On March 19th, the FDA official website showed that Aprocitentan (trade name Tryvio) developed by Idorsia was approved for the treatment of refractory hypertension patients.
Aprocitentan is a novel oral dual endothelin A/B receptor (ETA/ETB) antagonist that effectively inhibits the binding of ET-1 to ETA and ETB. It is the active metabolite of masitentan and has a longer half-life (48 h vs. 14 h).
The FDA approval was mainly based on the positive results of the Phase III PRECISION study. The study is a multi-center, blinded, randomized Phase III clinical trial, which is divided into three phases:
The first phase is a 4-week double-blind period, during which 730 patients were randomly assigned to the 12.5mg (n=243), 25mg (n=243) aprocitentan groups or the placebo group (n=244);
The second phase is a 32-week (4-36 weeks) single-blind period, during which patients receive 25 mg of aprocitentan (n=704) treatment;
The third phase is a 12-week (36-48 weeks) double-blind drug withdrawal period, during which patients are randomly reassigned to the 25 mg aprocitentan group (n=307) or the placebo group (n=307) in a 1:1 ratio.
The primary and key secondary endpoints of the study were the changes in systolic blood pressure from baseline to week 4 and week 40, respectively. At baseline, 63% of patients had received at least four antihypertensive medications.
The results showed that the study achieved the primary endpoint, which was that the reduction in sitting systolic blood pressure (SiSBP) in patients treated with aprocitentan was significantly greater than that in patients treated with placebo. Specifically, after 4 weeks of treatment with aprocitentan, the SiSBP in patients significantly decreased, and the differences between the 12.5mg and 25mg groups were -3.8mmHg (p=0.0042) and -3.7mmHg (p=0.0046), respectively, compared to the placebo group.
In addition, the study also achieved a key secondary endpoint, with patients receiving apocitentan treatment showing a sustained reduction in SiSBP compared to the placebo group during weeks 36-40, with a difference of -5.8 mmHg (p<0.0001) and a maintenance time of up to 48 weeks.
The most common adverse event in this study was mild to moderate fluid retention, and 7 patients stopped taking the drug because of this. Among them, in the first stage, the proportion of such events occurring in the 12.5mg and 25mg Aprocitentan groups and the placebo group was 9.1%, 18.4%, and 2.1%, respectively; In the second stage, the proportion reported by the Aprocitentan group was 18.2%; In the third stage, the reported proportions of the Aprocitentan group and the placebo group were 2.6% and 1.3%, respectively.
The CEO of Idorsia said when submitting the application for the listing of Aprocitentan that there had been no innovative mechanism products launched in the hypertension field for more than 30 years, and Aprocitentan would be a drug with a new mechanism to treat refractory hypertension.
