Idorsia reacquires the world-wide rights to aprocitentan
Ad hoc announcement pursuant to Art. 53 LR
- Aprocitentan, Idorsia’s oral, dual endothelin receptor
antagonist is currently under review with health authorities for
the treatment of patients with resistant hypertension.
- Idorsia will pay Janssen a conditional consideration up to a
total cap of CHF 306 million
- Idorsia is initiating activities to determine the best approach
to maximize the value of aprocitentan.
Allschwil, Switzerland –
September 6,
2023Idorsia Ltd (SIX: IDIA) today announced that it has
entered into an agreement with Janssen Biotech Inc., one of the
Janssen Pharmaceutical Companies of Johnson & Johnson, for the
return of rights for aprocitentan to Idorsia. In return, Idorsia is
committed to pay up to 306 million Swiss francs, subject to
marketing application approval by the US FDA and Europe’s EMA.
Jean-Paul Clozel, CEO of Idorsia, commented:
“I’m happy that we have come to an agreement for the return of
aprocitentan to Idorsia. Aprocitentan has demonstrated significant
and clinically meaningful sustained blood pressure lowering
benefits with a good safety profile, particularly suited to the
high-risk patient population with resistant hypertension.
Revolutionizing the use of endothelin receptor antagonism is
something the team at Idorsia knows all about. We will now
determine the best approach to maximizing the value of our exciting
new anti-hypertension therapy.”
The founding team at Idorsia brought the first oral, dual
endothelin receptor antagonist (ERA) to market, followed by the
discovery, development, and launch of a next generation oral, dual
ERA. The team will now evaluate options for realizing the value
which the company has created by successfully developing
aprocitentan, the first anti-hypertensive therapy which works via a
new mechanism of action in 30 years.
About the agreementIdorsia will reacquire the
development and commercialization rights for aprocitentan from
Janssen. In return, Idorsia will pay Janssen a conditional
consideration up to a total cap of CHF 306 million, depending on
Idorsia’s revenues, as follows:
- 30% of any consideration received by Idorsia from a potential
out-licensing or divestment of aprocitentan,
- 10% of any consideration received by Idorsia from a potential
out-licensing or the divestment of any other Idorsia product,
following the first approval of aprocitentan, and
- low- to mid-single digit royalties on total group product net
sales, beginning from the quarter after first aprocitentan
approval.
Janssen funding obligations to aprocitentan cease at the
effective date of the agreement. Janssen licenses to aprocitentan
IP (excluding pulmonary hypertension) will terminate and Janssen
will transfer the brand name and relating commercial materials to
Idorsia. Janssen will retain licenses in the pulmonary hypertension
field.
The agreement also eliminates the revenue-sharing agreement in
respect of ponesimod.
The agreement will be effective following receipt of the
clearance relating to the United States Hart-Scott Rodino Antitrust
Improvements Act of 1976.
André C. Muller, Chief Financial
Officer,
commented: “If
aprocitentan is approved in the US and Europe as we expect, Idorsia
would have an additional product in its portfolio giving the
company more strategic flexibility, and potentially allows Janssen
to recoup over time their investment in aprocitentan.”
About the regulatory status of aprocitentanA
new drug application (NDA) for aprocitentan was filed with the US
FDA in December 2022 (Prescription Drug User Fee Act (PDUFA)
current date: December 19, 2023), and the market authorisation
application (MAA) was submitted to the EMA at the end of January
2023.
Jean-Paul Clozel, concluded:“The review process
with the US FDA is progressing well, though it is likely to require
an extension to the review period of up to 3 months as the company
will provide additional Risk Evaluation and Mitigation Strategy
(REMS) materials to support a streamlined REMS which is designed
specifically for patients taking aprocitentan.”
About aprocitentan in resistant
hypertensionFull 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.
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 antihypertensives2, known as resistant hypertension3,4. 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.
Notes to the editor
The endothelin system in systemic
hypertensionEndothelin-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 ETA
and ETB receptors mediate harmful effects of ET-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.5,6
About difficult-to-control (resistant)
hypertensionHypertension (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
worldwide6 – 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.7
Patients with hypertension can often successfully control their
blood pressure by combining a healthier lifestyle with effective
medication. However, approximately 10% of patients have
difficult-to-control hypertension where the blood pressure remains
high despite receiving at least three antihypertensive medications
of different pharmacological classes, including a diuretic, at
optimal
doses,3,8 (also
categorized in hypertension guidelines and the medical community as
having resistant hypertension).
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.
The endothelin pathway has not been targeted by existing
anti-hypertensive therapies until now, thereby leaving this
relevant pathophysiologic pathway unopposed with currently
available medications.3,9,10 The endothelin system is also
activated in patients prone to developing resistant hypertension,
such as Black or African American patients, patients with obesity
or obstructive sleep apnea,11-13 and in comorbid conditions
frequently associated with resistant hypertension such as diabetes
and chronic kidney disease.14-17
About aprocitentanAprocitentan is an
investigational, novel, oral, dual endothelin receptor antagonist
(ERA), which potently inhibits the binding of ET-1 to ETA and ETB
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 PRECISION18,19
(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. 63% of randomized patients were
receiving at least 4 anti-hypertensive therapies at screening.
Key PRECISION findings19 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, a strong predictor of
cardiovascular mortality,1,2 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.
Key Literature
- Dolan E, et al. Superiority of ambulatory over clinic blood
pressure measurement in predicting mortality: the Dublin outcome
study. Hypertension 2005; 46:156–61
- Staplin N, et al. Relationship between clinic and ambulatory
blood pressure and mortality: an observational cohort study in
59 124 patients. Lancet. 2023;S0140-6736(23)00733-X.
- Williams B, et al. 2018 ESC/ESH guidelines for the management
of arterial hypertension. Eur Heart J 2018; 39: 3021–104.
- 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; Dec 3;400(10367):1927-1937.
About IdorsiaIdorsia 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 20-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, Japan, and
the US – 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 1,300 highly qualified specialists
dedicated to realizing our ambitious targets.
For further information, please
contactAndrew C. WeissSenior Vice President, Head
of Investor Relations & Corporate CommunicationsIdorsia
Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123 Allschwil+41 58
844 10 10investor.relations@idorsia.com •
media.relations@idorsia.com • www.idorsia.com
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or uncertainties materialize, or should underlying assumptions
prove incorrect, actual results may vary materially from those
described herein as anticipated, believed, estimated or
expected.
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