Phase 3 investigation of nemorexant for patients with insomnia 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 insomnia | June 2018
More knowledge – Powered by science Jean-Paul Clozel CEO 3 Phase 3 initiation in insomnia | 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 insomnia | June 2018
Phase 3 investigation of nemorexant for patients with insomnia Guy Braunstein Head of Global Clinical Development 5 Phase 3 initiation in insomnia | June 2018
Chronic insomnia disorder More than 1 type of disturbance present ≥ 3 nights/week for ≥ 3 months Difficulty Difficulty Waking Falling Asleep Staying Asleep Too Early Sleep-Onset Sleep-Maintenance Sleep-Offset Insomnia Insomnia Insomnia Distress or Impairment of life 6 Phase 3 initiation in insomnia | June 2018
Who gets insomnia and what is the impact ? Insomnia is a common problem Risk factors Impact • Age (more common with ageing) Physically and mentally fatigued, • anxious and irritable • Gender (women > men) Increased the risk of malaise, • • Lower socio-economic status fall, accidents, and injury • Physical disorder • Impaired daytime performance • Psychiatric disorder (depression, Decreased memory and • anxiety, alcohol and drug abuse) concentration, cognitive decline Leading cause of absenteeism and • reduced productivity, burden to society • Higher rate of mortality 7 Phase 3 initiation in insomnia | June 2018
How is insomnia treated, what are the limitations? Sleep hygiene Cognitive Pharmacological therapy Active behavioral therapy • Many have significant limitations • patient • Recommended first- • Insufficient acute effect: participation line therapy but lack of sustained effect through the night required inconsistently Insufficient long-term effect: • practiced lack of continued benefit over time Not easily accessible • Next morning residual effect • • Often not • Abuse potential, withdrawal effect reimbursed and rebound Active patient • May have significant adverse effects • participation required 8 Phase 3 initiation in insomnia | June 2018
The orexin system is crucial for the regulation of wakefulness Orexin stimulates orexin many wake-promoting pathways Dopamine (VTA) Histamine Acetylcholine (LDT, PPT) (TMN) LHA / PH Orexin Serotonin (raphe) LC OX 1 R Norepinephrine (LC) TMN OX 2 R Raphe OX 1 R and OX 2 R LTD / PPT OX 1 R and OX 2 R VTA OX 1 R and OX 2 R Sakurai, T. 2007 LHA = lateral hypothalamic area; PH = posterior hypothalamus LC = locus coeruleus; TMN = tuberomammillary nucleus; LDT = laterodorsal tegmental nucleus; VTA = ventral tegmental area; PPT = pedunculopontine nucleus 9 Phase 3 initiation in insomnia | June 2018
Nemorexant Dual orexin receptor antagonist Brain penetrating The orexin system is involved in the regulation of sleep and arousal Potent antagonist at OX1 and OX2 Dual orexin receptor receptors antagonism specifically targets excessive alertness, in contrast to treatments of insomnia that act via broad sedation of the CNS Nemorexant is investigational, in development and not approved or marketed in any country. 10 Phase 3 initiation in insomnia | June 2018
Nemorexant Translation: preclinical healthy subjects patients Desired profile High in vitro potency in vivo efficacy Quick absorption and short half-life fast onset of action, “appropriate” duration of action to act throughout the night, and to avoid next morning residual effect Safety is key • No deterioration of next-day performance No rebound, no withdrawal symptoms upon treatment cessation • No safety concerns • Nemorexant is investigational, in development and not approved or marketed in any country. 11 Phase 3 initiation in insomnia | June 2018
Nemorexant Clinical development Clinical pharmacology program Today Entry into man Phase 2 studies studies Phase 3 Single and multiple Two studies, in adults • • confirmatory ascending dose and elderly patients studies with insomnia Adults and elderly subjects • • All information required • Night time administration to design confirmatory Pharmacokinetic and • pivotal studies pharmacodynamic characterization Nemorexant is investigational, in development and not approved or marketed in any country. 12 Phase 3 initiation in insomnia | June 2018
Nemorexant Entry into man Phase 2 Phase 3 studies studies studies Ideal pharmacokinetic profile 25 mg 1000 Plasma concentrations (ng /ml) 800 • Fast absorption 600 • Short half life • No accumulation over time 400 200 0 0 24 48 72 96 120 144 168 Time (h) Nemorexant is investigational, in development and not approved or marketed in any country. 13 Phase 3 initiation in insomnia | June 2018
Nemorexant Entry into man Phase 2 Phase 3 studies studies studies Fast and time limited pharmacodynamic effect 25 mg Speed of eye movements (degree/sec) Adult Healthy Volunteer – Daytime dosing Elderly Healthy Volunteer – Daytime dosing Time (h) Person performing eye movement test Nemorexant is investigational, in development and not approved or marketed in any country. 14 Phase 3 initiation in insomnia | June 2018
Nemorexant Entry into man Phase 2 Phase 3 studies studies studies No pharmacodynamic effect on next morning Karolinska Sleepiness Scale Placebo 25 mg Score Very sleepy 9 8 Sleepy, but no effort 7 keeping awake 6 Neither alert nor 5 sleepy 4 Alert, 3 normal level 2 Very alert 1 Time after first dose (h) – measures 8 hours after dosing Nemorexant is investigational, in development and not approved or marketed in any country. 15 Phase 3 initiation in insomnia | June 2018
Purpose and objectives of the Entry into man Phase 2 Phase 3 studies studies studies Phase 2 program Purpose Objectives To provide necessary information To characterize the dose response to adequately design the confirmatory on objective and subjective sleep trials parameters To document the safety profile including adverse events, residual Focus in particular: effect, rebound and withdrawal • Dose definition • Patient population characterization • Endpoint definition 16 Phase 3 initiation in insomnia | June 2018
Two phase 2 studies completed Entry into man Phase 2 Phase 3 studies studies studies Informative design Adult study: classical parallel group design Elderly study: cross over design 4-week treatment to assess durability of effect 2-night treatment • • • Short treatment withdrawal at the end • 4 dose levels identical to adults • 4 dose levels (5 mg, 10 mg, 25 mg and 50 mg) • Placebo-controlled Placebo and active arms (zolpidem) Objective and subjective parameters • • • Objective and subjective sleep parameters In both studies, well-characterized insomnia patients Self-reported insomnia at entry Confirmed by polysomnography at baseline ≥ 30 minutes to fall asleep Mean LPS ≥ 20 min Sleep induction Sleep maintenance Wake time during sleep ≥ 30 minutes Mean WASO ≥ 30 min Total sleep time ≤ 6.5 h Mean TST < 420 minutes Total sleep time 17 Phase 3 initiation in insomnia | June 2018
Efficacy results in adult patients Entry into man Phase 2 Phase 3 studies studies studies • Statistically significant dose- response on primary endpoint (objective WASO by PSG) • Clinically relevant effect especially at 25 and 50 mg • Other sleep endpoints and assessments at subsequent time points generally aligned to primary results Modified Full Analysis Set Least Square Mean ± 95% CL nemorexant dose (mg) Zolpidem 10 mg Nemorexant is investigational, in development and not approved or marketed in any country. 18 Phase 3 initiation in insomnia | June 2018
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