DDR Focused Pipeline for a Broad Range of Solid Tumors

Pipeline Overview

 

ART0380 is an ataxia telangiectasia and Rad3-related protein (ATR) inhibitor with potential to induce DNA damage in sensitive cancer tissue while preserving DNA integrity in healthy tissue.

Mechanism of Action

ATR is an important signaling protein kinase in the cellular DNA Damage Response to replication stress and DNA breaks that occur as cells multiply.

Clinical Development of ART0380

ART0380 is an oral anticancer agent in development for the treatment of patients with solid tumors harboring defects in the DDR or undergoing high levels of replication stress.

ART0380 is being investigated for the treatment of multiple advanced solid tumors both as a monotherapy and a combination therapy with established as well as novel agents that cause DNA damage or suppress a cancer cell’s ability to repair DNA damage.

Clinical Trials

ART0380 is currently being evaluated in an open-label, multi-center, Phase I/IIa study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of ART0380 as monotherapy and in combination with gemcitabine or irinotecan in patients with advanced or metastatic solid cancers.

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ART0380 is also being studies in a phase II program evaluating multiple tumor types with genetic abnormalities indicative of sensitivity to ATR inhibition.

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ART0380 Profile

• Rapid absorption leads to a high concentration that can potentially induce DNA damage in sensitive DDR defective cancer tissue
• Quick elimination potentially preserves DNA integrity in DDR competent, normal tissue
• Clinical activity as monotherapy and in combination
• Clinically active in genetically selected cancers of high unmet need

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Polθ is a DNA repair enzyme that is highly expressed in cancer cells but is virtually absent in most healthy tissues. Certain DDR-defective cancer cells, some of which are resistant to standard of care therapies are highly dependent on Polθ for survival.

Artios is developing a leading franchise in inhibiting and understanding Polθ as a potent cancer target. Our Polθ program includes potentially first-in-class oral, potent, and highly selective reversible inhibitors targeting the Polθ polymerase domain.

Mechanism of Action

Polθ, a DNA polymerase, is involved in the DNA double strand break repair process of microhomology mediated end joining (MMEJ) that is utilized in many tumors.

Clinical Development

Artios’ Polθ inhibitors are oral anticancer agents in development for the treatment of patients across multiple solid tumor types, including PARP inhibitor resistant cancers and tumors harboring defects in DNA repair.

Artios will investigate Polθ inhibitors as both a monotherapy and as a combination therapy with PARP inhibitors.  Polθ also has the potential to be explored in combination with chemotherapies, ionizing radiation and immune oncology medicines.

Clinical Trials

ART6043 is being evaluated in open label, multi-center studies. They assess the safety, tolerability, pharmacokinetics, and clinical activity of each compound. They are administered orally, as monotherapy and in combination with other anticancer medicines in patients with advanced or metastatic solid tumors. ART6043 is an orally bioavailable, small molecule inhibitor of the Polθ polymerase and the ART6043 Phase I study commenced in 2023.

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Polθ Profile

• Selective tumor expression
• Low toxicity
• Therapeutic Index (TI) advantages for combination treatments
• Synergistic activity in combination

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Nucleases

Artios has an ongoing research collaboration and license agreement with Merck KGaA, a German-based healthcare and life sciences pharmaceutical company, to identify novel DDR nuclease inhibitors for the treatment of cancer. Artios has built a unique technology platform for prosecuting nucleases. Leveraging our expertise in DDR drug discovery and our bespoke DcoDeR platform, we have developed a portfolio of multiple nuclease programs, each of which has the potential to deliver a first-in-class therapy in this novel target class. Artios has granted Merck KGaA a sole license to certain intellectual property rights to research and develop compounds.

Nucleases are the molecular scissors responsible for cutting DNA. Misregulation of nucleases has been implicated in a wide variety of diseases, including cancer. Several clinically relevant synthetic lethalities have been reported (e.g. HRD and ALT) making nucleases attractive therapeutic targets. To date, DNA repair nucleases are a completely undrugged enzyme class and the full potential of targeting nucleases as a therapeutic strategy remains unexplored.

Radioligand LT (RLT)Sensitizers

Artios has an ongoing research collaboration and license agreement with Novartis, a global healthcare company based in Switzerland, to identify DNA Damage Response (DDR) targets and develop medicines to use in combination with Novartis’s proprietary radioligand therapies.

Combining the broad DDR expertise of Artios and Novartis’ experience with radioligand therapies, we will apply cutting edge technologies to identify avenues that increase the cancer sensitivity to radioligand therapies. Using the DcoDeR platform, Artios will study the DDR following treatment with radioligand therapies and use screening approaches to identify DNA Damage Response targets that enhance patient sensitivity to therapy.

Alternative Lengthening of Telomeres (ALT)

ALT is a DDR-mediated telomere maintenance mechanism that is an important survival mechanism in 10-15% of all cancers, with even higher prevalence in some cancer subtypes such as soft tissue sarcomas.

Artios’ DcoDeR platform encompasses an ALT discovery platform focused on identifying and developing new therapies that could foster potential partnerships to deliver first-in-class targets for ALT.