Idorsia submits European marketing authorisation application for aprocitentan
for the treatment of patients with resistant hypertension The application
includes data from the Phase 3 registration study of patients with resistant
hypertension, where aprocitentan demonstrated a sustained blood pressure
reduction over 48 weeks and was well-tolerated
Allschwil, Switzerland – Jan uary 31 , 202 3
Idorsia Ltd (SIX: IDIA) today announced that it has submitted a marketing
authorisation application (MAA) to the European Medicines Agency (EMA) for
aprocitentan, Idorsia’s investigational, novel dual endothelin receptor
antagonist, for the treatment of patients with resistant hypertension.
The MAA includes data from a comprehensive clinical and non-clinical
development program. In the Phase 3 registration study, PRECISION, aprocitentan
showed statistically significant and clinically meaningful reduction in blood
pressure (BP) which was maintained for up to 48 weeks when added to combination
background antihypertensive therapy in patients with resistant hypertension. In
PRECISION, aprocitentan was generally well tolerated with no major safety
concerns. The most frequent adverse event with aprocitentan was
mild-to-moderate edema/fluid retention.
Full results from the PRECISION study were published in November 2022 in The
Lancet “ A randomized controlled trial of the dual endothelin antagonist
aprocitentan for resistant hypertension ”. More details and commentary can be
found in the dedicated press release and an investor webcast featuring Prof.
Markus Schlaich, an investigator in PRECISION, which are available on Idorsia’s
corporate website: www.idorsia.com
Patients with uncontrolled blood pressure are at risk of major cardiovascular
events. 1 These risks are even higher for patients whose blood pressure is
uncontrolled despite treatment with three or more antihypertensives 2 , known
as resistant hypertension 3 , 4 . It has been more than 30 years since a new
anti-hypertensive therapy working by a new mechanism has been brought to
patients. By targeting a currently unopposed pathophysiologic pathway,
aprocitentan represents a potential novel, effective, and well-tolerated
treatment for resistant hypertension.
Idorsia is developing aprocitentan together with Janssen Biotech, Inc., one of
the Janssen Pharmaceutical Companies of Johnson & Johnson. Janssen Biotech has
sole commercialization rights worldwide.
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. 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 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 8 – 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. 9
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, 3, 10 .
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, but it is currently not
targeted therapeutically, thereby leaving this relevant pathophysiologic
pathway unopposed with currently available medications. 3 ,11 , 1 2 This
pathway is activated in patients prone to developing resistant hypertension,
such as Black or African American patients, patients with obesity or
obstructive sleep apnea, 1 3 -1 5 and in comorbid conditions frequently
associated with resistant hypertension such as diabetes and chronic kidney
disease. 1 6 -1 9
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 20 , 21 ( 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. At screening, 63% of all patients who were randomly assigned
were prescribed four or more antihypertensive drugs.
Key PRECISION findings 21
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 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. Discontinuation due to edema/fluid retention was reported for
seven patients.
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 Turnbull F. Blood Pressure Lowering Treatment Trialists’
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cardiovascular events: results of prospectively-designed overviews of
randomized trials. Lancet 2003; 362: 1527–35 Kumbhani DJ, et al. Resistant
hypertension: a frequent and ominous finding among hypertensive patients with
atherothrombosis. European Heart Journal (2013) 34, 1204–1214. Williams B, et
al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur
Heart J 2018; 39: 3021–104. Carey RM, et al. Resistant Hypertension: Detection,
Evaluation, and Management A Scientific Statement From the American Heart
Association. Hypertension. 2018;72:00-00. Dolan E, et al. Superiority of
ambulatory over clinic blood pressure measurement in predicting mortality: the
Dublin outcome study. Hypertension 2005; 46:156–61. 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; Available online 7 November 2022
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 broad
portfolio of innovative drugs in the pipeline, an experienced team of
professionals covering all disciplines from bench to bedside, state-of-the-art
facilities, and a strong balance sheet – the ideal constellation to translate
R&D efforts into business success.
Idorsia was listed on the SIX Swiss Exchange (ticker symbol: IDIA) in June
2017 and has over 1’200 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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Anhang Medienmitteilung PDF
