Positive Phase 3 study with aprocitentan demonstrates significant
antihypertensive efficacy in patients with resistant hypertension
Ad hoc announcement pursuant to Art. 53 LR Aprocitentan reduces blood pressure
compared to placebo by week 4 of treatment, the effect is maintained and
confirmed over a period of 48 weeks, and is generally well tolerated with no
major safety concerns Primary and key secondary endpoints were met with
statistical significance and clinically meaningful results – the effect was
consistent across multiple endpoints and methodologies of blood pressure
monitoring Idorsia to host an investor webcast to discuss PRECISION top-line
results tomorrow May 24 at 14:00hrs CEST
Allschwil, Switzerland – M ay 23 , 2022
Idorsia Ltd (SIX: IDIA) today announced positive top-line results of
PRECISION, the Phase 3 study investigating aprocitentan, Idorsia’s dual
endothelin receptor antagonist, for the treatment of patients whose blood
pressure is not adequately controlled despite receiving at least triple
antihypertensive therapy – known as resistant hypertension. Aprocitentan s
ignificantly reduc ed blood pressure when added to standardized combination
background antihypertensive therapy in patients with resistant hypertension
over 48 weeks of treatment.
Hypertension is one of the most common cardiovascular risk factors, and its
prevalence continues to rise. According to a recent study, there are more than
one billion people living with hypertension worldwide – a number which has
almost doubled in the past 40 years. 1
While many patients with hypertension are successfully treated with various
existing anti-hypertensive therapies, 10–20% of the hypertensive population
have blood pressure that remains high despite receiving at least three
antihypertensive medications of different pharmacological classes, including a
diuretic, at optimal doses, and they are categorized in hypertension guidelines
2 ,3,4 and in the medical community as having resistant hypertension. Certain
populations are at a particular high risk of developing resistant hypertension
later in life; these include patients with a high body mass index (BMI),
African Americans, post-menopausal women and patients with obstructive sleep
apnea. 5 , 6 , 7
It is estimated that by 2025, there could be approximately 10 million patients
in the US who could be classified as having resistant hypertension and a
similar number of patients in Europe. 3, 4 , 8 Uncontrolled hypertension can
lead to multiple cardiovascular and renal adverse outcomes, including stroke,
heart disease, and kidney failure. These co-morbidities increase a patient's
vulnerability and the complexity of their treatment. 9,10 ,11
Martine Clozel, MD and Chief Scientific Officer of Idorsia, commented:
“I have long been convinced that resistant hypertension is only resistant to
treatment because the endothelin system had not been tackled. The observation
of high endothelin levels in populations most at risk of developing resistant
hypertension, as well as the close association between endothelin and the
comorbidities often seen in patients with resistant hypertension, suggested
that endothelin is a key contributor to the problem. I believe the top-line
results from PRECISION support our initial hypothesis that endothelin is the
missing link when hypertension is not adequately controlled with existing
therapies.”
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 long half-life, a low potential for drug-drug
interaction and a mechanism of action that is ideally suited for the
pathophysiology of difficult-to-treat forms of hypertension.
About the PRECISION study 1 2 Danaietash P et al. J Clin Hypertension 2022 (in
press) ( NCT03541174 )
Idorsia, in consultation with regulatory agencies, designed a single,
international, multi-center, blinded randomized study with three sequential
treatment parts. The study design addressed both the 4-week placebo-controlled
efficacy of 12.5 and 25 mg aprocitentan (Part 1) and the durability of its
effects in long-term active treatment with 25 mg aprocitentan for a further 32
weeks (Part 2) followed by a 12-week placebo-controlled withdrawal period with
patients re-randomized to 25 mg or placebo (Part 3).
P atient population with established r esistant hypertensi on
To confirm a diagnosis of resistant hypertension and exclude pseudo resistant
hypertension, 1’965 patients entered a thorough 12-week screening period.
During the screening period, qualifying patients were transitioned to
guideline-recommended standardized background antihypertensive therapy of a
fixed-dose combination of a calcium channel blocker (amlodipine), an
angiotensin receptor blocker (valsartan) and a diuretic (hydrochlorothiazide)
for at least 4 weeks before entering a 4-week single-blind run-in period. In
this period, placebo was added to the background antihypertensive therapy.
Patients with systolic blood pressure consistently above 140 mmHg were then
randomized to the first treatment part.
Sustained reduction in systolic blood pressure after chronic treatment with
aprocitentan
In Part 1, the first double-blind treatment period of 4 weeks, a total of 730
patients were randomized to receive a tablet of aprocitentan 12.5 mg (N=243),
25 mg (N=243), or placebo (N=244) once daily. After 4 weeks of treatment, a
statistically significant and clinically meaningful reduction in the primary
endpoint measure of systolic blood pressure – assessed by measurement at trough
of unattended automated office blood pressure (AOBP) – was observed in both the
12.5 mg (p < 0.005) and 25 mg (p < 0.005) aprocitentan groups compared to
placebo.
Following the 4-week double-blind, placebo-controlled treatment period,
patients entered Part 2, a single-blind treatment period, where all patients
were treated with 25 mg aprocitentan for a further 32 weeks. The mean reduction
from baseline in systolic blood pressure was maintained during this treatment
period, for those patients who were on aprocitentan during Part 1. Patients
switching from placebo to aprocitentan rapidly achieved the same blood pressure
reduction as seen in Part 1.
This was followed by Part 3, a double-blind, placebo-controlled, randomized
withdrawal treatment period where 614 patients were re-randomized to
aprocitentan 25 mg or placebo for 12 weeks. After 4 weeks in the withdrawal
period, systolic blood pressure increased significantly on placebo compared to
aprocitentan 25 mg (p < 0.0001), the key secondary endpoint. This provided
replication of the treatment effect of aprocitentan and confirmed its durable
antihypertensive effect.
The reduction in systolic and diastolic blood pressure assessed by measurement
of unattended automated office blood pressure during the study, was confirmed
by the 24-hour ambulatory blood pressure monitoring (ABPM), demonstrating BP
reduction across the entire 24 h period (notably during the night).
Prof. Markus Schlaich, MD, FAHA , FESC , ISHF , The University of Western
Australia, Perth , and lead investigator in the PRECISION study commented:
“Despite the availability of many drug classes to target the serious and
growing problem of arterial hypertension around the world, we frequently
struggle to achieve BP control in many patients, particularly in those with
resistant hypertension. As a strong believer in the principles of targeting
underlying pathophysiologic mechanisms, the findings from this study
demonstrate the crucial contributions of the endothelin pathway and highlight
the enormous potential of aprocitentan to help improve blood pressure control
and thereby cardiovascular outcomes in this high-risk patient cohort. The
consistency of the observations made during the study and in particular the use
of the withdrawal study design after chronic use will set a new standard in the
evaluation of the treatment of resistant hypertension.”
About the safety of aprocitentan in PRECISION
The topline results show that aprocitentan was generally well tolerated with
no major safety concerns in this patient population at both doses and with a
low discontinuation from study treatment due to an adverse event in the first 4
weeks double-blind study period: 2.5% and 2.0% for aprocitentan 12.5 mg and 25
mg groups respectively versus 0.8% in the placebo group. Treatment-emergent
adverse events (TEAEs) during the 4-week double-blind study period 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 TEAEs reported over 3% incidence and higher than placebo was edema /
fluid retention.
There were no additional emerging safety findings in the subsequent treatment
period taking the total to 48 weeks. Importantly, the overall incidence of
Major Adverse Cardiac Events (MACE) reflected the expected occurrence in this
patient population. Approximately 30% of patients developed edema / fluid
retention, at one time point during the entire study duration, with >95% being
mild to moderate in intensity. Two ( < 1%) of these adverse events were serious
(both on aprocitentan 25mg). Only seven ( < 1%) of patients discontinued
treatment due to edema / fluid retention. Edema / fluid retention was mostly
reported by patients within the first 4-week double-blind study period (9.1%
and 18.4% for aprocitentan 12.5 mg and 25 mg groups respectively, versus 2.1%
in the placebo group).
Conclusion of the Phase 3 PRECISION study
Aprocitentan is an investigational treatment with a new mode of action for
patients whose hypertension is not adequately controlled despite the use of at
least three other classes of antihypertensives, including a diuretic.
Aprocitentan reduces blood pressure compared to placebo by week 4 of treatment
and the effect is maintained over a period of 48 weeks. The safety profile,
together with the long half-life, and low potential for drug-drug interactions
observed in the clinical pharmacology program, is conducive for a chronic
treatment to be used for patients who often have several comorbidities and are
treated with multiple pharmacological therapies. The effect demonstrated in the
Phase 3 study was consistent across multiple methodologies of blood pressure
monitoring and in key sub-populations.
Jean-Paul Clozel, MD and Chief Executive Officer of Idorsia, commented:
“I am delighted that in this patient population, where hypertension is so
difficult to control, the treatment effect of aprocitentan was clear and
consistent – despite aprocitentan being given on top of at least three
therapies. During the course of the 48 weeks of treatment we have collected
information on safety and efficacy which will allow us to fully characterize
the benefit of aprocitentan, especially for the sub-populations in greatest
need of new antihypertensives. I am very proud that Idorsia is once again at
the forefront of medical research.”
Alberto Gimona, Head of Global Clinical Development of Idorsia, concluded:
“A big ‘thank you’ goes to the investigators and their patients who took part
in this study. Their dedication has contributed to the outstanding conclusion
of PRECISION, and potentially to the availability of a new antihypertensive,
the first working via a new pathway for decades. Idorsia will now discuss the
results with health authorities with the aim to file the new drug application
with the US FDA by the end of the year, closely followed by other health
authorities. We will also make the detailed results of the Phase 3 study
available through scientific presentation and peer-reviewed publications.”
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.
Notes to the editor
The endothelin system in systemic hypertension 1 3
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 5
Additi onal aprocitentan data 1 6 Verweij P., et al. Hypertension. 2020
In May 2017, the results of a double-blind, randomized, placebo-controlled
with an active-reference arm, dose-finding study with aprocitentan in patients
with essential hypertension, were reported. The study evaluated the efficacy,
safety and tolerability of a once-a-day oral regimen of 4 dose levels of
aprocitentan (5, 10, 25, and 50mg) to identify the optimal doses for further
studies.
In this study, 490 patients were randomized to receive either aprocitentan 5,
10, 25, 50 mg, placebo, or lisinopril 20 mg once daily. After 8 weeks of
treatment the mean reduction from baseline in diastolic blood pressure - as
measured at trough with a novel automated office blood pressure device - ranged
between 6.3 and 12.0 mmHg in a statistically significant dose-dependent manner
for the aprocitentan groups versus a decrease of 4.9 mmHg in the placebo group
and a decrease of 8.4 mmHg in the lisinopril group (in the per-protocol
population comprised of 410 patients). Systolic blood pressure reductions
ranged from 10.3 to 18.5 mmHg in a statistically significant dose-dependent
manner in the aprocitentan groups and were 7.7 and 12.8 mmHg in the placebo and
lisinopril groups, respectively. These findings were confirmed in all
randomized patients (Intent-to-Treat principle) and by 24 hours Ambulatory
Blood Pressure Monitoring.
The safety population included 327 patients in the aprocitentan groups, 82
patients in the placebo group and 81 in the lisinopril group. Aprocitentan was
well tolerated across all four doses in this patient population.
Discontinuation from study treatment due to an adverse event ranged between
1.2% and 3.7% for the aprocitentan groups versus 6.1% in the placebo group and
3.7% in the lisinopril group. The overall frequency of adverse events was
similar to those observed in the placebo group. There were two cases of
increased liver enzymes above three times the upper limit of the normal range,
one in the placebo and one in the aprocitentan 5 mg group. Four cases of
peripheral edema were observed, two in the aprocitentan 25 mg group and two in
the aprocitentan 50 mg group. Mean body weight remained unchanged from baseline
in the aprocitentan 5, and 10 mg groups, increased by 0.4 kg in the
aprocitentan 25 and 50 mg groups, and by 0.3 kg in the placebo group and
decreased by 0.3 kg on lisinopril. There was an expected dose related decrease
from baseline in the hemoglobin concentration in the aprocitentan groups
(ranging from 1.3 to 6.7 g/L) versus increases of 2.2 and 0.1 g/L in the
placebo and lisinopril groups, respectively.
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.
Reference Bin Zhou, et al. The Lancet; 2017; 389(10064):37-55 R.M. Carey, et
al. Hypertension, 2018; 72, pp. e53-e90 Noubiap, J. J., et al., Heart 2019;
105:98-105. Carey RM, et al. Hypertension. 2019; 73(2):424-431. Coylewright,
M., et al. Hypertension, 2008; 51, 952-9. Roberie, D. R., et al. Curr Opin
Cardiol, 2012; 27, 386-91. Khan, A., et al. Int J Hypertens, 2013;
193010-193010. Lu Y, et al. Hypertension. 2022; 79(1):207-217. Daugherty, S.
L., et al. Circulation. 2012; 125(13):1635-42. Kumbhani, D. J., et al. Eur
Heart J. 2013; 34(16):1204-14 Muntner, P., et al. Hypertension. 2014;
64:1012–1021 Danaietash P et al. J Clin Hypertension 2022 (in press) Clozel M.
Can J Physiol Pharmacol 2022, Mar 4 online. Kedzierski RM, et al; Annu Rev
Pharmacol Toxicol. 2001; 41:851-76. Iglarz M, et al. Clin Sci 2010; 119:453-63
Verweij P., et al. Hypertension. 2020 ; 75:956–965
Investor webcast
An investor conference call and webcast will be held to discuss the Phase 3
results with aprocitentan. The call will start with presentations by senior
management, followed by a Q&A session (live access to the speakers).
Date: Tuesday May 24, 2022
Time: 14:00 CEST | 13:00 BST | 08:00 EDT
Webcast participants should visit Idorsia's website www.idorsia.com 10-15
minutes before the webcast is due to start.
Conference call participants should start calling the number below 10-15
minutes before the conference is due to start.
Dial-in: CH: +41 (0)44 580 71 45 | UK: +44 (0) 2071 928338| US: +1 646 741 3167
PIN: 483 8017
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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different from any future results, performances or achievements that may be
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prove incorrect, actual results may vary materially from those described herein
as anticipated, believed, estimated or expected.
Anhang Medienmitteilung PDF
