Phase 3 investigation of clazosentan for vasospasm post- aneurysmal subarachnoid hemorrhage Investor Webcast – June 2018
The following information contains certain “forward-looking statements”, relating to the company’s business, which can be identified by the use of forward-looking terminology such as “estimates”, “believes”, “expects”, “may”, “are expected to”, “will”, “will continue”, “should”, “would be”, “seeks”, “pending” or “anticipates” or similar expressions, or by discussions of strategy, plans or intentions. Such statements include descriptions of the company’s investment and research and development programs and anticipated expenditures in connection therewith, descriptions of new products expected to be introduced by the company and anticipated customer demand for such products and products in the company’s existing portfolio. Such statements reflect the current views of the company with respect to future events and are subject to certain risks, uncertainties and assumptions. Many factors could cause the actual results, performance or achievements of the company to be materially different from any future results, performances or achievements that may be expressed or implied by such forward-looking statements. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected. 2 Phase 3 initiation in vasospasm post-aSAH | June 2018
More knowledge – Powered by science Jean-Paul Clozel, MD CEO 3 Phase 3 initiation in vasospasm post-aSAH | June 2018
Our Strategic Priorities 1 Deliver at least three products to market 5 key priorities to ensure the 2 company’s success Build a commercial organization over the next 5 years 3 Bring Idorsia to profitability in a sustainable manner 4 Create a pipeline with a sales potential of CHF 5 billion 5 Utilize state-of-the-art technologies 4 Phase 3 initiation in vasospasm post-aSAH | June 2018
Phase 3 investigation of clazosentan for vasospasm post-aneurysmal subarachnoid hemorrhage Guy Braunstein, MD Head of Global Clinical Development 5 Phase 3 initiation in vasospasm post-aSAH | June 2018
Aneurysmal subarachnoid hemorrhage (aSAH) A sudden life-threatening bleeding occurring in the subarachnoid space aSAH is caused by the rupture of an aneurysm • Scalp – a weak, bulging spot on the wall of a cerebral artery Skull Prevalence: 9 in 100’000 worldwide – • Subarachnoid it is an orphan disease space Brain Emergency repair • is required to stop the hemorrhage Pre-treatment Brain surgery: Catheter intervention: Releasing of platinum coils Clipping of the aneurysm Ruptured aneurysm Coil Catheter Clip Brain artery 6 Phase 3 initiation in vasospasm post-aSAH | June 2018
Cerebral vasospasm post-aSAH Can occur between 4 and 14 days after aSAH securing Artery spasm • Cerebral vasospasm is a strong contraction of the arteries in the brain surrounding the hemorrhage Blood • Narrowing of the blood vessel limits blood flow decreasing the amount of blood supplied to the brain Baseline aSAH: 7 day after SAH: normal MCA cerebral vasospasm 7 Phase 3 initiation in vasospasm post-aSAH | June 2018
Clinical manifestations of vasospasm From asymptomatic detected by systematic Long-term consequence of vasospasm angiography to serious neurological symptoms Necrosis of an area of brain tissue • Physical deficit • Loss of consciousness • Social and emotional impact, affecting all aspects of someone’s life Blurred or double Focal numbness, weakness, vision paralysis Mood change, Cerebral Confusion agitation vasospasm Worsening Dizziness of headache Difficulty speaking or Brain infarct due being unable to speak to vasospasm 8 Phase 3 initiation in vasospasm post-aSAH | June 2018
Available therapy for vasospasm Hemodynamic therapy Rescue therapy No pharmacological therapy for cerebral vasospasm • Inducing high blood pressure in • Invasive neurovascular intervention an attempt to force a blood • Except for fasudil in Japan and − balloon angioplasty supply to the brain region Korea − intra-arterial administration of affected by the vasospasm • Nimodipine approved in most vasodilators countries for preventing Often needs to be repeated • ischemic events secondary to multiple times over the course of aSAH (but whether it acts on several days cerebral vasospasm is Requires highly-trained specialists • unproven) in an intensive care setting Clinical efficacy unproven in • randomized controlled trials • Is associated with medical risks 9 Phase 3 initiation in vasospasm post-aSAH | June 2018
Rationale for clazosentan for cerebral vasospasm Clazosentan Role of endothelin in cerebral vasospasm Cerebral vasospasm is caused by ETA selective ERA the release of vasoactive mediators after a bleed on the brain triggering vessels to contract Patients with cerebral Highly soluble vasospasm show high levels of endothelin in their cerebral spinal fluid Ideal for intravenous administration Blood Fast onset of action Endothelin is one of the most powerful, long-acting vasoactive mediators that causes blood vessels to contract 10 Phase 3 initiation in vasospasm post-aSAH | June 2018
Learning from clazosentan program Vasospasm ≈ day 4 to 14 Initial SAH Aneurism Asymptomatic Vasospasm- Hospital Delayed, event secured vasospasm related symptoms discharge 3 to 6 month outcome More than 1’800 patients treated with clazosentan providing significant experience in vasospasm post-aSAH and a CONSCIOUS well documented safety profile REVERSE From this program, we know: Which patients would benefit most • • What dose should be given How to manage the treatment and in particular the safety of clazosentan • How to measure treatment benefit short-term and long-term • This acquired knowledge is incorporated into the design of the REACT study Clazosentan is investigational, in development and not approved or marketed in any country. 11 Phase 3 initiation in vasospasm post-aSAH | June 2018
What we have learned through our experience with clazosentan… Sebastien Roux, MD Medical lead for clazosentan Clazosentan is investigational, in development and not approved or marketed in any country. 12 Phase 3 initiation in vasospasm post-aSAH | June 2018
Clazosentan Dose-dependent prevention of vasospasm CONSCIOUS-1 Phase 2 study – 80 angiographic endpoint All patients (per-protocol) Clazosentan 1 to 15 mg/h versus • 70 Patients with moderate/severe placebo post-clipping and coiling 60 *p = 0.0027 vasospasm (%) *p = 0.0003 50 40 *p < 0.0001 30 20 10 n = 85 n = 95 n = 95 n = 79 0 1 mg/h 5 mg/h 15 mg/h Placebo Clazosentan Stroke 2008 39:3015-21 Clazosentan is investigational, in development and not approved or marketed in any country. 13 Phase 3 initiation in vasospasm post-aSAH | June 2018
Clazosentan 5mg/hr dose is not high enough CONSCIOUS-2 Phase 3 study – clinical Overall incidence of death and vasospasm-related morbidity morbidity / mortality endpoint Patients who received surgical clipping • treated with 5mg/hr clazosentan Event rate (%) The Lancet. Neurology, 2011; 10(7):618-625 Clazosentan is investigational, in development and not approved or marketed in any country. 14 Phase 3 initiation in vasospasm post-aSAH | June 2018
Clazosentan 15mg/hr showed significant effect on morbidity / mortality CONSCIOUS-3 Phase 3 study – clinical Overall incidence of death and vasospasm-related morbidity morbidity / mortality endpoint Patients who received endovascular coiling treated • with 5 or 15mg/hr clazosentan Stroke. 2012; 43(6):1463-9 Clazosentan is investigational, in development and not approved or marketed in any country. 15 Phase 3 initiation in vasospasm post-aSAH | June 2018
Clazosentan 15mg/hr showed significant effect on primary endpoint CONSCIOUS-3 Phase 3 study – clinical Incidence of death and each component of vasospasm-related morbidity morbidity / mortality endpoint Consistent effect at 15 mg/hr on all • 25 morbidity events 21 21 18 20 16 Event rate (%) 15 13 15 10 10 7 6 7 5 5 3 Placebo 0 New cerebral Delayed ischemic Death Rescue therapy Clazosentan infarct neurological deficits (within 6 weeks) 5 mg/h Clazosentan Vasospasm-related 15 mg/h Stroke. 2012; 43(6):1463-9 Clazosentan is investigational, in development and not approved or marketed in any country. 16 Phase 3 initiation in vasospasm post-aSAH | June 2018
Clazosentan 10mg/hr dose showed similar results to CONSCIOUS-3 in Japanese patients Japanese study Phase 2 study – exploratory endpoint Overall incidence of death and vasospasm-related morbidity • Clazosentan significantly reduced vasospasm-related morbidity and mortality events Cerebrovasc Dis 2017;44:59–67 Clazosentan is investigational, in development and not approved or marketed in any country. 17 Phase 3 initiation in vasospasm post-aSAH | June 2018
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