Chronic Inflammatory Airway Diseases by Integritas Communications

Educational Objectives • Describe the overlapping pathophysiologic processes that contribute to chronic inflammation, hyperresponsiveness, and remodeling in the upper and lower airways, including implications for treatment • Discuss the clinical profiles and evidence for biologic therapies to address overactive cytokine signaling in patients with chronic inflammatory upper or lower airway diseases • Tailor biologic-based therapeutic regimens for patients with severe asthma, AR, and/or CRSwNP to account for underlying disease processes and overcome treatment-related barriers AR, allergic rhinitis; CRSwNP, chronic rhinosinusitis with nasal polyps.

THE UNIFIED AIRWAY MODEL What It Means for Patients and Clinicians

The Unified Airway Model Big Picture View

Bidirectional provocation with allergens

• AR • CRSwNP • CRSsNP • Nonallergic rhinitis • Mixed rhinitis • Otitis media • AERD/NSAID-ERD • Asthma • Eosinophilic COPD

Upper and lower airway diseases reflect a single pathologic process manifesting in different locations within the airway. AERD, aspirin-exacerbated respiratory disease; COPD; chronic obstructive pulmonary disease; CRSsNP; chronic rhinosinusitis without nasal polyps; NSAID-ERD, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease. Bachert C, et al. J Allergy Clin Immunol Pract. 2023;11(9):2630-2641.

The Unified Airway Model Supporting Evidence

Epidemiologic Evidence

In patients with CRSwNP • Up to 70% have comorbid asthma In patients with asthma • 40% have comorbid CRSwNP

Pathophysiologic Evidence

Severe eosinophilic asthma, CRSwNP, and NSAID-ERD are commonly characterized by eosinophilia and elevated levels of IL-4, IL-5, and IL-13

IL-4 Eosinophil

IL-13 IL-5

Functional and Pathophysiologic Evidence The upper and lower airways share common cell types and immune interactions

Ciliated epithelium

Upper airways

Goblet cell

Lower airways Th2

Mast cell

ILC2

Dendritic cell

Eosinophil

B cell

Macrophage

NK cell

Type 2 inflammation

Upper and lower airway diseases demonstrate common pathophysiologic manifestations. ILC, innate lymphoid cell; NK, natural killer; Th, T helper. Bachert C, et al. J Allergy Clin Immunol Pract. 2023;11(9):2630-2641.

Th1

ILC1

Type 1 inflammation

The Unified Airway Model

Disease Incidence and Socioeconomic Burden AR

25 -40 %

5th

% individuals in the world affected 1

most common chronic disease in the US2

$2-$4 billion

lost productivity annually2

CRS

5 -12 %

% individuals in1 the

33 -50 %

US affected

% have associated 3 nasal polyps

~$10,000

lost productivity annually per patient with refractory disease4

Asthma

>25 million individuals in the US affected

5 -15 asthma %

% have severe 5

MILLIONS of emergency department visits/year5

1. Nur Husna SM, et al. Front Med (Lausanne). 2022;9:874114; 2. Seidman MD, et al. Otolaryngol Head Neck Surg. 2015;152(1 suppl)S1-S43; 3. Bhattacharyya N, et al. Laryngoscope. 2019;129(9):19691975; 4. Chapurin N, et al. Am J Rhinol Allergy. 2023;37(2):227-231; 5. Centers for Disease Control and Prevention. https://www.cdc.gov/asthma/pdfs/asthma_facts_program_grantees.pdf.

The Unified Airway Model Impact of Comorbid Disease

CRS

Asthma

~40% of patients with diagnosed CRS had premorbid AR.1 Asthma and CRSwNP occur together in 40% to 70% of patients.2 Greater asthma severity has been linked to more radiologic evidence of CRS and higher risk of nasal polyps and allergic sensitization.3 Asthma is the most important independent risk factor for CRS recurrence.4 ~80% of patients with asthma have concurrent rhinitis.5,6 Patients with asthma who also have AR have more emergency department visits and asthma attacks.6 1. Tan BK, et al. J Allergy Clin Immunol. 2013;131((5)):1350–1360; 2. Bachert C, et al. J Allergy Clin Immunol Pract. 2023;11(9):2630-2641; 3. Lin DC, et al. Am J Rhinol Allergy. 2011;25(4):205-208; 4. Sella GCP, et al. J Allergy Clin Immunol Pract. 2020;8(1):302-309; 5. Hannikainen P, et al. Otolaryngol Clin North Am. 2023:S0030-6665(23)00156-1; 6. Bousquet J, et al. Clin Exp Allergy. 2005;35(6):723-727.

Patients With Comorbid Upper and Lower Airway Disease Have… Higher rates of nasal polyp recurrence and corticosteroid dependence

More difficult-to-treat asthma/CRSwNP symptoms More prone to asthma exacerbations Worse outcomes

…compared with patients with only upper OR lower airway disease. Laidlaw TM, et al. J Allergy Clin Immunol Pract. 2021;9:1133-1141.

A CLOSER LOOK AT AIRWAY PATHOPHYSIOLOGY

The Airway Epithelium AR and CRS

Normal Upper Airway Epithelium

Upper Airway Epithelium, Allergic Rhinitis Allergens

Mucus

Mucusa Cilia PRR

Tight Junction Ciliated Cell Adherens Junction

Goblet Cell

Mast Cell

Desmosomes Basal Cell Basement Membrane

Cysteinyl Leukotrienes Histamine etc. Basophil

Dendritic Cell Eosinophil

Upper Airway Epithelium, Chronic Rhinosinusitis Virus S aureus Bacteria

Lamina Propria ILC Fibroblast

Signaling Molecules

Dendritic Cell Neutrophil

Chemokines, cytokines etc tPA Macrophage

aMucus + lipopolysaccharides, mucins, surfactants, lactoferrin, defensins, protease inhibitors.

PRR, pattern recognition receptor; S aureus, Staphylococcus aureus; tPA, tissue plasminogen activator. Laulajainen-Hongisto AL, et al. Front Cell Dev Biol. 2020;8:204.

Dendritic Cell

Fibrin

ILC Blocking of tPA by Th cells

Thickening Basement Membrane Eosinophil Neutrophil

The Airway Epithelium Asthma

Normal Lower Airway Epithelium Mucusa

Lower Airway Epithelium, Asthma

Allergen

Cilia Club Cell Tight Junction

Signaling Molecules

PPR Clara Cell

Adherens Junction

Goblet Cell

Brush Ciliated Cell Cell Smooth Muscle Hypertrophy And Hyperplasia

Desmosomes Basal Cell Basement Membrane Smooth Muscle Cell

ILC

Mast Cell ILC Neutrophil

Dendritic Cell

aMucus + lipopolysaccharides, mucins, surfactants, lactoferrin, defensins, protease inhibitors.

APC, antigen-presenting cell. Laulajainen-Hongisto AL, et al. Front Cell Dev Biol. 2020;8:204.

Chemokines, cytokines etc

Eosinophil

Lamina Propria

Fibroblast

Allergen

Mucus

Nerve Cell

Thickening Basement Membrane APC Fibroblast

The Interactive Cytokine Networks T2

Nasal polyps

Allergens, Viruses, and Irritants

Microbiome Imbalance

Biofilm

S aureus

Goblet Cell

Tight Junction

Allergens

Airway Epithelium IL-4 Th0 Cell Th2 Differentiation

Dendritic Cell TSLP IL-33 IL-25 Eosinophil activation in bone marrow Eosinophil

Asthma

ILC2 IL-5

Th2 Cell IL-4

Barrier disruption IL-4

IL-13

Inflammatory cell trafficking to the tissue

PGD2, prostaglandin D2; TARC, thymus and activation-regulated chemokine. Maspero J, et al. ERJ Open Research. 2022;8:00576-2021.

IL-4 IL-13

M2 macrophage polarization Mast cell

IgE

Smooth muscle contractility

IL-13

Upregulation of chemokines (eg, eotaxin, TARC) Basophil

Goblet cell hyperplasia/ mucus production Basement membrane thickening

B-cell

B-cell class switching/ IgE production Leukotrienes, histamine, PGD2

IL-4

Fibrin deposition Nasal polyp formation (CRSwNP only)

Asthma and CRSwNP Asthma Only CRSwNP Only

The Interactive Cytokine Networks T2

Nasal polyps

• Alarmins

– IL-25, IL-33, TSLP – Produced by epithelial cells

• T2-high cytokines Asthma

– IL-4, IL-5, & IL-13 – Produced by Th2 and ILC2 cells

AR, asthma, and CRSwNP are predominantly driven by chronic T2 inflammation, sustained by close interactions between the innate and adaptive immune responses. Maspero J, et al. ERJ Open Research. 2022;8:00576-2021.

The Interactive Cytokine Networks

Non-T2: Alarmin-Mediated Inflammatory Pathways Nasal polyps

Irritants, pollutants, microbes, and viruses

TSLP IL-33 IL-6 IL-23

Asthma

• Non-T2 cytokines1-3

– IL-1β, IL-6, IL-8, IL-17, and TNF-α – Produced by Th17 and Th1 cells

GM-CSF IL-8 Th17 cell

Th1 cell

IL-17A IL-17E (IL-25)

IFN-γ TNF-α

• Neutrophilic or paucigranulocytic1-3

Neutrophil

CXCR2

CXCR2, C-X-C motif chemokine receptor 2; GM-CSF, granulocyte–macrophage colony-stimulating factor; TNF, tumor necrosis factor. 1. Kalchiem-Dekel O, et al. Chest. 2020;157(1):26-33; 2. Hinks TSC, et al. Eur Respir J. 2021;57(1):2000528; 3. Lambrecht BN, et al. Immunity. 2019;50(4):975-991. Image adapted from Corren J. J Allergy Clin Immunol Pract. 2019;7(5):1394-1403 and Israel E, Reddel HK. N Engl J Med. 2017;377(10):965-976.

The Interactive Cytokine Networks Non-T2: IL-6–Mediated Airway Inflammation

Nasal polyps

Homeostasis Infection

Exacerbations

Amplified Antimicrobial Response Tissue Damage Upgraded TLR Signaling

PAMPs TLR

Tight Junctions

IL-6 Trans-Signaling

Compromised Barrier Function

– IL-1β, IL-6, IL-8, IL-17, and TNF-α – Produced by Th17 and Th1 cells

• Neutrophilic or paucigranulocytic1-3

IL-33

IL-6 sIL-6R IL-6R shedding Asthma

• Non-T2 cytokines1-3

Neutrophils

sIL-6R IL-6 IL-8 IL-1β T cells Eosinophilia MIP-1β Macrophages YKL-40 Submucosal MMP3 Inflammation and Remodeling

MIP, macrophage inflammatory protein; MMP, matrix metalloproteinase; PAMP, pathogen-associated molecular pattern; R, receptor; sIL, soluble interleukin; TLR, Toll-like receptor; YKL-40, chitinase-3-like protein 1. 1. Kalchiem-Dekel O, et al. Chest. 2020;157(1):26-33; 2. Hinks TSC, et al. Eur Respir J. 2021;57(1):2000528; 3. Lambrecht BN, et al. Immunity. 2019;50(4):975-991. Image adapted from Jevnikar Z, et al. J Allergy Clin Immunol. 2019;143(2):577-590.

Pathophysiology AR

• IgE overproduction in response to common environmental allergens causes AR and atopic asthma • Mediators, such as histamine and leukotrienes, cause an immediate hypersensitivity reaction • Eosinophils and basophils recruited by Th2 cells in response to IL-4 and IL-5 perpetuate the allergic response, leading to a chronic inflammatory state

Hannikainen P, et al. Otolaryngol Clin North Am. 2023:S0030-6665(23)00156-1.

CRSwNP or CRSsNP

Phenotype

• ILC2/Th2 mediated • Key cytokines: IL-4, IL-5, IL-13 • Eosinophilic

Endotype

Pathophysiology CRSwNP

• Clinical phenotypes do not reflect the underlying inflammatory mechanisms1 • Endotypes represent the most prominent molecular components and can be useful in guiding therapeutic decision-making1

Phenotype

CRSwNP or CRSsNP T1

• ILC1/Th1 mediated

• ILC2/Th2 mediated

• ILC3/Th17 mediated

• Key cytokine: IFN-γ

• Key cytokines: IL-4, IL-5, IL-13

• Key cytokine: IL-17

• Neutrophilic

• Eosinophilic

• Neutrophilic

• Associated with asthma comorbidity, nasal polyps, anosmia, and allergic mucin2 • Comorbid CRS and asthma demonstrating T2 inflammation has the poorest outcome and most severe clinical manifestations2

T1, type 1; T3, type 3. Fokkens WJ, et al. Rhinology. 2020;58(suppl S29):1-464; 2. Hannikainen P, et al. Otolaryngol Clin North Am. 2023:S0030-6665(23)00156-1.

Endotype

Patterns of Inflammatory Endotypes CRS

All CRS

CRSsNP

CRSwNP

All CRS

CRSsNP

CRSwNP

19%

22%

21%

72%

27% 55%

17%

18% 87%

 T1 single  T2 single  T3 single  T1/2 mixed  T1/3 mixed  T2/3 mixed  T1/2/3 mixed  Untypeable

 T1 all  T2 all  T3 all

Although the majority of patients with CRSwNP exhibit T2 inflammation, ~one-third have mixed or non-T2 inflammatory components, which may have indications for biologic selection. Stevens WW., et al. J Allergy Clin Pract. 2019;7(8):2812-2820.e3.

Nasal Polyp Formation CRSwNP

Mucus layer

Nasal airway

Mucosal barrier

Loss of barrier, with increased abundance and decreased diversity of microbes

Inflammatory cells

Normal nasal mucosa and colonization with microbes

Submucosal gland

Nasal polyp Nasal airway

Recruitment and expansion of inflammatory cells, tissue swelling, inflammation, and deposition of crosslinked fibrin Image adapted from: Stevens WW, et al. J Allergy Clin Immunol. 2016;4(4):565-572.

Nasal airway

Tissue remodeling, with loss of submucosal glands in polyp and profound inflammatory cell expansion

Nasal Polyps CRSwNP

Nasal polyps

Graphic courtesy of Dr. Stella Lee.

The Unified Airway Model The Effects of Inflammation

• Mucus hypersecretion and airway hyperresponsiveness are apparent in both upper and lower airway diseases1 • Vasodilation and edema are the result of sinonasal inflammation and cause nasal congestion and rhinorrhea2 • Inflammation causes smooth muscle contraction in the lower airway, leading to bronchial hyperresponsiveness3 1. Bonser LR, Erie DJ. J Clin Med. 2017; 6(12):112; 2. Pelaia C, et al. J Clin Med. 2023;12(10):3371; 3. Camoretti-Mercado, Lockey RF. J Allergy Clin Immunol. 2021; 147(6):1983-1995.

Mucus Hypersecretion CRS

MUC5AC

TACE, EGFR, MAPK Inflammation

Oxygen species

CRS Release

Cytokines Mucosa remodeling

MARCKS

Activate

Accumulate Remodeling mediators

HBE16

PKC

Neutrophils MMPs TGF-β

Secrete

HNE

Mucus overexpression

PAR2

Ca2+

Calu-3 cell

PKC Inhibit PKC-specific antagonist

• Phenotype of CRS affects the expression of various mucins, especially in nasal polyps1 • Neutrophil elastase induces MUC5AC overexpression through several signaling pathways1 • Excess mucus production is commonly accompanied by goblet cell and submucosal gland cell hyperplasia1

Patients with mucus hypersecretion had more dyspnea, poorer asthma control with more exacerbations, and demonstrated more-frequent anosmia associated with CRSwNP than those without mucus hypersecretion.2 Ca2+, calcium ions; Calu-3, cultured human airway epithelial cells; EGFR, epidermal growth factor receptor; HBE, human bronchial epithelial; HNE, human neutrophil elastase; MAPK, mitogenactivated protein kinase; MARCKS, myristoylated alanine-rich C kinase substrate; MUC, mucin; PKC, protein kinase C; PAR2, protease-activated receptor 2; TACE, TNF-α-converting enzyme; TGF, transforming growth factor. 1. Tong J, and Gu Q. Curr Allergy Asthma Rep. 2020;20(11):63; 2. Martinez-Rivera C, et al. Respir Med. 2018;135:22-28.

Mucus Hypersecretion T2-High–Driven Asthma

Ciliated Cell

Normal

Asthma

Lumen

Mucus Plug

MUC5AC Tethering

MUC5B Cell

Airflow Obstruction MUC5AC Cell

Easily Transportable Mucus Gel

Eosinophil-rich mucus plug

Mucus hypersecretion Asthma epithelium

Eosinophil exotaxis

IL-13

• Substantial plugging in most patients with fatal asthma; persists in the same airways over time, increasing in frequency with disease severity1 • IL-13 mediated – Proliferation of hypersecretory MUC5ACexpressing mucus cells2,3 – Loss of ciliated cells2 – Increase in thiocyanate transport3

• Thiocyanate reacts with eosinophil peroxidase, promoting cross-linking of mucins, mucus gel stiffening, and resultant mucus plug formation

• IL-5 mediated ASM

IL-5

– Activation of eosinophils and release of granule proteins3

ASM, airway smooth muscle; GC, goblet cell. 1. Bonser LR, Erie DJ. J Clin Med. 2017; 6(12):112; 2. Seibold MA. Ann Am Thorac Soc. 2018;15(suppl 2):S98–S102; 3. Anai M, et al. Respirology Case Rep. 2022;11(1):e01074. Image adapted from Kavanaugh JE, et al. Breathe. 2021;17(4): 210144 and Bonser LR, Erie DJ. J Clin Med. 2017; 6(12):112.

Airway Hyperresponsiveness Asthma

• ASM cells contribute to1: – Hyperresponsiveness – Narrowing – Inflammation – Remodeling

• ASM contraction releases mast cell mediators2 • ASM may also drive mucus hypersecretion3

Compressed epithelium

ASM Allergens Environmental insults

Airway inflammation Secretion of chemokines, cytokines, and growth factors

ASM proliferation

Airway hyperresponsiveness and narrowing

ASM tone

Asthma

Contractile agonists

Airway remodeling ASM mass increase

CRS is tightly linked to airway hyperresponsiveness and asthma.4 1. Camoretti-Mercado, Lockey RF. J Allergy Clin Immunol. 2021; 147(6):1983-1995; 2. Ozier A, et al. J Allergy. 2011;2011:742710; 3. Martin JG. Eur Respir J. 2018;52(2):1801166; 4. Chen F, et al. Ann Allergy Asthma Immunol. 2014;113(6):609-613. Image adapted from Camoretti-Mercado, Lockey RF. J Allergy Clin Immunol. 2021; 147(6):1983-1995.

The Unified Airway Model Clinical Presentation

The key pathophysiologic processes underlying AR, CRSwNP, and severe asthma cause epithelial inflammation, airway hyperresponsiveness, and abnormal mucus production, resulting in clinical symptoms.1,2 AR1 • Nasal itching • Sneezing

CRSwNP2 • Hyposmia/Anosmia • Facial pressure or pain that lasts >12 weeks • Sleep disturbance and fatigue

• Anterior or posterior rhinorrhea • Nasal congestion/obstruction

1. Seidman MD, et al. Otolaryngol Head Neck Surg. 2015;152(1 suppl):S1-S42; 2. Pelaia C, et al. J Clin Med. 2023;12(10):3371.

Asthma2 • Shortness of breath • Chest tightness or pain • Expiratory wheeze • Cough

ADDRESSING CHALLENGES IN BIOLOGIC-BASED MANAGEMENT OF CHRONIC INFLAMMATORY UPPER AND LOWER AIRWAY DISEASES

Targeting Underlying Mechanisms of Disease

6 FDA-Approved Biologics for Asthma Agent

Target

Indication(s)

Omalizumaba

IgE

• Moderate to severe, persistent asthma inadequately controlled with ICS; (+) skin test or in vitro reactivity to aeroallergen; aged ≥6 years

Reslizumab

IL-5

• Severe asthma, eosinophilic phenotype; aged ≥18 years

Mepolizumaba

IL-5

• Severe asthma, eosinophilic phenotype; aged ≥6 years

Benralizumab

IL-5Rα

• Severe asthma, eosinophilic phenotype; aged ≥12 years

Dupilumaba

IL-4Rα

• Moderate to severe asthma, eosinophilic phenotype OR OCSdependent; aged ≥6 years

Tezepelumab

TSLP

• Severe asthma; aged ≥12 years

FDA, US Food and Drug Administration. aFDA approved for other diseases. Drugs @ FDA. https://www.accessdata.fda.gov/scripts/cder/daf/.

Targeting Underlying Mechanisms of Disease

3 FDA-Approved Biologics for Asthma and CRSwNP Agent

Target

Indication(s)

Omalizumaba

IgE

• Moderate to severe, persistent asthma inadequately controlled with ICS; (+) skin test or in vitro reactivity to aeroallergen; aged ≥6 years • CRSwNP inadequately controlled on INCS; aged ≥18 years

Reslizumab

IL-5

• Severe asthma, eosinophilic phenotype; aged ≥18 years

Mepolizumaba

IL-5

• Severe asthma, eosinophilic phenotype; aged ≥6 years • CRSwNP; aged ≥18 years

Benralizumabb

IL-5Rα

• Severe asthma, eosinophilic phenotype; aged ≥12 years

Dupilumaba

IL-4Rα

• Moderate to severe asthma, eosinophilic phenotype OR OCS-dependent; aged ≥6 years • Inadequately controlled CRSwNP; aged ≥18 years

Tezepelumab

TSLP

• Severe asthma; aged ≥12 years

INCS, intranasal corticosteroids. aFDA approved for other diseases. Drugs @ FDA. https://www.accessdata.fda.gov/scripts/cder/daf/.

Mechanisms of Action

Biologics FDA Approved for Both CRSwNP and Severe Asthma Anti-IgE

Anti–IL-5 mAb

Anti–IL-4Rα

IL-5

B cell

IL-4 Mepolizumab

IgE

IL-5Rα

βc

Dupilumab IL-4Rα

Omalizumab Mast cell

IgE binds with high affinity to mast cells and basophils mAb, monoclonal antibody. Kardas G, et al. Front Immunol. 2022;13:983852.

IL-4

IL-13

Dupilumab γc

IL-4Rα

IL-13Rα1

Eosinophil

IL-5 activates eosinophils, promoting proliferation and differentiation from bone marrow, and prolonging survival

IL-4 and IL-13 have pleiotropic effects, including goblet cell development, B-cell class switching to IgE, and T-cell differentiation (IL-4)

The Unified Airway Model

Ongoing Disease Burden and Unmet Needs Moderate to Severe AR

CRS

Asthma

No FDA-approved biologic to treat AR.

No current FDA-approved biologic specifically indicated in non-T2 CRS.

No current FDA-approved biologic specifically indicated in non-T2 asthma.

Patients with moderate to severe AR suffer from fatigue, mood changes, impaired cognitive function, depression, and anxiety.1

The presence of nasal polyps is associated with increased utilization and elevates the cost of health care.2,3

Despite multiple available biologic therapies, a substantial proportion of patients with asthma continue to experience uncontrolled disease.6

Patients with CRS struggle with the burden of anosmia and fatigue and are at increased risk for anxiety disorder and depression compared with the general population.4,5

Patients with uncontrolled asthma are at increased risk for death, have lower lung function, experience more-frequent exacerbations, suffer from high levels of medical and mental distress, and are more likely to miss work/school.7-9

1. Dierick BJH, et al. Expert Rev Pharmacoecon Outcomes Res. 2020;20(5):437-453; 2. Hunter TD, et al. J Med Econ. 2018;21(6):610-615; 3. Palmer JN, et al. Allergy Asthma Proc. 2019;40(1):48-56; 4. Kim JY, et al. J Allergy Clin Immunol Pract. 2020;8(2):721-727; 5. Nam JS, et al. Clin Otolaryngol. 2022;47(1):167-173; 6. Reibman J, et al. Ann Allergy Asthma Immunol. 2021;127(3):318-325.e2; 7. Heaney LG, et al. Chest. 2021;160(3):814-830; 7. Haselkorn T, et al. J Allergy Clin Immunol Pract. 2020;8(7):2243-2253; 8. Mullerova H, et al. J Asthma. 2021;58(4):459-470; 9. Trevor J, et al. Ann Allergy Asthma Immunol. 2021;127(5):579-587.

Targeting Underlying Mechanisms of Disease

FDA-Approved Biologics for Asthma in Ongoing Phase 3 Clinical Trials for CRSwNP Agent

Target

Indication(s)

Omalizumaba

IgE

• Moderate-to-severe, persistent asthma inadequately controlled with ICS; (+) skin test or in vitro reactivity to aeroallergen; aged ≥6 years • CRSwNP inadequately controlled on INCS; aged ≥18 years

Reslizumab

IL-5

• Severe asthma, eosinophilic phenotype; aged ≥18 years

Mepolizumaba

IL-5

• Severe asthma, eosinophilic phenotype; aged ≥6 years • CRSwNP; age ≥18 years

Benralizumabb

IL-5Rα

• Severe asthma, eosinophilic phenotype; aged ≥12 years • CRSwNP phase 3 clinical trial: ORCHID (NCT04157335)1

Dupilumaba

IL-4Rα

• Moderate-to-severe asthma, eosinophilic phenotype OR OCS-dependent; age ≥6 years • Inadequately controlled CRSwNP; aged ≥18 years

Tezepelumab

TSLP

• Severe asthma; aged ≥12 years • CRSwNP phase 3 clinical trial: WAYPOINT (NCT04851964)2

CR:, complete response letter; sBLA, supplemental biologics license. aFDA approved for other diseases; bFDA issued a CRL regarding the sBLA for benralizumab for patients with inadequately controlled CRSwNP based on the OSTRO phase 3 trial results and requested additional clinical data. 1. NCT04157335. https://clinicaltrials.gov/study/NCT04157335?cond=Chronic%20Rhinosinusitis%20With%20Nasal%20Polyps&term=benralizumab&rank=3; 2. NCT04851964. https://clinicaltrials.gov/study/NCT04851964?cond=Chronic%20Rhinosinusitis%20With%20Nasal%20Polyps&term=tezepleumab&rank=1.

Mechanisms of Action

Biologics in Late-Stage Clinical Trials for CRSwNP Tezepelumab1,a Viruses

Allergens

Pollutants

Tezepelumab Allergic Inflammation

Anti-TSLP Bacteria

Eosinophilic Inflammation

Th0

IL-5R

IL-13 Mast Cell

Dendritic Cell

IL-5

IL-4 IL-13 IgE

Other External Stimuli

Neutrophilic Inflammation

ILC2

Th2

B Cell

Physical Injury

Anti–IL-5 mAb IL-5

TSLP

Dendritic Cell Th0

Benralizumab

Leukotrienes

IL-17A

βc

Benralizumab

Th17

Eosinophil IL-13

IL-5Rα

Neutrophil Airway Smooth Muscle Cells

aTezepelumab is also in an ongoing clinical trial evaluating its efficacy in patients with comorbid asthma and AR.

1. Menzies-Gow A, et al. Respir Res. 2020;21(1):266; 2. Kardas G, et al. Front Immunol. 2022;13:983852.

Eosinophil

IL-5 activates eosinophils, promoting proliferation and differentiation from bone marrow, amd prolonging survival2

Targeting Underlying Mechanisms of Disease

Potential Biologics for Patients With AR Agent

Target

Potential Use

Omalizumab

IgE

• Adjunct to allergen immunotherapy in the treatment of AR1

Tezepelumab

TSLP

• Comorbid AR and asthma phase 2 clinical trial: TEZARS (NCT06189742)2

1. Dantzer JA, Wood RA. Clin Exp Allergy. 2018;48(3):232-240; 2. NCT06189742. https://clinicaltrials.gov/study/NCT06189742?cond=Allergic%20Rhinitis&term=tezepleumab&rank=1.

Patient Selection for Biologic Therapy

EPOS/EUFOREA 2023 Criteria for Biologic Treatment in CRSwNP Presence of Bilateral Polyps in a Patient Who Had FESS 3 Criteria Are Required

Criteria Evidence of T2 inflammation

Need for OCS or contraindication to OCS Significantly impaired QoL Significant loss of smell Diagnosis of comorbid asthma hpf, high-powered field; QoL, quality of life. Fokkens WJ, et al. Rhinology. 2020;58(suppl S29):1-464.

Cutoff Points Tissue eosinophils ≥10/hpf OR Blood eosinophils ≥250 cells/µL OR Total IgE ≥100 IU/mL ≥2 courses/year OR Long-term (>3 months) low-dose OCS SNOT-22 ≥40 Anosmic on smell test Regular need for ICS

Nasal Polyp Recurrence After FESS Mean Endoscopy Score

CRSwNP

Total

Polyp Edema

8 6 4 2 0

Preoperative (n=244)

6 months (n=197)

12 months (n=125)

Postoperative polyp recurrence occurs in ~40% of patients within 18 months. DeConde AS, et al. Laryngoscope. 2017;127(3):550-555.

18 months (n=129)

Preoperative Predictors of Nasal Polyp Recurrence CRSwNP

• Preoperative symptom score (eg, SNOT-22) is a good predictor of postoperative outcome1 • When loss of smell is a major symptom, improvement in olfactory function with OCS use predicts positive outcome of surgery1

• Comorbid asthma and AERD2 • S aureus superantigen2 • Eosinophilic infiltration2 • Biofilms and neutrophilic infiltrate2 • Lack of adherence to inhaled nasal corticosteroids2

• Primary surgery has better outcomes than revision surgery1 1. Fokkens WJ, et al. Rhinology. 2020;58(suppl S29):1-464; 2. De Corso E, et al. Am J of Rhinol Allergy. 2021;35(1):77-85.

How Many Surgeries Is Too Many?

When to Start Biologics in Recurrent CRSwNP Analyze Possible Therapeutic Options and Factors Influencing Decision

• Evaluate patient perspectives and expectations • Involve the patient in the decision • Educate of the patient

Factors Orienting Toward Surgery

• Good long-term disease control after previous surgery • Patient refusing long-term biologic therapy • Previous surgical sequelae that require revision surgery (eg, synechiae, mucocele, persistent septal deviation limiting penetration of topical steroids)

Adequate Initial Surgery

Revision Surgery May Be Proposed

YES

Biologic Therapy

• Define goal of surgery • Define approach based on the endotype • Personalize follow-up • Provide adequate postoperative medical therapy

Severe Asthma

No Severe Asthma

Discuss the clinical case in a multidisciplinary board

Choose biologics tailored to the patient’s endotype

In case of uncontrolled disease or recurrence

Possibility of salvage surgery or shift to another biologic, in case of uncontrolled disease

CSF, cerebrospinal fluid; GA, general anesthesia. De Corso E, et al. Acta Otorhinolaryngol Ital. 2023;43(Suppl 1):S3-S13.

Factors Orienting Toward Biologic

• Recurrence <3 years from previous surgery • Inadequate control of symptoms after previous surgery, in particular in case of smell impairment • Multiple previous surgeries • Severe complications (eg, CSF leak) • Clear predictors of failure (eg, NSAID-ERD) • Patient not fit for surgery (eg, coagulation disorders, contraindications to GA)

Patient Selection for Biologic Therapy

EPOS/EUFOREA 2023 Criteria for Biologic Treatment in CRSwNP Presence of Bilateral Polyps in a Patient Who Had FESS 3 Criteria Are Required

Criteria Evidence of T2 inflammation

Need for OCS or contraindication to OCS Significantly impaired QoL Significant loss of smell Diagnosis of comorbid asthma Fokkens WJ, et al. Rhinology. 2020;58(suppl S29):1-464.

Biomarkers

T2-High Inflammation Blood eosinophils

FeNO

IgE

≥150 cells/µL

≥20 ppb

Specific IgE, + skin prick

Biomarkers for T2-low inflammation have yet to be established. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. 2023. https://ginasthma.org.

What Can Biomarkers Tell Us? Asthma

 Diagnostic biomarkers – Screening (lung function) and identifying endotypes (IgE, blood eosinophils, FeNO)

 Prognostic biomarkers – Assessing severity (lung function)

 Predictive biomarkers – Biologic initiation (blood eosinophils, FeNO)

In severe asthma, biomarkers are particularly useful for identifying endotypes and predicting response to therapy. Wan XC, Woodruff PG. Immunol Allergy Clin North Am. 2016;36(3):547-557.

Patient Selection for Biologic Therapy

EPOS/EUFOREA 2023 Criteria for Biologic Treatment in CRSwNP Presence of Bilateral Polyps in a Patient Who Had FESS 3 Criteria Are Required

Criteria Evidence of T2 inflammation

Need for OCS or contraindication to OCS Significantly impaired QoL Significant loss of smell Diagnosis of comorbid asthma Fokkens WJ, et al. Rhinology. 2020;58(suppl S29):1-464.

Systemic Corticosteroid–Related Toxicities Numerous Body Systems Affected1-4

Cataracts Bruising Weight gain Muscle mass loss

Cerebrovascular disease Sleep apnea Infections Fractures VTE

Depression Anxiety Insomnia Dyspeptic disorders T2DM Osteoporosis

Acne Hypertension Renal impairment Adrenal insufficiency And more…

As little as 1 course of OCS/year on top of background high-dose ICS results in a statistically significant increase in OCS-induced morbidity.5 T2DM, type 2 diabetes mellitus; VTE, venous thromboembolism. 1. Sweeney J, et al. Thorax. 2016;71(4):339-346; 2. Sullivan PW, et al. J Allergy Clin Immunol. 2018;141(1):110-116.e7; 3. Price DB, et al. J Asthma Allergy. 2018;11:193-204; 4. Dalal AA, et al. J Manag Care Spec Pharm. 2016;22(7):833-847; 5. McDowell PJ, et al. Curr Treat Options Allergy. 2023;10:53-63.

Oral Corticosteroid Use How Much Is Too Much?

• >7 to 15 mg/day prednisone equivalent for >30 days is associated with the largest incidence of fractures1

– The incidence of other adverse events increases as OCS dose increases

• Recent updates to international guidelines in rheumatology recommend withdrawal of OCS when feasible2 – If OCS withdrawal is not possible:

• Short-term use of OCS as bridging therapy to control symptoms while waiting for immunosuppressive/biologic therapy to start working2 • ≤5 mg/day prednisone equivalent maintenance doses of OCS2

Effective communication is necessary among multidisciplinary providers to limit the overall OCS usage for each patient.

1. Manson SC, et al. Respir Med. 2009;103(7):975-994; 2. Fanouriakis A, et al. Ann Rheum Dis. 2024;83(1):15-29.

Patient Selection for Biologic Therapy

EPOS/EUFOREA 2023 Criteria for Biologic Treatment in CRSwNP Presence of Bilateral Polyps in a Patient Who Had FESS 3 Criteria Are Required

Criteria Evidence of T2 inflammation

Need for OCS or contraindication to OCS Significantly impaired QoL Significant loss of smell Diagnosis of comorbid asthma Fokkens WJ, et al. Rhinology. 2020;58(suppl S29):1-464.

Mucus Plugging Asthma

A greater degree of mucus plugging is associated with:  Increased airway obstruction1  Increased need for more asthma medication1  More-frequent asthma exacerbations1  Increased risk of persistent airway infections2

1. Chan R, et al. J Allergy Clin Immunol Pract. 2023;11(1):195-199; 2. Georas SN. J Clin Invest. 2018;128(3):906-909.

Assessing for Mucus Plugs Asthma

Visual scoring system based on the presence or absence of mucus plugs in each of the 20 bronchopulmonary segments on CT1 Mucus Score Rating1

Number of Lung Segments With Observed Mucus Plugging1

Low

>0 to 3.5

High

4 to 20

High mucus scores correlate with reductions in FEV1 and FVC that do not normalize with treatment, as well as with high RV/TLC, which is indicative of air trapping.2 FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity. 1. Dunican EM, et al. Ann Am Thorac Soc. 2018;15(suppl 3):S184-S191; 2. Dunican EM, et al. J Clin Invest. 2018;128(3):997-1009.

SUSTAINED REMISSION AND DISEASE MODIFICATION OF CHRONIC INFLAMMATORY AIRWAY DISEASE

EPOS 2020/EUFOREA Consensus Definitions for Treatment Goals Absence of Symptoms and Signs of Active Disease

CRSwNP

CURE

Sustained remission for >5 years

REMISSION

CONTROL

No symptoms/no endoscopic signs of active disease for ≥12 months

Absence of symptoms in the last month

On Treatment Fokkens WJ, et al. Rhinology. 2024. Online ahead of print.

Persistent Treatment

Off Treatment

How to Define a Response to Biologic Therapy CRSwNP

Defining Response to Biologic Treatment in CRSwNP Evaluation of 5 criteriaa:

• Reduced nasal polyp size (≥1) • Reduced need for OCS/salvage surgery • Improved quality of life (SNOT-22 <40 + >MCID) • Improved sense of smell (hyposmic by semi-objective smell test) • Reduced impact of comorbidities (defined by MCID for specific T2 disease test) Evaluate Treatment Response After 6 Months Evaluate Treatment Response After 12 Months aCutoff values for research purposes only.

MCID, minimum clinically important difference. Fokkens WJ, et al. Rhinology. 2024. Online ahead of print.

Re-evaluate before continuing:

Good-Excellent Response 4-5 criteria

• Reconsider diagnosis • Identify treatment traits

Moderate Response 2-3 criteria No-Poor Response 0-1 criteria

Consider:

• Discontinuing/Switching biologic • Salvage surgery (covered by biologic)

Disease Modification CRSwNP

Key Definitions in CRSwNP Treatable Traits

Co-existing conditions and, hence, therapeutic targets that can be identified by patient phenotype and/or endotype.

Remodeling

The persistent structural cell/tissue changes that manifest clinically. It results from host and environmental factors that may initiate and sustain the cascade of pro-inflammatory responses, related to duration of the disease and long-term uncontrolled inflammation, that drive sinonasal mucosal remodeling and nasal polyp formation.

Disease Modification

A treatment or intervention that affects the underlying pathophysiology of the disease and has a beneficial outcome on the course of the disease or slows down the progress of the disease.

Fokkens WJ, et al. Rhinology. 2024. Online ahead of print.

Consensus Definition for Clinical Remission in Asthma Modified Delphi Survey Approach

All the following criteria must be met for ≥12 months, with or without asthma treatment: 1. Sustained absence of significant asthma symptoms, based on validated instrument 2. Optimization and stabilization of lung function 3. Patient and HCP agreement regarding disease remission 4. No use of OCS therapy for exacerbation treatment or long-term disease control

HCP, healthcare provider. Menzies-Gow A, et al. J Allergy Clin Immunol. 2020;145(3):757-765.

ACAAI/AAAAI/ATS Criteria for Clinical Remission on Treatment Asthma

All the following criteria must be met over a 12-month period and may be applied to those receiving mAb therapy (biologic) for asthma: 1. NO exacerbations requiring a physician visit, emergency care, hospitalization, and/or OCS for asthma (ie, oral, injectable) 2. NO missed work or school over a 12-month period due to asthma-related symptoms 3. Stable and optimized pulmonary function results on all occasions, when measured over a 12-month period, with ≥2 measurements during the year 4. Continued use of controller therapies (ICS, ICS/LABA, leukotriene receptor antagonist) ONLY at lowmedium dose of ICS, or less, as defined by the most recent GINA strategy 5. ACT >20, AirQ <2, ACQ <0.75 on all occasions measured in the previous 12-month period, with ≥2 measurements during the year 6. Symptoms requiring 1-time reliever therapy (SABA ,ICS/SABA ,ICS/LABA) no more than once a month

AAAAI, American Academy of Allergy, Asthma & Immunology; ACAAI, American College of Allergy, Asthma and Immunology; ACT, Asthma Control Test; ACQ, Asthma Control Questionnaire; AirQ, Asthma Impairment and Risk Questionnaire; ATS, American Thoracic Society; SABA, short-acting beta-agonist. Blaiss M, et al. Ann Allergy Asthma Immunol. 2023;131:782-785.

Studies of Biologics for Clinical Remission Asthma

Criteria for Remission

Dupilumab 2021 QUEST Phase 3

Absence of symptomsa,b AND

Benralizumab

Tezepelumab

Mepolizumab

Multiple Biologics 2022 Danish Registry

2022 ANDHI Phase 3b

2023 XALOC-1

2022 NAVIGATOR Phase 3

2022 REDES

2022 CHRONICLE

ACQ-6 <1.5 or ≤0.75

ACQ-5 <1.5 or ACT ≥16

ACQ-6 ≤1.5a,b

ACT ≥20

Majority ≥50% ACQ ≤1.5 ACT ≥20

Not included

Pre-BD FEV1pp >80% OR Pre-BD FEV1 >20% from baseline; FEV1 >95% of baselined

Not included

Post-BD FEV1pp ≥80%

2022 2022 SIROCCO/ TRAVERSE CALIMA Phase 3 OLE

ACQ-5 <1.5

Optimized/stabilized lung function AND

Post-BD FEV1 pp ≥80%

Post-BD FEV1 ≥80% OR pre-BD FEV1 ≥100 mL

Pre-BD FEV1 increase ≥100 mL

No exacerbations; no OCSc



e



Prevalence of clinical remission

31.7%

36.4%

26.3%

28.7%

43%

14%-28.5%d

37%

35%

19%

aSustained absence of significant asthma symptoms based on validated instrument; bThere should be agreement between the HCP and patient regarding symptom improvement and remission;

cNo OCS use for exacerbations OR long-term disease control; dIncludes agreement between physician and patient assessments of control (CGI-C; Patient Global Impression of Severity); eIn this

analysis, exacerbations and OCS use were individually evaluated. BD, bronchodilator; CGI-C, clinical global impression of change; OLE, open-label extension; pp, percent predicted. Adapted from: Lugogo NL, et al. Chest. 2023;164(4):831-834.

Asthma Suppression After Cessation of Tezepelumab Severe Asthma

Tezepelumab may have a disease-modifying role in asthma

Although the sustained effects of tezepelumab gradually decreased after stopping treatment, neither the biomarkersa nor the clinical effectsb returned to baseline after 9 months since the last dose.

DESTINATION was a multicenter, randomized, placebo-controlled, double-blind, extension study of patients (aged 12-80 years) who completed NAVIGATOR or SOURCE clinical trials. After tezepelumab cessation at week 104, patients who initially enrolled in NAVIGATOR could enter a 36-week off-treatment extended follow-up. Change over time in ACQ-6 score, blood eosinophil count, FeNO levels, and prebronchodilator FEV1 was assessed in 569 patients. aBiomarkers include blood eosinophil count and FeNO levels; bClinical effects included change over time in ACQ-6 score and prebronchodilator FEV . 1 Brightling CE, et al. Eur Respir J. 2023; 62(suppl.67):OA1415.

Key Takeaways • Upper and lower airway inflammatory diseases are closely related and frequently coexist in the same patients • Patients who suffer from comorbid upper and lower airway diseases suffer from more-severe disease that is difficult to treat compared to those with upper OR lower airway disease

• Biologic therapy has demonstrated efficacy and safety in the treatment of severe asthma and CRSwNP, and new targeted biologics show promise in improving patient outcomes even more • A multidisciplinary approach that combines the expertise of allergists/immunologists, otolaryngologists, and pulmonologists is critical to caring for patients with chronic inflammatory airway disease