Positive phase III study with aprocitentan demonstrates significant antihypertensive efficacy in patients with resistant hypertension.

Aprocitentan significantly reduced blood pressure when added to standardized combination background antihypertensive therapy in patients with resistant hypertension over 48 weeks of treatment. Hypertension is one of the most common cardiovascular risk factors, and its prevalence continues to rise. According to a recent study, there are more than one billion people living with hypertension worldwide – a number which has almost doubled in the past 40 years.

While many patients with hypertension are successfully treated with various existing anti-hypertensive therapies, 10–20% of the hypertensive population have blood pressure that remains high despite receiving at least three antihypertensive medications of different pharmacological classes, including a diuretic, at optimal doses, and they are categorized in hypertension guidelines and in the medical community as having resistant hypertension. Certain populations are at a particular high risk of developing resistant hypertension later in life; these include patients with a high body mass index (BMI), African Americans, post-menopausal women and patients with obstructive sleep apnea.

About the PRECISION study ( Danaietash P et al. J Clin Hypertension 2022 (in press) (NCT03541174) Idorsia, in consultation with regulatory agencies, designed a single, international, multi-center, blinded randomized study with three sequential treatment parts. The study design addressed both the 4-week placebo-controlled efficacy of 12.5 and 25 mg aprocitentan (Part 1) and the durability of its effects in long-term active treatment with 25 mg aprocitentan for a further 32 weeks (Part 2) followed by a 12-week placebo-controlled withdrawal period with patients re-randomized to 25 mg or placebo (Part 3).

Patient population with established resistant hypertension: To confirm a diagnosis of resistant hypertension and exclude pseudo resistant hypertension, 1965 patients entered a thorough 12-week screening period. During the screening period, qualifying patients were transitioned to guideline-recommended standardized background antihypertensive therapy of a fixed-dose combination of a calcium channel blocker (amlodipine), an angiotensin receptor blocker (valsartan) and a diuretic (hydrochlorothiazide) for at least 4 weeks before entering a 4-week single-blind run-in period. In this period, placebo was added to the background antihypertensive therapy. Patients with systolic blood pressure consistently above 140 mmHg were then randomized to the first treatment part.

Sustained reduction in systolic blood pressure after chronic treatment with aprocitentan: In Part 1, the first double-blind treatment period of 4 weeks, a total of 730 patients were randomized to receive a tablet of aprocitentan 12.5 mg (N=243), 25 mg (N=243), or placebo (N=244) once daily. After 4 weeks of treatment, a statistically significant and clinically meaningful reduction in the primary endpoint measure of systolic blood pressure – assessed by measurement at trough of unattended automated office blood pressure (AOBP) – was observed in both the 12.5 mg (p<0.005) and 25 mg (p><0.005) aprocitentan groups compared to placebo. following the 4-week double-blind, placebo-controlled treatment period, patients entered part 2, a single-blind treatment period, where all patients were treated with 25 mg aprocitentan for a further 32 weeks. the mean reduction from baseline in systolic blood pressure was maintained during this treatment period, for those patients who were on aprocitentan during part 1. patients switching from placebo to aprocitentan rapidly achieved the same blood pressure reduction as seen in part 1. this was followed by part 3, a double-blind, placebo-controlled, randomized withdrawal treatment period where 614 patients were re-randomized to aprocitentan 25 mg or placebo for 12 weeks. after 4 weeks in the withdrawal period, systolic blood pressure increased significantly on placebo compared to aprocitentan 25 mg (p><0.0001), the key secondary endpoint. this provided replication of the treatment effect of aprocitentan and confirmed its durable antihypertensive effect.

The reduction in systolic and diastolic blood pressure assessed by measurement of unattended automated office blood pressure during the study, was confirmed by the 24-hour ambulatory blood pressure monitoring (ABPM), demonstrating BP reduction across the entire 24 h period (notably during the night).

About the safety of aprocitentan in PRECISION. The topline results show that aprocitentan was generally well tolerated with no major safety concerns in this patient population at both doses and with a low discontinuation from study treatment due to an adverse event in the first 4 weeks double-blind study period: 2.5% and 2.0% for aprocitentan 12.5 mg and 25 mg groups respectively versus 0.8% in the placebo group. Treatment-emergent adverse events (TEAEs) during the 4-week double-blind study period were reported in 27.6% and 36.7% of the patients treated with 12.5 and 25 mg aprocitentan, respectively, versus 19.4% in the placebo group. The most frequent TEAEs reported over 3% incidence and higher than placebo was edema / fluid retention.

There were no additional emerging safety findings in the subsequent treatment period taking the total to 48 weeks. Importantly, the overall incidence of Major Adverse Cardiac Events (MACE) reflected the expected occurrence in this patient population. Approximately 30% of patients developed edema / fluid retention, at one time point during the entire study duration, with >95% being mild to moderate in intensity. Two (<1%) of these adverse events were serious (both on aprocitentan 25mg). only seven (><1%) of patients discontinued treatment due to edema fluid retention. edema fluid retention was mostly reported by patients within the first 4-week double-blind study period (9.1% and 18.4% for aprocitentan 12.5 mg and 25 mg groups respectively, versus 2.1% in the placebo group).

Conclusion of the Phase III PRECISION study: Aprocitentan is an investigational treatment with a new mode of action for patients whose hypertension is not adequately controlled despite the use of at least three other classes of antihypertensives, including a diuretic. Aprocitentan reduces blood pressure compared to placebo by week 4 of treatment and the effect is maintained over a period of 48 weeks. The safety profile, together with the long half-life, and low potential for drug-drug interactions observed in the clinical pharmacology program, is conducive for a chronic treatment to be used for patients who often have several comorbidities and are treated with multiple pharmacological therapies. The effect demonstrated in the Phase III study was consistent across multiple methodologies of blood pressure monitoring and in key sub-populations.