On April 27, 2020 Ribon Therapeutics, a clinical-stage oncology company developing first-in-class therapeutics targeting stress response pathways, reported new preclinical data to be presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I. RBN-2397, a first-in-class PARP7 inhibitor, achieves complete tumor regressions in preclinical cancer models (Press release, Ribon Therapeutics, APR 27, 2020, View Source [SID1234556633]). RBN-2397 is Ribon’s lead program and is currently being evaluated in a Phase 1 clinical trial in advanced-stage solid tumors. In addition, in vitro data illustrate the immune-suppressive role PARP14 plays in the tumor microenvironment, suggesting PARP14 targeting could generate an anti-cancer inflammatory response similar to that seen using checkpoint inhibition.

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"The striking tumor regressions we observed in cancer models after dosing with single agent RBN-2397 is what encouraged us to move the program into the clinic so quickly and we look forward to sharing our Phase 1 data when it becomes available," said Kevin Kuntz, Ph.D., Senior Vice President of Molecular Discovery, Ribon Therapeutics. "These data continue to validate our strategy of targeting novel enzyme pathways, starting with the monoPARPs, where there are multiple targets that support tumor growth and immune suppression that can be inhibited therapeutically."

"Our data using primary cell and innovative human cancer models with a novel PARP14 inhibitor support the potential of PARP14 as a therapeutic target. We’ve clearly demonstrated the role of PARP14 in cancer immune suppression and that inhibiting it has the potential to yield responses on par with checkpoint inhibitors," said Heike Keilhack, Ph.D., Senior Vice President of Biological Sciences, Ribon Therapeutics. "Together with the RBN-2397 data, these findings further demonstrate the potential of our platform for both novel target discovery and validation, as well as clinical translation."

Abstract title: RBN-2397 – A First-in-Class PARP7 Inhibitor Targeting a Newly Discovered Cancer Vulnerability in Stress-Signaling Pathways (abstract ID: DDT02-01)
Oral Session: New Drugs on the Horizon – Part 2
Date: Tuesday, April 28, 2020
Time: 10:50 a.m. EDT

Data summary:
The company is presenting an overview of the discovery and preclinical testing of RBN-2397, a first-in-class PARP7 inhibitor targeting a novel cancer vulnerability. PARP7 acts as a brake on cytosolic nucleic acid sensing and the Type I interferon response in tumor cells. Inhibition of PARP7 by RBN-2397 restores Type I IFN signaling as demonstrated by the induction of STAT1 phosphorylation and upregulation of genes enriched for Type I IFN signaling in NCI-H1373 lung cancer cells. Oral dosing of RBN-2397 results in complete tumor regression in a NCI-H1373 lung cancer xenograft model and induces complete tumor regressions with tumor-specific adaptive immune memory in an immunocompetent cancer model. The therapeutic effect of RBN-2397 was shown to be dependent on tumor-derived Type I IFN signaling.

RBN-2397 is currently being studied in a Phase 1 multicenter clinical trial. Additional information on this clinical trial can be found on www.ClinicalTrials.gov (Study Identifier Number – NCT04053673).

Abstract title: RBN012759 – A Potent and Selective PARP14 Inhibitor Decreases Pro-tumor Macrophage Function and Elicits Inflammatory Responses in Tumor Explants (abstract ID: 1038)
Oral Session: Advances in Drug Design and Discovery
Date: Monday, April 27, 2020
Time: 12:20 p.m. EDT

Data summary:
PARP14 helps cancer cells survive and dampens immune responses in two ways: by promoting pro-tumor IL-4 driven gene expression and by downregulating IFN-γ signaling pathways in tumor associated immune cells such as macrophages. In a preclinical setting, Ribon describes the potential of PARP14 inhibition, evaluating RBN012759, the first potent and highly selective inhibitor of PARP14. Ribon demonstrated that RBN012759 effectively binds to and inhibits PARP14, and PARP14 inhibition with RBN012759 reversed IL-4 driven gene expression in macrophages. Treatment of primary tumor cultures with RBN012759 induces an inflammatory response similar to that seen using an anti-PD1/anti-CTLA4 checkpoint inhibitor combination.