CAMBRIDGE, MA, USA I September 14, 2021 I KSQ Therapeutics, a biotechnology company developing drugs to treat cancer and autoimmune diseases using its proprietary, integrated discovery platform to systematically screen the whole genome in cancer and immune cells, today announced the initiation of dosing in a Phase 1 clinical study of KSQ-4279, a first-in-class USP1 inhibitor, in patients with advanced solid tumors.

“This is an important milestone for KSQ as we initiate clinical development of KSQ-4279, a compound that offers great potential for robust and durable anti-tumor activity in a number of cancers,” said Qasim Rizvi, Chief Executive Officer of KSQ. “This is also a strong proof point for both our team and our CRISPRomics® platform, which quickly enabled us to identify and validate USP1 as a promising target that exploits synthetic lethality in cancers with specific DNA repair defects. This work was part of our broader efforts to run expansive genome-scale screens across both a diverse range of cancer cell lines and multiple immune cell types, including T cells, NK cells, and Tregs. We believe that the insights derived from our platform create tremendous opportunities to develop therapies with curative potential for a wide range of cancers, in particular solid tumors and autoimmune diseases.”

“KSQ-4279 showed tumor growth inhibition as a single agent and led to deep and durable tumor regressions when administered in combination with a PARP inhibitor in multiple preclinical tumor models,” said Frank Stegmeier, Ph.D., Chief Scientific Officer of KSQ. “Based on these data, we believe that KSQ-4279 has the potential to be an important treatment for many different tumor types. Additional preclinical data indicate combination opportunities beyond PARP inhibitors, which sets KSQ-4279 up as a potential pipeline of treatments within a single molecule.”

KSQ-4279 preclinical data highlights:

  • KSQ-4279 is active as a monotherapy in ovarian PDX models, with tumor regressions observed at doses well below its maximum tolerated dose.
  • KSQ-4279 activity is seen in cancers that harbor specific defects in homologous recombination (HR), a genetic driver event that is prevalent in several solid tumor types.
  • The combination of KSQ-4279 with a PARP inhibitor led to more pronounced antitumor activity than either agent alone across multiple ovarian and TNBC PDX models, leading to durable tumor regressions in settings where PARP inhibitors only achieved partial tumor control.
  • Preclinical safety data indicate that KSQ-4279 is well-tolerated.
  • KSQ-4279 induces cell cycle arrest and DNA damage leading to apoptosis and cell death in BRCA1 mutant cells.
  • Functional genomic resistance screens indicate that the major genetic drivers of resistance to USP1 and PARP inhibitors are distinct, indicating that combination treatment may be able to delay or prevent the emergence of resistance.

KSQ utilized its proprietary CRISPRomics platform to identify the deubiquitinating enzyme USP1 as an attractive cancer target with established roles in DNA damage repair processes that are distinct from PARP inhibitors and other approaches currently being tested in the clinic. Potent and highly selective inhibitors of USP1 were developed, and profiling of the clinical development candidate KSQ-4279 across a large collection of tumor models confirmed an enriched response rate in cancers with genetic alterations in BRCA1/2 or other HRD lesions.

This Phase 1 clinical trial is being conducted at five centers in the United States and is expected to enroll approximately 140 patients with advanced solid tumors. It is a dose-escalation and expansion study of KSQ-4279 as a monotherapy and in combinations. The study’s primary endpoint is to assess the safety of KSQ-4279 both alone and in combination, determine the maximum tolerated dose, and establish a recommended Phase 2 dose level. Secondary endpoints include characterizing the pharmacokinetics of KSQ-4279 and evaluating its preliminary antitumor activity both alone and in combination. The trial will also explore potential predictive biomarkers and other genetic factors and their correlation with clinical outcomes.

About KSQ Therapeutics

KSQ Therapeutics is advancing a pipeline of tumor- and immune-focused drug candidates to treat cancer and autoimmune disease across multiple drug modalities, including targeted therapies, adoptive cell therapies, and immunotherapies. KSQ’s proprietary CRISPRomics® discovery engine enables genome-scale, in vivo validated, unbiased drug discovery across broad therapeutic areas. For more information, please visit the company’s website at and follow @ksq_tx on Twitter.

SOURCE: KSQ Therapeutics