Etrasimod in Controlled Release Seen to Limit Heart Rate Changes, May Be Added to Trials

Etrasimod in Controlled Release Seen to Limit Heart Rate Changes, May Be Added to Trials

A controlled-release version of etrasimod could limit the changes in heart rate linked to an initial dose of this investigational medication, according to topline clinical trial data announced by Arena Pharmaceuticals, the company developing etrasimod.

Etrasimod (APD334) is an orally available sphingosine 1-phosphate (S1P) receptor modulator. It is being developed to treat inflammatory conditions including ulcerative colitis, Crohn’s disease, and atopic dermatitis (eczema), and a number of clinical trials are now underway.

By modulating S1P receptors, etrasimod is designed to ‘trap’ certain immune cells in lymph nodes (immune system structures), preventing them from driving inflammation elsewhere. However, receptors of this kind are also present in the heart, raising the potential for heart-related side effects. Etrasimod, in particular, may decrease the heart rate.

Previous clinical trial results suggested that etrasimod can be clinically beneficial for people with ulcerative colitis, but heart-related side effects were reported.

Controlled-release (CR) formulations are absorbed more slowly than conventional pills or tablets, and produce more stable blood serum levels of the therapy throughout the day. By reducing ‘therapy spikes’ (peak serum concentrations) within the body, CR formulations may limit unwanted side effects.

Arena, for this reason, developed a controlled-release formulation of etrasimod.

“Etrasimod currently has a potential best-in-class profile as a rapid-acting, non-titrated oral therapy with limited first-dose heart rate effect. It is exciting that Arena’s etrasimod CR program has the potential to further differentiate this profile,” Preston Klassen, MD, Arena’s executive vice president of research and development, said in a press release.

The new CR formulation of etrasimod, called etrasimod CR, was compared with the original formulation in a Phase 1 clinical trial.

According to Arena, the original formulation did indeed cause a change in heart rate. The CR formulation also affected heart rate, but  with a 75% lesser impact in the first four hours after the therapy was administered (the standard monitoring period). A treated persons’s heart rate slowed by “only low single digits” compared to the original formulation, it reported.

The rate at which heart rates changed was more than 50% lower with etrasimod CR.

Over 24 hours after administration,  heart rate effects of the CR formulation were consistently either less than, or comparable to, the original formulation.

Arena is now working to quickly develop etrasimod CR and integrate its use into ongoing clinical trial programs.

“This work … has the potential to improve etrasimod’s broad clinical utility. We intend to launch in ulcerative colitis with etrasimod and expect to move to etrasimod CR with other ongoing and future development programs across a broad range of immune-mediated inflammatory diseases,” Klassen said.

Arena has also filed a provisional patent application for etrasimod CR formulation.