XL495 / Exelixis - LARVOL DELTA

XL495 is a potent, selective, and orally bioavailable inhibitor of PKMYT1 (AACR 2025) - P1 | "Antitumor activity of XL495 in combination with irinotecan or gemcitabine was evaluated in a colorectal cancer CDX model. XL495 is potentially a best-in-class PKMYT1 inhibitor. PK assessments in conjunction with preclinical antitumor activity suggest that once-daily oral administration of XL495 may achieve clinical activity alone or in combination with DNA-damaging agents. XL495 is currently under investigation in a phase 1 first-in-human study in patients with advanced solid tumors (NCT06630247)."

First-in-human • Breast Cancer • Colorectal Cancer • Oncology • Solid Tumor • CCNE1 • CDK1 • PKMYT1

Enantioselective Suzuki-Miyaura Chemistry: Route Evolution for the Synthesis of PKMYT1 Inhibitor XL495. (PubMed, J Org Chem) - "A crystallization method for selectively purifying the target atropisomer was developed through high-throughput experimentation (HTE), enabling an enantiomeric excess (ee) of >95%. This new chemistry has been demonstrated and shows promise for utility at large scale, typical of a late-stage clinical and commercial route, due to significant improvements in overall yield, process mass intensity (PMI), and production efficiency."

Journal • PKMYT1

A Dose-escalation, Dose-finding, and Expansion Study of XL495 in Participants With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=9 | Terminated | Sponsor: Exelixis | N=124 ➔ 9 | Trial completion date: Nov 2027 ➔ May 2025 | Recruiting ➔ Terminated | Trial primary completion date: Nov 2027 ➔ May 2025; Company Decision

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Bladder Cancer • Genito-urinary Cancer • Kidney Cancer • Oncology • Solid Tumor • Urothelial Cancer

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) - "Progress of Phase 1 Clinical Trials for XB010 and XL495. Exelixis initiated clinical development of its XB010 and XL495 pipeline programs in 2024....The first-in-human, global phase 1 trial of XB010 is evaluating the compound in patients with locally advanced or metastatic solid tumors. The dose-escalation stage of the study is evaluating XB010 as a single agent and in combination with pembrolizumab to inform the cohort-expansion stage....The first-in-human phase 1 clinical trial of XL495 is evaluating the compound in patients with advanced solid tumors; the dose-escalation stage of the study is designed to determine the maximum tolerated dose of XL495....Exelixis plans to present preclinical data from the XL495 program at a scientific meeting in 2025."

P1 data • Trial status • Solid Tumor

A Dose-escalation, Dose-finding, and Expansion Study of XL495 in Participants With Locally Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=124 | Recruiting | Sponsor: Exelixis

Combination therapy • Metastases • New P1 trial • Bladder Cancer • Genito-urinary Cancer • Kidney Cancer • Oncology • Solid Tumor • Urothelial Cancer

Exelixis Announces Preliminary Fiscal Year 2023 Financial Results, Provides 2024 Financial Guidance, and Outlines Key Priorities and Milestones for 2024 (Exelixis Press Release) - "...expects to file IND applications for the XB628 PD-L1-NKG2A bispecific antibody and XL495 small molecule PKMYT1 inhibitor programs in the second half of 2024 if preclinical data continue to be supportive....Exelixis has two DC programs that may be the subjects of IND filings in 2025, including the XB371 TF-Topoisomerase I inhibitor ADC and XB064 ILT-2 monoclonal antibody programs, and the XB033 IL13Ra2-Topoisomerase I inhibitor ADC that may be the subject of an IND filing in 2026. In 2024, the company expects to designate two new programs to DC status, including a small molecule PLK4 inhibitor and an additional ADC."

IND • Oncology