625. LYMPHOMA: PRE-CLINICAL – CHEMOTHERAPY AND
`BIOLOGIC AGENTS: POSTER III |
`DECEMBER 06, 2014
`
`ONO-4059—a Potent and Selective Reversible Bruton’s
`Tyrosine Kinase (Btk) Inhibitor: Single Agent, Twice
`Daily (BD) Dosing and Dosing with Food Results in
`Sustained, High Trough Levels of ONO-4059, Translating
`into 100% Tumour Remission in a TMD-8 Xenograft Model
`
`Toshio Yoshizawa,1 Tomoko Yasuhiro,*,1 Hideyuki Honda,*,1 Kazuhito Kawabata, PhD*,2
`1Ono Pharmaceutical Co., Ltd., Osaka, Japan
`2ONO Pharmaceutical Co., Ltd., Osaka, Japan
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`Blood blood (2014) 124 (21) : 4502.
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`http://doi.org/10.1182/blood.V124.21.4502.4502
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`Abstract
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`Purpose: Bruton’s tyrosine kinase (Btk) is a key regulator of the BCR signaling pathway and abberant
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`BCR signaling has been implicated in the survival of malignant B-cells. The activated B-cell-like (ABC)
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`sub-type of Diffuse Large B-Cell Lymphoma (DLBCL) correlates with poor prognosis. There is still a high
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`unmet, medical need for new therapies, preferably chemo-sparing, to help treat patients with ABC-DLBCL
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`and CLL as well as other B-cell malignancies. ONO-4059 is a highly selective, orally bioavailable inhibitor
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`of Btk kinase activity with a potency (IC50) of 2.2 nM. ONO-4059 reversibly blocks BCR signaling and
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`B-cell proliferation and activation. Data from the ongoing Phase 1 study (ONO-4059POE001), where
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`ONO-4059 is administered as monotherapy (QD) demonstrated a best overall response rate of 47%
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`(7/15) in non-GCB DLBCL patients (Walter et al, ASCO 2014; Rule et al, EHA 2014). We hypothesized
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`that the efficacy of ONO-4059 could be further enhanced by increasing the drug trough concentration. To
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`address this, we examined different dosing regimens of ONO-4059 in an ABC-DLBCL xenograft model.
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`Methods: TMD-8 tumour cells (ABC-DLBCL cell line) were implanted sub-cutaneously into female
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`SCID mice. Randomization of mice occurred when mean tumour volume was 100-200 or 400-450 mm3.
`ONO-4059 was administered orally or mixed in food at doses up to 20 mg/kg/day and animals were
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`dosed QD or BD. Tumour volumes were measured twice a week after initiation of treatment, and tumour
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`SANDOZ INC.
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`IPR2023-00478
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`Ex. 1033, p. 1 of 2
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`volumes were determined using the formula volume (= width2 x length)/2. Animals were euthanized when
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`the tumours reached a maximum volume of 3,000 mm3.
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`Results: For the100-200 mm3 tumour groups, tumour growth inhibition at the final treatment day was
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`23% in QD, 72.9% in BD and 100% in dose mixed in food, groups respectively. For the 400-450 mm3
`tumour groups, no growth inhibition was observed in the QD group and, growth inhibitions of 27.5% in BD
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`and 100% in dose mixed in food were observed. Interestingly, the treatment with ONO-4059-containing
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`diets resulted in tumour remission in 10/10 animals, in both 100-200 and 400-450 mm3 treatment groups,
`whereas no tumour free animals were observed in the other treatment groups. The PK concentration and
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`phosphorylated Btk (pBtk) inhibition levels of those animals whose dose was mixed in with food were
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`higher than that of other treatment groups.
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`Conclusion: Our previous study demonstrated that 100% tumour remission can be achieved partially
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`with an ONO-4059 and GA101 or rituximab combination (Yoshizawa et al, ASH 2013). However, to date,
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`no orally bioavailable targeted-agent administered as monotherapy has demonstrated 100% tumour
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`remission in an advanced ABC-DLBCL xenograft model. Although the clinical data for ONO-4059 given
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`as monotherapy (QD) is very encouraging in both relapsed and refractory CLL/NHL patients, this data
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`indicates that a more frequent dosing regimen such as BD may be a more effective treatment, especially
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`for non-GCB DLBCL and warrants further investigation in the clinical setting, along with food effect
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`studies.
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`Disclosures
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`Yoshizawa: Ono Pharmaceutical Co., Ltd.: Employment. Yasuhiro: Ono Pharmaceutical Co., Ltd.:
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`Employment. Honda: Ono Pharmaceutical Co., Ltd.: Employment. Kawabata: Ono Pharmaceutical Co.,
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`Ltd.: Employment.
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`Author notes
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`*Asterisk with author names denotes non-ASH members.
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`© 2014 by the American Society of Hematology
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`SANDOZ INC.
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`IPR2023-00478
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