Clazosentan Fails to Meet Primary End Point in Phase 3 REACT Study of Aneurysmal Subarachnoid Hemorrhage

Jean-Paul Clozel, MD

According to an announcement by Idorsia, initial findings from the phase 3 REACT study (NCT03585270) of clazosenten showed that the agent failed to meet its primary end point of preventing clinical deterioration in patients presenting with aneurysmal subarachnoid hemorrhage (aSAH).¹

"I am very disappointed with the negative result of REACT,” Jean-Paul Clozel, MD, chief executive officer, Idorsia, said in a statement. "The study was based on strong scientific and medical rationale and executed diligently by a committed team of experts at Idorsia and by the investigators. On behalf of everyone at Idorsia, I’d like to thank the investigator teams and expert advisors for their tireless support to conduct this study in such a challenging medical condition."

The primary efficacy end point was the occurrence of clinical deterioration due to delayed cerebral ischemic (DCI) up to 14 days post-study drug initiation. Occurrence of clinically relevant cerebral infarction at day 16, as well as change in modified Raking Scale and Glasgow Outcome Scale-Extended score at week 12, as secondary end points for the trial. The trial also had radiological results and clinical end points evaluated by independent committees, blinded to treatment allocation.

REACT was a double-blind, placebo-controlled, parallel-group study that included 409 patients with documented aSAH from a ruptured cerebral aneurysm who were randomly assigned 1:1 to 15 mg/hr intravenous clozaosentan or placebo. Eligible patients were between 18 to 70 years old with World Federation of Neurological Societies grades 1-4 after recovery from the aneurysm-securing procedure and “thick and diffuse clots” on the admission CT scan.

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Clazosentan, a fast-acting endothelin A (ETA) receptor antagonist, has been previously approved as a preventive treatment for cerebral vasospasm, vasospasm-related cerebral infarction, and cerebral ischemic symptoms after aSAH in Japan. For context, the subarachnoid bleeding and subsequent release of endothelin-1 can lead to cerebral vasospasm, which typically starts 3 days after aSAH onset and peaks in intensity between 8 and 11 days.

The therapy has demonstrated a significant ability to prevent cerebral vasospasm before, first showcased in the phase 2 dose-finding CONSCIOUS 1 study (NCT00111085). That study, which featured 413 patients with aSAH, showed that moderate or severe vasospasm was reduced in a dose-dependent fashion from 66% in the placebo group to 23% in the 15 mg/hr clazosentan group (risk reduction, 65%; 95% CI, 47%-78%; P <.0001). In terms of safety, the therapy was found to be associated with increased rates of pulmonary complications, hypotension, and anemia.²

This was followed by 2 phase 3 studies, CONSCIOUS-2 and CONSCIOUS-3, to assess the effect of clazosentan on the incidence cerebral vasospasm-related morbidity and all-cause mortality. In CONSCIOUS-2, 5 mg/hr of clazosentan did not demonstrate a significant treatment effect, resulting in the premature termination of CONSCIOUS-3. The primary composite end point—all-cause mortality, vasospasm-related new cerebral infarcts or delayed ischemic neurological deficits, or rescue therapy—occurred in 27% of patients on placebo (n = 189) vs 24% and 15% of those treated with clazosentan 5 mg/hr or 10 mg/hr, respectively, in CONSCIOUS-3.³

REFERENCES
1. Idorsia announces the results of REACT a phase 3 study of clazosentan in patients following aneurysmal subarachnoid hemorrhage. News release. Idorsia. February 6, 2023. Accessed February 7, 2023. https://www.globenewswire.com/news-release/2023/02/06/2601762/0/en/Idorsia-announces-th%5B%E2%80%A6%5Dpatients-following-aneurysmal-subarachnoid-hemorrhage.html
2. Macdonald RL, Kassell NF, Mayer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): a randomized, double-blind, placebo-controlled phase 2 dose-finding trial. STROKE. 2008;39:3015-3021. doi:10.1161/STROKEAHA.108.519942
3. Macdonald RL, Higashida RT, Keller E, et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. STROKE. 2012;43:1463-1469. doi:10.1161/STROKEAHA.111.648980