Details

Autor(en) / Beteiligte

• Seitz, Lisa
• Jin, Lixia
• Leleti, Manmohan
• Ashok, Devika
• Jeffrey, Jenna
• Rieger, Aimee
• Tiessen, Renger G.
• Arold, Gerhard
• Tan, Joanne B. L.
• Powers, Jay P.
• Walters, Matthew J.
• Karakunnel, Joyson

Titel

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

Ist Teil von

• Investigational new drugs, 2019-08, Vol.37 (4), p.711-721

Ort / Verlag

New York: Springer US

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• Summary Adenosine suppresses antitumor immune responses via A 2a and A 2b 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 A 2a R/A 2b R 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.