Idorsia Ltd (SIX: IDIA) and Idorsia Pharmaceuticals Japan today announced that PIVLAZ™ (clazosentan) is now available to physicians in Japan to start treating aSAH patients. PIVLAZ is a potent, selective endothelin A (ET_A) receptor antagonist which targets the root cause of cerebral vasospasm.
PIVLAZ 150 mg, is indicated for the prevention of cerebral vasospasm, vasospasm-related cerebral infarction and cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage (aSAH) securing.

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 stop bleeding and 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 21.⁷ 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 20-50% of aSAH patients, and half of the patients with severe vasospasm develop cerebral infarction.^3,4,5,6 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 world⁸ and is therefore a significant problem in this country.

Satoshi Tanaka, Dr Med Sci. and President of Idorsia Pharmaceuticals Japan, commented:
“I am very proud to be launching Idorsia’s first product here in Japan, and I’m sure it will be the first of many innovative medicines from Idorsia, which will help many patients. I’m also proud of the Japanese team for bringing this important product to patients. The results with clazosentan are very impressive and represent a ground-breaking therapeutic advancement in the prevention of cerebral vasospasm. When listing PIVLAZ, the National Health Insurance system has recognized this innovative medicine as fulfilling an important medical need for patients facing a life-threatening condition. I know too that the expert physicians are very happy to finally have PIVLAZ for their patients, so that they can prevent the devastating consequences of cerebral vasospasm which occur even after the initial intervention has been successful. Together, we can change the lives of many Japanese patients.”

Jean-Paul Clozel MD and Chief Executive Officer of Idorsia commented:
“It is very fitting that the first product to reach patients comes from the research our team has been working on for many years. Finally, our perseverance has paid off and our drug can now treat the patients suffering from this unpredictable and devastating condition. This milestone also represents a transformation for Idorsia as we can now deliver innovation from the lab bench to the patients’ bedside.”

About the Japanese registration program
The approval of PIVLAZ was based on the results of a Phase 3 program with clazosentan in Japan, which were recently published in the Journal of Neurosurgery¹. The program demonstrated that 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 findings¹.

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. In the pooled analysis of secondary endpoints, vasospasm-related DIND was reduced by 60% (p = 0.0004) and vasospasm-related new cerebral infarcts were reduced by 55% (p<0.0001) in patients treated with clazosentan compared to placebo.

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).

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^{9,10,11,12,13,14} 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

1. 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
2. Daou BJ, et al. Clinical and experimental aspects of aneurysmal subarachnoid hemorrhage. CNS Neurosci Ther. 2019; 25(10):1096-1112.
3. 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.
4. Dankbaar JW, et al. Relationship between vasospasm, cerebral perfusion, and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Neuroradiology. 2009;51(12):813–819.
5. Frontera JA, et al. Defining vasospasm after subarachnoid hemorrhage: what is the most clinically relevant definition? Stroke. 2009;40(6):1963–1968.
6. Rabinstein AA, et al. Patterns of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke. 2005;36(5):992–997.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Macdonald R L, et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke. 2012; 43(6):1463-9.
13. 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.
14. 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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