XL309 / Insilico Medicine, Exelixis - LARVOL DELTA

USP1 inhibition: A journey from target discovery to clinical translation. (PubMed, Pharmacol Ther) - "RO7623066 (KSQ-4279) reported an acceptable safety profile during a phase I dose escalation study, with anemia being the most common side effect, and demonstrated robust pharmacokinetic, pharmacodynamic, and clinical activity. Other USP1 inhibitors, including SIM0501, XL309-101, and HSK39775, are currently in early clinical development. In this review, we provide an overview of the molecular function of USP1 and its importance as a therapeutic target in oncology, before focusing on the current state of preclinical and clinical development of USP1 inhibitors."

Journal • Review • Hematological Disorders • Oncology • Targeted Protein Degradation • BRCA1 • FANCD2 • FANCI • PCNA • USP1

XL309 is a potent, selective, and orally bioavailable USP1 inhibitor active as monotherapy and in combination with PARP inhibitors or irinotecan (AACR 2025) - P1 | "XL309 also elicited durable tumor regression in combination with saruparib and irinotecan in a CDX model, and with olaparib in a PDX model... XL309 is potentially a best-in-class USP1 inhibitor. PK assessments in conjunction with preclinical antitumor activity suggest that once daily oral administration of XL309 may achieve clinical activity alone or in combination with PARP inhibitors. XL309 is currently under investigation in a phase 1 first-in-human trial as monotherapy and in combination with olaparib in patients with advanced solid tumors (NCT05932862)."

Combination therapy • Monotherapy • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2 • PCNA • USP1

Exelixis to Present Positive Preclinical Data Across Its Pipeline Portfolio for Advanced Cancers at AACR 2025 (Businesswire) - "Exelixis will present preclinical data for XL495 and XL309, small molecules that have demonstrated synthetic lethality in the context of certain genetic anomalies frequently found in some tumors. Preclinical data will also be presented for the PD-L1xNKG2A-targeting bispecific antibody XB628 and the tissue factor-targeting antibody-drug conjugate XB371."

Preclinical • Oncology

Exelixis Announces Preliminary Fiscal Year 2024 Financial Results, Provides 2025 Financial Guidance and Outlines Key Priorities and Milestones for 2025 (Businesswire) - "Advance XL309 Phase 1 Program in PARP Inhibitor Refractory Setting and Beyond. XL309, Exelixis’ potentially best-in-class small molecule inhibitor of USP1, is currently being evaluated in a phase 1 study as a single agent and in combination with olaparib, a PARP1/2 inhibitor, in patients with advanced solid tumors. Enrollment in the dose escalation cohorts for XL309 monotherapy and olaparib combination are ongoing....Exelixis plans to present data from the XL309 program at a scientific meeting in 2025."

P1 data • Trial status • Solid Tumor

A Phase 1 Study of XL309 (ISM3091) Alone and in Combination in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=377 | Recruiting | Sponsor: Exelixis | N=66 ➔ 377 | Trial completion date: Dec 2025 ➔ Aug 2029 | Trial primary completion date: Jul 2024 ➔ Jan 2029

Combination therapy • Enrollment change • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor

First-in Human Phase I Study of ISM3091 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=66 | Recruiting | Sponsor: InSilico Medicine Hong Kong Limited | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Breast Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor

Exelixis and Insilico Medicine Enter into Exclusive Global License Agreement for ISM3091, a Potentially Best-in-Class USP1 Inhibitor (Businesswire) - "Exelixis...and Insilico Medicine...announced that the companies have entered into an exclusive license agreement granting Exelixis global rights to develop and commercialize ISM3091, a potentially best-in-class small molecule inhibitor of USP1, which has emerged as a synthetic lethal target in the context of BRCA-mutated tumors. Under the terms of the agreement, Insilico granted Exelixis an exclusive, worldwide license to develop and commercialize ISM3091, and other USP1-targeting compounds, in exchange for an upfront payment to Insilico of $80 million anticipated in the third quarter 2023. Insilico is also eligible to receive future development, commercial, and sales-based milestone payments, as well as tiered royalties on net sales."

Licensing / partnership • Oncology

First-in Human Phase I Study of ISM3091 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=66 | Not yet recruiting | Sponsor: InSilico Medicine Hong Kong Limited

Metastases • New P1 trial • Breast Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor

Insilico Medicine receives IND approval for novel AI-designed USP1 inhibitor for cancer (Eurekalert) - "Insilico Medicine...announced that the U.S. Food and Drug Administration (FDA) recently approved the initial investigational new drug (IND) application for ISM3091 for the treatment of patients with solid tumors.... Insilico has filed the IND submission to the U.S. FDA and the NMPA and expects to first initiate the study in the U.S. center in July 2023."

IND • New P1 trial • Oncology • Solid Tumor

ISM3091, a novel selective USP1 inhibitor as a targeted anticancer therapy (AACR 2023) - "In vitro data revealed that the combination of ISM3091 and olaparib, a PARPi, had synergistic activity in cell lines with HRD. ISM3091also displayed very favorable ADME propertiesand PK profiles, and GLP toxicology studies indicated that it was well tolerated without significant gastrointestinal toxicity or hematological toxicity. These data support the future clinical development of ISM3091 as a potential best-in-class USP1 inhibitor not only for PARPi-resistant/responsive HRD-mutant cancers, both, as a single agent as well as in combination with PARPi, but also for subsets of HR-proficient cancers."

Breast Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • BRCA1 • HRD • PCNA • USP1