Arena Pharma has a new drug candidate heading for clinical trials next year that it says could be a first-in-class option for decompensated heart failure (DHF).
The selective beta-3 adrenergic receptor antagonist—called APD418—was revealed at Arena’s R&D update in New York yesterday and is described by the company as a first-in-class calcium-independent myofilament derepressor that could be a “better and safer” option for heart failure patients.
Medical therapy hasn’t much changed for DHF in decades and—with more than a million hospitalizations for DHF every year—there is an urgent need for new treatment options that can keep patients out of hospital and treatment costs down.
Right now, there are no approved treatments proven to improve outcomes in DHF, according to Arena, and for many patients the only option is to use positive inotropes, drugs such as dobutamine and milrinone that push the heart muscle to pump more strongly. However, these drugs can increase the risk of death and have serious side effects such as low blood pressure and irregular heartbeats.
Arena’s chief medical officer Preston Klassen, M.D., explained that the beta-3 receptor is expressed more often in failing hearts and seems to suppress the contractility of heart muscle as a defense mechanism, protecting it from efforts by the sympathetic nervous system to keep the heart flogging away to maintain blood pressure.
Because it blocks beta-3 selectively, APD418 should be able to increase heart contractions without the acceleration in heart rate and elevated blood pressure that accompanies current drugs that also affect the beta-1 and beta-2 adrenergic receptors.
“The idea is that we can block the negative impact on contractility by antagonizing the receptor—essentially remove the brake—and actually increase cardiac performance in a safer environment,” according to Klassen. “Doing that would be unique…and has not been achievable to date,” he said.
The hypothesis has been tested in animal models and now Arena says it is preparing to file for approval to start clinical testing of APD418 in 2019.
Arena also outlined the trial designs and timings for its upcoming phase 3 trials for drugs already in clinical development. That includes S1P receptor modulator etrasimod, which is due to start late-stage testing in ulcerative colitis and Crohn’s disease as well as new indication atopic dermatitis next year.
Oral prostacyclin receptor agonist ralinepag is already in one phase 3 trial in pulmonary arterial hypertension (PAH) looking at exercise capacity and will start two more trials in 2019 that should provide data on cardiovascular outcomes at the time of filing—proposed for around the second half of 2021.
Arena also said it will move its cannabinoid receptor type 2 (CB2) agonist olorinab into additional phase 2 trials in gastrointestinal pain associated with Crohn’s disease and irritable bowel syndrome after reporting proof-of-concept data last month.