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Safety, tolerability, and pharmacology of AB928, a novel dual adenosine receptor antagonist, in a randomized, phase 1 study in healthy volunteers

  • Lisa Seitz
  • Lixia Jin
  • Manmohan Leleti
  • Devika Ashok
  • Jenna Jeffrey
  • Aimee Rieger
  • Renger G. Tiessen
  • Gerhard Arold
  • Joanne B. L. Tan
  • Jay P. Powers
  • Matthew J. Walters
  • Joyson KarakunnelEmail author
PHASE I STUDIES
  • 93 Downloads

Summary

Adenosine suppresses antitumor immune responses via A2a and A2b receptors expressed on intratumoral immune cells. This effect is mediated by increased cyclic adenosine 5′-monophosphate (AMP) levels and phosphorylation of cyclic AMP response element binding protein (CREB). We conducted a phase 1, placebo-controlled, single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study to assess the safety, tolerability, pharmacokinetics (PK), including food effect (FE), and pharmacodynamics (PD) of oral AB928, a novel dual A2aR/A2bR antagonist, in healthy volunteers. AB928 doses between 10 and 200 mg once daily and 100 mg twice daily were evaluated. The study enrolled 85 subjects (randomized 3:1, AB928:placebo), 40 each in the SAD and MAD cohorts, and 5 in the FE cohort. AB928 was well tolerated up to the highest dose tested and did not affect any physiologic parameters potentially sensitive to adenosine inhibition. No safety concern was identified. The PK profile of AB928 was linear and dose-proportional, and a clear PK/PD correlation was demonstrated. Significant inhibition of adenosine receptor-mediated phosphorylated CREB was observed at peak plasma concentrations in all dose cohorts and at trough plasma concentrations in the higher-dose cohorts. AB928 plasma levels ≥1 μM were associated with ≥90% adenosine receptor inhibition. In the postprandial state, the rate of AB928 absorption decreased but the extent of absorption was unchanged. Together, these data support further clinical development of oral AB928 in cancer patients.

Keywords

AB928 Adenosine signaling Adenosine receptor antagonist Immunotherapy Oncology Healthy volunteers 

Notes

Acknowledgements

The authors thank all of the healthy volunteers who participated in this study. We also thank PRA Health Sciences in the Netherlands for assistance with flow cytometry: Sijranke Post, Richard Draaijer, Tom Huizinga, Patrick Veerman, Frank Beltman, Riejanne Bax-Seigers, and Janet Stegehuis. Editorial assistance was provided by Marithea Goberville, PhD, Science Author, Inc.

Funding

Arcus Biosciences, Inc. (no grant number applies).

Compliance with ethical standards

Conflict of interest

LS, LJ, ML, DA, JJ, AR, JT, JP, MW, and JK are employees of Arcus Biosciences, Inc., and RT and GA are employees of PRA Health Sciences.

Ethical approval

This study was conducted in the Netherlands in accordance with the ethical principles that have their origin in the Declaration of Helsinki,and complied with the International Conference on Harmonization E6 Guideline for Good Clinical Practice and the European Union CTD Directive, as incorporated into Dutch Law. The protocol was approved by the institutional review board. The data were analyzed by PRA Health Sciences (safety and PK) and Arcus Biosciences, Inc. (PD).

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Lisa Seitz
    • 1
  • Lixia Jin
    • 1
  • Manmohan Leleti
    • 1
  • Devika Ashok
    • 1
  • Jenna Jeffrey
    • 1
  • Aimee Rieger
    • 1
  • Renger G. Tiessen
    • 2
  • Gerhard Arold
    • 3
  • Joanne B. L. Tan
    • 1
  • Jay P. Powers
    • 1
  • Matthew J. Walters
    • 1
  • Joyson Karakunnel
    • 1
    Email author
  1. 1.Arcus Biosciences, Inc.HaywardUSA
  2. 2.PRA Health SciencesGroningenThe Netherlands
  3. 3.PRA Health SciencesBerlinGermany

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