JERAYGO (aprocitentan) recommended for approval in Europe for the treatment of
resistant hypertension
Ad hoc announcement pursuant to Art. 53 LR Idorsia receives a positive opinion
from the Committee for Medicinal Products for Human Use for JERAYGO™
(aprocitentan) as the first and only endothelin receptor antagonist for the
treatment of resistant hypertension in adult patients in combination with at
least three antihypertensive medicinal products. A CHMP positive opinion is one
of the final steps before marketing authorization can be granted by the
European Commission – a final decision is expected in approximately two months.
Allschwil, Switzerland – April 26, 2024
Idorsia Ltd (SIX: IDIA) announced today that the Committee for Medicinal
Products for Human Use (CHMP), the scientific committee of the European
Medicines Agency (EMA), adopted a positive opinion for the use of JERAYGO™
(aprocitentan) for the treatment of resistant hypertension in adult patients in
combination with at least three antihypertensive medicinal products. The CHMP
has adopted a positive opinion for the use of 12.5 mg JERAYGO orally once
daily. The dose can be increased to 25 mg once daily for patients tolerating
the 12.5 mg dose and in need of tighter blood pressure (BP) control.
Detailed recommendations for the use of JERAYGO will be described in the
summary of product characteristics (SmPC), which will be published in the
European public assessment report (EPAR) and made available in all official
European Union languages after the marketing authorization has been granted by
the European Commission, expected in approximately two months.
Hypertension is one of the leading causes of cardiovascular disease worldwide,
impacting an estimated 1.3 billion people globally. 1 Approximately 10% of
these people have uncontrolled BP, despite receiving at least three
antihypertensive medications from different classes, at optimal doses and they
are categorized in hypertension guidelines 2,3 as having resistant
hypertension. Compared with adults whose hypertension is well controlled,
adults with uncontrolled hypertension have greater risk of heart attack, heart
failure, stroke, end-stage renal disease and death. 4
Jean-Paul Clozel, MD and Chief Executive Officer of Idorsia commented:
“Uncontrolled hypertension, particularly resistant hypertension, where blood
pressure remains uncontrolled despite the use of multiple antihypertensive
therapies, affects millions of Europeans and is a major public health issue
leading to a high risk of heart attack, heart failure, stroke and renal
disease, not to mention the increased risk of death. Idorsia has tackled this
need by developing aprocitentan, or JERAYGO, the brand name in Europe, an
endothelin receptor antagonist discovered by our team and optimized for the
treatment of resistant hypertension. As a result of our efforts, physicians and
patients in Europe are one step closer to having a new oral antihypertensive
therapy – the first in almost 40 years – that is working via a new therapeutic
pathway.”
The positive CHMP opinion is supported by a comprehensive clinical and
non-clinical development program. Aprocitentan was evaluated as a monotherapy
in a Phase 2 study in patients with hypertension, 11 and as an add-on therapy
in a Phase 3 study called PRECISION in patients with confirmed resistant
hypertension. 12 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 a
combination of background antihypertensive therapies 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.
The team at Idorsia has been working on the research and development of
endothelin receptor antagonists for more than 30 years, successfully bringing
three other molecules from this class to patients in different indications.
Endothelin (ET)-1, via its receptors (ET A and ET B ), mediates a variety of
effects such as vasoconstriction, fibrosis, cell proliferation, inflammation,
aldosterone production 7 and is upregulated in hypertension. Aprocitentan is a
dual ERA that inhibits the binding of ET-1 to ET A and ET B receptors and hence
the effects mediated by these receptors. 5 The effects of ET-1 bear many
similarities with the pathophysiology of hypertension, 6 ,8 and the resistance
to other antihypertensive drugs in some patients (often with risk factors such
as obesity, sleep apnea, older age, kidney failure, type 2 diabetes, and
African Americans), can be explained by an endothelin-dependent hypertension 8
. This is now confirmed by the efficacy of aprocitentan in the PRECISION study.
About the Phase 3 PRECISION study ( NCT03541174 ) 12
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 (SBP) 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 SBP 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 13
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 (the
primary endpoint). 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 (week 40) (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 night time 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).
The effect of aprocitentan was consistent across subgroups of age (including
patients ≥ 75 years), sex, race (including patients with Black or African
American origin), BMI, baseline urine albumin-to-creatinine ratio (UACR),
baseline estimated Glomerular Filtration Rate (eGFR) and medical history of
diabetes, and was consistent with the effect in the overall population.
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 with aprocitentan was mild-to-moderate
edema/fluid retention leading to discontinuation in seven patients during the
study. Edema/fluid retention 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).
Regulatory status of aprocitentan
The positive opinion recommending JERAYGO, is a scientific recommendation
issued by the EMA’s CHMP, which is sent to the European Commission (EC) for the
adoption of a decision on an EU-wide marketing authorization. An EC marketing
authorization through the centralized procedure is valid in all European Union
Member States, as well as the European Economic Area countries Iceland,
Liechtenstein and Norway, and Northern Ireland under the Northern Ireland
Protocol.
In March, TRYVIO™ (aprocitentan) was approved by the US Food and Drug
Administration (FDA).
Notes to the editor
References 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. Noubiap JJ, et al. Global
prevalence of resistant hypertension: a meta-analysis of data from 3·2 million
patients. Heart 2019; 105: 98–105. Williams B, et al. 2018 ESC/ESH guidelines
for the management of arterial hypertension. Eur Heart J 2018; 39: 3021–104.
Daugherty SL, et al. Incidence and prognosis of resistant hypertension in
hypertensive patients. Circulation. 2012 Apr 3;125(13):1635-42. Trensz F, et
al. Pharmacological characterization of aprocitentan, a dual endothelin
receptor antagonist, alone and in combination with blockers of the renin
angiotensin system, in two models of experimental hypertension. J Pharmacol Exp
Ther. 2019 Mar; 368(3):462-473. Iglarz M, et al. At the heart of tissue:
endothelin system and end-organ damage. Clin Sci 2010; 119:453-63. Rossi GP, et
al. Endothelin-1 stimulates steroid secretion of human adrenocortical cells ex
vivo via both ETA and ETB receptor subtypes. J Clin Endocrinol Metab. 1997, 82:
3445-3449 Clozel M. Aprocitentan and the endothelin system in resistant
hypertension. Can J Physiol Pharmacol 2022; 100:573-83. Whelton P.K., et al.
2018. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ ASH/ASPC/NMA/PCNA guideline for the
prevention, detection, evaluation, and management of high blood pressure in
adults: a report of the American College of Cardiology/American Heart
Association Task Force on clinical practice guidelines. Hypertension, 71:
e13–e115. Williams B, et al. 2018 ESC/ESH guidelines for the management of
arterial hypertension. Eur Heart J 2018; 39: 3021–104. Verweij P. et al.
Randomized Dose-Response Study of the New Dual Endothelin Receptor Antagonist
Aprocitentan in Hypertension. Hypertension. 2020;75:956–965 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 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
25-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 and North America –
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 750 highly qualified specialists dedicated to realizing our
ambitious targets.
For further information, please contact
Investors & Media
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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