VRTX531 / Vrise Therap - LARVOL DELTA

USP1 inhibition disrupts DNA repair and potentiates the cytotoxic effects of DNA-damaging agents via persistent DNA damage in cancer cells (AACR-NCI-EORTC 2025) - "Combined treatment with VRTX531 and DNA-damaging agents resulted in a synergistic increase in cytotoxicity, as reflected by significantly reduced cell viability relative to DNA damage alone. These findings underscore the broader therapeutic potential of USP1 inhibition in not only sensitizing cancer cells to DNA-damaging agents but also overcoming chemo-resistance driven by DDR pathway activation."

Oncology • FANCD2 • PCNA • USP1

Effectiveness of USP1 inhibitor (VRTX531) in gynecological cancers with diverse BRCA mutation status (AACR 2025) - "Our Previous work demonstrated that treatment with PARPi alone led not only to a delayed onset of response but also showed statistically significant variability between subjects, in contrast the combination of VRTX531 and PARPi led to rapid onset of response, followed by complete tumor regression with an TGI >98%, in a TNBC Xenograft of MDA-MB-436. USP1 inhibitor VRTX531, exhibits best-in-class pharmacokinetics, with exemplary safety profile, that supports its further development."

Breast Cancer • Gynecologic Cancers • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • BRCA • BRCA1 • BRCA2 • HER-2 • HRD • USP1

Role of USP1 in overcoming chemoresistance Independent of BRCA mutation status (AACR 2025) - "Cells were treated with Cisplatin to induce DNA damage, followed by treatment with VRTX531 a USP1 inhibitor and/or a PARP inhibitor assessed by in vitro cell based assays such as cell viability, γH2AX foci formation, and comet assay. These findings suggest that targeting USP1 in combination with PARP inhibition may be a promising therapeutic strategy to overcome chemoresistance, providing a potential treatment approach for tumors with or without BRCA mutations. Further investigation into the mechanistic underpinnings of this combination therapy is warranted to optimize its clinical application."

Oncology • BRCA • USP1

VRTX531: A Novel Best-in-Class USP1 Inhibitor for the Treatment of Triple-Negative Breast Cancer (SABCS 2024) - "USP1 inhibitors have the potential to overcome resistance to chemo and PARPi by targeting compensatory mechanisms that allow HR-deficient cancer cells to survive. USP1 inhibitor VRTX531, exhibited best-in-class pharmacokinetics, with exemplary safety profile, that supports its further development."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • BRCA1 • BRCA2 • USP1

VRTX531, a best-in-class USP1 inhibitor for Homologous Deficient Tumors (EORTC-NCI-AACR 2024) - "In-vivo data demonstrated early proof of concept for USP1 inhibitor for use in BRCA or HRR deficient tumors. USP1 inhibitors may overcome chemo- and PARPi resistance, by inhibiting the compensatory pathways that help revive the cancer cells which are HR Deficient.VRTX531 exhibited best-in-class pharmacokinetic properties, distinguishing it from other USP1 inhibitors currently in development with excellent safety and tolerability profile."

Late-breaking abstract • Breast Cancer • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2 • HRD • USP1

VRTX531: A potent inhibitor of USP1 for treatment of BRAC1/2mut and HRD+ cancers (ESMO-BC 2024) - "In combination studies with first and second-generation PARP inhibitors, VRTX531 demonstrated robust synergy. Conclusions VRTX531 exhibited profound activity alone and in combination with PARP inhibitors in BRCA1/2 mut and HRD+ tumours and is currently ongoing late-preclinical studies."

Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BRCA1 • BRCA2 • USP1

VRTX531, a potent and selective inhibitor of USP1 for treatment of BRAC1/2mut and HRD+ cancers (AACR 2024) - "VRTX531 exhibited exemplary pharmacokinetics and safety in preclinical studies and is expected to enter preclinical testing in H1, 2024. VRTX531 will be evaluated as a single agent and in combination with PARP1 inhibitor in patients with BRCA1/2 mut or HRD+ tumors that are naïve to PARP inhibitors and with prior PARP inhibitor history."

Late-breaking abstract • Oncology • BRCA1 • BRCA2 • USP1