Phase 1 Clinical Trial Of The Candidate Anti-Sickling Agent Aes-103 In Adults With Sickle Cell Anemia

Abstract Background Aes-103 (5-hydroxymethylfurfural, 5-HMF) is a putative anti-sickling agent that has undergone pre-clinical testing for potential treatment for sickle cell disease. It is an organic compound derived from dehydration of certain sugars, found commonly in small amounts in foods such as coffee and prunes. It binds to alpha subunits of hemoglobin and increases its oxygen affinity. At millimolar levels, it inhibits hypoxia-induced sickling in vitro and protects sickle cell mice against hypoxia-induced death. We investigated the safety, tolerability and pharmacokinetics of single oral doses of Aes-103 in a double-blind, placebo controlled, dose-escalation trial in adult patients with sickle cell anemia on hydroxyurea treatment and not on hydroxyurea treatment. Methods Adult patients with sickle cell anemia consented to an IRB-approved FDA investigational New Drug protocol at the NIH Clinical Center. After laboratory evaluation to screen for acceptable clinical status, they were hospitalized for three nights to receive oral dosing of Aes-103 or placebo (5:1 ratio of treatments) in a double-blind design, and vital signs, toxicity monitoring lab results and any adverse events were reviewed by a protocol safety committee, which approved escalation to the next higher dose of study drug. The patients were eligible to be hospitalized again at least one week later for a second, higher dose or placebo. After fasting, patients received oral doses of Aes-103 dissolved in orange juice. Doses were 300, 1000, 2000 or 4000 mg. A subgroup that took 4000 mg after fasting also took 4000 mg after a prescribed high fat meal during a second hospitalization and 1000 mg every 6 hours for four doses without fasting during a third hospitalization. Results Eighteen patients in steady state participated in the trial. The study drug was well tolerated at all doses tested. During the first 24 hours after dosing, a total of 11 adverse events (9 mild, 2 moderate, and zero severe) occurred distributed across a variety of categories in 6 of 15 patients on the Aes-103 arm, compared to 1 mild adverse event in 1 of 3 patients on the placebo arm. An additional 18 adverse events were temporally unrelated to Aes-103, 10 of which involved pain that appeared to be background sickle cell-related pain unrelated to dosing of study drug, seen also in 1 of the 3 placebo adverse events. No severe adverse events occurred in temporal relationship to the study drug. Pharmacokinetic and pharmacodynamic data are currently under analysis, and will be complete at the time of abstract presentation. Conclusions Aes-103 was safely tolerated without severe or recurrently observed complications over a 13-fold range of oral doses. A phase 2 randomized controlled study of Aes-103 or placebo is planned with daily dosing for twenty-eight days in patients with sickle cell anemia. Disclosures: Stern: AesRx, LLC: Equity Ownership.