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

Invest New Drugs. 2019 Aug;37(4):711-721. doi: 10.1007/s10637-018-0706-6. Epub 2018 Dec 19.

Abstract

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 receptor antagonist; Adenosine signaling; Healthy volunteers; Immunotherapy; Oncology.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Double-Blind Method
  • Female
  • Food-Drug Interactions
  • Healthy Volunteers
  • Humans
  • Male
  • Middle Aged
  • Purinergic P1 Receptor Antagonists / administration & dosage*
  • Purinergic P1 Receptor Antagonists / blood
  • Purinergic P1 Receptor Antagonists / pharmacokinetics
  • Young Adult

Substances

  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Purinergic P1 Receptor Antagonists