The Journal of Neurosurgery reports impact of clazosentan on cerebral
vasospasm-related morbidity and all-cause mortality after aneurysmal
subarachnoid hemorrhage Results published in the Journal of Neurosurgery show
that clazosentan significantly reduced the combined incidence of
vasospasm-related morbidity and all-cause mortality post-aSAH with no
unexpected safety findings. The pivotal studies in Japanese patients supported
the approval of Pivlaz™ (clazosentan) in Japan in January 2022, Pivlaz is
expected to be available in April 2022.
Allschwil, Switzerland – April 4 , 2022
Idorsia Ltd (SIX: IDIA) and Idorsia Pharmaceuticals Japan today announce the
publication of “ Effects of clazosentan on cerebral vasospasm - related
morbidity and all-cause mortality after aneurysmal subarachnoid hemorrhage: two
randomized phase 3 trials in Japanese patients ” in the Journal of Neurosurgery
1 . Clazosentan, a selective endothelin A (ET A ) receptor antagonist,
significantly reduced the combined incidence of vasospasm-related morbidity and
all-cause mortality post-aSAH with no unexpected safety findings 1 .
Aneurysmal subarachnoid hemorrhage (aSAH) is a sudden, life-threatening
bleeding occurring in the subarachnoid space, caused by the rupture of an
aneurysm. 2 ,3 An urgent intervention involving endovascular coil embolization
or microscopic clipping is required to prevent rerupture. 2 Clot hemolysis and
the release of vasoconstricting agents can contribute to cerebral vasospasm,
which typically begins approximately 3 days after aSAH onset, peaks in severity
at days 8–11, and resolves by day 21. 4 If untreated, cerebral vasospasm can be
a key factor of morbidity and mortality in patients with aSAH. 2 Cerebral
vasospasm may lead to delayed ischemic neurological deficit (DIND) in up to
40% of aSAH cases, and half of the patients with vasospasm develop cerebral
infarction. 3 With an occurrence of 22.5 per 100,000 person-years, aSAH is 2–3
times more frequent in Japan than in the rest of the world 5 and is therefore a
significant problem in this country.
Two prospective, multicenter, double-blind, randomized, placebo-controlled,
pivotal Phase 3 studies assessing the efficacy and safety of clazosentan in
reducing vasospasm-related morbidity and all-cause mortality events in adult
Japanese patients post-aSAH, were conducted in parallel in 57 neuro surgical
centers in Japan. Patients were randomized 1:1 to receive continuous infusion
of either 10 mg/hr of clazosentan or placebo within 48 hours of the onset of
aSAH for up to a cumulative maximum of 15 days after aSAH. Protocols were
identical, each study enrolling 221 patients, except for the securing
intervention, which was either endovascular coiling (JapicCTI-163369; the
“coiling study”) or surgical clipping (JapicCTI-163368; the “clipping study”).
Both studies showed that clazosentan, compared to placebo, reduced the
occurrence of cerebral vasospasm-related morbidity and all-cause mortality
events by >50% within 6 weeks post-aSAH with statistical significance (p < 0.01
for both studies). The composite endpoint, adjudicated blindly by an
independent committee, was defined by at least one of the following: Delayed
ischemic neurologic deficit (DIND) due to cerebral vasospasm / New cerebral
infarction due to cerebral vasospasm / All-cause death. The effect of
clazosentan on all-cause morbidity and mortality events within 6 weeks of aSAH
was also significant (p < 0.05) in a pre-planned pooled analysis of both
studies whereas a numerical trend was observed in each study on this endpoint.
The pooled analysis of secondary endpoints indicated that clazosentan decreased
the event rates for individual components of the primary composite endpoints.
In this analysis, vasospasm-related DIND was reduced by 60% (p = 0.0004) and
vasospasm-related new cerebral infarcts were reduced by 55% (p < 0.0001).
The studies confirmed the well-documented safety profile of clazosentan which
has now been studied in more than 2000 patients around the world. In these two
registration studies there were no unexpected safety findings.
Treatment-emergent adverse events occurring in >5% of the clazosentan group
(with a difference of >2% compared to placebo) were vomiting and signs of
hemodilution or fluid retention (i.e., hyponatremia, hypoalbuminemia, anemia,
pleural effusion, brain edema and pulmonary edema).
Teiji Tominaga, M.D., Ph.D., Professor & Chairman, Department of Neurosurgery,
Tohoku University Graduate School of Medicine commented:
“The studies we publish in the Journal of Neurosurgery confirm that treatment
with clazosentan significantly reduces the consequences that, as neurosurgeons,
we all dread after successfully repairing a ruptured brain aneurysm. The
results with clazosentan versus placebo were very impressive with a reduction
in the risk of vasospasm-related DIND by almost two thirds, a clear reduction
in the risk of vasospasm-related new cerebral infarcts by more than half, and –
consistent with this effect – the need for rescue therapy, such as balloon
angioplasty to open spastic vessels, was reduced by 57%.”
Professor Tominaga, concluded:
“Clazosentan is the only innovation in more than 20 years for the prevention
of cerebral vasospasm after SAH treatment and the associated new cerebral
infarctions and ischemic symptoms. I believe we can change the lives of many
patients suffering from this unpredictable and devastating condition.”
About PIVLAZ™ (clazosentan) 150 mg
PIVLAZ (clazosentan) is a potent, selective endothelin A (ET A ) receptor
antagonist which targets the root cause of cerebral vasospasm. PIVLAZ was
designed to inhibit ET-1–mediated cerebral vasospasm by blocking the
interaction between ET-1 and the ETA receptor. 7,8
In January 2022, the Japanese health authorities approved PIVLAZ™
(clazosentan) 150 mg, for the prevention of cerebral vasospasm,
vasospasm-related cerebral infarction and cerebral ischemic symptoms after
aneurysmal subarachnoid hemorrhage (aSAH) securing. Idorsia Japan is on track
to make PIVLAZ available to physicians to start treating patients in April
2022.
Notes to the editor
About REACT – the global registration program for clazosentan
REACT is a Phase 3 study to investigate the efficacy and safety of clazosentan
for the prevention of clinical deterioration due to vasospasm-related delayed
cerebral ischemia (DCI) in adult patients following aSAH. The Phase 3 study
incorporates the learnings from the clazosentan program 9,10,11 to identify
patients at high risk of vasospasm and delayed cerebral ischemia, the optimal
dose, the best measure to demonstrate efficacy, and an optimized set of patient
management guidelines to ensure patient safety. The study aims to randomize
approximately 400 patients – treated either with microsurgical clipping or
endovascular coiling – at around 95 sites across 15 countries and is expected
to conclude around the end of 2022. Patients are randomized to receive
continuous infusion of either clazosentan (15 mg/hr) or placebo
prophylactically, on top of local standard-of-care, for a period of up to 14
days. Clazosentan has been granted orphan drug designation in Europe (2003) and
the US (2006), providing an exclusivity period of 10 and 7 years, respectively,
after approval.
References Endo H, Hagihara Y, Kimura N, Takizawa K, Niizuma K, Togo O,
Tominaga T. Effects of clazosentan on cerebral vasospasm-related morbidity and
all-cause mortality after aneurysmal subarachnoid hemorrhage: two randomized
phase 3 trials in Japanese patients. J Neurosurg. Published online April 01,
2022; DOI: 10.3171/2022.2.JNS212914 Daou BJ, et al. Clinical and experimental
aspects of aneurysmal subarachnoid hemorrhage. CNS Neurosci Ther. 2019;
25(10):1096-1112. de Oliveira JG, et al. Comparison between clipping and
coiling on the incidence of cerebral vasospasm after aneurysmal subarachnoid
hemorrhage: a systematic review and meta-analysis. Neurosurg Rev. 2007; 30(1):
22-31. Dorsch NW, King MT. A review of cerebral vasospasm in aneurysmal
subarachnoid haemorrhage part I: incidence and effects. J Clin Neurosci. 1994;
1(1): 19-26. Etminan N, et al. Worldwide incidence of aneurysmal subarachnoid
hemorrhage according to region, time period, blood pressure, and smoking
prevalence in the population: a systematic review and meta-analysis. JAMA
Neurol. 2019; 76(5): 588-597. Fujimura M, et al. Preventive Effect of
Clazosentan against Cerebral Vasospasm after Clipping Surgery for Aneurysmal
Subarachnoid Hemorrhage in Japanese and Korean Patients. Cerebrovasc Dis.
2017;44(1–2):59–67. Vajkoczy P, et al. Clazosentan (AXV-034343), a selective
endothelin A receptor antagonist, in the prevention of cerebral vasospasm
following severe aneurysmal subarachnoid hemorrhage: results of a randomized,
double-blind, placebo-controlled, multicenter Phase IIa study. J Neurosurg.
2005;103(1):9–17. Roux S, et al. Ro 61-1790, a new hydrosoluble endothelin
antagonist: general pharmacology and effects on experimental cerebral
vasospasm. J Pharmacol Exp Ther. 1997;283(3):1110–1118. Macdonald R L, et al.
Randomized trial of clazosentan in patients with aneurysmal subarachnoid
hemorrhage undergoing endovascular coiling. Stroke. 2012; 43(6):1463-9.
Macdonald R L, et al. Clazosentan, an endothelin receptor antagonist, in
patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping:
a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). The
Lancet Neurology, 2011; 10(7):618-625. Macdonald R L, et al. Clazosentan to
Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid
Hemorrhage (CONSCIOUS-1). Stroke 2008; 39:3015-3021.
About Idorsia Pharmaceuticals Japan
Idorsia Pharmaceuticals Japan was established, under the leadership of Dr
Satoshi Tanaka, in 2018 to conduct clinical development and prepare the
commercialization of Idorsia's innovative and promising compounds for patients
in Japan.
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 1200 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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Anhang Medienmitteilung PDF
