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Phase 3 investigation of nemorexantfor patients with insomniaInvestor 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.

Phase 3 initiation in insomnia | June 20182

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Jean-Paul ClozelCEO


key priorities to ensure the company’s success over the next 5 years

Our StrategicPriorities 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


Phase 3 investigation of nemorexantfor patients with insomnia

Guy BraunsteinHead of Global Clinical Development


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


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


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 notreimbursed

• 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


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)

orexin

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


LHA = lateral hypothalamic area; PH = posterior hypothalamusLC = locus coeruleus; TMN = tuberomammillary nucleus; LDT = laterodorsaltegmental nucleus; VTA = ventral tegmental area; PPT = pedunculopontine nucleus

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

Dual orexin receptor antagonist


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 profileHigh in vitro potency

in vivo efficacy

Quick absorption and short half-lifefast onset of action, “appropriate” duration of action to actthroughout 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



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



0

200

400

600

800

1000

0 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 studies


Phase 2 studies



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 studies


Phase 2 studies



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 studies


Phase 2 studies



Purpose and objectives of the Phase 2 program

PurposeTo provide necessary information to adequately design the confirmatory trials

Focus in particular:• Dose definition

• Patient population characterization

• Endpoint definition

ObjectivesTo characterize the dose response on objective and subjective sleep parameters

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

Phase 3 studies


Phase 2 studies


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 patientsSelf-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

Phase 3 studies


Phase 2 studies


Efficacy results in adult patients

Modified Full Analysis SetLeast 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 studies


Phase 2 studies



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 SetLeast Square Mean ± 95% CL

Phase 3 studies


Phase 2 studies



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 studies


Phase 2 studies



Overview of adverse events in adultsPlacebo

N = 60

Nemorexant5 mg

N = 60

Nemorexant10 mg N = 58


Nemorexant50 mgN = 61

Zolpidem10 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 afterSafety Board adjudication*

- - 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



*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 elderlyPlacebo

N = 54

Nemorexant5 mg

N = 56



Nemorexant50 mgN = 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 after SafetyBoard adjudication

- - - - -

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 2 conclusion

Nemorexant

Efficacy• Dose response confirmed in adults and elderly subjects

on 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 studies


Phase 2 studies



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

Nemorexant

Efficacy1. Objective sleep parameters2. Subjective sleep parameters3. Daytime functioning assessed by a patient reported outcome instrument specifically

developed and validated by Idorsia according to FDA guidelines

Safety1. Adverse events, vital signs, biochemistry and hematology2. Next morning residual “hang-over” effect3. 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 studies


Phase 2 studies



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 studies


Phase 2 studies



Study design

Main studies 301 & 302

LD nemorexant

HD nemorexant

Placebo

V1 V3V2 V4 V5 V6 V7 EODBT, V8 V9 V10 V111st month 2nd month 3rd month EOT EOSRandomization

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

Run-in Placebo or Low (LD) or high dose (HD) nemorexantDouble-blind

Run-out

301: LD = 25 mg; HD = 50 mg302: LD 0 10 mg; HD = 25 mg

Extension study

V = Visit= polysomnography

nights

EODBT = End of double-blind treatmentEOT = End-of-Treatment EOS = End-of-Study

Phase 3 studies


Phase 2 studies



Study Design

Extension study 303

V1 V2 V3 V4 EOS, V7Week 13 Week 26 Week 44Randomization

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

Run out period Either Placebo, 10, 25 or 50mg nemorexantDouble-blind

Run out No treatmentNo blinding

EODBT, V5Week 40

EOT, V6Week 41Week 2

Run-out

10 mg nemorexant

25 mg nemorexant

50 mg nemorexant

10 mg nemorexant

25 mg nemorexant

50 mg nemorexant

Placebo

25 mg nemorexantPlacebo

Patients assigned to any nemorexant arms in the confirmatory studies will receive the same dosePatients 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 studies


Phase 2 studies



In summary:


• 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


InsomniaCompound: Nemorexant

Mechanism of action: Dual orexin receptor antagonismStatus: 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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