Phase 3 investigation of nemorexant for patients with insomnia - - PowerPoint PPT Presentation

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.

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More knowledge – Powered by science

Jean-Paul Clozel CEO

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key priorities to ensure the company’s success

• ver the next

5 years

Our Strategic Priorities

1 2 3 4 5

Deliver at least three products to market Build a commercial organization Bring Idorsia to profitability in a sustainable manner Create a pipeline with a sales potential of CHF 5 billion Utilize state-of-the-art technologies

5

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Phase 3 investigation of nemorexant for patients with insomnia

Guy Braunstein Head of Global Clinical Development

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More than 1 type of disturbance present ≥ 3 nights/week for ≥ 3 months

Chronic insomnia disorder

Difficulty Falling Asleep Difficulty Staying Asleep Waking Too Early Sleep-Onset Insomnia Sleep-Maintenance Insomnia Sleep-Offset Insomnia

Distress or Impairment of life

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Who gets insomnia and what is the impact ?

Risk factors

• Age (more common with ageing)
• Gender (women > men)
• Lower socio-economic status
• Physical disorder
• Psychiatric disorder (depression,

anxiety, alcohol and drug abuse) Impact

• Physically and mentally fatigued,

anxious and irritable

• Increased the risk of malaise,

fall, accidents, and injury

• Impaired daytime performance
• Decreased memory and

concentration, cognitive decline

• Leading cause of absenteeism and

reduced productivity, burden to society

• Higher rate of mortality

Insomnia is a common problem

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How is insomnia treated, what are the limitations?

Sleep hygiene

• Active

patient participation required Cognitive behavioral therapy

• Recommended first-

line therapy but inconsistently practiced

• Not easily accessible
• Often not

reimbursed

• Active patient

participation required Pharmacological therapy

• Many have significant limitations
• Insufficient acute effect:

lack of sustained effect through the night

• Insufficient long-term effect:

lack of continued benefit over time

• Next morning residual effect
• Abuse potential, withdrawal effect

and rebound

• May have significant adverse effects

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The orexin system is crucial for the regulation of wakefulness

Orexin stimulates many wake-promoting pathways

Norepinephrine (LC) Acetylcholine (LDT, PPT) Dopamine (VTA) Serotonin (raphe)

• rexin

Histamine (TMN) LHA / PH LC TMN Raphe LTD / PPT VTA Orexin OX1R OX2R OX1R and OX2R OX1R and OX2R OX1R and OX2R

Sakurai, T. 2007

Phase 3 initiation in insomnia | June 2018 9 LHA = lateral hypothalamic area; PH = posterior hypothalamus LC = locus coeruleus; TMN = tuberomammillary nucleus; LDT = laterodorsal tegmental nucleus; VTA = ventral tegmental area; PPT = pedunculopontine nucleus

The orexin system is involved in the regulation of sleep and arousal

Dual orexin receptor antagonist

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Nemorexant

Nemorexant is investigational, in development and not approved or marketed in any country.

Dual orexin receptor antagonism specifically targets excessive alertness, in contrast to treatments of insomnia that act via broad sedation of the CNS

Potent antagonist at OX1 and OX2 receptors Brain penetrating

Translation: preclinical healthy subjects patients

Nemorexant

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. Phase 3 initiation in insomnia | June 2018 11

Clinical development

Nemorexant

• Single and multiple

ascending dose

• Adults and elderly subjects
• Night time administration
• Pharmacokinetic and

pharmacodynamic characterization

• Two studies, in adults

and elderly patients with insomnia

• All information required

to design confirmatory pivotal studies Entry into man studies Clinical pharmacology program Phase 3 confirmatory studies Phase 2 studies Today

Phase 3 initiation in insomnia | June 2018 12 Nemorexant is investigational, in development and not approved or marketed in any country.

200 400 600 800 1000 24 48 72 96 120 144 168

Ideal pharmacokinetic profile

Nemorexant

Plasma concentrations (ng/ml)

• Fast absorption
• Short half life
• No accumulation over time

Time (h)

Phase 3 initiation in insomnia | June 2018 13 Nemorexant is investigational, in development and not approved or marketed in any country.

25 mg

Fast and time limited pharmacodynamic effect

Nemorexant

Elderly Healthy Volunteer – Daytime dosing

Person performing eye movement test

Adult Healthy Volunteer – Daytime dosing

25 mg

Speed of eye movements (degree/sec) Time (h)

Phase 3 initiation in insomnia | June 2018 14 Nemorexant is investigational, in development and not approved or marketed in any country.

No pharmacodynamic effect on next morning

Nemorexant

Karolinska Sleepiness Scale Score Very sleepy Sleepy, but no effort keeping awake Neither alert nor sleepy Alert, normal level Very alert

9 8 7 6 5 4 3 2 1

Time after first dose (h) – measures 8 hours after dosing

Placebo 25 mg

Phase 3 initiation in insomnia | June 2018 15 Nemorexant is investigational, in development and not approved or marketed in any country.

Purpose and objectives of the Phase 2 program

Purpose To provide necessary information to adequately design the confirmatory trials Focus in particular:

• Dose definition
• Patient population characterization
• Endpoint definition

Objectives To characterize the dose response

• n objective and subjective sleep

parameters To document the safety profile including adverse events, residual effect, rebound and withdrawal

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Informative design

Two phase 2 studies completed

Adult study: classical parallel group design

• 4-week treatment to assess durability of effect
• Short treatment withdrawal at the end
• 4 dose levels (5 mg, 10 mg, 25 mg and 50 mg)
• Placebo and active arms (zolpidem)
• Objective and subjective sleep parameters

Elderly study: cross over design

• 2-night treatment
• 4 dose levels identical to adults
• Placebo-controlled
• Objective and subjective parameters

In both studies, well-characterized insomnia patients

Self-reported insomnia at entry

≥ 30 minutes to fall asleep Wake time during sleep ≥ 30 minutes Total sleep time ≤ 6.5 h

Confirmed by polysomnography at baseline

Mean LPS ≥ 20 min Mean WASO ≥ 30 min Mean TST < 420 minutes Sleep induction Sleep maintenance Total sleep time

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Efficacy results in adult patients

Modified Full Analysis Set Least Square Mean ± 95% CL

• 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

Phase 3 initiation in insomnia | June 2018 18 Nemorexant is investigational, in development and not approved or marketed in any country.

nemorexant dose (mg) Zolpidem 10 mg

Efficacy results in elderly patients

• Statistically significant dose-

response on primary endpoint (objective WASO by PSG)

• Clinically relevant effect

especially at 10, 25 and 50 mg

• Other objective sleep

parameters generally aligned to primary results

Modified Full Analysis Set Least Square Mean ± 95% CL

Phase 3 initiation in insomnia | June 2018 19 Nemorexant is investigational, in development and not approved or marketed in any country.

nemorexant dose (mg)

Normal sleep architecture preserved

9.8 10 9.8 10.7 10 10.7 57.9 56.2 55.4 56.8 55.1 57.4 15.4 13 12.5 12.5 15 12.6 16.9 20.8 22.3 20 19.9 19.3 Zolpidem 50 mg nemorexant 25 mg nemorexant 10 mg nemorexant 5 mg nemorexant placebo S1 S2 SWS REM Sleep architecture maintained as total sleep time is dose dependently increased in exploratory endpoint Duration as % of Total Sleep Time (TST)

Total Sleep Time (min)

357 371 384 387 403 388

Phase 3 initiation in insomnia | June 2018 20 Nemorexant is investigational, in development and not approved or marketed in any country.

Overview of adverse events in adults

Placebo N = 60 Nemorexant 5 mg N = 60 Nemorexant 10 mg N = 58 Nemorexant 25 mg N = 60 Nemorexant 50 mg N = 61 Zolpidem 10 mg N = 60 Subjects with at least one AE [n (%)] Treatment-emergent AE 18 (30.0) 21 (35.0) 22 (37.9) 23 (38.3) 21 (34.4) 24 (40.0) Treatment emergent AE of special interest after SafetyBoardadjudication*

• 1 (1.7)

1 (1.7) 2 (3.3)

• Treatment-emergent AE related to study treatment

6 (10.0) 11 (18.3) 9 (15.5) 12 (20.0) 8 (13.1) 9 (15.0) Treatment-emergent AE leading to premature study discontinuation of double-blind treatment

• 2 (3.4)
• 1 (1.6)

1 (1.7) Treatment-emergent serious AE

• 2 (3.4)**
• 1 (1.6)***
• Treatment-emergent serious AE related to study

treatment

• Well tolerated at all tested doses with no evidence of dose-dependent adverse effects

Phase 3 initiation in insomnia | June 2018 21 Nemorexant is investigational, in development and not approved or marketed in any country.

*Mild excessive daytime sleepiness in 4 patients **Myocardial infarction on Day 12 in a 53 y.o. male patient with no concomitant medication; not related to study medication **Work accident (object fell on head) on Day 8 in a 21 y.o. female patient unrelated to dizziness or sleepiness; not related to study medication ***Angioedema caused by bee venom in a cosmetic cream on Day 4; not related to study medication

Overview of adverse events in elderly

Placebo N = 54 Nemorexant 5 mg N = 56 Nemorexant 10 mg N = 54 Nemorexant 25 mg N = 55 Nemorexant 50 mg N = 56 Subjects with at least one AE [n (%)] Treatment emergent AE 8 (14.8) 13 (23.2) 12 (22.2) 10 (18.2) 16 (28.6) Treatment emergent AE of special interest afterSafety Boardadjudication

• Treatment emergent AE related to study treatment

4 (7.4) 5 (8.9) 6 (11.1) 4 (7.3) 5 (8.9) AE leading to premature discontinuation of double- blind treatment

• 1 (1.8)

2 (3.6) Treatment emergent serious AE

• Well tolerated at all tested doses with no evidence of dose-dependent adverse effects

Phase 3 initiation in insomnia | June 2018 22 Nemorexant is investigational, in development and not approved or marketed in any country.

Phase 2 conclusion

Nemorexant

Efficacy

• Dose response confirmed in adults and elderly subjects
• n objective sleep primary endpoint : WASO
• Other endpoints results generally aligned to primary endpoints

Safety (in the limit of the study design)

• No sign of rebound or withdrawal symptoms
• No clinically relevant next morning hang-over effect
• Good safety and tolerability in both age groups at all dose levels

Three doses selected for Phase 3 in both age groups

• 10 mg, 25 mg and 50 mg

Phase 3 initiation in insomnia | June 2018 23 Nemorexant is investigational, in development and not approved or marketed in any country.

Phase 3 program concept: adults and elderly patients – 3 dose levels selected

Nemorexant

Efficacy 1. Objective sleep parameters 2. Subjective sleep parameters 3. Daytime functioning assessed by a patient reported outcome instrument specifically developed and validated by Idorsia according to FDA guidelines Safety 1. Adverse events, vital signs, biochemistry and hematology 2. Next morning residual “hang-over” effect 3. Withdrawal/physical dependence, and rebound Clinical pharmacology studies including…

• Driving performance, interaction (drugs, alcohol), abuse potential
• Safety in specific population (COPD, obstructive sleep apnea, liver and renal impairment)

Phase 3 initiation in insomnia | June 2018 24 Nemorexant is investigational, in development and not approved or marketed in any country.

Phase 3 program overview

Nemorexant

Design

• 3 double-blind, randomized, placebo-controlled,

multicenter international studies Doses

• 301: placebo, 25 mg & 50 mg
• 302: placebo, 10 mg & 25 mg
• 303: placebo, 10 mg, 25 mg, and 50 mg

Main studies (12 weeks) Extension study (40 weeks)

Duration

• 3-month treatment in main studies, 301 & 302,

and 9-month in extension study, 303 Sample size (combined adult and elderly)

• 900 patients/study
• Extension study: All subjects who complete

either 301 or 302

301: placebo, 25 mg & 50 mg 303: placebo, 10 mg, 25 mg & 50 mg 302: placebo, 10 mg & 25 mg

Phase 3 initiation in insomnia | June 2018 25 Nemorexant is investigational, in development and not approved or marketed in any country.

Study design

Main studies 301 & 302

LD nemorexant HD nemorexant Placebo

V1 V3 V2 V4 V5 V6 V7 EODBT, V8 V9 V10 V11 1st month 2nd month 3rd month EOT EOS Randomization

Screening 20-31days Treatment Period 84 days Safety Follow-up 30 days

Run-in Placebo or Low (LD) or high dose (HD) nemorexant Double-blind Run-out

301: LD = 25 mg; HD = 50 mg 302: LD 0 10 mg; HD = 25 mg

Extension study

V = Visit = polysomnography nights EODBT = End of double-blind treatment EOT = End-of-Treatment EOS = End-of-Study

Phase 3 initiation in insomnia | June 2018 26 Nemorexant is investigational, in development and not approved or marketed in any country.

Study Design

Extension study 303

V1 V2 V3 V4 EOS, V7 Week 13 Week 26 Week 44 Randomization

ID-078A301/02 Treatment Period 40 weeks Safety Follow up 30 days

Run out period Either Placebo, 10, 25 or 50mg nemorexant Double-blind Run out No treatment No blinding

EODBT, V5 Week 40 EOT, V6 Week 41 Week 2 Run-out

10 mg nemorexant 25 mg nemorexant 50 mg nemorexant 10 mg nemorexant 25 mg nemorexant 50 mg nemorexant Placebo 25 mg nemorexant Placebo

Patients assigned to any nemorexant arms in the confirmatory studies will receive the same dose Patients assigned to placebo in the confirmatory studies will be randomized to receive either placebo or 25 mg nemorexant in a 1:1 ratio

Phase 3 initiation in insomnia | June 2018 27 Nemorexant is investigational, in development and not approved or marketed in any country.

In summary:

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• From preclinical to phase 2: translation of product properties

− Promotes sleep and maintains a natural sleep architecture − PK/PD profile optimized to combine effect during the night with low residual next morning plasma concentration/no “hang-over” effect − Well tolerated at all dose levels tested (up to 50 mg)

• Phase 3 confirmatory program initiated

− Assessing the efficacy of nemorexant during the night and the impact on patient’s functioning during the day − To assess the safety, including residual “hang-over” effect, withdrawal symptoms, and rebound − In adult and elderly insomnia patients treated with nemorexant at three dose levels, 10 mg, 25 and 50 mg, for up to 12 months − Comprehensive clinical pharmacology program conducted in parallel

Nemorexant

Nemorexant is investigational, in development and not approved or marketed in any country.

Insomnia Compound: Nemorexant Mechanism of action: Dual orexin receptor antagonism Status: Phase 3

“It really annoys me when people say ‘if you were really tired, you would sleep’. If only it were that simple! Unless you have suffered from true insomnia, you have absolutely no idea what it’s like.”

• Patient

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