New Phase 3 data with aprocitentan for patients with resistant hypertension
has been presented at the American Society of Nephrology Kidney Week 2023
Allschwil, Switzerland – November 3, 2023
Idorsia Ltd (SIX: IDIA) announced today that further data for aprocitentan,
Idorsia’s investigational dual endothelin receptor antagonist for the treatment
of patients with resistant hypertension, were presented as an oral presentation
entitled “ Effects of aprocitentan on blood pressure lowering and proteinuria
in patients with chronic kidney disease and resistant hypertension ” by George
Bakris, MD, at the American Society of Nephrology (ASN) Kidney Week 2023.
Patients with hypertension can often successfully control their blood pressure
by combining a healthier lifestyle with effective medication. However,
approximately 10% of patients have resistant hypertension where the blood
pressure remains high despite receiving at least three antihypertensive
medications of different pharmacological classes, including a diuretic, at
optimal doses.
The Phase 3 PRECISION study demonstrated both the safety and the efficacy of
aprocitentan to significantly lower blood pressure (BP) in patients with
resistant hypertension on top of at least three antihypertensive medications of
different classes, including a diuretic. Detailed results were published in The
Lancet and presented as a Late-Breaking Science presentation during the
American Heart Association (AHA) Scientific Sessions in November 2022. More
details and commentary can be found in the dedicated press release and an
investor webcast featuring Prof. Markus Schlaich, an investigator in PRECISION.
The presentation at ASN Kidney Week 2023 focused on the effect of aprocitentan
on BP in a subgroup of 162 patients with stage 3 or 4 chronic kidney disease
(CKD), defined by an estimated glomerular filtration rate (eGFR) of 15 to <
60mL/min/1.73m2. The presentation included pre-specified exploratory analysis
(not adjusted for multiplicity) of aprocitentan on BP measured by an automated
Office BP measurement (AOBPM), and post-hoc analysis of ambulatory BP
monitoring (ABPM) and urinary albumin-to-creatinine ratio (UACR) – a marker of
kidney damage – in this patient population.
Both the 12.5 mg and 25 mg doses of aprocitentan resulted in a pronounced BP
reduction from baseline to week 4 compared to placebo in patients with CKD
stage 3 or 4. The mean change in office systolic BP at 4 weeks (for patients
with both baseline and week 4 values) was –13.7 mmHg for aprocitentan 12.5 mg,
–18.4 mmHg for 25 mg, and –6.5 mmHg for placebo, for a difference versus
placebo of –7.2 mmHg and –11.9 mmHg , respectively. The results from ambulatory
BP monitoring confirmed those derived from office measurements. The UACR at
week 4, was reduced by 28% for aprocitentan 12.5 mg, 44% for aprocitentan 25
mg, and remained stable (reduction of 4%) in the placebo group.
Aprocitentan was generally well tolerated; with the most common adverse events
being edema/fluid retention (18% and 24% of patients receiving aprocitentan
12.5mg and 25mg, respectively, versus 2% with placebo, at week 4). Adverse
events of fluid retention and edema were primarily peripheral edema of mild
intensity, mostly occurring during the first 4 to 8 weeks of treatment and were
effectively managed with additional diuretic therapy. Discontinuation due to
edema/fluid retention was reported for 3 out of 162 patients.
George Bakris, MD, Professor of Medicine and Director, Comprehensive
Hypertension Center, University of Chicago School of Medicine and an
investigator in the PRECISION study commented:
“It is great that the PRECISION study with aprocitentan included such a large
cohort of patients with resistant hypertension and CKD stage 3 or 4, as CKD is
a frequent cause – and consequence of – resistant hypertension. Very often
these high-risk patients are under-represented in clinical studies of
hypertension, but it is very important to include these patients in order to
translate the clinical data into a real-world situation. We found that
aprocitentan, when added to at least three other antihypertensive medications,
resulted in a substantial and clinically meaningful reduction of both office
and ambulatory blood pressure, as well as a reduction in albuminuria. It is
also important that the mechanism is not associated to an increased risk of
hyperkalemia, which often limits the use of anti-hypertensive medications in
patients with CKD.”
Alberto Gimona, Head of Global Clinical Development of Idorsia, concluded:
“While this prespecified subgroup analysis is exploratory in nature, I was
very glad to see the marked efficacy of aprocitentan in reducing blood pressure
and proteinuria in patients with CKD who are already heavily medicated. I was
also glad to see the safety results, while we did see an increased incidence of
edema and fluid retention in the first 4 to 8 weeks, this was mostly peripheral
edema, the incidence decreased rapidly, and was effectively managed with
additional diuretic therapy. In this frail population with a lot of
comorbidities, on top of other vasodilators, cases of edema were not
unexpected.”
In May 2022, Idorsia announced positive top-line results of the Phase 3
PRECISION study with aprocitentan for the treatment of patients with resistant
hypertension. Detailed results were published in The Lancet and presented as a
Late-Breaking Science presentation during the American Heart Association (AHA)
Scientific Sessions in November 2022. More details and commentary can be found
in the dedicated press release and an investor webcast featuring Prof. Markus
Schlaich, an investigator in PRECISION. A new drug application (NDA) for
aprocitentan was accepted for review by the US FDA. Following the provision of
additional Risk Evaluation and Mitigation Strategy (REMS) materials to support
a streamlined REMS designed specifically for aprocitentan, the company is
working towards a PDUFA date of March 19, 2024. A market authorisation
application (MAA) was submitted to the EMA at the end January 2023.
Notes to the editor
The endothelin system in systemic hypertension
Endothelin-1 (ET-1) is a potent vasoconstrictor that also induces
neurohormonal activation, vascular hypertrophy and remodeling, cardiac
hypertrophy and fibrosis, and endothelial dysfunction. In hypertension, both ET
A and ET B receptors mediate harmful effects of ET-1. 2 As a vasoconstrictor,
co-mitogenic agent, linking pulse pressure and vascular remodeling, and
mediator of aldosterone and catecholamine release, endothelin is a key player
in hypertension and end-organ damage. 3, 4
About difficult-to-control (resistant) hypertension
Hypertension (high blood pressure) is one of the most common cardiovascular
risk factors, and its prevalence continues to rise. According to a recent
study, there are more than 1.3 billion people living with hypertension
worldwide 4 – a startling number, which has almost doubled in the past 40
years. Left uncontrolled, people have a greater risk of life-threatening
conditions such as heart attack, stroke, and chronic kidney disease. 5
Patients with hypertension can often successfully control their blood pressure
by combining a healthier lifestyle with effective medication. However,
approximately 10% of patients have difficult-to-control hypertension where the
blood pressure remains high despite receiving at least three antihypertensive
medications of different pharmacological classes, including a diuretic, at
optimal doses, 1 , 6 (also categorized in hypertension guidelines and the
medical community as having resistant hypertension).
The endothelin pathway has been implicated in the pathogenesis of
hypertension, especially in volume- and salt-dependent forms, which are a
common feature in patients with resistant hypertension. The endothelin pathway
has not been targeted by existing anti-hypertensive therapies until now,
thereby leaving this relevant pathophysiologic pathway unopposed with currently
available medications. 1,7 , 8 The endothelin system is also activated in
patients prone to developing resistant hypertension, such as Black or African
American patients, patients with obesity or obstructive sleep apnea, 9 -1 1 and
in comorbid conditions frequently associated with resistant hypertension such
as diabetes and chronic kidney disease. 1 2 -1 5
About aprocitentan
Aprocitentan is an investigational, novel, oral, dual endothelin receptor
antagonist (ERA), which potently inhibits the binding of ET-1 to ET A and ET B
receptors. Aprocitentan has a low potential for drug-drug interaction and a
mechanism of action that is ideally suited for the pathophysiology of resistant
hypertension.
About PRECISION 1 6 , 17 ( NCT03541174 )
PRECISION was a multicenter, blinded, randomized, parallel-group, Phase 3
study, which was performed in hospitals or research centers in Europe, North
America, Asia, and Australia. Patients were eligible for randomization if their
sitting systolic blood pressure was 140 mm Hg or higher despite taking
standardized background therapy consisting of three antihypertensive drugs,
including a diuretic. The study consisted of three sequential parts: Part 1 was
the 4-week double-blind, randomized, and placebo-controlled part, in which 730
patients were randomized to aprocitentan 12.5 mg (n=243), aprocitentan 25 mg
(n=243), or placebo (n=244) in a 1:1:1 ratio; Part 2 was a 32-week single
(patient)-blind part, in which all patients received aprocitentan 25 mg
(n=704); and Part 3 was a 12-week double-blind, randomized, and
placebo-controlled withdrawal part, in which patients were re-randomized to
aprocitentan 25 mg (n=307) or placebo (n=307) in a 1:1 ratio. The primary and
key secondary endpoints were changes in unattended office systolic blood
pressure from baseline to week 4 and from withdrawal baseline to week 40,
respectively. Secondary endpoints included 24-h ambulatory blood pressure
changes.
At baseline, 69.2% of patients were obese or severely obese, 54.1% had
diabetes, 22.2% had stage 3-4 chronic kidney disease and 19.6% had congestive
heart failure. 63% of randomized patients were receiving at least 4
anti-hypertensive therapies at screening.
Key PRECISION findings 17
The least square mean change in office SBP at 4 weeks was –15.3 mmHg for
aprocitentan 12.5 mg, –15.2 mmHg for 25 mg, and –11.5 mmHg for placebo, for a
difference versus placebo of –3.8 mmHg (p=0.0042) and –3.7 mmHg (p=0.0046),
respectively. Office diastolic blood pressure (DBP) also decreased with both
aprocitentan doses compared to placebo (–3.9 mmHg for the 12.5 mg dose and –4.5
mmHg for the 25 mg dose). Office SBP and DBP were maintained during Part 2 in
patients previously receiving aprocitentan and decreased within the first 2
weeks of Part 2 before stabilizing in those previously receiving placebo. In
Part 3, office SBP after 4 weeks of withdrawal (the key secondary endpoint)
increased significantly with placebo compared to aprocitentan ( 5.8 mmHg ; p <
0.0001). Office DBP also increased with placebo compared to aprocitentan (5.2
mmHg; p < 0.001). The difference between the two groups remained up to week 48.
The results from ambulatory BP monitoring, a strong predictor of
cardiovascular mortality, 1 8 , 19 confirmed those derived from office
measurements. At the end of Part 1, aprocitentan, after placebo correction,
decreased both the 24-hour ambulatory SBP ( –4.2 mmHg for the 12.5 mg dose and
–5.9 mmHg for the 25 mg dose) and DBP (–4.3 mmHg for the 12.5 mg dose and –5.8
mmHg for the 25 mg dose). The placebo-corrected SBP lowering effect was –5.1
mmHg and –7.4 mmHg during the nighttime and –3.8 mmHg and –5.3 mmHg during the
daytime, for the 12.5 mg and 25 mg doses, respectively. In Part 3, after 4
weeks of withdrawal (week 40), both the 24-hour ambulatory SBP and DBP
increased with placebo compared with aprocitentan (6·5 mm Hg and 6·8 mm Hg
respectively).
Treatment-emergent adverse events (TEAEs) during the 4-week double-blind study
period (Part 1) 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 adverse event was fluid retention which was reported more
frequently with aprocitentan than with placebo in a dose-dependent fashion
(9.1%, 18.4%, and 2.1% for patients receiving aprocitentan 12.5 mg, 25 mg and
placebo, during Part 1, respectively; 18.2% for patients receiving aprocitentan
25 mg during Part 2; and 2.6% and 1.3% for patients on aprocitentan 25 mg and
placebo, during Part 3, respectively). Fluid retention was generally
mild-to-moderate, was primarily peripheral edema and was manageable by current
clinical practice including use of diuretics. Discontinuation due to
edema/fluid retention was reported for seven patients.
About Dr George Bakris, MD
Dr Bakris is a Nephrologist/Certified Hypertension Specialist trained at the
Mayo Clinic and the University of Chicago Medicine. He is a Professor of
Medicine and Director of the Am. Heart Assoc. Comprehensive Hypertension Center
at the University of Chicago Medicine. He has published over 1000 peer-reviewed
articles and book chapters in the areas of diabetic kidney disease,
hypertension, and nephropathy progression. He is the Editor or Co-Editor of 24
books in the areas of Diabetic Kidney Disease Progression and Hypertension.
Additionally, he is the Co-Editor of the 3rd and new 4 edition of Hypertension:
A Companion to Braunwald’s: The Heart.
Dr Bakris has served on the Cardiorenal Advisory Board of the FDA and
consultant to CMS. He has also served on many national guideline committees,
including The Joint National Committee JNC 7 executive committee and writing
group, the American Diabetes Association (ADA) Clinical Practice Guideline
Committee (2002-2004 and 2020-2022), and the National Kidney Foundation
(K-DOQI), Blood Pressure and Diabetes Guideline committees. He Chaired the ADA
Blood Pressure Consensus Report (2017) and served on the ACC/AHA writing
committee on the Resistant Hypertension Consensus report (2018). He is also the
senior author on the recent ADA/KDIGO Consensus Report for approaches to
diabetic kidney disease (2022).
Dr Bakris is the past president of the American College of Clinical
Pharmacology and the American Society of Hypertension (ASH). He is the
recipient of the Irvine Page-Alva Bradley Lifetime Achievement Award-Am Heart
Assoc. BP Council (2019). He serves on numerous editorial boards and is the
current Editor-in-Chief of Am J Nephrology, and Editor, UpToDate, Nephrology
section, Hypertension Section, and Assoc. Ed of Diabetes Care and Am. Heart J.
Plus. Dr. Bakris serves as a consultant to Idorsia.
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endothelin system and end-organ damage. Clin Sci 2010; 119:453-63. NCD Risk
Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence
and progress in treatment and control from 1990 to 2019: a pooled analysis of
1201 population-representative studies with 104 million participants. Lancet
2021; 398:957-80. Daugherty SL, et al. Incidence and prognosis of resistant
hypertension in hypertensive patients. Circulation. 2012 Apr 3;125(13):1635-42.
Noubiap JJ, et al. Global prevalence of resistant hypertension: a meta-analysis
of data from 3·2 million patients. Heart 2019; 105: 98–105. Dhaun N, et al.
Role of endothelin-1 in clinical hypertension: 20 years on. Hypertension 2008;
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hypertension. Can J Physiol Pharmacol 2022; 100:573-83. Grubbs AL, et al.
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patients. Arterioscler Thromb Vasc Biol 2002; 22: 1122–7. Parrinello G, et al.
Central obesity and hypertension: the role of plasma endothelin. Am J Hypertens
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endothelin-1 and blood pressure. J Hypertens 1999; 17: 61–6. Takahashi K, et
al. Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia
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2 diabetes: clinical correlates and association with complications. J Hypertens
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the kidney--beyond BP. Br J Pharmacol 2012; 167: 720–31. Rossignol P, et al.
The double challenge of resistant hypertension and chronic kidney disease.
Lancet 2015; 386: 1588–98. Danaietash P et al. Identifying and treating
resistant hypertension in PRECISION: A randomized long-term clinical trial with
aprocitentan. J Clin Hypertension 2022 Jul;24(7):804-813. Schlaich MP, et al. A
randomized controlled trial of the dual endothelin antagonist aprocitentan for
resistant hypertension. The Lancet, 2022; Dec 3;400(10367):1927-1937. Dolan E,
et al. Superiority of ambulatory over clinic blood pressure measurement in
predicting mortality: the Dublin outcome study. Hypertension 2005; 46:156–61.
Staplin N, et al. Relationship between clinic and ambulatory blood pressure and
mortality: an observational cohort study in 59 124 patients. Lancet.
2023;S0140-6736(23)00733-X.
About Idorsia
Idorsia Ltd is reaching out for more – We have more ideas, we see more
opportunities and we want to help more patients. In order to achieve this, we
will develop Idorsia into a leading biopharmaceutical company, with a strong
scientific core.
Headquartered near Basel, Switzerland – a European biotech-hub – Idorsia is
specialized in the discovery, development and commercialization of small
molecules to transform the horizon of therapeutic options. Idorsia has a
20-year heritage of drug discovery, a broad portfolio of innovative drugs in
the pipeline, an experienced team of professionals covering all disciplines
from bench to bedside, and commercial operations in Europe, Japan, and the US –
the ideal constellation for bringing innovative medicines to patients.
Idorsia was listed on the SIX Swiss Exchange (ticker symbol: IDIA) in June
2017 and has over 1,300 highly qualified specialists dedicated to realizing our
ambitious targets.
For further information, please contact
Andrew C. Weiss
Senior Vice President, Head of Investor Relations & Corporate Communications
Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123 Allschwil
+41 58 844 10 10
investor.relations@idorsia.com • media.relations@idorsia.com • www.idorsia.com
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