^Ad hoc announcement pursuant to Art. 53 LR
* Idorsia receives a positive opinion from the Committee for Medicinal
Products for Human Use for JERAYGO(TM) (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(TM)
(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
(https://classic.clinicaltrials.gov/ct2/show/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= 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(TM) (aprocitentan) was approved by the US Food and Drug
Administration (FDA).
Notes to the editor
References
1. 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.
2. Noubiap JJ, et al. Global prevalence of resistant hypertension: a meta-
analysis of data from 3·2 million patients. Heart 2019; 105: 98-105.
3. Williams B, et al. 2018 ESC/ESH guidelines for the management of arterial
hypertension. Eur Heart J 2018; 39: 3021-104.
4. Daugherty SL, et al. Incidence and prognosis of resistant hypertension in
hypertensive patients. Circulation. 2012 Apr 3;125(13):1635-42.
5. 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.
6. Iglarz M, et al. At the heart of tissue: endothelin system and end-organ
damage. Clin Sci 2010; 119:453-63.
7. 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
8. Clozel M. Aprocitentan and the endothelin system in resistant hypertension.
Can J Physiol Pharmacol 2022; 100:573-83.
9. 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.
10. Williams B, et al. 2018 ESC/ESH guidelines for the management of arterial
hypertension. Eur Heart J 2018; 39: 3021-104.
11. Verweij P. et al. Randomized Dose-Response Study of the New Dual Endothelin
Receptor Antagonist Aprocitentan in Hypertension. Hypertension.
2020;75:956-965
12. 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.
13. 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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may vary materially from those described herein as anticipated, believed,
estimated or expected.
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