When Sleep Is Exhausting: Improving Diagnosis and Outcomes in Patients With Idiopathic Hypersomnia

Michael Thorpy, MD, Thomas Scammell, MD, and Caitlin Kindberg, discuss idiopathic hypersomnia in this CME activity titled "When Sleep Is Exhausting: Improving Diagnosis and Outcomes in Patients With Idiopathic Hypersomnia." For the full presentation, please visit us at www.peervoice.com/DRF870.

1. PeerVoice

When Sleep Is Exhausting: Improving Diagnosis and Outcomes in Patients
With Idiopathic Hypersomnia

Learning Objectives
Recognize health risks associated with idiopathic hypersomnia

Differentiate idiopathic hypersomnia from other conditions that
cause excessive daytime sleepiness (EDS)

Explain how to establish a confirmatory diagnosis of idiopathic
hypersomnia

Propose effective, individualized, evidence-based management
strategies for patients with idiopathic hypersomnia

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2. PeerVoice

Part 1 of 4: The Health Impact of Idiopathic Hypersomni
What Are We Learning?

Michael Thorpy, MD

Professor of Neurology

Albert Einstein College of Medicine
New York, New York

Thomas Scammell, MD

Professor of Neurology

Harvard Medical School

Sleep Medicine Division Head

Beth Israel Deaconess Medical Center
Boston, Massachusetts

Caitlin Kindberg
Patient Advocate
Nashville, Tennessee

Copyright © 2010-2024, PeerVoice

3. PeerVoice
Disclosures

Michael Thorpy, MD, has a financial interest/relationship or affiliation in the form of:
Advisory Board for Alkermes PLC; Avadel Pharmaceuticals; Axsome Therapeutics;
Centessa Pharmaceuticals; Eisai Co., Ltd.; Harmony Biosciences, LLC; Idorsia
Pharmaceuticals Ltd; Jazz Pharmaceuticals Inc; NLS Pharma AG; Suven Life Sciences Ltd.;
Takeda Pharmaceutical Company Limited; XWPharma Ltd.; and Zevra Therapeutics.

Thomas Scammell, MD, has a financial interest/relationship or affiliation in the form of:
| Consultant for Avadel Pharmaceuticals; Jazz Pharmaceuticals Inc; Paladin Labs Inc.; and

BB Takeda Pharmaceutical Company Limited.
Grant/Research Support from Harmony Biosciences, LLC; Jazz Pharmaceuticals Inc; and

Takeda Pharmaceutical Company Limited.

Caitlin Kindberg has no financial interests/relationships or affiliations in relation to this
| activity.

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4. PeerVoice

Early Impacts of Sleepiness

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5. PeerVoice

Academic, Social, and Professional Impacts of Sleepiness

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6. PeerVoice

Sleep Study and Diagnosis

the night-time

Naps spread throughout

Total sleep =
time (in min.)

Sleep efficiency 96.3% Time in bed 20:04
Sleep latency 8.0 Total sleep time 15:20
(in min.)

REM periods 6 Sleep onset 03:20
REM lat

(in in) 127.5 REM onset o

MSLT: Multiple Sleep Latency Test; REM: rapid eye movement.

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7. PeerVoice

Hopes vs Reality of Treatment

IH idiopathic hypersomnia.

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EL BETTER

CAREER
GOALS

NAPs.
NO ONE

GETS IT

SUPPORT
GROUP

Hopes Reality

1 will feel rested

Lam still sleepy

| will figure out what caused my IH

| am obsessively researching sleep

I will be able to access my
medications

| am battling my insurance to
approve medications

I will be able to afford my
medications and visits

| am spending so much money on
healthcare

| will find a medication that has
minimal side effects

I am still looking for a medication
that works for me

| will have the energy to work

lam exhausted at work

Iwill be able to start enjoying my
hobbies again

I am feeling like my hobbies are
a chore

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8. PeerVoice

Treat the

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Epidemiology of Idiopathic Hypersomnia

+ Rare disease, with unknown prevalence

+ Estimates suggest a prevalence of 15 per 100,000 population
+ Onset of symptoms is typically between 10-30 years old

+ Diagnosis is typically delayed until age 28-35 years

* Familial cases?

+ A higher prevalence in females

+ Spontaneous remissions reported in some patients

Trotti LM et al. Neurotherapeutics. 202118:20-31.

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10. PeerVoice

IH: A Distinct Neurologic Sleep Disorder

IH is a chronic, debilitating neurologic sleep disorder characterized by nonrestorative
sleep despite normal or longer than normal periods of sleep

Bedrich Roth deseribes IM with 2 forms:
Polysymptomatic

Dom pogo ES abating ape eos is

en srr ston iy

en Elm osa A

dde EDS ond Monosymptometic pere en

OREM symptoms) + EDS only Soest a again
es

1990 2014
Bedrich Roth al describe NS idlopattic Bassetti and Aldrich identity Iaioparhic ‘Ongoing debate.
inroduced"Sieep | hypersomnia with sleep hypersormnio ‘3 clinical types of I hypersomnia tolump, split or
drunkenness” ‘drunkenness: 1.Classie: with ond without ‘combine with
+ Dificuity coming to + Slospiness thot is not overwhelming tong sleep time narcolepsy
‘complete wakefuness. + Longnon-refroshing naps up to several hours duration classieation
+ Confusion + Prolonged nocturnal sleep
+ Disorientation + Difficulty in awakening in the morning
+ Poor motor coordination 2.Nareolopsy-like:
+ Slowness + Overwhelming hypersomnolence
+ Deep and prolonged sleep + Short refreshing nops
+ Awake without diffeuties
3. Mixed:

+ Cinical features of both groups
CNS: central nervous system: EDS: excessive daytime sleepiness.
Lammers GJ et al. Sleep Med Rev. 2020/52101308,

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Prevalence of NT1, NT2, and IH in 2017

Prevalence of Central Disorders of Hypersomnolence (CDH) by Age Group

60 ma NTI 97
mm NT2 38.8
mi 13.9

20

Cases Per 100,000 People

0-4 5-9 10-14 15-17 18-34 35-44 45-54 56-64
Age, Years

NTE: narcolepsy type Y NT2: narcolepsy type 2.
Anon-interventional, cross-sectional study using data from the IBM MarketScan Commercial Claims and Encounters Database.

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Symptom Burden in IH

Excessive
daytime
sleepiness
irrepressible need
to sleep or
daytime lapses
into sleep

Sleep ine
Difficulty waking with
returns to sleep,
irritability, and confusion

Schneider LD et al. Nat Sc Sleep. 202315:89-101

Saad R et al. Sleep Epidem. 2023:3100058.
Morse AM, Naik S. CNS Drugs. 2023:37:305-322.

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Long, unrefreshing

naps
Unrefreshing naps
lasting >1 hour

: Prolonged
night-time sleep
Main sleep period of
210 hours, often
unrefreshing in nature

Cognitive impairment
Including memory problems
and attention deficit; also
termed “brain fog”

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13. PeerVoice

(ICSD

gnostic Crite R 2023)

+ Daily periods of irrepressible need to sleep or daytime lapses into sleep occurring
for at least 3 months
+ Absence of cataplexy
* PSG and MSLT findings are not consistent with a diagnosis of NTI or NT2
+ Presence of at least one of the following:
— MSLT shows a mean sleep latency of <8 minutes
— Total 24-hour sleep time is 2660 minutes (typically 12-14 hours on 24-hour
polysomnographic monitoring, performed after correction of chronic sleep
deprivation, or by wrist actigraphy in association with a sleep log averaged over
at least 7 days with unrestricted sleep)
» Sleepiness after an adequate trial of increased nocturnal time in bed, preferably
confirmed by at least a week of actigraphy
+ Hypersomnia and MSLT findings are not better explained by another sleep
disorder or use of drugs/medications

ICSD: International Classification of Sleep Disorders; PSG: polysomnography.
American Academy of Sleep Medicine; 2023. International Classification of Sleep Disorders, third edition, text revision (ICSD-3-
TR) ISBN 978-0-9657220-9-4,

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14. PeerVoice

IH: It's More Than Just Sleepiness

MEMORY

Poor recall
Losing things

ATTENTION LEARNING

/ Difficulty processing
concentrating information

Easily distracted Difficulty learning
Automatic behavior new things

‘Adapted from Hypersomnolence Australia. https://www.hypersomnolenceaustralia.org aulsingle-post/idiopathic-hypersomnia
causes-more-than-just-sleepiness. Accessed 22 April 2024.

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Social Impact of IH

Quote from survey
participant:
# don't know if my IH is a
cause of my depression
or if IH is a side effect of

my depression. One
+ Online survey of 106 adults with IH (mean age, 26; seems to feed into the

range, 18-39 years) other quite often.”

+ About 2/3 reported concomitant depression and
2/3 had anxiety

+ 98% reported that IH made their social lives harder

Davidson, Blattner, Scammell, Zhou; unpublished.

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16. PeerVoice

Social Impact of IH (Cont'd)

Quot

Main contributors: Sleepiness (83%), long sleep
(75%), brain fog (75%)

56% felt they had too few friends, and 57% felt
isolated from others

69% now in a romantic relationship; of those,
39% cohabitating, 36% married

89% said IH impacted their sex lives, with sleep
inertia the most common factor (89%)
Davidson, Blatner, Scammell Zhou; unpublished.

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17. PeerVoice

Impairment in Functioning and QoL in Patients With IH: The Real

World Idiopathic Hypersomnia Outcomes Study (ARISE)

US-based virtual cross- All Participants Participants
sectional survey Participants WithLST Without LST
comprising multiple (N= 75) (n= 37) (n = 38)

patient-reported outcome À, 7
measures: 2 en] 34.1(107) | 33.7(10.7) | 34.4 (10.9)
1. FOSQ-10 mesa
2. Neuro-QoL Female, n(%) | 61(813) | 27(730) | 34(895)
3. BC-CCI Patient-reported sleep duration, mean (SD)
4. PHQ-9 ;
5. WPAISHP Approximate:
hours of sleep
ina typical 116 (3.4) | 143 (27) 8.9 (11)
24-hour
period

BO-CCI British Columbia Cognitive Complaints Inventory; FOSQ-10: Functional Outcomes of Sleep Questionnaire, short version: LST: long sleep time:
Neuro-QoL: Quality of Life in Neurological Disorders Social Roles and Stigma domains; PHQ-9: Patient Health Questionnaire; SD: standard deviation;
\WPAISHP: Work Productivity and Activity Impairment Questionnaire: Specific Health Problem.

Stevens J et al Nat Sci Sleep. 2023:15:593-606.

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ARISE Study: Functional Outcomes of Sleep Questionnaire

FOSQ-10 Assesses Impact of Sleep Disorder on Daily Activities

8)
¿A Previously reported
A 2 normal control value:
a 8 178 (SD = 31)
Ho
SE
©
+
He
AT
A ©
HA
4 ©
= ©
All Participants Participants
participants with LST without LST

Participants showed impairment in daily functioning
Stevens J et al Nat Sci Sleep. 202315:593-606,

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ARISE Study: Quality of Life in Neurological Disorders

(Neuro-QoL) Stigma Domains

n= 38

Mean (SD) = 55.2 (49)

ian (Q1 03) = 558 (528, 57.8)
19, 66

M

Worse Scores

Clinical population
~-= reference T-score:

Neuro-Qol Stigma T-Score

HT „ 497 (60 :95)
E 40
35 y -
All Participants Participants
participants with LST without LST

Participants had high perception of negativity, prejudice, and discrimination
Stevens J et al Nat Sci Sleep. 202315:593-606,

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ARISE Study: British Columbia Cognitive Complaints Inventory

(BC-CCI) and Patient Health Questionnaire (PHQ-9)

BC-CCI total score

Mean (SD) 10.8 (4.8) 116 (4.9) 10.1(46)
BC-CCI score categories, n (%)

Moderate cognitive complaints (9-14) 27 (36.0) 12 (32.4) 15 (39.5)

Severe cognitive complaints (15-18) 20 (267) 13 (85.1) 784)
PHQ-9 total score

Mean (SD) 123 (6.4) 141 (52) 106 (51)
PHQ-9 score categories (severity of depressive symptoms), n (%)

Moderate (10-14) 24 (32.0) 11297) 13 (34.2)

Moderately severe (15-19) 19 (25.3) 13 (35.1) 6 (15.8)

Severe (20-27) 7(9.3) 5 (13.5) 2(5.3)

Stevens J et al Nat Sci Sleep. 2023:15:593-606.

Participants
reported
moderate to
severe cognitive
complaints and
depressive
symptoms

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21. PeerVoice

ARISE: Work Productivity and Activity Impairment
Questionnaire Specific Health Problem (WPAI:SHP)

Better Scores
WPAI:SHP Score, % Impairment

Absenteeism Presenteeism Absenteeism+ Overall
Presenteeism Activity

Stevens J et al Nat Sci Sleep. 2023:15:593-808.

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Part 2 of 4: The Challenges of Symptom Overlap:
Differentiating Idiopathic Hypersomnia From Narcolepsy

Michael Thorpy, MD

Professor of Neurology

Albert Einstein College of Medicine
New York, New York

Thomas Scammell, MD

Professor of Neurology

Harvard Medical School

Sleep Medicine Division Head

Beth Israel Deaconess Medical Center
Boston, Massachusetts

Caitlin Kindberg
Patient Advocate
Nashville, Tennessee

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23. PeerVoice
Disclosures

Michael Thorpy, MD, has a financial interest/relationship or affiliation in the form of:
Advisory Board for Alkermes PLC; Avadel Pharmaceuticals; Axsome Therapeutics;
Centessa Pharmaceuticals; Eisai Co., Ltd.; Harmony Biosciences, LLC; Idorsia
Pharmaceuticals Ltd; Jazz Pharmaceuticals Inc; NLS Pharma AG; Suven Life Sciences Ltd.;
Takeda Pharmaceutical Company Limited; XWPharma Ltd.; and Zevra Therapeutics.

Thomas Scammell, MD, has a financial interest/relationship or affiliation in the form of:
| Consultant for Avadel Pharmaceuticals; Jazz Pharmaceuticals Inc; Paladin Labs Inc.; and

BB Takeda Pharmaceutical Company Limited.
Grant/Research Support from Harmony Biosciences, LLC; Jazz Pharmaceuticals Inc; and

Takeda Pharmaceutical Company Limited.

Caitlin Kindberg has no financial interests/relationships or affiliations in relation to this
| activity.

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Patient Case: Amanda, a 28-Year-Old Wom:

Presentation and Chief Complaint

* Presents with complaints of being “tired all the time” and states that she sleeps
>1 hours per day

* Chief complaint: “| haven't been performing well at work because | have low energy
levels. My thinking is unclear, and | have decreased focus at work. Daytime naps are

not refreshing. Sometime, | feel depressed because my colleagues and friends don't
understand what I'm going through.”

Medical History and Medications

Physical Examination

+ No history of sleep disorders or significant
medical conditions

+ Hypothyroidism

* Medications: Antihistamines for seasonal

allergies

+ BMI: 26 kg/m?
+ BP: 119/79 mmHg

* No signs of obstructive sleep apnea or
other sleep-related breathing disorders

‘BME body mass index; BP: blood pressure.

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Two Types of Narcolepsy: NT1 and NT2

Narcolepsy type 1 (NTI; narcolepsy with cataplexy)

+ Sleepiness
At least one of the following:

— Low orexin-A level in spinal fluid

— Cataplexy and a positive Multiple Sleep Latency Test (MSLT)® or SOREM on PSG

muy Narcolepsy type 2 (NT2; narcolepsy without cataplexy)

* Sleepiness
+ Positive MSLT

a Positive MSLT: Mean sleep latency of <8 minutes and 22 sleep-onset REM periods.

REM sleep latency <15 minutes on the preceding nocturnal sleep study may be included in the tally.

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Idiopathic Hypersomnia Features

imam | ypes of sleepiness in IH | |

Background sleepiness: Persistent drowsiness throughout the day
Excessive daytime sleepiness (97.7%°)

MSLT shows average sleep latency <8 min. and <2 SOREMs
Or, 24-hour sleep time 211 hours

fue Subjective sleepiness (symptom description by patients) |

Having trouble waking up and functioning with normal alertness (78.8%)
Difficulty remembering things (71.8%)

SOREM sleep onset rapid eye movement
Trotti LM et al. Sleep Med. 2020.75:343-349,

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Clinical Features of Narcolepsies and Idiopathic Hypersomnia

NTI NT2 IH

<2 SOREMs on
PSG/MSLT

No cataplexy

Normal CSF
Sleep inertia
CSF <110 pg/ml. Unrefreshing naps

May have long

Cataplexy
sleep (11/24 hours)

Circadian
dysrhythmia

More Common in NTI More Common in IH

ESS: Epworth Sleepiness Scale.
Khan Z Trotti LM. Chest. 2015:148:262-273,

Peervoice

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Some Objective Differences Between Hypersomnias

NTI 50-65% 26+16 63% 85-95%

NT2 30-50% 40 +21 60% 40-50%

IH 70-80% 54+18 1% 12-25%
insufficient sleep) 50-60% 76 +39 7% 12-25%

HLA: human leukocyte antigen: SOREMP: sleep-onset rapid eye movement periods.
Baumann CR et al. Sleep. 2014;37:1035-1042.

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How Can Sleepiness Be Measured?

Subjective measures of sleepiness

+ Epworth Sleepiness Scale
+ _ Karolinska Sleepiness Scale

Objective measures of sleepiness

+ Multiple Sleep Latency Test (measures ability to fall asleep)
Maintenance of Wakefulness Test (measures ability to stay awake)

24-Hour Polysomnography (PSG)

Sleep timing and duration

- Actigraphy
+ Sleep diary

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Idiopathic Hypersomnia Severity Scale (IHSS)

Designed to measure severity of IH symptoms (at time of diagnosis and
across treatments)

14 questions relevant to IH:

— Ideal duration of night-time sleep

—Sleep inertia (how hard it is to wake up and function properly)
—Long naps and whether naps are restful

— Impact of IH on driving and other daily tasks

Scoring:

—<22 = normal

— 22-30 in treated IH patients
—>31 in untreated IH patients

Dauviliers Y et al. Neurology. 2019;92:01754-e1762

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Epworth Sleepiness Scale

How likely are you to nod off or fall asleep in the following situations?
O = Would never nod off; 1 = Slight chance of nodding off;
2 = Moderate chance of nodding off; 3 = High chance of nodding off

1 Sitting and reading Sat

U Watching TV 2

1 Sitting, inactive, in a public place (eg, in a meeting, theater, 0-10 = Normal range in
or dinner event) healthy adults

U As a passenger in a car for an hour or more without
stopping for a break 11-14 = Mild sleepiness

U Lying down to rest when circumstances permit 15-17 = Moderate

U Sitting and talking to someone sleepiness

1 Sitting quietly after a meal without alcohol :

U Ina car, while stopped for a few minutes in traffic or at a light | SE CONTES

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MSLT demonstrates poor test-retest reliability;
MSL on the MSLT is often >8 minutes

MSLT is a more reproducible and stable feature in NTI vs NT2 or IH

Trotti LM et al. J Clin Sleep Med. 2013:9.8:789-795,
Lopez R et a. Sleep. 2017.40(12). dot10.1083/steep/zsx164
Ruoff C et al J Clin Sleep Med. 2018:14165-74

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Caitlin’s Sleep Diary

Time you Time it took
went to you to fall
bed asleep

Time you
got up for
the day

Tuesday 2/20 5:41 AM | 7h54m 25 25 None

| Wednesday 2/21 5:51 AM 8h 42m o 75 3:14 PM 24m
[Thursday 2/22 5:30 AM | 8h19m 50 50 None
Friday 2/23 5:32 AM 7h 40m 25 50 None
Saturday 2/24 6:10 AM 8h l4m 75 25

Monday 2/26 5:52AM | 7h24m 25 75 None
¡Tuesday 2/27 5:40 AM 8h 39m 25 25 None
[Wednesday 2/28 7:30 AM 8h 50m o 25 | 2:44 PM 59m
[Thursday 2/29 7:00 AM 8h 12m 25 50 None
Friday 3/1 6:53 AM 7h 59m 25 50 None
Saturday 3/2 4:41AM | 7h37m 25 25 None
Sunday 3/3 8:59 AM Th 46m 75 75 None
Monday 3/4 8:34 AM 8h 39m 50 50 None

#of Amount of
awakenings time awake

Day & Date
2024

Total
sleep time!

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Other Causes of Chronic Sleepiness

Insufficient sleep
Psychiatric disorders: Depression, anxiety, schizophrenia

Disorders that disrupt sleep: Obstructive sleep apnea, periodic limb
movements of sleep, pain, etc.

Circadian rhythm disorders (trying to wake up when your body clock says
you should still be sleeping)

Sedating medications: Benzodiazepines, antipsychotics, epilepsy medications

Neurological disorders: Parkinson’s, Alzheimer's, multiple sclerosis, traumatic
brain injury, Prader Willi syndrome, etc.

Medical disorders: Hypothyroidism, adrenal insufficiency, kidney or liver
failure, obesity

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Part 3 of 4: Treating Patients With Idiopathic Hypersomnia:
Balancing Patient Care and Life-Long Health Considerations

Michael Thorpy, MD

Professor of Neurology

Albert Einstein College of Medicine
New York, New York

Thomas Scammell, MD

Professor of Neurology

Harvard Medical School

Sleep Medicine Division Head

Beth Israel Deaconess Medical Center
Boston, Massachusetts

Caitlin Kindberg
Patient Advocate
Nashville, Tennessee

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36. PeerVoice
Disclosures

Michael Thorpy, MD, has a financial interest/relationship or affiliation in the form of:
Advisory Board for Alkermes PLC; Avadel Pharmaceuticals; Axsome Therapeutics;
Centessa Pharmaceuticals; Eisai Co., Ltd.; Harmony Biosciences, LLC; Idorsia
Pharmaceuticals Ltd; Jazz Pharmaceuticals Inc; NLS Pharma AG; Suven Life Sciences Ltd.;
Takeda Pharmaceutical Company Limited; XWPharma Ltd.; and Zevra Therapeutics.

Thomas Scammell, MD, has a financial interest/relationship or affiliation in the form of:
| Consultant for Avadel Pharmaceuticals; Jazz Pharmaceuticals Inc; Paladin Labs Inc.; and

BB Takeda Pharmaceutical Company Limited.
Grant/Research Support from Harmony Biosciences, LLC; Jazz Pharmaceuticals Inc; and

Takeda Pharmaceutical Company Limited.

Caitlin Kindberg has no financial interests/relationships or affiliations in relation to this
| activity.

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Back to Amanda

Presentation and Current Medications

* 28-year-old woman

+ Presents with complaints of being “tired all the time,” despite >11 hours of sleep per day
+ Antihistamines for seasonal allergies

Physical Examination

+ BMI: 26 kg/m?
* BP: 119/79 mmHg

* No signs of obstructive
sleep apnea or other sleep-
related breathing disorders

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24-Hour Sleep Study/PSG Results and Diagnosis

MSLT: One sleep-onset REM period
Sleep latency: 6 minutes

Total sleep time: 710 minutes (11 hrs 50 minutes)

Extended polysomnography (PSG) study: Total sleep time
of 12.25 hours (24-hour study)

Idiopathic hypersomnia diagnosed

Wants to begin treatment

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38. PeerVoice

Medication Approaches

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Patient-centric approach
— Every patient has unique needs, and these recommendations aren't one-size-fits-all

Physical health
— Nutrient-dense foods and smaller meals
— Low intensity exercise for shorter time frame (eg, yoga or walk for 30 mins)

Mental health

— Cognitive behavioral therapy

— Meditation and journaling

Social support groups through Hypersomnia Foundation, Wake Up Narcolepsy, Project
Sleep, Narcolepsy Network, Facebook groups

Careers that promote wakefulness (standing or walking around, working with others,
minimal computer work)

Consistent bed and wake time; minimal or timed naps

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Pharmacological Trials in Idiopathic Hypersomnia

Treatment Patient Population Conclusion
Modafinil! IH without LST (n = 31) TEEN i cipecbindkCn
on CG: 1.0 point
' 65% responders; improvement
2 E =
Sodium oxybate? | Treatment-refractory IH (n = 46) On ERS ES Eons Phase 3
5 > = 35% responders; improvement ;

Pitolisant® Treatment-refractory IH (n = 65) on ESS: 15 points Retrospective

Mazindol® Treatment-refractory IH (n = 37) Improvement on ESS: 48 points | Retrospective

Flumazenils Refractory hypersomnolence (n = 153) | 62.8% responders Retrospective
Primary hypersomnia (n = 41), 64% improvement in daytime | etrospectives
narcolepsy without cataplexy (n = 12) | sleepiness

Clarithromycin? ara)
IH (n= 10); NT2 (n = 4); subjective ern E
a) Improvement on ESS: 3.9 points | Phase 2

RCT: randomized controlled trial.
Schinkelshoek MS et al. Curr Sleep Medicine Rep. 2019:5:207-214. 1 Mayer et al J Sleep Res. 2016, 2. Dauviliers et al Lancet Neurol. 2022.

3. Leu-Semenescu et al. Sleep Med. 2014, 4 Nittur et a. Sleep Med. 2018. 5. Trott et al J Clin Sleep Med. 2016. 6, Trott et al. J Psychopharmacol. 2014,
7.Trottiet al. Ann Neurol. 2015,

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40. PeerVoice
Modafinil Study Data

+ 31patients with IH (without long sleep time)
+ Improvement on Epworth Sleep Scale (ESS),

V2 (Baseline) V5 (End of

Treatment)

ical Global Impression of Severity (CGI)

diff)

Delta

P(diff) T Valu

Effect

Placebo] 14.00 (13.55, 15.45) | 13.00 (1015, 15.14) 23918 | .6376
Modafinil 15.00 (12.57,16:3) | 800 (6.42, 1.58)
MWT
Placebo] 13.51(8.85,18.89) | 132(9.42 2133) | 019 (-2.94, 5.96) NS 1104
Modafinil (n = 15)| 12.50 (8.70, 18.47) | 15.00 (10.88, 26.01) | 3.00 (0.11, 9.61)
cal
Placebo] 6.00 (5.45, 6.12) 5.50 (4.94, 5.92) -23247| 612
Modafinil (n= 16)| 6.00 (5.46, 6.16) 5.00 (3.64, 5.24)
Modafinil is not approved for the treatment of IH in adults.

MW: Maintenance of Wakefulness Test.
Mayer G et al J Sleep Res. 2015:2474-81.

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41. PeerVoice

Pitolisant in Drug-Resistant Idiopathic and Symptomatic

Hypersomnia

+ 65 treatment refractory IH patients:

— 49LST
— 16 w/o LST
+ Responders: ESS fall of 23
Patients IH ng Sleep Time W/O Long Sleep Time P
Maximum daily dosage 40 mg (30-40) 40 mg (25-40) 99
Time on drug (months) 4 (2-14) 7 (2-12.5) 85
ESS at baseline 17 (14-18) 17 (16-20.5) 23
ESS with pitolisant 14 (12-17) 16 (13-17) 34
Responders (%) 37 31 .69

Pitolisant is not approved for the treatment of IH in adults.

W/O: without
Leu-Semenescu $ et al. Sleep Med. 2014:15:681-687.

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42. PeerVoice

Pitolisant in Adult Patients With IH: Phase 3 INTUNE Study to

Assess Safety and Efficacy

+ INTUNE was a phase 3 randomized, placebo-controlled, double-blind
withdrawal study

+ 213 patients were enrolled and dosed in the study, of which 139 were randomized

+ Topline results showed no statistically significant difference between the
therapy and placebo in the primary endpoint of improving excessive daytime
sleepiness (EDS)

« Positive trends favoring pitolisant were observed in other prespecified
endpoints including Idiopathic Hypersomnia Severity Scale (IHSS) and Sleep
Inertia Questionnaire (SIQ)

+ Safety and tolerability profile in adult patients with IH was consistent with
established safety profile of pitolisant

National Institutes of Health (NH). clinicaltrials gov. NCTOS1S6047.

Harmony Biosciences. https// www harmonybiosciences.com/newsroom/harmony -biosciences-announces-topline-data-from-phase-3-intune-
study/. Accessed 23 April 2024,

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43. PeerVoice

Low-Sodium Oxybate in People With IH: Long-Term Efficacy

and Safety

+ Phase 3 study design: 106 participants, mostly female (71%); mean (SD) age was

41.0 (13.8) years
Study Timeline
Treatment at study entry
HR A Low-sodium]
* High-sodium oxybate 5 oxybate
= Stable-| S A
(5x0). 2 Open-labell |"gose | || (xB) Open-labell | Safety
* SXB + alerting agent,n= 4 I] titration | period he Ly extension [4 follow-up
+ Alerting agent only, n = 82 (OLT) any 3 (OLE) period
- Treatment naive, n = 66 Go-1aweeks) (weeks) © | Placebo 7 (24 weeks) (2 weeks)
Screening period
(530 days) Double-blind randomized
withdrawal period (DBRWP)
(2 weeks)

Low-sodium oxybate is approved for the treatment of IH in adults.

DBRWP: double-blind randomized withdrawal period: LXB: low-sodium oxybate; OLE: open-label extension; OLT: open-label titration and optimization
Period; SDP: stable-dose period: SXB: high-sodium oxybate,

Morse AM et al. Clin Sleep Med. 2023/19:811-1822.

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44. PeerVoice

Low-Sodium Oxybate: Epworth Sleepiness Scale (ESS)

—- Total miTT
2 wm DB LXB

8 -11- DB Placebo
Y
a
a
a
2
=
S
2
2

BL OLT OUT OLT End End End OLE OLE OLE End

wi wa W8 OLT SOP DBRWP W2 we wia OLE

ESS scores decreased (improved) during the open-label extension (OLE) (mean [SD], study
baseline: 16.3 [2.8]; OLE week 2: 6.7 [4.7]; OLE end: 5.3 [3.7])

DB: double-blind: miTT: modified intent-to-treat; W: week
Morse AM et a. J Clin Sleep Med. 2023;1%181-1822.

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45. PeerVoice

Low-Sodium Oxybate: Idiopathic Hypersomnia Symptom

Severity (IHSS)

5 e —- Total miTT
a 1-08 LXB
3° -#- DB Placebo
ö

E

a

8

E

a

2

E

5

8

=

BL OLT ‘OLT OLT End End End OLE OLE OLE End
wi wa W8 OLT SDP DBRWP W2 we wia OLE

IHSS total scores trended toward a decrease
(study baseline: 32.6 [7.3]; OLE week 2: 16.2 [8.9]; OLE end: 14.8 [8.6]).

Morse AM et al. Clin Sleep Med.2023/19:81-1822.

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46. PeerVoice

Low-Sodium Oxybate in People With IH: Safety

TEAE, n (%)

Participants with 21 TEAE 123 (80)

Preferred term in 25% of total participants
Nausea 34 (22)
Headache 27 (18)
Dizziness 19 (12)
Anxiety 7m
Vomiting 7m)

TEAE: treatment-emergent adverse event.
Dauviliers Y et al. Lancet Neurol. 2022:2153-65,

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47. PeerVoice

Treatment Opti

+ Lower-sodium oxybate (LXB) is the first and only drug approved for the treatment
of IH in adults
Prior treatment approaches for EDS in IH similar to narcolepsy

AASM 2021 guideline updates recommend the following for IH in adults:
Modafinil (strong)
Clarithromycin (conditional)
Methylphenidate (conditional)

+ Pitolisant (conditional)

* Sodium oxybate (conditional)

Lower-sodium oxybate (LXB) was not available at time guidelines were published

AASM: American Academy of Sleep Medicine.
Maski K et al J Clin Sleep Med. 202117:1881-1893.

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48. PeerVoice

Medications Under Development for IH

Phase

Mechanism of Action of Development

Clarithromycin GABA-A antagonist 2
= Blocks reuptake of dopamine,
Serdexmethyiphanidate norepinephrine, serotonin 2

Se Histamine H3 receptor inverse
Pitolisant agonist 3
Once-nightly oxybate GABA-B agonist 3
ALKS-2680 Orexin receptor 2 agonist 2
TAK-360 Orexin receptor 2 agonist 2?

National institutes of Health (NIH). clincaltrials gov. NCTON46600; NCTOS668754; NCTOS458128; NCTOSI56047; NCTO6358950,
‘Neurology Live. https://www:neurologylive.com/view/alkermes-initiates-phase-2-vibrance-1-tril-narcolepsy-agent-alks-2680.

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49. PeerVoice

Danavorexton Improves Sleepiness in People With IH

E m Danavorexton 112 mg M Placebo
4 39.9

ci à +

LS Mean Sleep Latency
on MWT, Minutes

5 10.5
me E

2 8

4 6
Hours Post Infusion Overall

+ Results from Phase lb study of danavorexton, an IV orexin receptor 2 agonist in 12 people with IH
+ Side effects: frequent urination, dizziness, runny nose

IV: intravenous.
Mignot E et al. Sleep. 2023:46:2504049.

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50. PeerVoice

An Individualized Patient-Centric Approach to Care in the

Management of IH

What are the key considerations when developing a treatment plan for
patients with IH? What strategies can help improve treatment success?

Long sleep episodes: Assess if the patient experiences prolonged sleep episodes
at night and/or sleep inertia.

Daytime sleepiness: Evaluate the presence and severity of daytime sleepiness.
Impact on functioning: Understand how IH affects the patient's daily life and functioning.

Current medications: Take into account any medications the patient is currently taking.

ao»

Previous treatment experience: Consider the patient's history with medications
for sleepiness.

6. Long-term consequences of treatment: Consider the long-term consequences of
treatment, especially when the patient has comorbidities.

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51. PeerVoice

Summary

EA Each person is unique, and their treatment should be tailored to their symptoms

Medications and other treatments should target not just the obvious symptoms
(eg, sleepiness) but also broader issues that impact daily life

Healthcare providers may not be aware of the broader impacts of IH, so feel free
to bring up all issues

when making treatment decisions for patients with IH

Engage patients and consider their individual perspectives in shared decision-

Incorporate the latest clinical trial data from recently FDA-approved therapies |
making discussions to enhance treatment outcomes and patient satisfaction |

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52. PeerVoice

Part 4 of 4: Key Learnings for Clini ‘ice: What Will You Do?

Michael Thorpy, MD

Professor of Neurology

Albert Einstein College of Medicine
New York, New York

Thomas Scammell, MD

Professor of Neurology

Harvard Medical School

Sleep Medicine Division Head

Beth Israel Deaconess Medical Center
Boston, Massachusetts

Caitlin Kindberg
Patient Advocate
Nashville, Tennessee

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53. PeerVoice
Disclosures

Michael Thorpy, MD, has a financial interest/relationship or affiliation in the form of:
Advisory Board for Alkermes PLC; Avadel Pharmaceuticals; Axsome Therapeutics;
Centessa Pharmaceuticals; Eisai Co., Ltd.; Harmony Biosciences, LLC; Idorsia
Pharmaceuticals Ltd; Jazz Pharmaceuticals Inc; NLS Pharma AG; Suven Life Sciences Ltd.;
Takeda Pharmaceutical Company Limited; XWPharma Ltd.; and Zevra Therapeutics.

Thomas Scammell, MD, has a financial interest/relationship or affiliation in the form of:
| Consultant for Avadel Pharmaceuticals; Jazz Pharmaceuticals Inc; Paladin Labs Inc.; and

BB Takeda Pharmaceutical Company Limited.
Grant/Research Support from Harmony Biosciences, LLC; Jazz Pharmaceuticals Inc; and

Takeda Pharmaceutical Company Limited.

Caitlin Kindberg has no financial interests/relationships or affiliations in relation to this
| activity.

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