Idorisa initiates phase 3 study of clazosentan

Idorsia is initiating a Phase 3 study, REACT, to investigate the efficacy and safety of ‘clazosentan’ for the prevention of clinical deterioration due to vasospasm-related delayed cerebral ischemia in patients following an aneurysmal subarachnoid hemorrhage, it announced on Monday.

The firm described aneurysmal subarachnoid hemorrhage (aSAH) as a sudden life-threatening bleeding occurring in the subarachnoid space.

It is caused by the rupture of an aneurysm, with emergency surgical repair required to stop the hemorrhage.

The bleeding and the release of a vasoconstrictor, endothelin, by the neighboring vascular endothelium, caused many patients to experience vasospasm - constriction of arteries in the brain.

Idorisa said that diminished blood flow to the brain and as a consequence, about one third of patients experienced worsening of their neurological condition.

Patients with thick and diffuse blot clots were said to be at a “significantly higher” risk of experiencing cerebral vasospasm.

At present, patients with vasospasm were typically treated with hemodynamic therapy, or more invasive neurovascular intervention such as balloon angioplasty or intra-arterial administration of vasodilators.

“It is very frustrating to see our patients survive the initial trauma of the brain hemorrhage and seemingly make a recovery, only for the vasospasm to take hold and cause significant long-term damage,” said University of Maryland chief of cerebrovascular surgery E Francois Aldrich.

“Current 'rescue' therapy for cerebral vasospasm involves invasive neurovascular intervention that often needs to be repeated multiple times over the course of several days, needs to be performed by highly-trained specialists in an intensive care setting, and is itself associated with medical risks.

“Clazosentan may avoid or reduce this considerable ordeal for the patient, and the healthcare team.”

Several studies had built Idorsia’s understanding of clazosentan, an intravenous endothelin receptor antagonist, regarding its impact on preventing or reversing cerebral vasospasm, the board said.

The studies suggested that clazosentan had the potential to prevent vasospasm-related delayed cerebral ischemia and to decrease the need for invasive neurovascular intervention.

“We know that endothelin plays a major role in cerebral vasospasm after aSAH,” said Idorsia managing director and chief scientific officer Martine Clozel.

“Clazosentan is an endothelin receptor antagonist which was optimised for its potential to be active in the brain and adapted to intensive care administration.”

Clozel said clinical studies with clazosentan had built a “deep understanding” of its role in preventing or reversing cerebral vasospasm.

“I am confident that we can now show that clazosentan can prevent vasospasm-related clinical deterioration in high risk patients.”

Idorsia said REACT was a prospective, multi-centre, double-blind, randomised, placebo-controlled, parallel-group, Phase 3 study to assess the efficacy and safety of clazosentan in preventing clinical deterioration due to vasospasm-related delayed cerebral ischemia, in adult patients with aSAH.

Approximately 400 patients, regardless of whether their hemorrhage had been treated with surgical clipping or endovascular coiling, were expected to be enrolled.

Patients would be enrolled from 100 trial sites across 15 countries, who would be randomised to either 15 mg/hr clazosentan or placebo for a treatment period of up to 14 days.

The study was expected to run for around 27 months.

REACT would enroll aSAH patients identified as being at high-risk of developing delayed ischemic neurological deficit because of high volume of their hemorrhage, as assessed by CT scan on hospital admission.

Patients experiencing asymptomatic moderate-to-severe cerebral vasospasm within 14 days of securing the aneurysm could also be included.

“REACT builds on the learnings from previous clinical studies with clazosentan, which have served to identify the optimal treatment dose and the characteristics of the patient that are most likely to benefit from treatment,” said Idorsia’s managing director and head of global clinical development Guy Braunstein.

“Those studies have also established an extensive safety profile with over 1'800 patients treated.”

Braunstein said that, compared to current acute intra-arterial intervention that only targets vasospasm in major blood vessels, clazosentan reached the smaller blood vessels.

“It therefore has a potential to an effect across the whole brain circulation.”