[PPT] - Efficacy and Safety of Daridorexant in Adult and Elderly Patients PowerPoint Presentation

SLIDE 1

Efficacy and Safety of Daridorexant in Adult and Elderly Patients with Insomnia

Dr Tom Roth

Division of Sleep Medicine and Research Center, Henry Ford Health System, Detroit, USA

SLIDE 2

Type of Potential Conflict Details of Potential Conflict Grant/Research Support n Consultant Eisai, Idorsia, jazz, Merck, Takeda, Philips, Novartis ,seq Speakers’ Bureaus Financial support Other



1. Consultancy agreement between the speaker and Idorsia Pharmaceuticals Ltd 2. 3.

SLIDE 3

Daridorexant, a new dual orexin receptor antagonist optimized for onset and duration
f action at optimally effective doses, dose-dependently (5–50 mg) improved night-

time efficacy, without residual effects, in adult and elderly patients with insomnia in phase 21,2

These pharmacological properties lead us to hypothesize that daridorexant could also

improve the impaired daytime functioning frequently observed in insomnia

We therefore developed and validated a new patient-reported outcome instrument to

specifically assess daytime functioning in patients with insomnia

Rationale

1. Dauvilliers et al. Ann Neurol. 2020;87(3):347-56 2. Zammit et al. Neurology 2020;94(21):e2222-32

SLIDE 4

This phase 3 trial was designed to measure the impact of daridorexant on objective

and subjective sleep parameters as well as on daytime functioning, and to evaluate safety, in patients with moderate to severe insomnia

Sleep variables were assessed using PSG (WASO, LPS) and a sleep diary

questionnaire (sTST)

Daytime functioning was assessed using a newly developed and validated

patient-reported outcome instrument, the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ)

Objective

LPS, latency to persistent sleep; PSG, polysomnography; sTST, subjective total sleep time; WASO, wake after sleep onset

SLIDE 5

Lower scores indicate improvements in

patient-perceived daytime functioning Patient-reported outcome instrument validated according to FDA guidance1

IDSIQ - Insomnia Daytime Symptoms and Impacts Questionnaire

NRS, numeric rating scale

Items are ranked on a NRS scale from 0-10

“Sleepiness/Tiredness” domain score (0-40) “Mood” domain score (0-40) “Alert/cognition” domain score (0-60)

Measures

1 Clear-Headed 2 Concentrate 3 Forgetful 4 Worried 5 Frustrated 6 Irritable 7 Stressed 8 Energetic 9 Effort 10 Refreshed 11 Mentally Tired 12 Physically Tired 13 Sleepy 14 Awake

11. How mentally tired did you feel today ?

Not at all mentally tired Very mentally tired

19:30

1.

FDA. 2009. Patient-Reported Outcome Measures: Use in Medical Product

Development to Support Labeling Claims. Available at: https://www.fda.gov/media/77832/download (Accessed: 06 July 2020)

SLIDE 6

Daily assessment of sleep and daytime functioning

Daridorexant 50 mg

V9

1st month 2nd month 3rd month EOT EOS

Randomization (1:1:1) Stratified by age (<65; ≥65 years)

EODBT

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

Nightly oral DB treatment with placebo or daridorexant 25 mg or 50 mg

SB placebo run-in (13-24 days) SB placebo run-out (7 days)

Daridorexant 25 mg Placebo

Phase 3, multi-center, double-blind, randomized, placebo-controlled, PSG study

Study Design

DB, double-blind; EODBT, end of double-blind treatment; M, month; SB, single-blind; V, visit

Two consecutive PSG nights Single PSG night

Extension study V1 V2 V3 V4 V5 V6 V7 V8 V9

V10 V11

SLIDE 7

Endpoints

AESI, adverse event of special interest; BWSQ; benzodiazepine withdrawal symptoms questionnaire; ISB, independent safety board; VAS, visual analog scale

Primary efficacy

WASO
LPS

Secondary efficacy

sTST
IDSIQ sleepiness domain

Other efficacy

IDSIQ alert/cognition domain score
IDSIQ mood domain score
Total IDSIQ score

Key safety

AEs
AESIs (Adjudicated by ISB),
Next-morning sleepiness (VAS)
Withdrawal (BWSQ)
Rebound insomnia

Type I error rate (5%) was controlled across the primary and secondary endpoints assessed at Month 1 and Month 3 for each active dose (25 and 50 mg) comparison vs placebo (16 comparisons)

SLIDE 8

Patient Disposition

3326 screened 2022 entered run-in 930 randomized  Adults (18-64 yr) and elderly (≥65 yr)  Insomnia disorder (DSM-5)  ISI score ≥15  No other sleep disorder

Key entry criteria

 History of sleep-related breathing disorder  History of suicidal ideation/attempt  Acute/unstable psychiatric conditions (inc.

depression)

 For ≥3 of 7 consecutive nights:  ≥30 min to fall asleep  Wake time during sleep ≥30 min  Total sleep time ≤6.5 h  Usual bedtime 21:30–00:30  Time in bed 6–9 h

Sleep diary criteria

 Mean LPS ≥20 min (neither night <15 min)  Mean WASO ≥30 min (neither night <20 min)  Mean TST < 7 h  PLMAI ≥15/h  AHI ≥15/h

PSG criteria (two consecutive nights)

853* completed DB treatment 847§ completed run-out

AE, n=20
Withdrawal by subject, n=25
Lack of efficacy, n=15

Discontinuation of DB treatment

Lost to follow-up, n=5
Other, n=8
Death, n=1

* One patient in placebo group and two patients in daridorexant 50 mg group were randomized in error and discontinued from study before receiving DB treatment

§ One patient did not start run-out treatment

AHI, Apnea/hypopnea index; PLMAI, Periodic limb movement disorder with arousal index

AE, n=1
Withdrawal by subject, n=3

Discontinuation of SB treatment

Other, n=1

SLIDE 9

Patient Population

Placebo (N=310) Daridorexant 25 mg (N=310) Daridorexant 50 mg (N=310) Demographics Female Sex – % 68 69 64 Age – mean ±SD, years 55 ± 15 56 ± 15 56 ± 15 ≥65 – % 39 39 39 Race– % Black or African American 9 6 10 Asian 1 1 US region - % 34 32 31 Baseline sleep characteristics, mean ±SD WASO – min 103 ± 41 98 ± 39 96 ± 38 LPS – min 67 ± 40 67 ± 39 64 ± 37 sTST – min 316 ± 53 310 ± 60 313 ± 58 ISI 19 ± 4 19 ± 4 19 ± 4 Baseline daytime characteristics (IDSIQ) , mean ±SD IDSIQ sleepiness domain score (0-40) 22 ± 7 22 ± 7 23 ± 7 IDSIQ alert/cognition domain score (0-60) 32 ± 10 32 ± 10 32 ± 11 IDSIQ mood domain score (0-40) 19 ± 9 19 ± 9 20 ± 9 IDSIQ total score (0-140) 74 ± 25 73 ± 25 75 ± 25

SLIDE 10

Improvement in WASO

Two-sided p-values are versus placebo and statistically significant under the control of type I error Mixed effects model for repeated measures adjusted for: baseline value, age group (< 65; ≥ 65 years), treatment, time point, interaction of treatment by visit, and baseline by visit. LSM, least squares mean Analysis set: Full analysis set