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

Dr Tom RothDivision of Sleep Medicine and Research Center, Henry Ford Health System, Detroit, USA

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.

• Daridorexant, a new dual orexin receptor antagonist optimized for onset and duration of 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):347-562. Zammit et al. Neurology 2020;94(21):e2222-32

• 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

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

o Daytime functioning was assessed using a newly developed and validatedpatient-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

• 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 allmentallytired

Verymentallytired

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)

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 nightsSingle PSG night

Extension study

V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11

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)

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

Patient PopulationPlacebo(N=310)

Daridorexant25 mg

(N=310)

Daridorexant50 mg

(N=310)Demographics

Female Sex – % 68 69 64Age – mean ±SD, years 55 ± 15 56 ± 15 56 ± 15

≥65 – % 39 39 39Race– %

Black or African American 9 6 10

Asian 0 1 1

US region - % 34 32 31

Baseline sleep characteristics, mean ±SDWASO – min 103 ± 41 98 ± 39 96 ± 38LPS – min 67 ± 40 67 ± 39 64 ± 37sTST – min 316 ± 53 310 ± 60 313 ± 58ISI 19 ± 4 19 ± 4 19 ± 4

Baseline daytime characteristics (IDSIQ) , mean ±SDIDSIQ sleepiness domain score (0-40) 22 ± 7 22 ± 7 23 ± 7IDSIQ alert/cognition domain score (0-60) 32 ± 10 32 ± 10 32 ± 11IDSIQ mood domain score (0-40) 19 ± 9 19 ± 9 20 ± 9IDSIQ total score (0-140) 74 ± 25 73 ± 25 75 ± 25

Improvement in WASO

Two-sided p-values are versus placebo and statistically significant under the control of type I errorMixed 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 meanAnalysis set: Full analysis set

PlaceboDaridorexant 25 mgDaridorexant 50 mg

Improvement in LPS

Two-sided p-values are versus placebo and statistically significant under the control of type I errorMixed 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 meanAnalysis set: Full analysis set

PlaceboDaridorexant 25 mgDaridorexant 50 mg

Improvement in sTST

Two-sided p-values are versus placebo and statistically significant under the control of type I errorMixed 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 meanAnalysis set: Full analysis set

PlaceboDaridorexant 25 mgDaridorexant 50 mg

Improvement in IDSIQ Sleepiness/Tiredness Domain Score

Two-sided p-values are versus placebo and for 50 mg (but not 25 mg), are statistically significant under the control of type I errorMixed 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; NS, non-significantAnalysis set: Full analysis set

PlaceboDaridorexant 25 mgDaridorexant 50 mg

IDSIQ total score, mood domain, and alert/cognition domainImprovement in Daytime Function

Alert/cognition domain Mood domainTotal IDSIQ score

Nominal two-sided p-values (versus placebo) are not under type 1 error rate control (not adjusted for multiplicity)Analysis set: Full analysis set

PlaceboDaridorexant 25 mgDaridorexant 50 mg

Adverse eventsOverall Safety

No. of patients (%)Placebo(N=309)

Daridorexant25 mg

(N=310)

Daridorexant50 mg

(N=308)Patients with ≥1 adverse event

105 (34.0) 117 (37.7) 116 (37.7)Patients with a given adverse event (≥2% in any group)

Nasopharyngitis 20 (6.5) 21 (6.8) 20 (6.5)Headache 12 (3.9) 16 (5.2) 19 (6.2)Accidental overdose 5 (1.6) 4 (1.3) 8 (2.6)Fatigue 2 (0.6) 7 (2.3) 7 (2.3)Dizziness 2 (0.6) 6 (1.9) 7 (2.3)Nausea 3 (1.0) 1 (0.3) 7 (2.3)Somnolence 6 (1.9) 11 (3.5) 5 (1.6)Fall 8 (2.6) 1 (0.3) 1 (0.3)

Adverse events of special interest (post-adjudication)Symptoms related to excessive daytime sleepiness 1 (0.3) 2 (0.6) 1 (0.3)Symptoms related to complex sleep behavior* 0 2 (0.6) 1 (0.3)Suicidal ideation/self-injury 0 0 0

*including hallucinations/sleep paralysisOne fatal SAE (cardiac arrest), not considered treatment-related by investigator (daridorexant 25 mg)Analysis set: Safety set

Mean values for VAS morning sleepiness were increased at months 1 and 3

No evidence of Residual Sleepiness in the Morning

VAS morning sleepiness (mm), mean ±SD

Placebo(N=280)

Daridorexant 25 mg

(N=286)

Daridorexant 50 mg

(N=286)Baseline

37 ± 19 37 ± 19 38 ± 19

Change from baseline to Month 1

5 ± 13 8 ± 14 10 ± 15

Change from baseline to Month 3

12 ± 18 16 ± 19 15 ± 19

Analysis set: Safety set

Mean values for WASO, LPS, and sTST at run-out were improved from baseline

No evidence of Rebound Insomnia after Termination

(minutes) mean ±SD

Placebo(N=280)

Daridorexant 25 mg

(N=286)

Daridorexant50 mg

(N=286)WASO

Change from BL to run-out (V9*) -20.4 ± 45.8 -8.6 ± 55.5 -2.5 ± 52.4

LPS

Change from BL to run-out (V9*) -27.8 ± 47.2 -17.2 ± 56.7 -15.0 ± 55.8

sTST

Change from BL to run-out† 42.3 ± 52.7 42.3 ± 53.8 42.9 ± 59.6

*First night immediately off treatment†mean value based on eDiary entries performed in the 7 days immediately after the PSG night at V9Analysis set: Treatment withdrawal set

No evidence of Withdrawal effects

BWSQ score, mean ±SD

Placebo(N=280)

Daridorexant 25 mg

(N=286)

Daridorexant50 mg

(N=286)Last assessment on DB treatment

1.9 ± 3.3 2.1 ± 3.2 2.0 ± 3.1

Change from last DB assessment to V9

-0.5 ± 1.8 -0.4 ± 1.7 -0.3 ± 1.7

Change from last DB assessment to V10

-0.7 ± 2.3 -0.6 ± 2.3 -0.6 ± 2.3

Analysis set: Treatment withdrawal set

• BWSQ scores (assessing potential withdrawal) were decreased in all treatment groups at each run-out assessment

• No AEs suggestive of withdrawal were observed

• Daridorexant improved daytime functioning at Month 1 and 3, as measured by reductions in IDSIQ total score and its constituent domains o Daridorexant 50 mg significantly improved sleepiness/tiredness domain scores using the

new validated IDSIQ PRO tool, indicating patients felt less sleepy and more energetic during the day

• Daridorexant 25 and 50 mg significantly improved sleep onset, sleep maintenance, and total sleep time at Month 1 and 3. Treatment effects were larger for daridorexant 50 mg

• Safety was comparable with daridorexant 25 mg and 50 mg, with no dose-limiting safety findings and no observed next-morning sleepiness, or signals suggestive of rebound insomnia or withdrawal effects

Summary

• The authors would like to thank:

• All study investigators (75 sites across 10 countries)

• IDMC members: A. Krystal, G.J. Lammers, K. Kim

• ISB members: Y. Dauvilliers, G. Plazzi, T. Scammel

• The participants, study staff, and nursing teams for their participation in this research

• The authors would also like to acknowledge Yosef Mansour (medical writing support) and

Nicolas Weber (technical support), who are employees of Idorsia Pharmaceuticals Ltd.

Acknowledgments