The Lancet and AHA late-breaking science session reports significant and
sustained effect of aprocitentan on lowering blood pressure for patients with
resistant hypertension The Lancet reports that in patients with resistant
hypertension, aprocitentan was well-tolerated and superior to placebo in
lowering blood pressure at week 4 with a sustained effect at week 40 Upon
approval, aprocitentan would represent the first new anti-hypertensive
mechanism in more than 30 years Idorsia to host an investor webcast to discuss
the data shared at AHA and in The Lancet manuscript tomorrow November 8 at
15:00hrs CET
Allschwil, Switzerland – November 7 , 2022
Idorsia Ltd (SIX: IDIA) today announced the publication of “ A randomized
controlled trial of the dual endothelin antagonist aprocitentan for resistant
hypertension ” in The Lancet . The publication reports the results from the
Phase 3 PRECISION study, which found aprocitentan, Idorsia’s investigational,
novel dual endothelin receptor antagonist, significantly reduced blood pressure
(BP) and maintained the effect for up to 48 weeks when added to combination
background antihypertensive therapy in patients with difficult-to-control
(resistant) hypertension. In parallel, these data were presented by Prof.
Markus Schlaich, an investigator in PRECISION, as a Late-Breaking Science
presentation during the American Heart Association (AHA) Scientific Sessions
2022.
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. 2,3
Compared with adults whose hypertension is well controlled, adults with
uncontrolled hypertension have greater risk of heart attack, stroke, end-stage
renal disease and death. 4
The endothelin (ET) pathway has been implicated in the pathogenesis of
hypertension, but it is currently not targeted therapeutically, thereby leaving
this relevant pathophysiologic pathway unopposed with currently available
medications. 4-6 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, 7 - 9 and in comorbid conditions
frequently associated with resistant hypertension such as diabetes and chronic
kidney disease. 10 -1 3
Prof. Markus Schlaich, MD, FAHA, FESC, ISHF, The University of Western
Australia / Royal Perth Hospital and an investigator in the PRECISION study
commented:
“For decades, healthcare providers have been challenged to help their patients
with resistant hypertension achieve better blood pressure control, using
treatment options that do not address all of the known mechanisms of the
condition. The Phase 3 PRECISION study establishes aprocitentan as a promising
new therapeutic approach to achieve sustained blood pressure lowering in
addition to guideline recommended triple antihypertensive therapy with both
office and ambulatory blood pressure measurements. I’m particularly happy to
see a pronounced reduction in nighttime blood pressure, which is superior to
other blood pressure measures in predicting cardiovascular mortality. 1 4 ,1 5
”
About PRECISION 1 6 ( 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
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 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).
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 fluid
retention leading to discontinuation in seven patients during the study. 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).
Jean-Paul Clozel, MD and Chief Executive Officer, commented:
“Literature tells us that a 5 mmHg reduction in office SBP has been associated
with a 10% relative risk reduction in major cardiovascular events. 1 7 This is
of particular relevance in patients at high risk of cardiovascular events. 3 ,
1 8 As we publish in T he Lancet today, aprocitentan, by targeting a currently
unopposed pathophysiologic pathway, provided clinically meaningful lowering of
systolic and diastolic blood pressure in patients with treatment-resistant
hypertension over 48 weeks with manageable adverse effects. The authors
conclude that aprocitentan represents a novel, effective, and well-tolerated
treatment for resistant hypertension.”
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. 1 4 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. 1 9 , 20
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 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 will be responsible for the regulatory submission for
the treatment of patients whose hypertension is not adequately controlled. 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.
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 the High
Blood Pressure Research Council of 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 400 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.
Key Literature 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, Nansseu JR, Nyaga
UF, Sime PS, Francis I, Bigna JJ. Global prevalence of resistant hypertension:
a meta-analysis of data from 3·2 million patients. Heart 2019; 105: 98–105.
Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH guidelines for the
management of arterial hypertension. Eur Heart J 2018; 39: 3021–104. Daugherty
SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Margolis KL, O'Connor PJ, Selby
JV, Ho PM. Incidence and prognosis of resistant hypertension in hypertensive
patients. Circulation. 2012 Apr 3;125(13):1635-42. 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, Anstadt MP,
Ergul A. Saphenous vein endothelin system expression and activity in African
American patients. Arterioscler Thromb Vasc Biol 2002; 22: 1122–7. Parrinello
G, Scaglione R, Pinto A, et al. Central obesity and hypertension: the role of
plasma endothelin. Am J Hypertens 1996; 9: 1186–91. Phillips BG, Narkiewicz K,
Pesek CA, Haynes WG, Dyken ME, Somers VK. Effects of obstructive sleep apnea on
endothelin-1 and blood pressure. J Hypertens 1999; 17: 61–6. Takahashi K,
Ghatei MA, Lam HC, O'Halloran DJ, Bloom SR. Elevated plasma endothelin in
patients with diabetes mellitus. Diabetologia 1990; 33: 306–10. Solini A,
Zoppini G, Orsi E, 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, Massy ZA,
Azizi M, et al. The double challenge of resistant hypertension and chronic
kidney disease. Lancet 2015; 386: 1588–98. Dolan E, Stanton A, Thijs L, et al.
Superiority of ambulatory over clinic blood pressure measurement in predicting
mortality: the Dublin outcome study. Hypertension 2005; 46:156–61. Cardoso CRL,
Salles GC, Salles GF. Prognostic importance of on-treatment clinic and
ambulatory blood pressures in resistant hypertension: A cohort study.
Hypertension 2020; 75:1184–94. 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. The Blood Pressure
Lowering Treatment Trialists’ Collaboration. Pharmacological blood pressure
lowering for primary and secondary prevention of cardiovascular disease across
different levels of blood pressure: an individual participant-level data
meta-analysis. Lancet 2021; 397: 1625-36. The Blood Pressure Lowering Treatment
Trialists’ Collaboration. Blood pressure-lowering treatment based on
cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014;
384: 591–8. 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
Investor webcast
An investor conference call and webcast will be held to discuss the data
shared at AHA and in The Lancet manuscript. The call will start with
presentations by Martine Clozel, MD, Chief Scientific Officer at Idorsia and
Prof. Markus Schlaich, MD, FAHA, FESC, ISHF, The University of Western
Australia / Royal Perth Hospital and an investigator in the PRECISION study
followed by a Q&A session.
Date: Tuesday , November 8 , 2022
Time: 1 5 :00 CET | 1 4 :00 GMT | 0 9 :00 EST
Dial-in procedure: Participants are required to register in advance of the
conference (link already open for registration) using the link provided below.
Upon registration, each participant will be provided with participant dial in
numbers, and a unique personal PIN. In the 10 minutes prior to the call start
time, participants will need to use the conference access information provided
in the e-mail received at the point of registering. Participants may also use
the Call Me feature instead of dialing the nearest dial in number.
Online Registration: LINK
Webcast participants should visit Idorsia's website www.idorsia.com 10-15
minutes before the webcast is due to start.
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
The above information contains certain 'forward-looking statements', relating
to the company's business, which can be identified by the use of
forward-looking terminology such as 'estimates', 'believes', 'expects', 'may',
'are expected to', 'will', 'will continue', 'should', 'would be', 'seeks',
'pending' or 'anticipates' or similar expressions, or by discussions of
strategy, plans or intentions. Such statements include descriptions of the
company's investment and research and development programs and anticipated
expenditures in connection therewith, descriptions of new products expected to
be introduced by the company and anticipated customer demand for such products
and products in the company's existing portfolio. Such statements reflect the
current views of the company with respect to future events and are subject to
certain risks, uncertainties and assumptions. Many factors could cause the
actual results, performance or achievements of the company to be materially
different from any future results, performances or achievements that may be
expressed or implied by such forward-looking statements. Should one or more of
these risks or uncertainties materialize, or should underlying assumptions
prove incorrect, actual results may vary materially from those described herein
as anticipated, believed, estimated or expected.
Anhang Medienmitteilung PDF
