BTK Inhibition Transforming the Landscape of Chronic Spontaneous Urticaria Treatment

Chair Jonathan A. Bernstein, MD, discusses chronic spontaneous urticaria in this CME activity titled “BTK Inhibition Transforming the Landscape of Chronic Spontaneous Urticaria Treatment.” For the full presentation, downloadable Practice Aids, and complete CME information, and to apply for credit, please visit us at https://bit.ly/3P0cnvi. CME credit will be available until May 6, 2025.

1. BTK Inhibition Transforming
the Landscape of Chronic
Spontaneous Urticaria Treatment

Jonathan A. Bernstein, MD
Professor of Clinical Medicine

University of Cincinnati College of Medicine

Division of Rheumatology, Allergy and Immunology

Partner of Bernstein Allergy Group and Bernstein Clinical Research Center
Cincinnati, Ohio

Copyright © 2000-2024, PeerView

2. Unraveling CSU
Exploring Pathophysiology and Biomarkers

Jonathan A. Bernstein, MD
Professor of Clinical Medicine

University of Cincinnati College of Medicine

Division of Rheumatology, Allergy and Immunology

Partner of Bernstein Allergy Group and Bernstein Clinical Research Center
Cincinnati, Ohio

2000-2024, PeerView

3. Manifestations of Urticaria’

Urticaria is a poorly understood and underestimated clinical condition
characterized by the sudden onset of itchy wheals and/or angioedema,
which usually resolve within 24 and 72 hours, respectively

A wheal has three typical features Angioedema is characterized by

+ Asharply circumscribed superficial
central swelling of variable size and
shape, almost invariably surrounded
by reflex erythema

A sudden, pronounced erythematous
or skin-colored deep swelling in the
lower dermis and subcutis or
mucous membranes

An itching or sometimes burning

rn Tingling, burning, tightness, and

sometimes pain rather than itch
A fleeting nature, with the skin returning
to its normal appearance, usually within
30 min to 24 h

A resolution slower than that of wheals
(can take up to 72 h)

1. Zuberbier Y et al, Alergy. 2022:77:734-766, PeerView.com

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4. Classification of Urticaria on the Basis
of Duration and Relevance of Eliciting Factors!

Urticaria is considered acute (<6 weeks) or chronic (>6 weeks)

Urticaria is classified as spontaneous (no specific eliciting factor involved)
or inducible (specific eliciting factor involved)

Chronic Spontaneous Urticaria Inducible Urticaria
(CSU) (CIndu)

Spontaneous appearance

of whealls, angioedema, or both
for >6 weeks because of known
or unknown causes

1. Zuberbier T et al. Alergy. 2022:77:734-768,

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Recommended
Classification
of Chronic Urticaria

Cold urticaria

Delayed pressure urticaria
Solar urticaria

Heat urticaria

Vibratory angioedema
Cholinergic urticaria

Contact urticaria

Aquagenic urticaria
Symptomatic dermographism

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5. CSU: Associated Clinical Symptoms’

Gastrointestinal symptoms.

1.RadonieHoesl'S eta. Gin Rev Alergy Immunol. 2018:54 80-101. PeerView.com

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6. CSU: Prevalence and Duration!

a A
revalence 8888 Duration

+ 1% to 5% prevalence in the general + People with CSU who develop
population angioedema tend to experience

+ Women are twice as likely as men longersasting sympioms
to have CSU + CSU generally lasts 1-5 years but

+ Can develop at any age but most can last for decades

common between 30-50 years
fe) fe) O
{) | | 6%

only swelling
1.Gömez RM et al. Front ray. 20223905677. 2. Maurer Meta. Adv Ther 2024:41:14.33. 3. Koki P et al Nat Primers, 2022.8:61. =
4. Zuberier Y eta. Allergy, 2022.77:734-766. 5. Armstrong AW. Dermatol The. 202312: 1620-1046, PeerView.com

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7. Immunopathogenesis of CSU:
Mast Cells and Basophils Are the Drivers!

+ Activation of mast cells (MCs) and basophils
results in histamine and cytokine release with
subsequent dermal inflammation

+ Dermal MCs express many activating
receptors and few inhibitory surface receptors

+ The number and variety of surface receptors
and their respective ligands make dermal MCs
uniquely sensitive to changes in
their environment

1. Bernstein Je a. J Alergy Cin Immunol. 2023 [Epub ahead of pnt, PeerView.com

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8. Mechanisms of Mast Cell Activation in CSU!

+ Two overlapping mechanisms of mast cell and basophil activation have been proposed in CSU

+ Both mechanisms involve cross-linking of FceRI and activation of downstream signaling pathways,
and they may co-occur in the same patient

Type | Type Ilb

Type | autoimmunity is mediated via
IgE against various autoallergens Mast cell
IL-24

Tissue factor ry

Tissue transglutaminase 2 Allergen IgE Nag
Thyroglobulin
0) 1

IgG anti-FceRI

Type Ilb autoimmunity is mediated IgG antilgE
predominantly via IgG directed à AS
utoallergen
against the IgE receptor FeeRI =
or FeeRl-bound IgE Release
of mediators

1 Bemstein Je a. Alergy Cin Immunol 2023 [Epub ahead of prin 2. Ka P et al. Allergy Cn Immunol. 2087141: 1 166-1167 N
3 Ko tJ Alergy ol 047.0 TRATE > PeerView.com

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9. Unmet Needs in CSU

Refractor
to standard
therapy

Delayed
diagnosis

+ Average time from symptom onset Includes second-generation
to diagnoels is 2 years’ antihistamines as first-line
- Patients try to treat the disease therapy and omalizumab*
before seeking medical care? — mAb that blocks IgE antibody
— Symptoms may not be occurring in the peripheral circulation
when the patient visits an HCP? and downregulates IgE

receptors on mast cells

— Complex differential diagnosis?

4. Armstrong AW etal. Dermatol Ther. 2023:13:1029-1648. 2. Maurer M at a. Adv Thr. 2024:41:14-33.3. Metz M et a. J Alergy Clin Immunol Pract.
20219-2274-2283. 4, Yosipoiten G etal. Dermatol Ther. 2023:13-1847-1860. 5. Sanchez Borges Met al world Alergy Organ J 2021:14-100546

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+ Even at increased doses
may not be well controlled’

Approximately 40%-45%
of patients respond
to antihistamines

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10. CSU Management!

What to Do in Every CSU Patient

© -—- _ “
Cause Look for indicators of CSU because of autoimmunity
type 1 and autoimmunity type 2b
0 nn |
For example, check for chronic inducible urticaria,
CET era
For example, identify problems with sleep, distress,
CMT Sac
Components Assess potential biomarkers or predictors of treatment response

SO — |)

* including review of patent photo documentation. * Diterental Bond count, CRPIenthvocyte sedkmentation rte, IgG ant-TPO, total IE. m
1.Metz M et al. J Alergy Cin Immunol Pract. 2021:92274-2283, PeerView.com

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11. Recommended Diagnostic Algorithm for Chronic Urticaria!

Wheals Angioedema

Recurrent unexplained fever?
Joint/bone pain? Malaise?
a

x Cn]
Autoinflammatory ‘Average wheal
disease? duration >24 h?

Signs of v:
in biopsy

Are symptoms
inducible?

sise} 2nsoubelg

‘Acquired = Chronic spontaneous Chronic inducible
hereditary Alo _| [Urticarial vasculitis urticaria urticaria

1. Zuberbier T et al, Alergy. 2022:77.734-766 PeerView.com

quouneel

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12. CONFIRM: Rule Out Differential Diagnoses’

Differential Diagnoses of Urticaria

+ Urticarial vasculitis
+ Bradykinin-mediated angioedema (eg, HAE)

+ Maculopapular cutaneous mastocytosis (urticaria pigmentosa) and indolent systemic mastocytosis
with involvement of the skin

+ Mast cell activation syndrome (MCAS)

+ Exercise-induced anaphylaxis

+ Cryopyrin-associated periodic syndromes (CAPS; urticarial rash, recurrent fever attacks, arthralgia or
arthritis, eye inflammation, fatigue, and headaches)—that is, Familial Cold Autoinflammatory Syndrome
(FCAS), Muckle-Wells Syndrome (MWS), or Neonatal Onset Multisystem Inflammatory Disease (NOMID)

+ Schnitzler’s syndrome (recurrent urticarial rash and monoclonal gammopathy, recurrent fever attacks,
bone and muscle pain, arthralgia or arthritis, and lymphadenopathy)

+ Gleich's syndrome (episodic angioedema with eosinophilia)

+ Wells syndrome (granulomatous dermatitis with eosinophilia/eosinophilic cellulitis)
+ Bullous pemphigoid (prebullous stage)

+ Adult-onset Still's disease (AOSD)

4. Metz M et a. J Alergy Cin Immunol Prat 2021:92274-2283, 2. ZuberbierT ta. Alergy. 2022.77734-76. PeerView.com

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13. CAUSE: Determining the Underlying Cause of CSU!

Recommendation

+ Physicians should explore patients with CSU for underlying
causes by asking relevant questions and by using more

specific tests, where indicated and available

Specialists should measure total IgE and IgG anti-TPO
and, if available, use basophil testing to assess patients
with CSU for type 1 and type 2b autoimmunity

1. Metz M et a. J Alorgy Cin Immunol Pract 2021:9:2274-2283, PeerView.com

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14. COFACTORS: Relevant Conditions
That Can Modify Disease Activity!

Condition/ Issue Aspects of the Physical Exam

to Be Considered That Should Lead to Further Investigation

Food intolerance Increased disease activity in association with foods

r + Increased disease activity in association
Drug intolerance with NSAIDs

Increased disease activity in association with stress,
anxiety, depression, or sleep impairment

Chronic infection (eg, tonsilitis, sinusitis, dental
Chronic infection infection, UTI)
+ Recurrent Gl problems

Stress

1. Metz M et a. J Alorgy Cin Immunol Pract 2021:9:2274-2283, PeerView.com

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15. COMORBIDITIES Associated With CSU!

Diagnostic Tests That Should
Be Done if Clues Are
Obtained From History
and Physical Exam

Condition/ Questions and Aspects of the

Issue to Be Physical Exam That Should Lead
Considered to Further Investigation

+ Adult female patient with positive family

Hashimoto’s history for autoimmune disease? TSH, FT4,
thyroiditis + Signs or symptoms suggestive of if indicated IgG anti-TPO
hyperthyroidism or hypothyroidism?
Mental +» Do you feel depressed? HADS, CU-Q2oL,
disorders + Do you feel overly anxious? if indicated referral to specialist
ce + In addition to spontaneous whealing, Provocation tests
aban can you also make your wheals appear? for chronic inducible urticaria
urticaria
1. Metz M et a. J Alorgy Cin Immunol Pract 2021:9:2274-2283, PeerView.com

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16. CONSEQUENCES: Burden of Disease!

Embarrassment

Difficulty with ADLs; Stress and
work/school impairment anxiety

Substantial Burden
on Patients

Sleep

ession
disturbances Depressi

Social

isolation

1.0/Donnei BF. Immunol Allergy Cin North Am.2014:34:89-104, 2. Schaefer P. Am Fam Physician. 2011:83:1078-1084. 3. Berino AM etal. Eur Ann Alloy
Cin immuno. 2006;38 149-152 4. Baird! e al. Alergy 2003/58:821-823. 5. Sussman G et al. 2015 Word Congress of Dermatology (WCD 2015) Poster. m
6. Balp MM et al. WCO 2015. Poster. 7. Nelson HS et al Ann Allergy Asthma Immunol. 2000.84:517-522. 8. ODonnel BF et al. Br Dermatol. 1997:138:197-201. PeerView.com

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17. COMPONENTS: Diagnostic and Prognostic Biomarkers Associated
With Longer Duration, Higher Activity, and Response to Treatment!

Measurement:
low total IgE,
positive BHRA

treatment

Measurement:

low total IgE, positive BHRA,
history of previous
immunosuppressive treatment,
low basophil FoeRI expression

1. Metz M et al. J Alorgy Cin Immunol Pract 2021;9:2274-2288,

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[Good response
to cyclosporine

Poor response
to omalizumab

treatment

Measurement

elevated IgG anti-TPO,
high CSU severity/activity

Poor response
to treatment
with sgAHs

Measurement:
elevated prothrombin
fragment 1+2, elevated
D-dimer, elevated CRP,
elevated mean platelet
volume, elevated IL-6

Measurement:
presence of concomitant CindU,
ASST positivity, high D-dimer,
high UAS, high CRP, previous
corticosteroid treatment, low blood
basophil and eosinophil counts

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18. COURSE: Assessing Disease Activity Impact and Control!

UAS/UAST for Asses:
Score eals
0 None None
1 Mild (<20 wheals/24 hours) Mild (present but not annoying or troublesome)
Moderate (troublesome, but does not interfere
2 Moderate (20-50 wheals/24 hours) with normal daily activity or sleep)
4 Intense (>50 wheals/24 hours or Intense (severe pruritus, which is sufficiently troublesome
large confluent areas of wheals) to interfere with normal daily activity or sleep)
Wheals (number) Itch (severity)
0 = none 0 = none
1 = <20 wheals 1=mild = Daily UAS Fer
2 = 20-50 wheals 2 = moderate = (0-6) (0-42)
3 = >50 wheals 3 = severe
Once daily ‘Once daily

1. Chung WH eta. J Formos Med Assoc. 2016:115:968-080, PeerView.com

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19. International Guidelines for Treatment of Chronic Urticaria‘

Start with a standard dose of second-generation
H, antihistamines

If needed, increase second-generation
H, antihistamine dose (up to 4x)

Consider referral

If inadequate control on high dose: after
2-4 weeks or earlier, if symptoms are intolerable

Add on to second-generation
H, antihistamine: omalizumab>

Bs
ES If needed, increase dose and/or shorten interval

ss

Ss Ifinadequate control: within 6 months

2 3 4 or earlier, if symptoms are intolerable
pes

33° Add on to second-generation H, antihistamin:

55 cyclosporined

* Seconduine and thine treatment apply only for chronic ua. ® 300 mg every 4 weeks. Upto 600 mg every 2 weeks. © Up o 5 mal body weight ñ
1. ZuberbierT etal. Alorgy.2022.77.734-788, PeerView.com

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20. Treatment Response to Antihistamines

CSU is typically treated with antihistamines,
but disease remains uncontrolled
for up to 50% of people living with CSU,
and there are few available treatment options

Additional safe and effective
alternative treatment options are needed

1. Staevska Meta. J Alergy Cin Immunol. 2010:125 676-682. 2. Maurer Met al. Alloray.2011:66:317-330, PeerView.com

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21. Assessing BTK Inhibitors in CSU
Effectiveness, Safety Profile, Mechanism
of Action, and Implications for Guidelines

Jonathan A. Bernstein, MD
Professor of Clinical Medicine

University of Cincinnati College of Medicine

Division of Rheumatology, Allergy and Immunology

Partner of Bernstein Allergy Group and Bernstein Clinical Research Center
Cincinnati, Ohio

> 2000-2024, PeerView

22. Therapeutic Targets for CSU: A Central Role for BTK!

TSLP. ne
D CB, wenige - MEN
a “~_IE-autoallergen complex

IgG anti-FceRI

1. Bernstein J et a J Alergy Cin Immunol. 2023 [Epub ahead of pint, PeerView.com

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23. Approved and Investigational Systemic Therapies
for Chronic Urticaria’?

Biologic Cellular/Pathway Target of Treatment

Reduction of free IgE

Ge Reduction of FceRI expression on MCs
Dupltuma Reduces GE ves in bp nivale
Remibrutinib + Inhibits BTK

Rilzabrutinib + Inhibits BTK

Benralizumab + Targets IL-5R

Tezepelumab + Binds TSLP

Lirentelimab + SIGLEC-8

Barzolvolimab + Anti-KIT

Secukinumab + Binds to IL-17

Approval Status

Phase of

Development for CSU

Approved for CSU since 2014

Approved but not for CSU

Not approved

Not approved
Approved but not for CSU
Approved but not for CSU

Not approved

Not approved
Approved, but not for CSU

D NNN NO

POC completed

1. Maurer Metal. J Alergy Cin Immunol Pract 20219: 1067-1078, 2. einicatias gov.

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24. Omalizumab for Refractory CSU!

CIUICSU 0

und Ti

+ Anti-IgE monoclonal
as Approved doses 24-week treatment period
2014 ft patents aged ASTERIA! cjHaninstamines fj Omalzumab 75, 150,300 mg vs placebo

212 years with CSU
who have not responded
to antihistamines ı 1210

Phase 3 clinical trial ASTERIA II, APProved doses 12-week treatment period
program consisted of H, antihistamines ‘Omalizumab 75, 150, 300 mg vs placebo
of three randomized,

double-blind, placebo-
controlled studies in

patients with moderate to
severe H, antihistamine

Up to 4x approved dose
refractory CIUICSU GLaciaL 9H anthistamine plus 24-week treatment period
LTRA or H, antihistamine, ‘Omalizumab 300 mg vs placebo
or all three in combination
Q Efficacy endpoint, week 12
J Every 4 weeks injection
1. Xela (omatzumab) Prescribing Information m
ip accessdata (a govdrugsatäe SocelabeV2021/10307085250 pat, 2. Casale TE etal. J Allergy Cin Immune! Pract 2015:3749-50. PeerView.com

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25. Omalizumab:

Proportion of Responders by Treatment Group’

Patients With UAS7 <6

Patients With UAS7 = 0

mm Paco
mm Omatzumab 150 mg
80 i M Omatzumae 300 m9 gg i
70 : 70 !
588 | !
80, ! 52.4 © i
& 50 H & 50 E
y 41.4 H g 40 :
340 i 540 H 33.7
30 : & 30 u i
204 15.1 a 20 !
10 ! 101 69 ! 48
0 ! 0 i
ASTERIA 1/11 GLACIAL ASTERIA 1/11 GLACIAL

1. Casale TB tal J Alergy Cin Immunol Prat 2015:3743-50.0

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26. Phase 3 Trial of Dupilumab in CSU: Overview of CUPID’

==

Adults and adolescents (212 years); + Primary: itch severity score (ISS7)
Patients with dlagnosie:of, CSU refractory, + Secondary: urticaria activity score (UAS7),
to H, antihistamine hives severity score (HSS7), angioedema

+ Randomized, double-blind, parallel activity score (AAS7), urticaria control test
assignment, placebo-controlled study (UCT), quality of life, Patient Global

+ Study A: omalizumab naive; study B: intolerant Assessment, percent of patients receiving
or incomplete responder to omalizumab SOC, safety

Studies A and B, two arms: dupilumab vs
placebo (on top of sedating H, antihistamine—
SOC—in both arms)

1. Maurer Metal. JAm Acad Dermatol, 2022:87:A846. PeerView.com

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27. Phase 3 Trial of Dupilumab in CSU
Results From CUPID A!

Reduction in + 63% reduction with dupilumab vs 35% with standard of care (antihistamines)
itch severity

(primary endpoint + A 10.24-point reduction with dupilumab and a 6-point reduction with standard of care
in United States) (P= 0005)

Reduction in 65% reduction with dupilumab vs 37% with standard of care

urticaria activity severity A 20.53-point reduction with dupilumab and a 12-point reduction with standard of care
(primary endpoint in EU) (P= .0003)

Occurrence of TEAE generally similar between two groups (50% dupilumab, 59% placebo)
Most common AEs were injection-site reactions (11% dupilumab, 13% placebo)

Safety results

1 Maurer Metal. J Am Acad Dermatol. 2022:87-AB48, PeerView.com

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28. Phase 3 Trial of Dupilumab in CSU:
Results From CUPID B*

Cas |

During the 24-week treatment period, patients received dupilumab or placebo
every 2 weeks added to standard of care antihistamines

Treatment dosage

+ Did not reach statistical significance in an interim analysis despite numeric improvements
observed across key endpoints

«nose pmewavrcom/new‘leseshegeneron-and-santproieupdate-o-ongsingdupsen-tuphamaernispontaneaut unica phase program |
See nn 2 = PeerView.com

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29. Other Ongoing Studies of Dupilumab in CSU‘?

MASIA EU | + Estimated completion 2024
CUPID + Efficacy of dupilumab in CSU refractory to H, antihistamine
(Study C) and omalizumab naive

LIBERTY-CSU + Estimated completion 2025
CUPIDKids + Children 22 to <12 years of age

1. tips encata govistudy/NCTO4180488. 2. tips Icinicahias govstuay/NCTOSS26521 PeerView.com

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30. Remibrutinib: REMIX-1 and REMIX-2 Phase 3 Studies!

Phase 3, randomized, placebo-controlled studies of remibrutinib 25 mg BID administered orally

Primary endpoint Primary analysis"

+ +

12 2

weets E

'emibrutinib 25 mg twice dail

Adult patients with a
diagnosis of

CSU (for 26 mo Follow-up or extension
inadequately co

by second-generation
Hy-AHs'

Remibrutinib 25 mg
twice daily

Primary endpoints ‘Secondary endpoints
+ Scenario 1: Change from baseline in UAS7 at week 12 + Percentage of patients with UAS7<6 and UAS7=0 at week 12
+ Scenario 2: Change from baseline in ISS7 and HSS7 at week 12 | | + Percentage of patients with UAS76 at week 2

+ Occurrence of treatment-emergent and serious AEs during the study

Primary analysis was conducted afer all patents completed week 24 or isconinued eater and when a minimum o 150 patents across both REMIX studies completed the treatment
period at week 52 Presence of itch and hives fr 28 consecutive weeks prior lo screening despie the use ofa second generation Hy AH; UAST of 216, 1567 of 26, and HSS7 of 26
‘uring the 7 days pro 1 randomization (day 1). Patients may continue receiving rembrui ina separate extension shy. wat
1-Mosnaim G et al AAAA! 2024, Poster L28 PeerView.com

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31. Remibrutinib: Improvement Over Time
in UAS7 Change From Baseline

REMIX-1 REMIX-2
o o I Remibrutnib.
25mg B10
a 5 M Placebo
sá 3
su 5
6 g-10 6
53 5
H
Sg-s Ss
5 E 5
28 20 2
254 254
0123456789 10112 0123456789 0112
Time, weeks Time, weeks
ao ve Mo. of vato
pons teak va Pa each va
Reb 23000 29 0 20 31 20520 Zu 2 25 2 240 27 2 Reng BOT 20 20620 97 E79 27 am 20 a0 et
483 10 190 148 tad fet 109 12 18 138 100 105 108 Powe 49 5 mo Me We 142 M 198 108 190 nz 197 1

1. Saini SS et a ACAA! 2023, Abstract LB001 PeerView.com

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32. Remibrutinib: Change From Baseline in UAS7
at Week 12 in REMIX-1 and REMIX-2 Studies!

REMIX-1 Bu Rembruind 25 mg REMIX-2
twice daily
Anti-igE ' Antidge MM Placebo AntigE ‘ Anti-igE
Bun: Exposed | Biologic Naive Biologic Exposed ! Biologic Naive
n=49 1 ns2it n=104 n=8 n=49 1 n=208 n=104
8 ° 1 se > T t T
3 1 33, 1
5s * ' ES * !
s Ll Ss 1
A 10 ! ge” !
5 8: 2
3. 1265 ı 2: - 4214 | 41.64
3 ® N 1446 FE H
E E
-20 \ 22 2 1
5 1 OB 25 1996 1 1953
És ! SE 2 !
—— Fi as
576 1 an 62 7.82 1 7.88
C1023t0-120P 1 (-909t0-4.15)° (120510359 1 (-1046t0-5:31

* Ful analysis set using a linear mixed model with repeated measures; imputed data. Treatment difference in LS mean (85% CI)
4. Moanaim G etal AAAAI 2024, Poster 28

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33. Remibrutinib: Complete Response (UAS7 = 0)
at Week 12 in REMIX-1 and REMIX-2 Studies!

MM Remibrutinib 25 mg

REMIX-1 fice daly REMIX-2
MM Placebo
60 ss 1 © di 1 di
& Anti-IgE 1 Anti-IgE E Anti-lgE H Anti-lgE
$ Biologic Exposed 1 Biologic Naive s Biologic Exposed ı Biologic Naive
'
ï ; ï |
5 5
B 3 E
2 337 1 3 I
= =
2 1 24 2 292 oa
3 2
E E E
2% ! £ 2 1
2 N 125 2 H
1 82 1
3 si al E ' 40
= | | E E | E r=
BS teen a to e a
Week 12 Week 12
“Tia tart ezrin ot nn PeerViewcom

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34. Remibrutinib: Overview of Safety!

Pooled REMIX-1 and REMIX-2

Remibrutinib 25 mg twice daily, n (%)*® Placebo, n (%)
(n = 606) (n = 306)
Overall AEs° 388 (64) 198 (64.7)
Infection AEs 199 (32.8) 104 (43)
Serious AEs 20 (3.3) 7(23)
Serious infection AEs 4(0.7) 2 (0.7)
aren son 809
Death 0 0

* Safety set. ? Number of patients experiencing 21 event. Overall AES include infection AES =
‘Moai Get a AM 2004, Pont Le, PeerView.com

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35. PeerView.com/WQU827

Rilzabrutinib: Oral BTK Inhibitor

RILECSU (NCT05107115)

Randomized, double-blind, placebo-controlled, multicenter,

dose-ranging phase 2 study of rilzabrutinib followed by
an OLE phase in patients with moderate to severe CSU
who remain symptomatic despite the use of H, antihistamine
treatment and who are naive to omalizumab

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36. Improving Quality of Life With CSU

Comprehensive Multidisciplinary Approaches

Jonathan A. Bernstein, MD
Professor of Clinical Medicine

University of Cincinnati College of Medicine

Division of Rheumatology, Allergy and Immunology

Partner of Bernstein Allergy Group and Bernstein Clinical Research Center
Cincinnati, Ohio

Copyright © 2000-2024, Peerview

37. Basic Considerations in the Management of CSU!

Goals
of treatment

Treat until CSU is gone and as efficiently and safely
as possible, aiming at a continuous UAS7
complete control, and a normalization of quality of life

Therapeutic
approach involves

The search for and, if possible, elimination
of underlying caus
The avoidance of eliciting factors;

Tolerance induction;

The use of pharmacological treatment to prevent
mast cell mediator release and/or the effects

of mast cell mediators

1. Zuberbier Tet al. Alergy. 2022:77:734-768,

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~

‘As much as needed and as little as possible (ie, stepping

up or down treatment according to course of disease)

mm"

d treatment
inflammatory pro

+ Reduction of physical

and emotional

+ Reduction in functional

aut adi

+ Dietary management

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38. Chronic Urticaria:
Management Decisions and Treatment Adjustments’

Assess
+ Diagnostic procedures + Patient preferences
+ Comorbidities + Adverse events of treatment
+ Severity (use UCT and PROMS)

Adjust
+ Step up f inadequate control
+ Change if adverse events occur

Adj

+ Step down i symptom free for 3-6 months Pr
Act + Mod treatment and eat comorbidities
+ Look atnonpharmacologc interventions (especaly in CingU")

+ Educate the patient

UCT score uct <12

Control level Uncontrolled Completely controlled

Action Step up if Continue therapy Step down, b
and try to optimize a by red
9 interv

"For indU, individual decisions are based on estimated trigger exposure (eg, cold-urtcai in wine) A
4. Zuberbie Tet al. Army 202277734766 PeerView.com

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39. Five-Principle Patient Charter
for Improved Chronic Urticaria Care!

| deserve access to
| deserve an accurate and | deserve access to innovative treatments that

timely diagnosis of my CU specialty care for my CU reduce the burden of CU on
my daily life

| deserve to be free of
unnecessary treatment-

| expect a holistic treatment
approach to address all the

related side-effects during
the management of my CU

components of my life
impacted by CU

4. Maurer Metal. Adv Ther 2024:41:1433, PeerView.com

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40. Patient Treatment Goals in CSU!

A Nove receptor 5902095 I
(M Someuhatimporant [Not tal important. II Not applicable

enorme A
oo

+- Sonmar oto Er J Doma 2203028026, pains. PeerView.com

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41. Patient Treatment Goals in CSU!

I Very important MI Quite important fll Moderately important
M Somewhat important — IN Not at all important D Not applicable

Have no more visible skin changes M RE i SS SS SS SS ST COR EDEN
Be free of itching SE A SS SS CRE ME RR |
Be healed of all skin defects SE i i i i ST SG FT SS 0
Finda clear diagnosis and therapy SN EN RE DE DE CE CE DE SE: VU
Be less helpless against the disease SN EE RE DE DE DRE ME (UE DR A
Have confidence in the therapy M RE RE EE ME ME ST D (OO D
Have no fear that the disease will become worse M M I I RE ER [IS 10 O me
Be less dependent on doctor and clinic visits Tag i! i! iS SS SSC Se UN AE Re

No longer have burning sensations on your skin SS SS
0 10 20 30 40 50 60 70 80 90 100

Patients, %

1. Sommer Reta. Eur J Dermatol 20200 259-206 PeerView.com

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42. Patient Education and Shared Decision-Making in CSU‘?

+ Patients should be informed of potential side effects of their treatment as part
of shared decision-making education

« Discussion of the patient's treatment goals is also a key part of shared
decision-making

— Address all aspects of a patients life that are negatively impacted by CSU

+ Patient-reported outcomes, such as UAS7, should be included in monitoring
disease activity and treatment response, along with available biomarkers and
clinical characteristics

+ Considering patient-specific barriers to treatment adherence (eg, cost, side effects)
is an important part of treatment selection and optimization

1. Maurer Met al Ady Ther 2028:41:1433. 2. Lima Het al Alergy Asthma Cin Immunol. 2017:13:8. PeerView.com

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43. Multidisciplinary Care in CSU‘?

Atopic diseases

Asthma, allergic rhinitis,
atopic dermatitis, food allergy

Psychiatric and mental disorders

Autoimmune diseases

es, Hashi disease, vitiligo,
RA, psoriasis
celiac disease, TA

1. Papapitolou Net al. Front Allrgy 2022::1008145. 2. Kor Petal. Nat Primers. 202261. PeerView.com

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44. Only up to 40%-50% of patients
with chronic hives respond
to high-dose antihistamines

+

Other treatment options:
are needed

The BTK inhibitor, remibrutinib, has the

potential to become a novel oral treatment

option that may address unmet needs of

patients with CSU inadequately controlled

by second-generation H,-antihistamines

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Conclusions

Biologics have opened up the field
of urticaria and provided some
additional treatment options

+

Biologics have improved
hives remarkably

Challenge to define specific phenotypes
and corresponding endotypes with
point-of-care biomarkers that can lead
to more targeted therapies; many other
biologics are in development

Awhole new understanding
to CSU

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