Clazosentan (DB06677): A Comprehensive Monograph

1.0 Executive Summary

Clazosentan is a potent, highly selective, intravenously administered small molecule antagonist of the endothelin-A (ETA) receptor.[1] It was developed as a targeted therapy to prevent cerebral vasospasm and its ischemic consequences following aneurysmal subarachnoid hemorrhage (aSAH), a life-threatening form of stroke.[3] The drug's mechanism is rooted in its ability to block the action of endothelin-1, the body's most powerful endogenous vasoconstrictor, which is released in large quantities after aSAH and is a key mediator of arterial narrowing in the brain.[2]

The clinical development of Clazosentan is characterized by a significant and persistent paradox: while the drug has unequivocally demonstrated a powerful, dose-dependent ability to reduce the incidence and severity of angiographic vasospasm, this success on a key pathophysiological marker has not consistently translated into improved long-term neurological function or reduced all-cause mortality in large, global clinical trials.[4] This disconnect highlights the multifactorial nature of delayed cerebral ischemia (DCI) after aSAH, suggesting that large-vessel vasospasm is only one component of a more complex secondary injury cascade.

This complex efficacy profile has led to a unique and divergent global regulatory landscape. Despite extensive investigation in multiple Phase III trials, Clazosentan has not received marketing approval from the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).[8] In stark contrast, based on positive results from dedicated regional registration studies, the drug has been approved and is marketed as PIVLAZ in Japan and South Korea for the prevention of vasospasm and its complications.[10] This report provides a comprehensive analysis of Clazosentan, detailing its chemical properties, pharmacology, clinical trial history, safety profile, and the factors underpinning its complex journey from bench to bedside.

2.0 Introduction: The Clinical Challenge of Cerebral Vasospasm and the Rationale for Endothelin Receptor Antagonism

2.1 Pathophysiology of Aneurysmal Subarachnoid Hemorrhage and Delayed Cerebral Ischemia

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular event caused by the rupture of an intracranial aneurysm, leading to the extravasation of blood into the subarachnoid space.[11] Even after the ruptured aneurysm is surgically or endovascularly secured to prevent re-bleeding, patients remain at high risk for secondary brain injury. The most significant of these complications is delayed cerebral ischemia (DCI), which typically occurs between 3 and 14 days after the initial hemorrhage and is a leading cause of poor neurological outcome and mortality in aSAH survivors.[6]

For decades, the primary driver of DCI was believed to be cerebral vasospasm—a prolonged, severe, and often unpredictable narrowing of the large-capacitance cerebral arteries.[13] This vasospasm can critically reduce cerebral blood flow, leading to ischemic strokes and profound neurological deficits.[2] While vasospasm is a major contributor, it is now understood that DCI is a multifactorial process also involving microvascular dysfunction, cortical spreading depolarizations, and neuroinflammation.[9] Nonetheless, the prevention and treatment of large-vessel vasospasm remain a central goal of neurocritical care for aSAH patients.

2.2 The Role of Endothelin-1 as a Key Mediator

The molecular rationale for targeting vasospasm with Clazosentan is compelling and centers on the peptide endothelin-1 (ET-1). Following aSAH, the breakdown of red blood cells in the cerebrospinal fluid triggers a massive and sustained release of ET-1 from the vascular endothelium.[4] ET-1 is the most potent endogenous vasoconstrictor identified, exerting its effects by binding to two G protein-coupled receptor subtypes: the endothelin-A (ETA) receptor and the endothelin-B (ETB) receptor.[9]

The ETA receptor is located predominantly on vascular smooth muscle cells. Its activation by ET-1 initiates a phosphatidylinositol-calcium second messenger cascade, resulting in a powerful and long-lasting contraction of the vessel wall.[1] Studies have consistently shown that ET-1 levels are markedly elevated in the cerebrospinal fluid of aSAH patients and that the severity of vasospasm correlates with these levels.[4] This direct link established the ETA receptor as a high-priority therapeutic target for a drug designed to prevent aSAH-induced vasospasm.

2.3 Introduction of Clazosentan

Clazosentan was specifically developed as a selective, competitive antagonist of the ETA receptor.[2] As a small molecule formulated for continuous intravenous infusion, it was designed for use in the critical care setting during the peak window of vasospasm risk. By blocking the binding of ET-1 to its receptor on cerebral arteries, Clazosentan is intended to directly counteract the primary vasoconstrictive stimulus, thereby preventing or reversing vasospasm, preserving cerebral blood flow, and ultimately reducing the incidence of DCI and improving patient outcomes.[2]

3.0 Chemical Identity and Physicochemical Properties

3.1 Nomenclature, Synonyms, and Development Codes

Clazosentan is identified by a variety of names and codes used throughout its development and in different regulatory jurisdictions.

• Generic Name: Clazosentan [1]
• Brand Name: Pivlaz (Approved in Japan and South Korea) [10]
• Development Codes & Synonyms: ACT-108475, AXV-034343, AXV-343434, Ro 61-1790, RO-61-1790, VML-588 [1]
• Salt Form: The drug is often formulated as its sodium salt, Clazosentan Sodium (UNII: 0L77PK62L1; CAS Number: 503271-02-1).[1]

3.2 Chemical Structure and Classification

Clazosentan is a synthetic, achiral small molecule.[1]

• IUPAC Name: N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(1H-1,2,3,4-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-methylpyridine-2-sulfonamide.[1]
• Chemical Formula: $C_{25}H_{23}N_{9}O_{6}S$.[1]
• Molecular Weight: Average: 577.58 g·mol⁻¹; Monoisotopic: 577.149200671 Da.[1]
• Chemical Classification: The compound belongs to the class of organic compounds known as pyridinylpyrimidines. Its structure incorporates several key functional groups, including a pyridine, a pyrimidine, a tetrazole, a sulfonamide, and a diaryl ether moiety.[1]

3.3 Key Identifiers and Physicochemical Properties

The fundamental identifiers and computed physicochemical properties of Clazosentan are summarized in Table 1. These properties, particularly its low water solubility and high polar surface area, dictate its formulation for intravenous use and influence its pharmacokinetic behavior. The molecule violates Lipinski's Rule of Five, primarily due to its high polar surface area and hydrogen bond acceptor count, which is not uncommon for highly specific, targeted inhibitors designed for intravenous administration.[1]

Table 1: Key Identifiers and Physicochemical Properties of Clazosentan

Property	Value	Source(s)
DrugBank ID	DB06677	1
CAS Number	180384-56-9	1
UNII	3DRR0X4728	1
InChIKey	LFWCJABOXHSRGC-UHFFFAOYSA-N	1
SMILES	CC1=CN=C(C=C1)S(=O)(=O)NC2=C(C(=NC(=N2)C3=CC(=NC=C3)C4=NNN=N4)OCCO)OC5=CC=CC=C5OC	[15, 18]
Water Solubility	0.0428 mg/mL	1
logP	2.03 (ALOGPS), 2.83 (Chemaxon)	1
pKa (Strongest Acidic)	3.53	1
pKa (Strongest Basic)	2.11	1
Polar Surface Area	200.11 Ų	1
Rule of Five Violation	Yes	1

3.4 Formulation and Administration

Clazosentan is formulated as a concentrate for solution for infusion and is administered exclusively via continuous intravenous infusion, typically using a constant infusion pump.[2] This route of administration is necessary due to its poor oral bioavailability and the need to maintain steady-state plasma concentrations in the critically ill target patient population.[1] Dosing in clinical trials and practice is specified as a constant rate, such as 5 mg/h, 10 mg/h, or 15 mg/h, administered for up to 14-15 days post-aSAH.[6]

4.0 Pharmacology: Mechanism of Action and Pharmacodynamics

4.1 Molecular Target: The Endothelin-A (ETA) Receptor

The sole pharmacological target of Clazosentan is the human Endothelin-1 receptor, also known as the Endothelin-A (ETA) receptor.[1] This receptor is encoded by the EDNRA gene and is a member of the G protein-coupled receptor (GPCR) superfamily.[1] In the vasculature, ETA receptors are densely expressed on smooth muscle cells. Upon binding of the endogenous ligand ET-1, the receptor activates G proteins of the Gq/11 family, which in turn stimulate phospholipase C. This leads to the generation of inositol trisphosphate ($IP_3$) and diacylglycerol (DAG), culminating in an increase in intracellular calcium concentration and subsequent smooth muscle cell contraction and vasoconstriction.[1]

4.2 Mechanism of Selective Antagonism

Clazosentan functions as a potent, competitive, and highly selective antagonist of the ETA receptor.[2] It binds to the ETA receptor with high affinity, in the nanomolar range, thereby preventing the endogenous vasoconstrictor ET-1 from binding and activating the receptor.[5] A key feature of Clazosentan is its selectivity; it exhibits an approximately 1000-fold greater affinity for the ETA receptor compared to the ETB receptor.[5] This selectivity is clinically important because ETB receptors have a dual role: those on smooth muscle cells also mediate vasoconstriction, but those on endothelial cells mediate the release of vasodilators like nitric oxide. By selectively blocking only the ETA receptor, Clazosentan is designed to inhibit the primary pathological vasoconstrictor pathway while potentially sparing the vasodilatory functions of the ETB receptor.

4.3 Pharmacodynamic Effects

The primary and intended pharmacodynamic effect of Clazosentan is the inhibition of ET-1-mediated vasoconstriction.[17] In the setting of aSAH, where ET-1 levels are pathologically elevated, this antagonism directly counteracts the stimulus for cerebral vasospasm.[2] This leads to a relaxation of arterial smooth muscle, or a prevention of its contraction, resulting in vasodilation. The ultimate physiological goal is to improve or maintain adequate cerebral blood flow to brain regions at risk of ischemia.[3] Clinical trials have robustly confirmed this pharmacodynamic effect, demonstrating a clear, dose-dependent reduction in the incidence and severity of angiographically confirmed cerebral vasospasm in aSAH patients treated with Clazosentan.[4]

5.0 Clinical Pharmacokinetics (ADME Profile)

The pharmacokinetic profile of Clazosentan has been well-characterized in healthy volunteers and in the target patient population, defining its absorption, distribution, metabolism, and excretion (ADME) properties.

5.1 Absorption and Distribution

As Clazosentan is administered exclusively by intravenous infusion, absorption is complete and instantaneous.[2] Following administration, the drug distributes within the body with a volume of distribution at steady state ($V_{ss}$) of approximately 18 to 21.5 L.[5] This volume is comparable to that of the extracellular fluid, indicating that the drug primarily remains within the plasma and interstitial fluid compartments with limited penetration into tissues.[5] Plasma concentrations decline in a biphasic manner upon cessation of the infusion.[25]

5.2 Metabolism and Excretion Pathways

A defining characteristic of Clazosentan's pharmacokinetics is its elimination pathway, which is largely independent of metabolic enzymes.[5]

• Metabolism: The drug undergoes minimal hepatic metabolism. In vitro studies identified only a single, minor hydroxylated metabolite formed by the cytochrome P450 isoenzyme CYP2C9.[25] This limited metabolic clearance means that drug-drug interactions involving the CYP450 system are unlikely to be clinically significant.
• Excretion: Clazosentan is predominantly eliminated from the body in its unchanged form. The primary pathway involves active uptake into hepatocytes by the organic anion-transporting polypeptides OATP1B1 and OATP1B3, followed by excretion into the bile.[14] Human mass balance studies confirm this, with approximately 80% of an administered dose recovered in the feces and only 15% in the urine, almost entirely as the parent compound.[25]

5.3 Pharmacokinetic Parameters

• Clearance: Clazosentan exhibits intermediate clearance, with reported values around 35 to 37.7 L/h.[5]
• Half-life: The disposition of the drug is biphasic. It has a rapid distribution half-life of approximately 9 minutes and a relatively short terminal elimination half-life of about 2 hours.[5] This short half-life necessitates continuous infusion to maintain therapeutic concentrations.
• Proportionality: The drug demonstrates dose-proportional pharmacokinetics, meaning that exposure (as measured by plasma concentration and area under the curve) increases linearly with the infusion rate.[5]

5.4 Considerations in Special Populations

• Hepatic Impairment: Because hepatic uptake and biliary excretion are the primary routes of elimination, liver function significantly impacts Clazosentan's pharmacokinetics. Drug exposure (AUC) increases with the severity of liver impairment: 1.4-fold in patients with mild (Child-Pugh A), 2.4-fold in moderate (Child-Pugh B), and 3.8-fold in severe (Child-Pugh C) impairment.[24] Consequently, dose reduction is recommended for patients with moderate (reduce to half) and severe (reduce to one-fourth) hepatic impairment.[24]
• Renal Impairment: Given that renal clearance is a minor elimination pathway, the pharmacokinetics of Clazosentan are not significantly altered even in subjects with severe renal impairment. Therefore, no dose adjustment is required based on kidney function.[24]
• Age, Sex, and Ethnicity: While some minor variations have been observed (e.g., slightly higher exposure in females, decreased clearance with age in patients), these are not considered clinically relevant, and no dose adjustments are recommended based on these demographic factors.[24] Studies have shown similar pharmacokinetic profiles in Caucasian and Japanese subjects.[24]

6.0 Clinical Development and Efficacy Analysis

The clinical development of Clazosentan is a compelling narrative of scientific success on a surrogate endpoint that did not consistently translate to success on clinical outcomes. This journey, marked by large-scale trials with divergent results, provides crucial lessons on the complexities of treating secondary brain injury after aSAH.

6.1 Phase II Dose-Finding: The CONSCIOUS-1 Trial

The CONSCIOUS-1 trial (NCT00111085) was a Phase IIb, randomized, double-blind, placebo-controlled study designed to identify the optimal dose of Clazosentan for preventing vasospasm.[4] The study enrolled 413 patients with aSAH whose aneurysms were secured by either surgical clipping or endovascular coiling. Patients were randomized to receive a continuous intravenous infusion of Clazosentan at 1, 5, or 15 mg/h, or a matching placebo, for up to 14 days.[4]

The primary endpoint was the incidence of moderate or severe angiographic vasospasm, assessed by a blinded central review of digital subtraction angiography performed 7 to 11 days after the hemorrhage.[4] The results were unequivocally positive and demonstrated a powerful, dose-dependent effect. The incidence of moderate or severe vasospasm was 66% in the placebo group. This was reduced significantly in all Clazosentan arms, with the most profound effect seen in the 15 mg/h group, where the incidence was only 23%. This corresponded to a 65% relative risk reduction compared to placebo, a result that was highly statistically significant ($p<0.0001$).[4] While the trial was not powered for clinical outcomes, it successfully established proof-of-concept for the drug's mechanism and identified effective doses, paving the way for Phase III studies.[4]

6.2 The CONSCIOUS Program (Phase III): Divergent Outcomes in Clipped vs. Coiled Aneurysms

Building on the success of CONSCIOUS-1, two large Phase III trials were initiated to determine if the reduction in vasospasm translated into improved clinical outcomes. The program was designed with separate trials for patients based on the method of aneurysm repair.

6.2.1 CONSCIOUS-2: Failure to Meet Primary Endpoint in Surgically Clipped Patients

The CONSCIOUS-2 trial (NCT00558311) enrolled 1,157 patients with aSAH whose aneurysms were secured by surgical clipping.[13] Patients were randomized 2:1 to receive Clazosentan at a dose of 5 mg/h or placebo.[13] The primary endpoint was a composite of vasospasm-related morbidity and all-cause mortality at 6 weeks, which included death, new vasospasm-related cerebral infarcts, delayed ischemic neurological deficit (DIND), or the need for rescue therapy.[27]

The trial failed to meet its primary endpoint.[13] The event rate was 21% in the Clazosentan group compared to 25% in the placebo group. This represented a non-significant relative risk reduction of 17% ($p=0.10$).[13] Furthermore, there was no improvement in long-term functional outcome as measured by the extended Glasgow Outcome Scale (GOSE) at 12 weeks; in fact, there was a non-significant trend toward worse outcomes in the treatment group.[27] These disappointing results led to the premature termination of the parallel CONSCIOUS-3 trial.[6]

6.2.2 CONSCIOUS-3: Dose-Dependent Success on Primary Endpoint but Not Functional Outcome in Endovascularly Coiled Patients

The CONSCIOUS-3 trial (NCT00940095) enrolled patients with aSAH whose aneurysms were secured by endovascular coiling.[6] Patients were randomized to receive Clazosentan at 5 mg/h, 15 mg/h, or placebo.[6] Although halted early, 571 patients were treated.[6]

The results were mixed and dose-dependent. The 5 mg/h dose arm showed no significant benefit over placebo. However, the 15 mg/h dose of Clazosentan significantly reduced the primary composite endpoint of vasospasm-related morbidity and all-cause mortality. The event rate was only 15% in the 15 mg/h group compared to 27% in the placebo group, a statistically significant result (odds ratio 0.474; $p=0.007$).[6] Despite this success on the primary endpoint, the trial once again failed to demonstrate a benefit in long-term functional outcome. There was no significant improvement in GOSE scores at 12 weeks for either dose of Clazosentan compared to placebo.[6]

6.3 The REACT Trial: Investigating a High-Risk Population

The REACT trial (NCT03585270) was a subsequent Phase 3 study designed to test Clazosentan 15 mg/h in a population deemed to be at the highest risk for vasospasm: patients with thick and diffuse subarachnoid clots on their admission CT scan.[16] The primary endpoint was more focused: the occurrence of clinical deterioration due to DCI within 14 days.[32]

Despite the enriched high-risk population and a targeted clinical endpoint, the REACT trial also failed to demonstrate a significant benefit.[16] The rate of clinical deterioration due to DCI was 15.8% in the Clazosentan group versus 17.2% in the placebo group, a difference that was not statistically significant ($p=0.734$).[32] This negative result largely ended the pursuit of regulatory approval for Clazosentan in the United States and Europe.[16]

6.4 The Japanese Registration Program: A Pathway to Approval

In contrast to the global trial program, dedicated Phase 3 studies conducted in Japan yielded positive results. Two registration trials (JapicCTI163369 and JapicCTI163368) evaluated Clazosentan 10 mg/h in Japanese patients after aSAH treated by coiling or clipping.[11] Both studies demonstrated that Clazosentan significantly reduced the occurrence of the composite endpoint of cerebral vasospasm-related morbidity and all-cause mortality compared to placebo ($p<0.01$ for both studies).[11] Based on this robust regional data, Clazosentan was approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) in 2022.[10]

This regional success suggests that the drug's benefit may be more apparent in specific contexts. The discrepancy between the global and Japanese trial results could stem from several factors. The incidence of aSAH is at least twice as high in Japan, which may be linked to genetic or pathophysiological differences where ET-1-mediated vasospasm plays a more dominant and critical role in determining outcomes.[11] Alternatively, more uniform patient characteristics and highly standardized protocols of care within the Japanese healthcare system may have reduced variability, allowing a clearer signal of the drug's effect to emerge. This provides compelling evidence that a sub-population of aSAH patients exists who can derive significant benefit from Clazosentan, even if that group was not readily identifiable within the more heterogeneous global trial populations.

Table 2: Summary of Major Phase II/III Clinical Trials of Clazosentan

Trial Name	Phase	NCT ID	Patient Population (Aneurysm Securement)	N	Dosing Arms (IV)	Primary Endpoint	Primary Endpoint Result	Functional Outcome (GOSE/mRS) Result
CONSCIOUS-1	IIb	NCT00111085	aSAH (Clipping or Coiling)	413	1, 5, 15 mg/h vs. Placebo	Angiographic Vasospasm	Significant Reduction (65% RRR at 15 mg/h; $p<0.0001$)	No significant effect
CONSCIOUS-2	III	NCT00558311	aSAH (Clipping)	1157	5 mg/h vs. Placebo	Vasospasm-related Morbidity/All-cause Mortality	Not Met (17% RRR; $p=0.10$)	No significant effect
CONSCIOUS-3	III	NCT00940095	aSAH (Coiling)	571	5, 15 mg/h vs. Placebo	Vasospasm-related Morbidity/All-cause Mortality	Met for 15 mg/h (OR 0.474; $p=0.007$)	No significant effect
REACT	III	NCT03585270	High-Risk aSAH (Clipping or Coiling)	409	15 mg/h vs. Placebo	Clinical Deterioration due to DCI	Not Met ($p=0.734$)	No significant effect
Japanese Program	III	JapicCTI163368/9	aSAH (Clipping or Coiling)	N/A	10 mg/h vs. Placebo	Vasospasm-related Morbidity/All-cause Mortality	Met ($p<0.01$ for both studies)	N/A

6.5 Critical Analysis: The Disconnect Between Angiographic Efficacy and Functional Outcomes

The entire clinical development program of Clazosentan is defined by a critical disconnect: the drug's powerful and reproducible effect on a surrogate endpoint (angiographic vasospasm) did not reliably predict its effect on patient-centered clinical outcomes (neurological function and survival). The CONSCIOUS-1 trial provided definitive proof that blocking the ETA receptor effectively prevents the narrowing of large cerebral arteries.[4] However, the subsequent failures of CONSCIOUS-2 and REACT to improve clinical outcomes, and the mixed results of CONSCIOUS-3, strongly imply that DCI and poor outcomes after aSAH are not solely the result of large-vessel vasospasm.[6] Other pathophysiological mechanisms not targeted by Clazosentan—such as microcirculatory constriction, inflammation, apoptosis, and cortical spreading depolarizations—must play a significant role in the secondary brain injury that ultimately determines a patient's functional status.[9] Therefore, while preventing angiographic vasospasm is a valid mechanistic goal, it appears to be an insufficient strategy on its own to improve overall outcomes in a broad, unselected population of aSAH patients. The drug's failure in global trials should not be seen as a failure of the ET-1 hypothesis, but rather as a lesson that DCI is a more complex syndrome than previously appreciated, requiring a multi-pronged therapeutic approach.

7.0 Safety and Tolerability Profile

The safety profile of Clazosentan has been extensively documented in clinical trials involving over 2,000 patients.[11] While generally manageable in an intensive care unit (ICU) setting, treatment with Clazosentan is associated with a higher incidence of specific adverse events compared to placebo, most of which are mechanistically related to its vasodilatory properties.[7]

7.1 Overview of Treatment-Emergent Adverse Events

A meta-analysis of randomized controlled trials confirmed that adverse events were significantly increased by Clazosentan compared to placebo (Risk Ratio 1.54).[7] The most consistently reported treatment-emergent adverse events of special interest are hypotension, pulmonary complications, and anemia.[6]

Table 3: Summary of Common and Serious Adverse Events (vs. Placebo in CONSCIOUS-3)

Adverse Event	Placebo (n=189)	Clazosentan 5 mg/h (n=194)	Clazosentan 15 mg/h (n=188)
Pulmonary Complications	21%	36%	37%
Anemia	10%	13%	13%
Hypotension	7%	11%	16%
Data derived from the CONSCIOUS-3 trial.[6, 38]

7.2 Detailed Review of Events of Special Interest

• Hypotension: As a potent vasodilator, Clazosentan frequently causes a dose-dependent decrease in blood pressure.[2] This is a critical consideration in aSAH patients, where maintaining adequate cerebral perfusion pressure is paramount. In the controlled environment of an ICU, this adverse effect is considered manageable with the judicious use of vasopressor agents and fluid management.[16]
• Pulmonary Complications: An increased incidence of pulmonary complications, including pulmonary edema and pleural effusion, is a consistent finding across trials.[6] This is believed to be a consequence of systemic vasodilation leading to fluid shifts and increased hydrostatic pressure in the pulmonary circulation. Careful management of fluid balance to maintain a state of euvolemia (normal fluid volume) is the recommended strategy to mitigate this risk.[16]
• Anemia: A higher rate of anemia or decreased hemoglobin has also been consistently reported in patients receiving Clazosentan.[6] The mechanism is thought to be related to hemodilution resulting from fluid retention secondary to the drug's systemic effects.[9]

7.3 Contraindications and Potential Drug Interactions

• Contraindications: The primary contraindication is a known hypersensitivity to Clazosentan or any of its components.[2] Caution is strongly advised in patients with pre-existing severe hypotension that is refractory to treatment, as the drug's vasodilatory effects could be dangerous.[2] Given its reliance on hepatic uptake for clearance, caution is also warranted in patients with moderate to severe liver impairment, and dose adjustments are necessary.[2]
• Drug Interactions: The most significant potential drug interaction is with other antihypertensive agents, as concomitant use could lead to additive hypotensive effects requiring careful blood pressure monitoring and dose adjustments.[2] A specific study found no clinically significant pharmacokinetic or pharmacodynamic interaction between Clazosentan and nimodipine, a calcium channel blocker commonly used in aSAH patients.[5] As Clazosentan undergoes minimal CYP450 metabolism, interactions with inhibitors or inducers of this system are considered a low risk.[2]

8.0 Global Regulatory Landscape and Development History

The development of Clazosentan was initiated by Actelion, with early involvement from Vanguard Medica Ltd., and is now spearheaded by Idorsia Pharmaceuticals, a company that spun off from Actelion's R&D division.[5] The drug's journey through global regulatory systems has been markedly divergent, reflecting the complex and conflicting clinical trial data.

8.1 United States (FDA)

The FDA granted Clazosentan Orphan Drug Designation for the "Treatment of cerebral vasospasm following subarachnoid hemorrhage" on February 16, 2006.[8] This status provides incentives for the development of drugs for rare diseases. However, following the repeated failure of large Phase III trials (CONSCIOUS-2 and REACT) to meet their primary clinical endpoints, the path to approval in the U.S. was effectively closed.[16] Consequently, the Orphan Drug Designation was officially withdrawn or revoked on September 19, 2023.[8] To date, Clazosentan is not approved by the FDA for any indication.[8]

8.2 Europe (EMA)

Similar to the U.S., Clazosentan received an Orphan Designation (EU/3/03/182) from the European Commission on December 12, 2003, for the "treatment of aneurysmal subarachnoid haemorrhage".[21] The sponsorship was transferred from Actelion to Idorsia in 2017.[41] While this designation remains, it is not a marketing authorization, and it requires that the drug's benefit be confirmed at the time of an approval application.[41] Given the negative outcomes of the large global trials, an application for marketing authorization has not been successfully pursued, and Clazosentan is not approved for use in the European Union.[9]

8.3 Japan (PMDA) and South Korea

The regulatory story in Asia is entirely different. Based on a dedicated Japanese Phase 3 program that demonstrated a statistically significant reduction in vasospasm-related morbidity and mortality, the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) approved Clazosentan on January 20, 2022.[10] It is marketed under the brand name PIVLAZ for the prevention of cerebral vasospasm, vasospasm-related cerebral infarction, and cerebral ischemic symptoms after aSAH.[11] Following this success, the drug was also approved in South Korea in December 2023.[9] This regional success, standing in stark contrast to the setbacks in the West, underscores the possibility that clinical, genetic, or systemic factors present in the Japanese patient population allow the drug's benefit to be more clearly realized.

9.0 Expert Synthesis and Future Directions

9.1 Consolidated Risk-Benefit Assessment

Clazosentan presents a nuanced risk-benefit profile. The primary, proven benefit is a potent and reliable reduction in the incidence and severity of angiographic cerebral vasospasm following aSAH.[4] In certain patient populations and at an adequate dose (10-15 mg/h), this can translate to a reduction in a composite endpoint of vasospasm-related clinical complications.[6] The risks are significant but manageable within an ICU setting, consisting primarily of hypotension, pulmonary complications from fluid shifts, and anemia, all of which are direct consequences of the drug's powerful vasodilatory mechanism.[6] The central limitation of the drug is the consistent failure to demonstrate an improvement in long-term, patient-centered functional outcomes or all-cause mortality in broad, heterogeneous global populations.[6] Therefore, the benefit is currently confined to a specific set of vasospasm-related events, while the risks are systemic and the impact on overall recovery remains unproven in most populations studied.

9.2 Defining the Optimal Patient Population and Clinical Niche

The cumulative evidence suggests that Clazosentan is not a universal treatment for all aSAH patients. Its clinical niche appears to be in patients where large-vessel, ET-1-mediated cerebral vasospasm is the dominant, rate-limiting factor in their potential for neurological decline. The REACT trial's focus on patients with a high clot burden was a rational attempt to identify this group, though it was unsuccessful.[32] The success in Japan strongly suggests that a responsive phenotype exists, potentially defined by genetic predisposition, specific clinical characteristics, or the nature of the initial hemorrhage.[11] In clinical practice, its use should be considered for patients at the highest risk of severe vasospasm, where the potential benefit of preventing ischemic events directly related to arterial narrowing outweighs the risks of systemic side effects. It should be viewed as an adjunct to, not a replacement for, comprehensive neurocritical care, including the use of standard therapies like nimodipine.[9]

9.3 Unanswered Questions and Potential for Future Research

The story of Clazosentan leaves several critical questions unanswered, pointing toward future research directions.

1. Biomarker Identification: Can genetic, proteomic, or clinical biomarkers be identified that predict which patients (regardless of ethnicity) will respond to Clazosentan with improved functional outcomes? This would allow for a personalized medicine approach.
2. Combination Therapies: Since DCI is multifactorial, could Clazosentan be more effective when combined with agents targeting other injury pathways, such as inflammation or microthrombosis?
3. Therapeutic vs. Prophylactic Use: Most large trials focused on prophylaxis. The REVERSE study (NCT02560532) explored its role in treating established vasospasm, a potential application that warrants further investigation.[40]

9.4 Concluding Remarks

Clazosentan stands as a landmark molecule in neurocritical care pharmacology—a triumph of rational drug design that successfully targets a key pathophysiological mechanism. Its clinical development journey serves as a profound and cautionary lesson: success on a well-established surrogate endpoint like angiographic vasospasm does not guarantee improvement in overall patient outcomes, especially in a complex, multifactorial disease like DCI. While its development has stalled in Western countries, its approval and use in Japan and South Korea confirm that it holds tangible value for a specific, yet-to-be-fully-defined, patient population. Clazosentan remains an important, albeit niche, therapeutic tool, whose story has fundamentally advanced our understanding of secondary brain injury after aSAH and will shape the design of future neuroprotective trials.

Works cited

1. Clazosentan: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed October 31, 2025, https://go.drugbank.com/drugs/DB06677
2. What is Clazosentan used for? - Patsnap Synapse, accessed October 31, 2025, https://synapse.patsnap.com/article/what-is-clazosentan-used-for
3. Clazosentan | AXV034 | CAS#180384-56-9 | endothelin receptor antagonist | MedKoo, accessed October 31, 2025, https://www.medkoo.com/products/6739
4. Clazosentan to Overcome Neurological Ischemia and Infarction ..., accessed October 31, 2025, https://www.ahajournals.org/doi/10.1161/strokeaha.108.519942
5. A pharmacokinetic study of clazosentan in patients with aneurysmal subarachnoid haemorrhage | Request PDF - ResearchGate, accessed October 31, 2025, https://www.researchgate.net/publication/226467782_A_pharmacokinetic_study_of_clazosentan_in_patients_with_aneurysmal_subarachnoid_haemorrhage
6. Randomized Trial of Clazosentan in Patients With Aneurysmal Subarachnoid Hemorrhage Undergoing Endovascular Coiling | Stroke - American Heart Association Journals, accessed October 31, 2025, https://www.ahajournals.org/doi/10.1161/strokeaha.111.648980
7. Efficacy and Safety of Clazosentan After Aneurysmal Subarachnoid Hemorrhage: An Updated Meta-Analysis - PubMed, accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/37462365/
8. Search Orphan Drug Designations and Approvals - accessdata.fda ..., accessed October 31, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=217105
9. Full article: Evaluating clazosentan sodium for the treatment of aneurysmal subarachnoid hemorrhage - Taylor & Francis Online, accessed October 31, 2025, https://www.tandfonline.com/doi/full/10.1080/14737175.2025.2564708?src=exp-la
10. Comparison of Clazosentan and Nimodipine on Vasospasm and Vasospasm-Related Outcomes after Aneurysmal Subarachnoid Hemorrhage - :: Journal of Korean Neurosurgical Society, accessed October 31, 2025, https://www.jkns.or.kr/journal/view.php?number=7762
11. Media release - Idorsia, accessed October 31, 2025, https://www.idorsia.com/investors/news-and-events/media-releases/media-release-details?id=2672197
12. Pivlaz approved in Japan for aSAH-related vasospasm - Medthority, accessed October 31, 2025, https://www.medthority.com/news/2022/1/idorsia-receives-pmda-japan-approval-of-pivlaz-clazosentan-sodium-150-mg-to-treat-cerebral-vasospasm/
13. CONSCIOUS-2 study with clazosentan does not meet primary endpoint | Fierce Biotech, accessed October 31, 2025, https://www.fiercebiotech.com/biotech/conscious-2-study-clazosentan-does-not-meet-primary-endpoint
14. Clinical Pharmacology of Clazosentan, a Selective Endothelin A ..., accessed October 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7890197/
15. Clazosentan - Wikipedia, accessed October 31, 2025, https://en.wikipedia.org/wiki/Clazosentan
16. Media release - Idorsia, accessed October 31, 2025, https://www.idorsia.com/investors/news-and-events/media-releases/media-release-details?id=2925662
17. pmc.ncbi.nlm.nih.gov, accessed October 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7890197/#:~:text=Clazosentan%20inhibits%20the%20ETA,the%20bile%20in%20unchanged%20form.
18. Clazosentan | C25H23N9O6S | CID 6433095 - PubChem, accessed October 31, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Clazosentan
19. Report on the Deliberation Results December 13, 2021 ... - PMDA, accessed October 31, 2025, https://www.pmda.go.jp/files/000264059.pdf
20. CLAZOSENTAN - precisionFDA, accessed October 31, 2025, https://precision.fda.gov/ginas/app/ui/substances/bd280e39-3c41-47c2-96ca-ee5d5ca14430
21. Doc. Ref. EMEA/351854/2009 P/109/2009 EUROPEAN MEDICINES ..., accessed October 31, 2025, https://www.ema.europa.eu/en/documents/pip-decision/p-109-2009-european-medicines-agency-decision-16-june-2009-granting-product-specific-waiver-clazosentan-emea-000369-pip01-08-accordance-regulation-ec-no-1901-2006-european-parliamen_en.pdf
22. Clazosentan (Ro 61-1790; VML 588; AXV-034343) | CAS 180384-56-9 | AbMole BioScience, accessed October 31, 2025, https://www.abmole.com/products/clazosentan.html
23. Effects of the selective endothelin A (ET(A)) receptor antagonist Clazosentan on cerebral perfusion and cerebral oxygenation following severe subarachnoid hemorrhage - preliminary results from a randomized clinical series - PubMed, accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/17700991/
24. Influence of different degrees of liver impairment on the pharmacokinetics of clazosentan, accessed October 31, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3018026/
25. Clinical Pharmacology of Clazosentan, a Selective ... - Frontiers, accessed October 31, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.628956/full
26. Study Details | NCT00111085 | Clazosentan in Preventing the Occurrence of Cerebral Vasospasm Following an Aneurysmal Subarachnoid Hemorrhage (aSAH) | ClinicalTrials.gov, accessed October 31, 2025, https://www.clinicaltrials.gov/study/NCT00111085?term=AREA%5BInterventionSearch%5D(CLAZOSENTAN)&rank=6
27. Clazosentan, an endothelin receptor antagonist, in patients with ..., accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/21640651/
28. (PDF) Randomised Trial of Clazosentan, an Endothelin Receptor Antagonist, in Patients with Aneurysmal Subarachnoid Hemorrhage Undergoing Surgical Clipping (CONSCIOUS-2) - ResearchGate, accessed October 31, 2025, https://www.researchgate.net/publication/230666137_Randomised_Trial_of_Clazosentan_an_Endothelin_Receptor_Antagonist_in_Patients_with_Aneurysmal_Subarachnoid_Hemorrhage_Undergoing_Surgical_Clipping_CONSCIOUS-2
29. CONSCIOUS 3 | Boston Medical Center, accessed October 31, 2025, https://www.bmc.org/stroke-and-cerebrovascular-center/research/completed-studies/conscious-3
30. Randomized trial of clazosentan in patients with aneurysmal ..., accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/22403047/
31. Abstract 43: Effect of Clazosentan on Clinical Outcome After Aneurysmal Subarachnoid Hemorrhage and Endovascular Coiling: Results of the CONSCIOUS-3 Study - ResearchGate, accessed October 31, 2025, https://www.researchgate.net/publication/359353480_Abstract_43_Effect_of_Clazosentan_on_Clinical_Outcome_After_Aneurysmal_Subarachnoid_Hemorrhage_and_Endovascular_Coiling_Results_of_the_CONSCIOUS-3_Study
32. REACT: a randomized trial to assess the efficacy and safety of clazosentan for preventing clinical deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage - PubMed, accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/39126720/
33. design of a randomized phase 3 trial to assess the efficacy and safety of clazosentan for prevent - eScholarship, accessed October 31, 2025, https://escholarship.org/content/qt3f06c01t/qt3f06c01t.pdf
34. Clazosentan Fails to Meet Primary End Point in Phase 3 REACT Study of Aneurysmal Subarachnoid Hemorrhage | NeurologyLive, accessed October 31, 2025, https://www.neurologylive.com/view/clazosentan-fails-meet-primary-end-point-phase-3-react-study-aneurysmal-subarachnoid-hemorrhage
35. Clazosentan: First Approval - PubMed, accessed October 31, 2025, https://pubmed.ncbi.nlm.nih.gov/35362854/
36. PIVLAZ (clazosentan) – Idorsia's first commercial product – now available for patients in Japan, accessed October 31, 2025, https://ml-eu.globenewswire.com/Resource/Download/5ed1bd47-b58c-487f-9d13-8551244d7c80
37. Endothelin Receptor Antagonists for Aneurysmal Subarachnoid Hemorrhage | Stroke, accessed October 31, 2025, https://www.ahajournals.org/doi/10.1161/strokeaha.112.666693
38. Clinical Research Study With Clazosentan to Evaluate Its Effects on Preventing Complications Due to the Narrowing of the Blood Vessels (Vasospasm) in the Brain, Caused by Bleeding Onto the Surface of the Brain (REACT) - Mayo Clinic, accessed October 31, 2025, https://www.mayo.edu/research/clinical-trials/cls-20482115
39. Study Details | NCT02560532 | Evaluation of the Efficacy and Safety of Clazosentan in Reversing Cerebral Vasospasm in Adult Subjects With Aneurysmal Subarachnoid Hemorrhage | ClinicalTrials.gov, accessed October 31, 2025, https://www.clinicaltrials.gov/study/NCT02560532?term=AREA%5BInterventionSearch%5D(CLAZOSENTAN)&rank=1
40. EU/3/03/182 - orphan designation for treatment of aneurysmal ..., accessed October 31, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-03-182
41. Clazosentan sodium - Drug Targets, Indications, Patents - Patsnap Synapse, accessed October 31, 2025, https://synapse.patsnap.com/drug/4f03107fedaf4fafa4f11d2e36a85906
42. Study Details | NCT02560532 | Evaluation of the Efficacy and Safety of Clazosentan in Reversing Cerebral Vasospasm in Adult Subjects With Aneurysmal Subarachnoid Hemorrhage | ClinicalTrials.gov, accessed October 31, 2025, https://clinicaltrials.gov/study/NCT02560532