POLQ and RBM6 depleted by WRN inhibition. In conclusion, we report a series of WRN inhibitors that engage a novel cryptic binding site and show a distinct mechanism of inhibition to WRN inhibitors currently in clinical development."

Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • BRIP1 • MSI • POLQ • RBM6 • RECQL • RECQL4 • RECQL5 • WRN

Studying WRN inhibitors with dSTRIDE-WRN assay [WITHDRAWN] (AACR 2025) - "WRN inhibitors, such as HRO761, exploit the synthetic lethality of MSI-H cancers by trapping WRN on DNA, inducing genomic instability, and selectively killing tumor cells...By providing a direct readout of WRN's enzymatic function, the assay offers valuable insights into the molecular mechanisms underlying WRN-targeting therapies. This platform holds the potential for advancing the development and evaluation of WRN inhibitors in MSI-H cancers and beyond."

Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

SNV5686 a differentiated inhibitor of Werner helicase with potent activity against both WT WRN and WRN-C727S mutant proteins for treatment of MSI-H tumors (AACR 2025) - "In vivo, oral administration of low daily doses of SNV5686 potently depletes WRN and induces p21 in tumors and leads to deep tumor regression in an MSI-H colorectal xenograft model.Irreversible WRN inhibitors and the non-covalent inhibitor HRO761 leverage binding to CYS727 in the active site to attain potency and selectivity, and published data show that mutation of CYS727 severely abrogates their activity. Furthermore, toxicology studies with SNV5686 have not revealed adverse findings in hematology or clinical chemistry supporting the potential to combine with standard of care agents including chemotherapy. These data support the clinical investigation of SNV5686 for tumors characterized by MSI-H."

MSI-H • Microsatellite Instability • Oncology • CDKN1A • EGFR • MSI • WRN

NTX-452: a non-covalent, potent, selective and highly efficacious WRN inhibitor with best-in-class potential for the treatment of MSI-H tumors (AACR 2025) - "Washout studies using covalent inhibitors revealed that substantial target engagement was lost in MSI-H cells within 24- hours, suggesting rapid WRN resynthesis may limit sustained target inhibition...The preclinical profile of non-covalent NTX-452 was characterized and compared to clinical-stage WRN inhibitors, including those from Novartis (HRO761, non-covalent) and Roche/Vividion (RO7589831, covalent)...Moreover, NTX-452 promoted durable tumor regression and complete responses in MSI-H PDX models that were refractory to immunotherapy (anti-PD1) or chemotherapy. Lastly, resistance to clinical stage WRN inhibitors was explored and the potential for NTX-452 efficacy in WRN inhibitor resistant cell lines and tumors was evaluated.Taken together, our results highlight the broad, best-in-class potential of NTX-452 in MSI-H tumors and support its advancement to clinical evaluation."

MSI-H • Endometrial Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

Comparative analysis of WRN inhibitors HRO761 and VVD-133214 in a cancer cell panel: insights into MSI status-dependent drug responses (AACR 2025) - "Further, transcriptomic profiling elucidated discrete transcriptional landscapes modulated by each inhibitor, shedding light on their divergent pharmacological mechanisms. This study not only showcases our proficiency in high-throughput screening and bioinformatics but also contributes a wealth of knowledge regarding the MSI-dependent therapeutic responses to WRN-targeted agents, potentially informing future clinical strategies in cancer treatment."

Gastric Cancer • Oncology • Solid Tumor • MSI • WRN

YF087 is a potent and selective inhibitor of WRN, specifically targeting MSI-H cancer cells (AACR 2025) - "YF087 is more effective than both WRN reversible inhibitor HRO761 and irreversible inhibitor RG6457 in the SW48 cellular anti-proliferation assay in the presence of 50% human serum. YF087 also possesses favorable preclinical ADME profiles suitable for clinical development. Based on these findings, YF087 is currently in IND-enabling studies to support phase 1 clinical trial in MSI-H/dMMR cancer patients."

IO biomarker • Late-breaking abstract • MSI-H • Tumor mutational burden • Colorectal Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Ovarian Cancer • MSI • TMB • WRN

Novel WRN drug resistant CDX models (AACR 2025) - "The drug resistant tumor tissues were collected after the in vivo drug resistance appeared as regrowth of tumors under 20 mg/kg HRO761 and 5 mg/kg VVD-214 treatment and dissected for primary cell culture to get the drug resistant cell line by escalating drug concentrations in vitro. The WRN inhibitors resistant cell lines were genotype and phenotype checked by STR and IC50 of cell growth when reached the drug resistant index more than 5 times of that of parental cells and indicated that different WRN inhibitors resistant HCT116 cell lines were successfully established and helpful for the discovery of anti-cancer drugs targeted on resistant to WRN inhibitors."

Microsatellite Instability • Oncology • MSI • WRN

Study of HRO761 Alone or in Combination in Cancer Patients With Specific DNA Alterations Called Microsatellite Instability or Mismatch Repair Deficiency. (clinicaltrials.gov) - P1 | N=123 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | N=184 ➔ 123

dMMR • Enrollment change • Mismatch repair • MSI-H • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor

Microsatellite instable cancer cells acquire on-target resistance mutations to WRN helicase inhibitors. (PubMed, Mol Cancer Ther) - "In this study, we characterized resistance mechanisms using the clinical candidate HRO761 and two novel inhibitors in MSI cell lines and xenograft models...This chemotype-specific resistance profile suggests opportunities for developing next-generation inhibitors that retain activity against resistant variants and for implementing rational treatment strategies with existing inhibitors. Overall, our findings demonstrate that on-target resistance to WRN inhibitors emerges rapidly in dMMR backgrounds but also highlight potential approaches to overcome resistance, supporting continued development of WRN-targeted therapies for MSI cancers."

Journal • Tumor mutational burden • Metabolic Disorders • Microsatellite Instability • Oncology • MSI • TMB • WRN

Study of HRO761 Alone or in Combination in Cancer Patients With Specific DNA Alterations Called Microsatellite Instability or Mismatch Repair Deficiency. (clinicaltrials.gov) - P1 | N=327 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | Trial completion date: May 2029 ➔ Aug 2027 | Trial primary completion date: May 2029 ➔ Aug 2027

dMMR • Enrollment closed • Mismatch repair • MSI-H • Trial completion date • Trial primary completion date • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor

Structural insights into WRN helicase reveal conformational states and opportunities for MSI-H cancer drug discovery. (PubMed, Commun Biol) - "Biochemical and biophysical data demonstrate how nucleotide and inhibitor binding remodel these conformations and suggest that known clinical inhibitors (HRO761 and VVD-133214) function by locking WRN in inactive, 'off-DNA' states. Resistance emerged rapidly in vitro, through acquired point mutations as well as altered WRN expression. Together, our findings provide a structural framework for the WRN structural cycle and support the development of next-generation 'on-DNA' inhibitors to overcome resistance."

Journal • MSI-H • Metabolic Disorders • Microsatellite Instability • Oncology • MSI • WRN

In situ detection of WRN activity and R-loops accumulation at DNA double-strand breaks using the STRIDE platform (AACR-NCI-EORTC 2025) - "Treatment with the selective WRN inhibitor HRO761 produced a time-dependent reduction of WRN-associated DSB signal, demonstrating the assay's ability to monitor pharmacological inhibition of WRN. Using dSTRIDE-R-loops, we observed increases in R-loops at DSBs following treatment with hydroxyurea (HU) and camptothecin (CPT), consistent with the induction of replication stress through nucleotide depletion and topoisomerase I inhibition, respectively.Together, these assays extend the STRIDE technology to interrogate two interrelated processes central to cancer biology: WRN function and R-loop dynamics at DNA breaks. dSTRIDE-WRN provides a direct, quantitative tool for evaluating WRN activity and inhibition in MSI-H cancers, while dSTRIDE-R-loops enables sensitive detection of R-loops at sites of genome instability. By combining spatial precision with biological relevance, the dSTRIDE assays offer a powerful platform to advance understanding of replication stress and..."

Late-breaking abstract • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • TOP1 • WRN