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
hypertensionEndothelin-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 ETA
and ETB 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)
hypertensionHypertension (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
worldwide4 – 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,9-11 and
in comorbid conditions frequently associated with resistant
hypertension such as diabetes and chronic kidney
disease.12-15
About aprocitentanAprocitentan is an
investigational, novel, oral, dual endothelin receptor antagonist
(ERA), which potently inhibits the binding of ET-1 to
ETA and ETB 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
PRECISION16,17
(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 findings17 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,18,19 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, MDDr 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.
Key Literature
- Williams B, et al. 2018 ESC/ESH guidelines for the management
of arterial hypertension. Eur Heart J 2018; 39: 3021–104.
- Kedzierski RM, et al. Endothelin system: the double-edged sword
in health and disease. Annu Rev Pharmacol Toxicol. 2001;
41:851-76.
- Iglarz M, et al. At the heart of tissue: 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; 52:452-9.
- Clozel M. Aprocitentan and the endothelin system in resistant
hypertension. Can J Physiol Pharmacol 2022; 100:573-83.
- Grubbs AL, et al. Saphenous vein endothelin system expression
and activity in African American 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 1996; 9: 1186–91.
- Phillips BG, et al. Effects of obstructive sleep apnea on
endothelin-1 and blood pressure. J Hypertens 1999; 17: 61–6.
- Takahashi K, et al. Elevated plasma endothelin in patients with
diabetes mellitus. Diabetologia 1990; 33: 306–10.
- Solini A, et al. Resistant hypertension in patients with type 2
diabetes: clinical correlates and association with complications. J
Hypertens 2014; 32: 2401–10; discussion 10.
- Dhaun N, Webb DJ, Kluth DC. Endothelin-1 and 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 IdorsiaIdorsia 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 contactAndrew
C. WeissSenior Vice President, Head of Investor Relations &
Corporate CommunicationsIdorsia Pharmaceuticals Ltd,
Hegenheimermattweg 91, CH-4123 Allschwil+41 58 844 10
10investor.relations@idorsia.com • media.relations@idorsia.com •
www.idorsia.com
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