New Phase 3 data with aprocitentan for patients with resistant
hypertension has been presented at the European Society of
Hypertension Annual Meeting 2023
Allschwil, Switzerland – June
26, 2023
Idorsia Ltd (SIX: IDIA) today announced that further data for
aprocitentan, Idorsia’s investigational dual endothelin receptor
antagonist evaluating the treatment of patients with resistant
hypertension, were presented as an oral presentation entitled
“Effects of the dual endothelin antagonist aprocitentan on
ambulatory blood pressure indices in patients with resistant
hypertension – results from the PRECISION study” by Prof. Markus
Schlaich, MD, at the European Society of Hypertension’s 32nd
European Meeting of Hypertension and Cardiovascular Protection.
The Phase 3 PRECISION study demonstrated both the safety and the
efficacy of aprocitentan to lower office blood pressure (BP) in
patients with resistant hypertension. The presentation focused on
the effects on relevant indices of ambulatory BP measurements
(ABPM), including post-hoc analysis of patients at high risk of
cardiovascular events based on night-time BP values. Ambulatory BP,
and particularly nighttime ambulatory BP, is a better predictor of
cardiovascular outcomes than office BP.1,2
One aspect of ABPM is the ability to record the variation of BP
during a 24-hour period. The placebo-corrected systolic BP-lowering
by aprocitentan at week 4 was more pronounced during
night-time (–5.1 and
–7.4 mmHg) compared with
daytime (–3.8 and –5.3mmHg) for the 12.5 and 25mg
doses, respectively. Physiologically BP is on average 10% lower
during the night, a phenomenon called “dipping”. Patients who don't
achieve this 10% decrease are called “non-dippers” and are at
increased risk of cardiovascular events3. At baseline, non-dipper
(defined as participants with average night-time decrease of less
than 10%) rates were 66%, 62%, and 60% for the 12.5mg, 25mg of
aprocitentan, and placebo groups, respectively. In non-dippers,
aprocitentan induced a particularly pronounced reduction in
night-time systolic BP compared with dippers for both 12.5mg
(-11.25 vs -2.79mmHg; p<0.01) and 25mg
(-13.12 vs -6.29mmHg; p<0.01). After 4 weeks of
treatment, normalization of the dipping pattern was achieved in
44%, 40% and 31% of non-dippers for 12.5mg, 25mg of aprocitentan,
and placebo, respectively.
Another aspect of the ambulatory BP is the proportion of times
that the BP exceeds normal values of the total number of recorded
BP measurements during day, night, and over 24 h, known as BP load.
The change in BP load for both daytime and night-time was more
pronounced with both doses of aprocitentan (-18.7/-24.5% for
12.5mg; -20.7/-21.1% for 25mg) compared to placebo (-9.2/-6.6 %;
p<0.001 for all comparisons).
Prof. Markus Schlaich, MD, FAHA, FESC, ISHF, The
University of Western Australia / Royal Perth Hospital and an
investigator in the PRECISION study commented:“The
detailed analysis of the PRECISION study with aprocitentan in
patients with resistant hypertension continues to excite the expert
community. We know that ambulatory blood pressure is a better
predictor of cardiovascular outcomes than office blood pressure,
particularly the nighttime measure. Aprocitentan was associated
with substantial lowering of ambulatory blood pressure, which was
even more pronounced during the night. It restored the normal
‘dipping’ pattern of blood pressure variation over 24 hours in many
patients who had an abnormal pattern and also reduced the
percentage of abnormally elevated blood pressure readings known as
‘BP load’. These findings support the initial positive results and
the potential use of aprocitentan and tackling the endothelin
pathway for the first time for these patients who are at high-risk
of negative cardiovascular outcomes.”
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 filed with the US FDA in
December 2022, and the 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-1.5 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.6,7
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
worldwide7 – 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.8
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,4,9 (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.4,10,11
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,12-14
and in comorbid conditions frequently associated with resistant
hypertension such as diabetes and chronic kidney
disease.15-18
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
PRECISION19,20
(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 findings20 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,1,2 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 Prof. Markus Schlaich, MD
Markus Schlaich is a nephrologist and a European
Society of Hypertension (ESH) accredited hypertension specialist.
He is a Fellow of the American Heart Association (FAHA), the
European Society of Cardiology (FESC), and the International
Society of Hypertension (ISHF). He served as an Executive Committee
of the ISH from 2018-2020 and is currently on the Management Board
of the global ISH May Measurement Month campaign. Markus is
President of Hypertension Australia and a Trustee of the Foundation
for High Blood Pressure Research.
Markus has a strong background in clinical research with a focus
on the pathophysiology of hypertension, involvement of the kidneys,
and hypertension mediated organ damage. He has a specific interest
in treatment modalities targeting the sympathetic nervous system
and other relevant pathways such as the endothelin system to
improve BP control and thereby outcomes for patients with difficult
to control hypertension. For his work he received the Björn Folkow
Award from the European Society of Hypertension (ESH) and the
Arthur C. Corcoran Award from the AHA Hypertension Council, both in
2021. He has authored more than 450 articles in peer-reviewed
journals and serves on the Editorial Board of Hypertension and
Journal of Hypertension. Prof. Schlaich serves as a consultant to
Idorsia.
About the collaboration agreement with Janssen Biotech,
Inc.In 2017, Idorsia entered into a collaboration
agreement with Janssen Biotech, Inc., one of the Janssen
Pharmaceutical Companies of Johnson & Johnson, to jointly
develop aprocitentan and any of its derivative compounds or
products. Idorsia received a one-time milestone payment of USD 230
million. Both parties have joint development rights over
aprocitentan. Idorsia has conducted the Phase 3 development and is
overseeing the regulatory review for the treatment of patients with
difficult-to-control hypertension. The costs are shared equally
between both partners. Janssen Biotech, Inc. has sole
commercialization rights worldwide, whereas Idorsia is entitled to
receive tiered royalties on annual net sales in each calendar year
(20% up to USD 500 million, 30% from USD 500 million up to USD 2.0
billion, and 35% above USD 2.0 billion) for the licensed products
in the collaboration indications. Janssen Biotech, Inc. will
oversee the Phase 3 development and submission for any additional
indications.
Key Literature
- 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.
- Gavriilaki M, et al. Nighttime dipping status and risk of
cardiovascular events in patients with untreated hypertension: A
systematic review and meta-analysis. J Clin Hypertens (Greenwich).
2020 Nov;22(11):1951-1959.
- 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.
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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