AesRx believes Aes-103 is the most promising compound for sickle cell disease (SCD) currently in human trials. To AesRx's knowledge, Aes-103 is the only agent which is in or near clinical trials that directly blocks cell sickling. It offers the possibility of truly modifying the course of SCD and changing the lives of SCD patients.
Aes-103 is currently in a Phase 2 trial which is being conducted as part of a multi-phase collaboration with the National Institutes of Health (NIH).Aes-103: Small Molecule That Targets Cell Sickling
Scientists have been working for many years to discover a treatment for sickle cell disease (SCD). Although numerous anti-sickling agents have been studied, hydroxyurea, an agent that induces synthesis of fetal hemoglobin, is the only drug that is approved for the treatment of SCD. However, hydroxyurea has significant side-effects which limit its use in patients with SCD and the drug is not effective for many patients.
5-hydroxymethyl-2-furfural (Aes-103) is a first-in-class, orally bioavailable small molecule (Da 126). Aes-103 affects sickle cells in at least two ways.
First, it is an allosteric modifier of hemoglobin which binds to both normal and sickle hemoglobin. When bound to sickle hemoglobin, Aes-103 stabilizes it in the high oxygen-affinity R-state. This is important because sickle hemoglobin cannot polymerize (sickle) when in the R-state. Thus, Aes-103 has direct anti-sickling activity.
Second, data recently developed at the NIH indicates Aes-103 can stabilize red blood cell membranes against shear stress. In order for red blood cells to pass through narrow capillaries, the cell shape needs to be able to flex. Reduced flexibility due to sickle cell disease increases the amount of shear stress. Shear stress can result in ruptured cell membranes, in turn leading to cell death. Thus, Aes-103 may both stabilize sickle hemoglobin in the R-state (thereby reducing sickling) and improve the stability of sickle red blood cell membranes.
The National Institutes of Health, Sickle Cell Disease Reference Laboratory (SCDRF) has screened over 700 compounds sent to them from researchers, universities and companies. The SCDRL has identified Aes-103 as one of the most potent anti-sickling compounds it has tested and uses it as the positive control in their in vitro anti-sickling assay.
AesRx is collaborating with the NIH to develop Aes-103 through the initial Phase 2 trial.
Current Phase 2 Clinical Trial
The current Phase 2 clinical trial, which began in September 2013, is part of AesRx’s on-going collaboration with the NIH. A double-blind, placebo controlled 28-day trial of Aes-103 in patients with stable sickle cell disease, its primary endpoint is safety and tolerability of multiple doses of Aes-103. Aes-103’s effects on sickle cell-related clinical endpoints as well as pharmacokinetic and pharmacodynamic measures are also being examined.
Phase 1/2a Trial of Aes-103
In 2013, AesRx completed a Phase 1/2a trial of Aes-103 which was conducted at the NIH Clinical Center in Bethesda, MD. The study was a double-blind, placebo controlled single ascending dose trial investigating the safety and tolerability of the drug in patients with stable sickle cell disease. Doses of Aes-103 of 300mg, 1000mg, 2000mg, and 4000mg were administered. The drug was found to be safe and well tolerated. AesRx anticipates presenting the results of this trial at a major scientific conference later in 2013.
Phase 1 Trial of Aes-103
AesRx completed a Phase 1 trial of Aes-103 in 2012. The study was a double-blind, placebo controlled single ascending dose trial investigating the safety and tolerability of the drug in healthy volunteers. Doses of Aes-103 of 300mg, 1000mg, 2000mg, and 4000mg were administered. Results of this study were presented at the 2012 Annual Meeting of the American Society of Hematology (ASH abstract). The drug was found to be safe and well tolerated.
The study also included a pharmacodynamic analysis of the ability of Aes-103 to increase the blood oxygenation of the healthy volunteers when they were subjected to a hypoxic challenge. Because the binding site of Aes-103 is the same for both healthy and sickle hemoglobin, it was hypothesized the drug would stabilize the healthy hemoglobin in the high oxygen-affinity R-state. If so, the healthy volunteers subjected to a hypoxic challenge would show higher blood oxygen levels (measured by SpO2) with Aes-103 than those without. This is what happened, providing evidence that the pharmacodynamic activity of Aes-103 in healthy volunteers is consistent with its proposed mechanism of action in sickle cell patients. Details of the hypoxic challenge in healthy volunteers are provided below.
Phase 1 Trial of Aes-103: Hypoxic Challenge Details
The hypoxic challenge test was conducted in the following manner: using face masks and air tanks containing 12% oxygen (compared to 21% oxygen in normal air at sea level), subjects inhaled the 12% hypoxic mixture for 5 minutes at a time just prior to starting the dose of study medication (Aes-103 or placebo, double-blind) and then again at each of the time intervals 0.75, 2, 4 and 8 hours after the dose. A fingertip oxygen sensing probe connected to a pulse oximeter provided continuous measurement of SpO2 values (percentage of hemoglobin containing an oxygen molecule) and the SpO2 values were recorded every 20 seconds during the hypoxic challenge as well as during a 3-minute recovery period (during which normal air was inspired).
The figure above compares the fall in mean SpO2values of placebo and the 2000mg dose of Aes-103 during a hypoxic challenge given at the 2-hour time point post-dose. The mean change in SpO2 levels from start is shown for each one-minute interval of the 5-minute hypoxic challenge. The elevated blood oxygenation from Aes-103 relative to placebo (shown by a less severe decrease in SpO2 during the hypoxic challenge) begins to become apparent after one minute of hypoxia, when the SpO2 levels of both placebo and drug subjects fall by 5 units and the Aes-103 induced improvement in SpO2 is thereafter maintained for the remainder of the challenge period. It is noteworthy that the difference between placebo and drug becomes larger as the level of hypoxia in the subjects increases. In vivo studies in animal models also suggest the impact of Aes-103 is greater when the level of hypoxia increases. Since the level of hypoxic challenge in this initial human study was moderate (no clinical symptoms of hypoxia were present), the impact of Aes-103 should be even greater when the hypoxic challenge is more extreme.
In Vivo and In Vitro Work
The potential activity of Aes-103 as a treatment for SCD has been examined in a number of in vitro and in vivo experiments.
An animal model of sickle cell disease indicates:
- Aes-103 reduces hypoxia induced mortality in sickle cell mice (British Journal of Haematology, 128, 552–561, with Aes-103 referred to as 5-hydroxymethyl-2-furfural or 5HMF).
In vitro data in human blood indicates:
- Aes-103 reduces hypoxia induced sickling (British Journal of Haematology, 128, 552–561, with Aes-103 referred to as 5-hydroxymethyl-2-furfural or 5HMF).
- Aes-103 increases oxygen affinity of Hb of blood from healthy controls and from sickle cell patients on or not on hydroxyurea.
In vitro data in human SCD blood indicates:
- Aes-103 reduces the fragility of oxygenated human sickle cell blood to shear stress.