Pivlaz (clazosentan) / Idorsia, Nxera Pharma - LARVOL DELTA

Preventing Fluid Retention After Subarachnoid Haemorrhage During Administration of Endothelin Receptor Antagonist. (PubMed, Adv Exp Med Biol) - "Prevention of delayed cerebral infarction (DCI) due to cerebral vasospasm after subarachnoid haemorrhage (SAH) has been done with intravenous Rho kinase inhibitors (ROCKI), ozagrel sodium (TXA2I), selective ROCKI infusion (ROCKI i.a.), and cerebrospinal fluid (CSF) drainage. The endothelin receptor antagonist (ERA, clazosentan) became available in 2022 and is said to be highly recommended for DCI prevention, while fluid retention such as pleural effusion and pulmonary oedema accumulation is often experienced...We examined the results of blood sampling on admission, echocardiography, chest computed tomography (CT), with postoperative DCI, and hydrocephalus requiring cerebrospinal fluid shunt (hydro), and symptomatic fluid retention requiring albumin and furosemide (third fluid space)...Our experience suggests that age may be the most influential factor. Based on these results, we have also found that by avoiding the use of ERA in patients older than 80 years,..."

Journal • Cardiomyopathy • Cardiovascular • CNS Disorders • Congestive Heart Failure • Heart Failure • Respiratory Diseases • Subarachnoid Hemorrhage • Ventriculomegaly • NPPB

Symptomatic Vasospasm Refractory to Clazosentan after Subarachnoid Hemorrhage of Ruptured Vertebral Artery Dissecting Aneurysm: Clinical Implications from Two Contrasting Cases. (PubMed, Medicina (Kaunas)) - "These results imply the limited effectiveness of clazosentan in cases of thick and diffuse SAH after a ruptured VADA, even in good-clinical-grade patients treated with less invasive modalities. The HU values may become a simple quantitative marker for predicting symptomatic vasospasms and chronic hydrocephalus."

Journal • Retrospective data • Cardiovascular • CNS Disorders • Hematological Disorders • Subarachnoid Hemorrhage • Ventriculomegaly

Postoperative Management of Aneurysmal Subarachnoid Hemorrhage (PubMed, No Shinkei Geka) - "In Japan, fasudil hydrochloride and ozagrel sodium are widely used to prevent vasospasms; however, their effects are sometimes insufficient. This was demonstrated in a recent randomized phase 3 trial, leading to the approval of clazosentan by the Pharmaceuticals and Medical Devices Agency in Japan. Recent advances in our understanding of subarachnoid hemorrhage will facilitate improved management to reduce the incidence of DCI."

Journal • Review • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage

Successful administration of clazosentan in subarachnoid hemorrhage patient with severe heart failure. (PubMed, Surg Neurol Int) - "Neither cerebral vasospasm nor cardiopulmonary complications were observed. This case highlights the importance of a multidisciplinary approach in managing complex patients with severe cardiac comorbidities undergoing clazosentan therapy."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Disorders • Respiratory Diseases • Subarachnoid Hemorrhage

Letter to the editor: "Beyond nimodipine: advanced neuroprotection strategies for aneurysmal subarachnoid hemorrhage vasospasm and delayed cerebral ischemia". (PubMed, Neurosurg Rev) - "It highlights the pharmacological advantages of nicardipine, cilostazol, and clazosentan over nimodipine in managing cerebral vasospasm and delayed cerebral ischemia. Emphasizing the need for personalized medicine, it advocates for integrating genetic screening and advanced monitoring techniques to tailor treatments to individual patient profiles. This approach could significantly improve clinical outcomes by optimizing drug efficacy and minimizing adverse effects."

Journal • Metastases • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage

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, J Neurosurg) - P3 | "Clazosentan administered for up to 14 days at 15 mg/hour had no significant effect on the occurrence of clinical deterioration due to DCI. Clinical trial registration no.: NCT03585270 (ClinicalTrials.gov) EU clinical trial registration no.: 2018-000241-39 (clinicaltrialsregister.eu)."

Clinical • Journal • Cardiovascular • CNS Disorders • Hematological Disorders • Subarachnoid Hemorrhage • Vascular Neurology

Letter to editor: Beyond nimodipine: advanced neuroprotection strategies for aneurysmal subarachnoid hemorrhage vasospasm and delayed cerebral ischemia. (PubMed, Neurosurg Rev) - "This critique discusses neuroprotective strategies for aneurysmal subarachnoid hemorrhage (SAH), excluding Nimodipine, emphasizing alternatives like verapamil, albumin, and cilostazol. The letter underscores the need for comprehensive safety assessments and long-term outcome studies to enhance practical application. Highlighting ongoing trials and emerging therapies like clazosentan and TAK-044, it advocates for future research directions focused on large-scale RCTs and combination therapies, such as cilostazol and Nimodipine, which have demonstrated synergistic benefits in reducing delayed cerebral ischemia (DCI) and improving patient outcomes."

Journal • Metastases • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage

Beyond nimodipine: advanced neuroprotection strategies for aneurysmal subarachnoid hemorrhage vasospasm and delayed cerebral ischemia. (PubMed, Neurosurg Rev) - "Eicosapentaenoic acid, dapsone and clazosentan showed a good balance between effectiveness and favorable pharmacokinetics...Nicardipine, cilostazol, Rho-kinase inhibitors, and clazosentan proved their better pharmacokinetic profiles compared with nimodipine without prejudice with effective and safe neuroprotective role. However, the number of trials conducted is significantly lower than for nimodipine. Aneurysmal SAH-associated vasospasm remains an area of ongoing preclinical and clinical research where the search for new drugs or associations is critical."

Journal • Metastases • Review • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage

The effectiveness and safety of clazosentan in treating aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis. (PubMed, J Clin Neurosci) - "Clazosentan demonstrates efficacy in reducing vasospasm, moderate to severe vasospasm, DCI, and the need for rescue therapy in aSAH patients, but does not significantly improve functional outcomes or mortality rates. While associated with specific adverse events, clazosentan may be a valuable adjunctive therapy in the management of aSAH, particularly in a high-risk population for vasospasm."

Journal • Retrospective data • Review • Cardiovascular • Cerebral Hemorrhage • Hematological Disorders • Hypotension • Subarachnoid Hemorrhage

Prophylactic management of cerebral vasospasm with clazosentan in real clinical practice: a single-center retrospective cohort study. (PubMed, Front Neurol) - "After clazosentan was approved for use in Japan, the conventional postoperative management protocol, composed of intravenous fasudil chloride and oral cilostazol (control group, April 2021 to March 2022), was changed to the clazosentan protocol (clazosentan group, April 2022 to March 2023). A postoperative management protocol centering on clazosentan was associated with the reduced vasospasm-related symptomatic infarction and improved clinical outcomes compared to the conventional management protocol in Japanese clinical practice. Clazosentan might be a promising treatment option for counteracting cerebral vasospasm after aneurysmal SAH."

Journal • Retrospective data • Cardiovascular • Hematological Disorders • Respiratory Diseases • Subarachnoid Hemorrhage

Comparison of efficacy between clazosentan and fasudil hydrochloride-based management of vasospasm after subarachnoid hemorrhage focusing on older and WFNS grade V patients: a single-center experience in Japan. (PubMed, Neurosurg Rev) - "Clazosentan was more effective than fasudil-based management in preventing DCI and reducing vasospasm-related M/M. Clazosentan could be used safely in older patients and those with WFNS grade V, although clinical outcomes in these patients were comparable to those of conventional treatment."

Journal • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage

Factors Influencing Discontinuation of Clazosentan Therapy in Elderly Patients with Aneurysmal Subarachnoid Hemorrhage: A Retrospective Study from a Japanese Single Center. (PubMed, Med Sci Monit) - "CONCLUSIONS Our results suggest that approximately 20% of SAH patients suffered from intolerable respiratory symptoms attributable to hypoxemia. We found that both reduced day-to-day urine volume variation and older age are independent risk factors for drug discontinuation."

Journal • Retrospective data • Cardiovascular • Hematological Disorders • Ischemic stroke • Pulmonary Disease • Subarachnoid Hemorrhage

Cardiopulmonary Events of the Elderly (≥75 Years) during Clazosentan Therapy after Subarachnoid Hemorrhage: A Retrospective Study from a Tertiary Stroke Center in Japan. (PubMed, Medicina (Kaunas)) - "These results suggest that elderly patients are more vulnerable to fluid retention and have a higher risk of cardiopulmonary complications during clazosentan therapy than younger patients. Careful monitoring of urine volume and weight gain and caution regarding age- and therapy-related hemodynamic insufficiencies are required."

Retrospective data • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Disorders • Hypotension • Respiratory Diseases • Subarachnoid Hemorrhage

Pharmacotherapy in SAH: Clinical Trial Lessons. (PubMed, CNS Neurol Disord Drug Targets) - "To date, nimodipine is the only evidence-based treatment of vasospasm. However, extensive research is currently underway to identify novel substances with magnesium sulphate, cilostazol, clazosentan and fasudil, demonstrating promising results...Statins may benefit some patients by reducing the incidence of vasospasm and delayed ischemic events. As several clinical trials are underway, it is expected that in the years to come, more therapeutic options will be added to the attending physician's armamentarium."

Journal • Cardiovascular • Cerebral Hemorrhage • Subarachnoid Hemorrhage

Initial real-world experience of clazosentan for subarachnoid hemorrhage in Japan. (PubMed, World Neurosurg X) - "Clinical outcomes of the new protocol were comparable to those of conventional protocol. Clazosentan may simplify anti-vasospasm treatment. Fluid retention was a specific side-effect of clazosentan, which requires attention especially in the first half of the CVS period."

Journal • Real-world • Real-world evidence • Hematological Disorders • Subarachnoid Hemorrhage

Sosei Group Announces Marketing Approval for PIVLAZ (clazosentan sodium) 150 mg in South Korea (GlobeNewswire) - "Sosei Group Corporation...announces that PIVLAZ (clazosentan sodium) 150 mg has received marketing approval from the Ministry of Food and Drug Safety (MFDS) in South Korea for the prevention of cerebral vasospasm, vasospasm-related cerebral infarction, and cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage (aSAH) securing....The MFDS approval is based on scientific and clinical data from an extensive Japanese Phase 3 program submitted by Idorsia Pharmaceuticals Korea...In South Korea, the Marketing Authorization of PIVLAZ™ is held by IPK and will become commercially available to patients in early 2025."

Launch non-US • Non-US regulatory • CNS Disorders

Pharmacological Prevention of Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage. (PubMed, Neurocrit Care) - "We provide a brief overview of agents currently being studied for prevention of aVSP and DCI after aSAH. Future studies may need to identify subpopulations of patients who can benefit from these drugs and perhaps redefine acceptable outcomes to demonstrate impact."

Journal • Cardiovascular • CNS Disorders • Hematological Disorders • Hypotension • Subarachnoid Hemorrhage • Vascular Neurology

A network meta-analysis of therapeutic and prophylactic management of vasospasm on aneurysmal subarachnoid hemorrhage outcomes. (PubMed, Front Neurol) - "Statins (0.79 [0.62-1]), tirilazad (0.82 [0.69-0.97]), CSF drainage (0.47 [0.29-0.77]), and clazosentan (0.51 [0.36-0.71]) significantly decreased the incidence of vasospasm. Cilostazol was the only treatment associated with improved neurological outcomes by 3 months in the primary (OR 1.16, 95% CI [1.05-1.28]) and secondary analyses (OR 2.97, 95% CI [1.39-6.32])...The link between vasospasm and neurological outcome appears questionable. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=116073, identifier: PROSPERO CRD42018116073."

Retrospective data • Review • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage

Real-world data of clazosentan in combination therapy for aneurysmal subarachnoid hemorrhage: a multicenter retrospective cohort study. (PubMed, Neurosurg Rev) - "Initially, we explored the efficacy of clazosentan combination therapy with cilostazol, statin, and antiepileptic drugs. Clazosentan combination therapy could potentially result in favorable outcomes for aSAH patients to prevent post-aSAH vasospasm-related DCI. The add-on effect of fasudil to combination therapy did not demonstrate a significant impact in reducing aSAH-related vasospasm or improving outcomes at discharge."

Combination therapy • Journal • Real-world • Real-world evidence • Retrospective data • Cardiovascular • Hematological Disorders • Hypotension • Respiratory Diseases • Subarachnoid Hemorrhage

Idorsia sells its Asia Pacific (ex-China) operations – including select license rights to products – to Sosei Heptares for a total consideration of CHF 400 million (GlobeNewswire) - "Idorsia Ltd...today announced the sale of its operating businesses in the Asia Pacific (ex-China) region ('Territory'), including assignment of PIVLAZ (clazosentan) and license rights to daridorexant in those territories, to Sosei Group Corporation (TSE: 4565; ‘Sosei Heptares’) for a total consideration of CHF 400 million."

M&A • Chronic Obstructive Pulmonary Disease • CNS Disorders • Respiratory Diseases

Efficacy and Safety of Clazosentan After Aneurysmal Subarachnoid Hemorrhage: An Updated Meta-Analysis. (PubMed, Neurosurgery) - "Clazosentan decreased vasospasm-related DCI and angiographic vasospasm but did not improve functional outcomes or mortality. Adverse events were increased by clazosentan."

Journal • Retrospective data • Cardiovascular • Hematological Disorders • Subarachnoid Hemorrhage

Letter to the Editor. Clazosentan was superior to placebo, but was the comparison appropriate? (PubMed, J Neurosurg) - No abstract available

Journal

Clinicians' preferences for managing aneurysmal subarachnoid hemorrhage using endothelin receptor antagonists. (PubMed, Front Neurol) - "The endothelin receptor antagonist (ERA) clazosentan is being investigated for the medical prevention of cerebral vasospasm and associated complications, such as delayed cerebral ischemia (DCI), after aneurysmal subarachnoid hemorrhage (aSAH)...The likelihood of DCI occurring after aSAH can therefore be considered a clinically relevant endpoint in aSAH treatment development. Thus, evaluations of ERAs might focus on whether improvements (i.e., reductions) in the likelihood of DCI justify the risks of adverse events."

Journal • Cardiovascular • Critical care • Hematological Disorders • Hypotension • Subarachnoid Hemorrhage

Letter: Clinical Benefit of Clazosentan in Vasospasm After Subarachnoid Hemorrhage: Are We There Yet? (PubMed, Neurosurgery) - No abstract available

Journal • Hematological Disorders • Subarachnoid Hemorrhage

The REACT study: design of a randomized phase 3 trial to assess the efficacy and safety of clazosentan for preventing deterioration due to delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. (PubMed, BMC Neurol) - P3 | "In the REACT study, clazosentan is evaluated on top of standard of care to determine if it reduces the risk of clinical deterioration due to DCI after aSAH. The selection of patients with thick and diffuse clots is intended to assess the benefit/risk profile of clazosentan in a population at high risk of vasospasm-related ischemic complications post-aSAH. TRIAL REGISTRATION (ADDITIONAL FILE 1): ClinicalTrials.gov (NCT03585270). EU Clinical Trial Register (EudraCT Number: 2018-000241-39)."

Journal • P3 data • Cardiovascular • CNS Disorders • Hematological Disorders • Subarachnoid Hemorrhage • Vascular Neurology