Preclinical Translational Research Suggests a Clinical Trial Strategy for a Novel MALT1 Inhibitor ONO-7018/CTX-177 Against Malignant Lymphomas

Introduction Malignant lymphomas, relapsed or refractory B Cell Non-Hodgkin Lymphoma like B-cell diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), are still clinically intractable as patients with these lymphomas carry a dismal prognosis. Genome sequence analysis data on these lymphomas suggest that the gene mutations of mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) -upstream molecules, such as CD79A/B and CARD11, eventually promotes the activation of MALT1's protease activity; this protease activity of MALT1 is known as a key growth or survival regulator for intractable lymphomas that carry these mutations. Previously, we reported the generation of a novel small molecule inhibitor, CTX-177 (currently renamed to ONO-7018 by Ono Pharmaceutical Co., Ltd.), which acts on MALT1 with high potency and specificity. In addition, we showed that ONO-7018 demonstrated preclinical efficacy along with target engagement in several lymphoma models (Morishita D et al., Blood (2020) 136 (Supplement 1): 3-4.).

Results To identify potential strategies for a clinical trial of ONO-7018, we conducted translational research to elucidate (1) combination strategies with other key medications, (2) patient selection biomarkers to illuminate sensitivity to ONO-7018 and (3) pharmacodynamics (PD) markers to monitor the suppression of MALT1.

After searching for combination strategies (1), ONO-7018 exhibited synergistic combination effect with a BTK inhibitor in vitro along with target inhibition. In addition, the MALT1 inhibitor showed an anti-tumor effect against an ABC-DLBCL cell line derived xenograft (CDX) model. Thus, combination treatment with BTK inhibitor is expected to be the treatment strategy of ONO-7018. Next, regarding biomarkers of sensitivity (2), we found that ONO-7018 selectively inhibits the in vitro growth of cell lines expressing cleaved forms of MALT1 substrates. Additionally, in vivo data from CDX and patient derived xenograft model were consistent with in vitro data. Interestingly, CRISPR-Cas9 mediated A20 knockout attenuates the sensitivity of cell line model toward ONO-7018 treatment. Given these findings, these cleaved forms of MALT1 substrates and the loss of function gene mutation on A20 could become biomarkers to illuminate sensitivity to ONO-7018. Finally, to identify pharmacodynamic markers of ONO-7018 (3), panel analysis of cytokine production following CD3/CD28 stimulation was conducted. Before starting this experiment, we confirmed that ONO-7018 could inhibit the cellular activity of the two T-cell receptor signaling stimulated forms of MALT1 splice variants. Consistent with the inhibitory mode of ONO-7018 on these MALT1 splicing forms, some cytokines’ production was clearly abrogated; these cytokines could be potential PD markers in a clinical trial.

Conclusion The results from these translational research studies support the preparation of a clinical trial by clearly defining patient stratification biomarkers, combination strategies, and PD monitoring. These data underscore the potential therapeutic impact of ONO-7018 as a single-agent or combination partner with other inhibitors like BTK inhibitor and elucidate the sensitivity and response of ONO-7018 for the treatment of malignant lymphomas.

Morishita:Chordia Therapeutics lnc: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties. Mizutani:Chordia Therapeutics inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties. Yamakawa:Chordia Therapeutics Inc.: Current Employment, Current holder of stock options in a privately-held company. Arikawa:Chordia Therapeutics Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Tozaki:Chordia Therapeutics inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company, Patents & Royalties; Kyowa Kirin Co., Ltd.: Current Employment, Patents & Royalties: Japanese Patent Application No.2002-078819; Honda Motor Co., Ltd.: Current equity holder in publicly-traded company. Kataoka:JCR Pharmaceuticals Co., Ltd: Research Funding; Kyowa Kirin Co Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd: Research Funding; Asahi Kasei Asia Pacific Co., Ltd.: Research Funding; National Cancer Center Research Institute: Other: na; MOCHIDA PHARMACEUTICAL CO.,LTD.: Research Funding; Chordia Therapeutics Inc.: Research Funding; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Eisai Co., Ltd.: Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in publicly-traded company; Takeda Pharmaceutical Company Limited.: Research Funding; Novartis Pharma K.K.: Consultancy; CHUGAI PHARMACEUTICAL CO., LTD.: Consultancy, Research Funding; Department of Medicine, Keio University School of Medicine: Other: na. Yoda:Chordia Therapeutics inc.: Research Funding. Izutsu:Beigene, AstraZeneca, Ono Pharmaceutical, AbbVie, Novartis, Chugai: Consultancy; Eizai, Chugai, Janssen, AstraZeneca, Novartis, Bristol Myers Squibb, Kyowa Kirin ,AbbVie, Ono Pharmaceutical , Eli Lilly, MSD, Daiichi Sankyo, Symbio, Takeda: Honoraria; MSD, AstraZeneca, AbbVie, Eizai, Incyte, Janssen, Yakult, Kyowa Kirin, Ono Pharmaceutical, Daiichi Sankyo,　 Chugai, Beigene, Genmab, Loxo Oncology: Research Funding. Minami:Takeda: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria. Ogawa:Astellas: Speakers Bureau; Otsuka Pharmatheutical: Research Funding; Chordia Threapeutics: Consultancy, Current equity holder in publicly-traded company, Research Funding; Astrazeneca: Speakers Bureau; 2014-191287: Patents & Royalties; PCT/JP2014/062112 (WO01): Patents & Royalties; Novartis: Honoraria, Speakers Bureau; 62/187386 (US01): Patents & Royalties; 15/353395 (US03): Patents & Royalties; MSD: Speakers Bureau; Sysmex: Honoraria; ASAHI Genomics: Current equity holder in publicly-traded company; Esai Pharmatheutical: Consultancy; Pfaizer: Speakers Bureau; 2013-526957 (JP02): Patents & Royalties; Kirin/Chugai: Speakers Bureau; The Mitsubishi foundation: Honoraria; The Chemo-Sero-Therapeutic Research Institute: Speakers Bureau; DaiichiSankyo: Speakers Bureau; Nanpu Hospital: Research Funding; 2013-096582 (JP01): Patents & Royalties; 2015-239547: Patents & Royalties; Clinical Research Support Center Kyushu: Research Funding.