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 ongoing 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. The effects of Aes-103 on sickle cell-related clinical endpoints as well as pharmacokinetic and pharmacodynamic measures are also being examined.
Phase 1/2a Trial of Aes-103
n 2013, AesRx completed a Phase 1/2a trial of Aes-103 conducted at the NIH Clinical Center in Bethesda, MD. The study assessed the safety and tolerability of Aes-103 in stable SCD patients, as well as its pharmacokinetic and pharmacodynamic properties. Results of this study were presented at the 2013 Annual Meeting of the American Society of Hematology (ASH 2013 Poster).
In a double-blind, placebo-controlled, dose-escalation trial, 18 adult patients with stable SCD on or not on hydroxyurea treatment were given single oral doses of Aes-103 of 300, 1000, 2000 or 4000 mg, as well as 1000 mg q.i.d. for one day. Overall, Aes-103 was shown to be safe and well tolerated and no patients were discontinued due to adverse events.
For those patients (n=15 dose sessions) presenting with measurable pain at baseline (a score of 2 or more on the 0-10 Numerical Pain Rating Scale [NPRS]), pain was reduced in a dose-dependent and time-dependent manner in patients receiving Aes-103 compared to those receiving placebo. Reductions in pain became apparent starting about 1-2 hours after Aes-103 administration. Pain differences between Aes-103-treated and placebo-treated patients were in the range of 3-4 points on the NPRS scale. The differences between treatments peaked at 8 hours post-dose (p≤0.005) and persisted at 12 hours (p≤0.05) and 24 hours (p≤0.05) post-dose. Reductions in pain were highly correlated with the presence of Aes-103 in the red blood cell lysate (correlation coefficient = –0.917; p<0.0001). In contrast, patients with no pain shortly prior to dosing showed no change in pain levels over the next 24 hours in both the placebo and Aes-103 groups.
Additional signals of potential anti-sickling activity were observed, including higher hemoglobin levels in patients receiving Aes-103 compared to placebo, as well as a reduction in LDH (a biomarker of red blood cell hemolysis). Red blood cell (RBC) sickling is a hallmark of sickle cell disease and, among other symptoms, results in more rapid RBC death in sickle cell patients than in those without the disease. Rapid RBC death in turn leads to anemia (lower levels of hemoglobin) and a rupturing of the RBC membrane, which releases LDH into the bloodstream.
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.
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 indicate:
- 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 indicate:
- 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 indicate:
- Aes-103 reduces the fragility of oxygenated human sickle cell blood to shear stress (Shear Stress Poster).