Artios Pharma Publishes Preclinical Data on The First Selective Small Molecule Polθ Polymerase Inhibitor in Nature Communications


• Artios’ small molecule Polθ inhibitor elicits BRCA-gene synthetic lethality and PARP inhibitor synergy
• Genetic screening reveals biomarkers within the PARP inhibitor resistance setting to enable patient stratification in clinical development of Polθ inhibitors
• Artios’ Polθ program on-track for first-in-human studies before year-end 2021
• Polθ program developed using Artios’ DDR-based platform and small molecule drug design capabilities

Artios Pharma Limited (Artios), a leading DNA Damage Response (DDR) company exploiting a broad DDR-based platform and small molecule drug design capabilities to develop a diverse pipeline of product candidates for the treatment of cancer, today announced the publication of a peer reviewed article titled, “Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance” in Nature Communications. Using novel small molecule tool compounds, the preclinical data generated in collaboration with researchers at the Institute for Cancer Research, London, and Cancer Research U.K., validates the Company’s approach to developing a potential first-in-class Polθ inhibitor, which demonstrated potent, selective Polθ inhibition, BRCA-gene synthetic lethality in a potentially PARP-resistant setting, and PARP inhibitor synergy.

Professor Chris Lord, Professor of Cancer Genomics at The Institute of Cancer Research, London and study co-leader, said: “Polθ is an ideal DNA damage response drug target as it is tumor specific, overexpressed in many tumors and found at low levels in healthy tissues. These results show that Polθ inhibitors exhibited exquisite selectivity and on-target activity, affecting only Polθ-Mediated End Joining and not other forms of DNA repair. This specificity, combined with demonstrated synthetic lethality with BRCA mutations, as well as synergy with a PARP inhibitor, suggest small molecule Polθ inhibition has broad utility for targeted clinical development in genetic backgrounds that are reliant on Polθ activity. I look forward to seeing how Polθ inhibitors perform in clinical trials and hope they will be able to benefit patients by opening up a new way of overcoming drug resistance.”

Dr. Graeme Smith, Chief Scientific Officer of Artios Pharma, said: “This preclinical dataset further strengthens the scientific foundation of our Polθ inhibitor program. This publication is a testament to the deep scientific heritage and expertise in DNA damage response that drives the Artios discovery platform and pipeline. The extensive efforts of our team have delivered insights into the genetics and mechanisms that underlie the activity of Polθ inhibitors, leaving us well positioned to pursue a strategic development plan in the clinic across a wide range of opportunities.”

Dr. Niall Martin, Chief Executive Officer at Artios Pharma, said: “These published results provide a clear rationale for three high-value opportunities for Polθ inhibitors: in the monotherapy setting to treat Polθ dependent cancers; in combination with PARP inhibitors to expand the utility of this important drug class; and in combination with DNA damaging therapies such as ionizing radiation to provide effective and widespread use of these agents. We are on track to launch our Polθ clinical program before year end, building upon our strong execution which includes strategic partnerships with Merck KGaA and Novartis, and our ongoing Phase 1 study of ART0380, a potential best-in-class ATR inhibitor.”

Publication highlights include:

• Artios’ small molecule Polθ inhibitors provided nanomolar potent, selective, allosteric inhibition of the polymerase function of DNA polymerase Polθ, selectively inhibiting Theta-Mediated End Joining DNA repair without targeting Non-Homologous End Joining or Homologous Recombination.
• Inhibiting Polθ elicited DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumor cells and enhanced the effects of a PARP inhibitor.
• Genetic screening revealed defects in the Shieldin complex causing both PARP inhibitor resistance and synthetic lethality with Polθ inhibition, thus identifying a subset of PARP inhibitor resistant disease with the potential to be specifically targeted with Polθ inhibitors.
• Sensitivity of BRCA1, Shieldin-defective tumours to Polθ inhibition was confirmed in vivo laying the foundations for preclinical and clinical development.

Published on: 17.06.21

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