The Many Faces of Ige-Mediated Disease – a Symposia Series

The many faces of IgE-mediated disease – a symposia series

EAACI 2021 Congress 10th, 11th & 12th July − lunchtime symposia

Chaired by: Professor Marcus Maurer

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On IgE in asthma and nasal polyposis: your questions answered demand

On IgE-mediated food allergy: need for a revolution demand

Complete control of CSU - mission (im)possible? Mon 12 13:00 July CEST

Chaired by: Prof. Marcus Maurer Complete control of CSU – Mission (im)possible? Professor Marcus Maurer Professor Zenon Brzoza Charité - Universitätsmedizin Berlin, Germany University Hospital in Opole, Poland Housekeeping ?

Please use the chat The recording will be Please scan the QR code function to submit available to watch after to complete the questions to the faculty the virtual symposium evaluation form Marcus Maurer Charité - Universitätsmedizin Berlin, Germany

Professor Maurer is Professor of Dermatology and Allergy and Head of Dermatological Allergology at the Department of Dermatology and Allergy and Allergie-Centrum-Charité, Charité - Universitätsmedizin Berlin

Zenon Brzoza University Hospital in Opole, Poland

Professor Brzoza is a specialist in internal diseases and allergology and Head of the Department of Internal Diseases with Division of Allergology at the University Hospital in Opole Disclosures

§ Marcus Maurer is or was a § Zenon Brzoza is or was a speaker speaker and/or advisor for Allakos, and/or advisor for Novartis and Almirall Hermal, Amgen, Bayer, AstraZeneca. BioCryst, Blueprint, CellDex, Dyax, FAES, Genentech, GIInnovation, Innate Pharma, Leo, Lilly, Merckle Recordati, Kyowa Kirin, Moxie, MSD, Novartis, Pharvaris, Riemser, Sanofi Aventis, Shire, Takeda, Third Harmonic Bio, Tribute Pharmaceuticals, UCB, and Uriach. Over 50 years of IgE: key milestones

Phase III trials of anti- Receptor of human Role of IgE in Structure of the high- Phase III trials of anti- IgE omalizumab in IgE (FcεRI) found histamine release affinity IgE receptor IgE omalizumab in chronic spontaneous on basophils2 understood2 (FcεRI) determined2 allergic asthma4-6 urticaria7-9 1970 1970s 1989 2001 − 2005 2013 − 2015

1966-7 2002 2020 IgE IgE Phase III trials of discovered1 structure anti-IgE omalizumab described3 in nasal polyposis10

FcεRI, high-affinity IgE receptor; IgE, immunoglobulin E

1. Johansson SG. Curr Allergy Asthma Rep 2011;11:173–7; 2. Saito H, et al. Allergol Int 2013;62:3–12; 3. Wan T, et al. Nat Immunol 2002;3:681–6; 4. Busse WW, et al. J Allergy Clin Immunol 2001;108(2):184–190; 5. Solèr M, et al. Eur Respir J. 2001;18(2):254–261; 6. Humbert M, et al. Allergy 2005;60:309–316; 7. Kaplan A et al. J Allergy Clin Immunol. 2013;132(1):101–109;.8. Maurer M et al. N Engl J Med 2013;368:924–935; 9. Saini SS et al. J Invest Dermatol. 2015;135(1):67–75; 10. Gevaert et al. J Allergy Clin Immunol 2020;146:595-60520 IgE plays a role in many diseases Mastocytosis Allergic rhinitis Vernal Allergic Bronchopulmonary keratoconjunctivitis Aspergillosis

Nasal polyposis Food allergy

Atopic Eosinophilic dermatitis gastroenteritis IgE Allergic Chronic asthma spontaneous urticaria

Allergic fungal Bullous Pemphigoid / rhinosinusitis Pemphigus vulgaris

Chronic inducible Systemic lupus Eosinophilic urticaria Navinés-Ferrer A, et al. J Immunol Res. 2016; 8163803. erythematosus Humbert M et al. J Allergy Clin Immunol Pract 2019;7:1418-29 eosophagitis The many faces of IgE in allergic and non- allergic disease

Food Allergy / Allergic asthma CSU FcεRI receptor Antigen T CELL specific IgE Granules

Mediators Autoreactive IgE Self-antigen

MAST CELL Antigen B CELL Local IgE SA enterotoxin

IgE T CELL IgG Nasal polyposis

FcεRI, high-affinity IgE receptor; IgE/G, immunoglobulin E/G 1. Wernersson S and Pejler G. Nat Rev Immunol. 2014;14:478–94; 2. Kaplan A and Greaves M. Clin Exp Allergy. 2009;39:777–87; 3. Bachert C, et al. J Allergy Clin Immunol. 2021: In Press The goal of CSU treatment is to treat the disease until it is gone

We recommend aiming at Consensus-based complete symptom control in urticaria, considering as much as possible the safety and the quality 90% of life of each individual patient

EAACI/GA²LEN/EDF/WAO guidelines (2018)

Zuberbier T, et al. Allergy. 2018;73:1393–414 Targeting complete response of CSU

No disease activity Disease control (no wheals, no itch, (complete control) no angioedema)

Complete response

Normal QoL (no impact on QoL)

QoL, quality of life Symptom severity (UAS7) is associated with least impact on QoL…

P<0.0001 16 13.8 (0.3) 14

12 P<0.0001

10 8.9 (0.3)

8 P<0.0001 6 5.6 (0.4) P=0.0003 LS Mean (SE) of LS Mean DLQI total score DLQI total 4 2.3 (0.4) 2 0.8 (0.4) 0 CompleteNo control Well-controlled Mild activity Moderate activity Severe activity activity activity UAS7 disease state UAS7=0 UAS7=1–6 UAS7=7–15 UAS7=16–27 UAS7=28–42

In patients at Week 20 of the Phase IIb QGE031C2201 study DLQI, dermatology life quality index; LS mean, least squares mean; QoL, quality of life; SE, standard error; UAS7, weekly urticaria score Giménez-Arnau AM, et al. EADV 2020 …and less sleep interference

P<0.0001

12 10.9 (0.2)

10 P<0.0001 8 5.8 (0.2) 6 P<0.0001

4 P<0.0001 2.9 (0.2)

LS Mean (SE) of WSI score LS Mean 2 1.0 (0.2) 0.2 (0.2) 0 CompleteNo control Well-controlled Mild activity Moderate activity Severe activity activity activity UAS7 disease state UAS7=0 UAS7=1–6 UAS7=7–15 UAS7=16–27 UAS7=28–42

In patients at Week 20 of the Phase IIb QGE031C2201 study LS mean, least squares mean; SE, standard error; UAS7, weekly urticaria score; WSI, Weekly Sleep Interference Maurer M, et al. AAD 2021. Virtual Meeting Experience Why do our How can patients fail to targeting IgE help reach complete to achieve the response? aim of treatment?

IgE, immunoglobulin E Why do our patients fail to reach complete response? Unmet needs persist despite available treatments

Poor adherence to Delays in referral treatment guidelines

Incomplete control of urticaria Delays in diagnosis/ Limited treatment misdiagnosis options

Maurer M, et al. Allergy. 2017;72:2005–16; Maurer M, et al. Clin Exp Allergy. 2019;49:655‒62 Why the misdiagnosis or delay in diagnosis? ASSURE-CSU Incorrect or incomplete diagnosis leads to inappropriate or suboptimal treatment

§ In ASSURE-CSU real-world study, diagnosis took an average of 24 months from symptoms onset

Mean (SD) age at symptom onset: 42.3 (16.5) years 2 years Mean (SD) age at diagnosis: 44.2 (15.9) years

4.8 years Mean (SD) age at enrollment: 48.8 (15.5) years

§ Mean (SD) disease duration from symptom onset to diagnosis was 24 (63) months and mean disease duration was 4.8 years, illustrating the significant burden of CSU on patients and healthcare systems as a result of a suboptimal patient journey

SD, standard deviation Maurer M, et al. Allergy. 2017;72:2005–16 Physicians may not be aware of the best practice for diagnosis of CSU

§ Physicians may mistake symptoms for an allergy and search in the wrong direction § There is often a considerable delay before patients are referred to a specialist § Physicians may not use photos and other tools to help their diagnosis § Physicians often do not take into account coexisting angioedema or inducible urticarias symptoms as factors negatively influencing successful treatment

Giménez-Arnau A, et al. J Eur Acad Dermatol Venerol. 2015;29(Suppl 3):3–11 International guidelines provide an algorithm to guide diagnosis of specific chronic urticaria subtypes

Wheals Angioedema

Recurrent unexplained fever? Joint/bone pain? Malaise ACE inhibitors treatment? History

Autoinflammatory disease? Average wheal duration >24h? HAE or AAE? Remission after stop? Diagnostic

Signs of vasculitis in biopsy? Are symptoms inducible? tests

Provocation Test Treatment

Chronic spontaneous Chronic inducible ACE-Inh induced Acquired/ hereditary AID10 Urticarial vasculitis HAE I-III AAE urticaria urticaria AE

Histamine and other mast cell Interleukin-1 Bradykinin mediators

AAE, Acquired angioedema due to C1-inhibitor deficiency; ACE-Inh, angiotensin-converting enzyme inhibitor; AE, angioedema; AID, auto-inflammatory disease; HAE, hereditary angioedema Zuberbier T, et al. Allergy. 2018;73:1393–414 Why might diagnosed patients not receive optimal treatment? Many physicians do not adhere to international urticaria guidelines ~40% of physicians report deviating from international guidelines

~80% of physicians report deviating from national guidelines

Kolkhir P, et al. World Allergy Organ J. 2018;11(1):14 The goal of the international urticaria guidelines is to treat till the disease is gone First Line Approved dose 2nd generation

H1-antihistamines (2G H1-AH) Insufficient control: in 2–4 weeks* (or sooner if symptoms are intolerable) Second Line to specialist Increase dose up to 4-fold 2G H1-AH Consider referral

Insufficient control: in 2–4 weeks* (or sooner if symptoms are intolerable)

Third Line H1-AH can be Add on to 2G H1-AH: Omalizumab maintained alongside Insufficient control: within 6 months* omalizumab or (or sooner if symptoms are intolerable) ciclosporine A treatment) of the specialist Fourth Line Under the supervision Add on to 2G H1-AH: Ciclosporine

NOTE: Short course (max. 10 days) of corticosteroids may also be used at all times if exacerbations demand this

*Response measured as (clinically) significant improvement in different scores (not UAS7) The therapeutic algorithm remains the same for inducible urticarias. Montelukast is excluded in the 2018 update

H1-AH, H1-antihistamines; UAS7, weekly urticaria score Zuberbier T, et al. Allergy. 2018;73:1393–414 Guidelines recommend the use of the UAS7, UCT and CU-Q2oL to track treatment success

We recommend that patients with CSU be assessed for disease activity, impact, and control at every visit (consensus-based)

Disease activity QoL impairment Disease control

The Urticaria Activity Score (UAS7) and The CU-Q oL and AE-QoL are The Urticaria Control Test (UCT) is Angioedema Activity Score (AAS) are 2 recommended for assessing quality of recommended for assessing disease recommended for assessing disease life impairment in patients with CSU control in patients with activity in patients with CSU (consensus- (consensus-based) CSU (consensus-based) based)

However, physicians may not use the correct tools to identify patients who do not reach complete control or use the results to inform treatment decisions

AE-QoL, Angioedema Quality of Life questionnaire; CU-Q2oL, Chronic Urticaria Quality of Life Questionnaire; PRO, patient-reported outcome; QoL, quality of life Zuberbier T, et al. Allergy. 2018;73:1393–414 AWARE RWE shows that the majority of CSU patients receiving standard-dosed H1-AHs are not escalated to up-dosed H1-AHs despite uncontrolled disease

Percentage of patients (UCT <12) escalated to up-dosed H1-AHs following no response to the approved H1-AH dose

Baseline 3 month visit 6 month visit 9 month visit 12 month visit

5.6% 1.6% 0% 6.7% 0%

11/195 2/124 0/90 5/75 0/66 patients patients patients patients patients

H1-AH, H1-antihistamines; RWE, real world evidence; UCT, Urticaria Control Test Maurer M, et al. Clin Exp Allergy. 2019;49:655‒62 There is little evidence for the efficacy of switching from one H1-AH to another H1-AH, and combining of H1-AHs is less effective than up-dosing

100

80 Desloratadine 60 Levocetirizine Fexofenadine 40 Azelastine in prutitus (%) prutitus in Mean Mean reduction 20 Levocetirizine Fexofenadine

0 Double Triple Up-dosed combination combination H1-AH (n=16) (n=38) (n=13)

H1-AH, H1-antihistamines Schulz S, et al. Hautarzt. 2009;60:564‒8 Escalation of H1-AH dose improves treatment responses, but a large majority of patients still do not achieve good control of CSU

Effectiveness of up-dosing with H1-AH compared with standard dose therapy Chart Title 100% 10% 8% 12% 80% 30% 35% Equal or less good 47% 60% Slightly better Significantly better 29% Patients 40% 37% Symptom-free only during up-dosing 20% 20% 23% 28% 21% 0% 2 tablets daily 3 tablets daily 4 tablets daily (n=108) (n=72) (n=85)

H1-AH, H1-antihistamines Weller K, et al. PLoS One. 2011;6:e23931 AWARE RWE evidence shows that approximately 90% of patients did not receive biologic treatment despite being uncontrolled Percentage of patients (UCT <12) escalated to biologic treatment following no response to up-dosed H1-AHs

Baseline 3 month visit 6 month visit 9 month visit 12 month visit

11.1% 1.1% 1.5% 1.9% 0%

37/333 2/187 2/132 2/106 0/109 patients patients patients patients patients

H1-AH, H1-antihistamines; RWE, real world evidence; UCT, Urticaria Control Test Maurer M, et al. Clin Exp Allergy. 2019;49:655‒62 What can we do to improve outcomes for patients, to ensure as many as possible achieve complete control?? UCARE centres and referral networks play a key role in improving patient care

The UCARE network and Centers of Reference and Excellence for speciﬁc diseases can help to improve the management of CSU

§ Serve as referral and second opinion centers for difficult-to-treat patients § Improve understanding of management options, knowledge, and awareness of diseases by research, clinical studies, education, and advocacy activities

CSU, chronic spontaneous urticaria Maurer M, et al. Allergy. 2016;71:1210–1218 Adhering to treatment guidelines is key in improving patient outcomes First Line Approved dose 2nd generation

H1-antihistamines (2G H1-AH) Insufficient control: in 2–4 weeks* (or sooner if symptoms are intolerable) Second Line to specialist Increase dose up to 4-fold 2G H1-AH Consider referral

Insufficient control: in 2–4 weeks* (or sooner if symptoms are intolerable)

NOTE: Short course (max. 10 days) of corticosteroids may also be used at all times if exacerbations demand this

H1-AH, H1-antihistamines; UAS7, weekly urticaria score Zuberbier T, et al. Allergy. 2018;73:1393–414 AWARE RWE shows that progressing patients to the next-line of recommended treatment is associated with an improvement in UCT scores

UCT scores before and after UCT scores before and after escalation to up-dosed H1-AHs escalation to biologics

15 12.6 15 14.0 12 11.7 9.5 12 11.0 8.8 9 9.0 9.0 7.5 6.8 9 6 5.4 6.0 6 5.0 4.1 UCT score UCT 3 score UCT 3 NA‡ NA‡ NA‡ 0 0 Baseline 3 months 6 months 9 months 12 months Baseline 3 months 6 months 9 months 12 months

Before H1-AH updosing After H1-AH updosing Before escalation to biologic After escalation to biologics

‡No patients were escalated at this visit H1-AH, H1-antihistamines; NA, not applicable; RWE, real world evidence; UCT, Urticaria Control Test Maurer M, et al. Clin Exp Allergy. 2019;49:655‒62 How can targeting IgE help to achieve the aim of treatment? Marcus Maurer What is the pathophysiological basis of CSU? CSU symptoms occur as a result of mast cell activation driven by activation of the FcεRI pathway

CAUSES MODULATORS

Type I autoimmune response Stress (also referred to as autoallergic)1 Mast cell activation/ Food degranulation Type IIb autoimmune response1,2 Infections

CSU symptoms: Hives, itch and/or angioedema

CSU, chronic spontaneous urticaria; FcεRI, high-affinity IgE receptor 1. Kolkhir P, et al. J Allergy Clin Immunol. 2017;139:1772–81; 2. Kaplan A and Greaves M. Clin Exp Allergy. 2009;39:777–87 Mast cell activation by auto antigen crosslinking of FcεRI-bound IgE

MAST Type I autoimmune response1–4 CELL Auto antigen (autoallergic) Immunoglobulin E (IgE) FcεRI receptor § Crosslinking induced by auto Granules

BTK antigens (e.g., IL-24, TPO) Mediators recognized by IgE (>50% of patients)

HISTAMINES, CYTOKINES, CHEMOKINES, PROTEASES, ETC.

CSU SYMPTOMS: ITCH, HIVES, ANGIOEDEMA

BTK, Bruton’s tyrosine kinase; CSU, chronic spontaneous urticaria; CU, chronic urticaria; FcεRI, high affinity IgE receptor; IgE, immunoglobulin E; IL, interleukin; TPO, thyroid peroxidase 1. Wernersson S and Pejler G. Nat Rev Immunol. 2014;478–94; 2. Kaplan A and Greaves M. Clin Exp Allergy. 2009;39:777–87; 3. Metz M and Maurer M. Curr Opin Allergy Clin Immunol. 2012;12:406–11; 4. Schmetzer O, et al. J Allergy Clin Immunol. 2018;142:876–82 Mast cell activation by IgG anti-FcεRI crosslinking of FcεRI

MAST Type IIb autoimmune response CELL Immunoglobulin G (IgG) Immunoglobulin E (IgE)

§ Crosslinking induced by IgG anti FcεRI receptor

FcεRI (35‒40% of patients) Granules

BTK Mediators

HISTAMINES, CYTOKINES, CHEMOKINES, PROTEASES, ETC.

CSU SYMPTOMS: ITCH, HIVES, ANGIOEDEMA

BTK, Bruton’s tyrosine kinase; CSU, chronic spontaneous urticaria; FcεRI, high affinity IgE receptor; IgE/G, immunoglobulin E/G Kaplan A and Greaves M. Clin Exp Allergy. 2009;39:777–87 Mast cell activation by IgG anti-IgE cross-linking FcεRI-bound IgE

MAST Type IIb autoimmune response CELL Immunoglobulin G (IgG) Immunoglobulin E (IgE)

§ Crosslinking induced by IgG anti FcεRI receptor

FcεRI (35–40% of patients) Granules

BTK § Crosslinking induced by IgG anti- Mediators IgE (5–10% of patients)

HISTAMINES, CYTOKINES, CHEMOKINES, PROTEASES, ETC.

CSU SYMPTOMS: ITCH, HIVES, ANGIOEDEMA

BTK, Bruton’s tyrosine kinase; CSU, chronic spontaneous urticaria; FcεRI, high affinity IgE receptor; IgE/G, immunoglobulin E/G Kaplan A and Greaves M. Clin Exp Allergy. 2009;39:777–87 What therapies are being explored to target the pathophysiology of CSU? CSU has a complex pathophysiology, with many potential therapeutic targets

Image adapted from Kocaturk E, et al. 2017 BTK, Bruton’s tyrosine kinase; CRTH, chemoattractant receptor-homologous molecule expressed on Th2 cells (DP2); H1/4R, histamine 1/4 receptor; Ig, immunoglobulin; IgE, immunoglobulin E; IL, interleukin; LTR, leukotriene receptor; NK, neurokinin; C5, complement 5; PI3 K, phosphoinositide 3-kinase; S1P, sphingosine-1-phosphate; SHIP, SH2-containing inositol phosphatase 1; Syk, spleen tyrosine kinase; TSLP, thymic stromal lymphopoietin aCurrently available, bunder investigation, chypothetical 1. Kocatürk E, et al. Clin Transl Allergy. 2017;7:1; 2. Kolkhir P, et al. J Allergy Clin Immunol. 2017;139:1772–81; 3. Arm J, et al. Clin Exp Allergy. 2014;44:1371–85; 4. Min T and Saini S. Allergic Asthma Immunol Res. 2019;11:470–81. Many of the therapeutic targets can be found in the mast cell activation pathway

TSLPc FcγRIIb1 C5ac Currently hypothetical FcyRIIBc BTK2 Receptor- CD300a1 • Remibrutinib C5aR bound IgE • Fenebrutinib c SHIP-1 Currently hypothetical CRTH2c P13K • RN473 CD300ac NK-1Rc c 1 Syk Siglec-8 Siglec-8 BTK IL-4Rc S1P • Lirentelimab (AK002)

MAST IL4-R1 CELL • Dupilumab free IgEb IL-11 • Canakinumab Leukotrienes1 histamine c • Anakinra TNF leukotrienesa • Montelukast IL-1b prostaglandin other cytokinesc *Omalizumab is approved for the treatment of CSU. aCurrently available, bunder investigation, chypothetical BTK, Bruton’s tyrosine kinase; CRTH, chemoattractant receptor-homologous molecule expressed on Th2 cells (DP2); CSU, chronic spontaneous urticaria; C5, complement 5; IgE, immunoglobulin E; IL, interleukin; NK, neurokinin; TSLP, thymic stromal lymphopoietin 1. Kocatürk E, et al. Clin Transl Allergy. 2017;7:1; 2. Angst D, et al. J Med Chem. 2020;28;63:5102–18 Anti-IgE is currently the only approved treatment aside from H1-AHs, with a number being investigated

TSLPc C5ac Receptor-bound IgE • Ligelizumab FcyRIIBc

Receptor- C5aR bound IgE c SHIP-1 CRTH2c P13K CD300ac NK-1Rc c Syk Siglec-8 Free IgE BTK IL-4Rc • Omalizumab* S1P • Ligelizumab • UB221 MAST • LP0201 (FB-825) CELL • GI-301 free IgEb IL-1 histamine TNFc leukotrienesa IL-1b prostaglandin other cytokinesc *Omalizumab is approved for the treatment of CSU. aCurrently available, bunder investigation, chypothetical BTK, Bruton’s tyrosine kinase; CRTH, chemoattractant receptor-homologous molecule expressed on Th2 cells (DP2); CSU, chronic spontaneous urticaria; C5, complement 5; H1-AH, H1-antihistamines; IgE, immunoglobulin E; IL, interleukin; NK, neurokinin; TSLP, thymic stromal lymphopoietin 1. Kocatürk E, et al. Clin Transl Allergy. 2017;7:1; 2. Metz M and Maurer M. Curr Opin Allergy Clin Immunol. 2012;12:406–11 As mentioned, at present the only approved treatment aside from H1-AHs is anti-IgE omalizumab, however, another is currently being investigated

What is the rationale for this and how do these anti-IgE molecules differ from each other? IgE targets two different IgE-receptors with varying contributions to disease FcεRI1–3 Allergen VL VH IgE (high-affinity receptor)

L Cε1C Fc Fab’2 Cε2 • Present in high density on Cε3 Cε4 Kd ≈ 3 10-10 M Kd ≈ 10-8 M basophils and mast cells α2 α1 FcεRII • Mediates release of FcεRI inflammatory mediators α β γ γ (CD23) IgE-mediated N N allergen N presentation FcεRII/CD231,3 Mast cells, to T cells Mast cell Basophils Monocytes, Basophil APC (low-affinity receptor) Dendritic & B cells, & Eosinophils Langerhans cells T cell • Downregulatory signal for IgE TH2 cytokine production, synthesis IgE-mediated mediator release IL-4 , IL-5, etc. • Present on APCs • Induces T-cell activation in the Skin reaction, Inflammation presence of specific allergen and bronchoconstriction (pulmonary eosinophilia) IgE, leading to inflammation

APC, antigen presenting cell; FcεRI, high-affinity IgE receptor; FcεRII/CD23, low-affinity IgE receptor; IgE, immunoglobulin E; Kd, dissociation constant; IL, interleukin; TH, T-helper 1. Sutton B and Davies A. Immunol Rev. 2015;268:222‒35; 2. Arm J, et al. Clin Exp Allergy. 2014;44:1371–85; 3. Gasser P, et al. Nat Commun. 2020;11:165 Ligelizumab binds to a different IgE epitope compared with omalizumab 1 Ligelizumab

• Recognizes a different IgE epitope than IgE omalizumab • Important overlap in IgE binding with that of FcεRI (only minor overlap with FcεRII/CD23) • Binds IgE distant from FcεRII/CD23 binding site and sterically similar to FcεRI • Interacts with open IgE conformation similar to FcεRI FcεRI Ligelizumab Omalizumab 2 Omalizumab FcεRII / CD23 • Directly competes with FcεRII/CD23 for IgE binding with physical steric overlap • Binds farther from the FcεRI site • Inhibits IgE-FcεRI interaction by steric hindrance

FcɛRI, high-affinity IgE receptor; FcɛRII/CD23, low-affinity IgE receptor; IgE, immunoglobulin E Gasser P, et al. Nat Commun. 2020;11:165 Ligelizumab inhibits IgE binding to FcεRI more potently than to CD23 FcεRIα CD23 IgE inhibition profiles α 2.5 Ligelizumab IgG ] 2.5 Ligelizumab IgG RI 450

ε Ligelizumab Omalizumab IgG Omalizumab IgG 2.0 2.0 ] FcεRI > FcεRII/CD23 450 1.5 1.5 IC50 IC50 [OD 1.0 IC50 1.58 nM 1.0 IC50 13.4 nM 0.08 nM 3.6 nM

IgE binding to Fc to binding IgE 0.5 0.5 IgE: complex antigen 0.0 binding to CD23 [OD 0.0 10-2 100 102 100 101 102 Mast cells/basophil activation Anti-lgE concentration [nM] Anti-lgE concentration [nM]

3000 Ligelizumab IgG 10,000 Ligelizumab IgG Omalizumab Omalizumab IgG Omalizumab IgG 8,000 FcεRII/CD23 > FcεRI 2000 6,000 IC 50 IC50 IC 1.16 nM 4,000 1000 50 IC50 0.92 nM [Geom. MFI] MFI] [Geom. 0.36 nM 2,000 0.18 nM

Surface IgE on basophils AP and transport across epithelial 0 on CD23 to binding IgE 0 -1 0 1 2 -2 -1 0 1 2 10 10 10 10 [geom. cells RPMI8866 MFI] 10 10 10 10 10 barriers Anti-lgE concentration [nM] Anti-lgE concentration [nM]

AP, antigen presentation; FcɛRI, high-affinity IgE receptor; CD23, low-affinity IgE receptor; IgE/G, immunoglobulin E/G; IC50, concentration for 50% inhibition; nM, nanomolar; OD, optical density Gasser P, et al. Nat Commun. 2020;11:165 Ligelizumab downregulates IgE production in human PBMCs more strongly than omalizumab

• Human PBMC were stimulated Untreated Control IgG with anti-CD40 + IL-4 in * NS NS ** presence of anti-IgE antibodies 30 • Numbers of IgE producing 20 B cells were measured

10 • Ligelizumab, but not omalizumab, has the ability to Number of IgE expressing expressing IgE of Number cells [per 250,000 PBMCs] 250,000 [per cells 0 recognize FcεRII/CD23-bound

μM) μM) IgE on B cells which may Omalizumab Ligelizumab Untreated Control IgG contribute to the observed IgG IgG Unstimulated reduction of IgE production in LigelizumabOmalizumab IgG (0.5 IgG (0.5 PBMC cultures

IgE/G, immunoglobulin E/G; IL, interleukin; NS, not significant; PBMC, peripheral blood mononuclear cells Gasser P, et al. Nat Commun. 2020;11:165 Based on the mode of action, ligelizumab may be more potent for FcεRI-driven diseases

FcεRI FcεRII/CD23 IgE

Mast cells Basophils APC B-cells AEC capture Degranulation & mediator release presentation transport CSU, food allergy Allergic asthma

Ligelizumab Omalizumab

AEC, airway epithelial cell; APC, antigen presenting cell; FcεRI, high-affinity IgE receptor; FcɛRII/CD23, low-affinity IgE receptor; IgE, immunoglobulin E 1. Sutton B and Davies A. Immunol Rev. 2015;268:222‒35; 2. Arm J, et al. Clin Exp Allergy. 2014;44:1371–85 What evidence is there to confirm IgE as a therapeutic target in CSU? Omalizumab resulted in significantly greater improvements in weekly ISS vs placebo

ASTERIA II1 ASTERIA I2 GLACIAL3 OMA OMA OMA OMA OMA OMA OMA Placebo 75 mg 150 mg 300 mg Placebo 75 mg 150 mg 300 mg Placebo 300 mg 0.0 0 0.0 Baseline(SD)mean

n=79 n=82 n=82 n=79 14.4 14.5 14.1 14.2 Baseline(SD)mean 13.8 14.0 -1 (3.5) (3.6) (3.8) (3.3) (3.6) (3.6) -2.5 -2 n=80 n=77 n=80 n=81 -2.5 n=83 n=252 -3 -3.6 -4.0 -4 -26% -5.0 -5.1 -26% -5.0 -5.9 -5 -36% -6 -6.5 -6.7 values

NS values -7.5 -8.1 -7 P=0.0010 P=0.0012 -7.5 -8.6 -42% -8 P<0.01 -43% P<0.001 -9.8 -9 -48% -9.4 Week 12 in weekly ISS weekly in 12 Week -10.0

Week 12 in weekly ISS weekly in 12 Week -62% -10.0 -56% to baseline from Change to Week 12 in weekly ISS weekly in 12 Week to P<0.0001 Change from baseline to to baseline from Change P<0.001 -10 -67% -71% to baseline from change Mean

Omalizumab 75 mg is not licensed for CSU/CIU; omalizumab 150 mg is not licensed for CSU/CIU in some countries. Change from baseline to Week 12 in weekly ISS was the primary endpoint; data are for modified intention-to-treat (mITT) population; p values are vs placebo. CIU, chronic idiopathic urticaria; ISS, Itch Severity Score; NS, not significant; OMA, omalizumab; SD, standard deviation 1. Maurer M, et al. N Engl J Med. 2013;368:924−35; 2. Saini S, et al. J Invest Dermatol. 2015;135:67–75; 3. Kaplan A, et al. J Allergy Clin Immunol. 2013;132:101−9 Omalizumab significantly improved HRQoL (measured using DLQI) vs placebo at Week 12

ASTERIA II1 ASTERIA I2 GLACIAL3,4

Baseline Omalizumab Omalizumab Omalizumab Omalizumab Omalizumab Omalizumab Omalizumab Placebo Baseline Placebo Baseline Placebo mean DLQI 75 mg 150 mg 300 mg mean DLQI 75 mg 150 mg 300 mg mean DLQI 300 mg score: 12.6 12.6 13.0 12.7 score: 14.0 12.8 13.6 13.0 score: 13.0 13.8 0 0 0 n=79 n=82 n=82 n=79 n=80 n=77 n=80 n=81 n=82 n=79 n=82

Improvement in HRQoL Improvement -2 in HRQoL Improvement in HRQoL Improvement score -2

-5 -6.1 -4 -4 -5.1 -6.1 -6.3 -7.5 -22% -44% -8.3 -6 -6 NS -47% NS-13.8 -8.0 p=0.02 -10.2 -8 -10 -49% -8 NS -9.7 -54% P<0.001 -10.3

-17.9 -10 Week12 DLQI in score Week12 DLQI in score

-66% to baseline from Change -51% Change from baseline to to baseline from Change -10 -73% Change from baseline to to baseline from Change p<0.0001 -78% Week12 overall in DLQI -12 -74% -12 -15 LSM difference – 4.7 (95% CI – 6.3,-3.1) p<0.001 Mean DLQI Mean DLQI Mean DLQI score at 6.5 5.1 4.7 2.5 score at 7.9 6.5 5.6 2.7 score at 7.9 4.1 Week12 Week12 Week12

Omalizumab 75 mg is not licensed for CSU/CIU; omalizumab 150 mg is not licensed for CSU/CIU in some countries. Data are for mITT population; p values are vs placebo; mean % reduction from baseline is also shown. Differences between the omalizumab 75 mg group and placebo were not evaluated for statistical significance in accordance with the hierarchy of endpoints (type I error control plan). CI, confidence interval; CIU, chronic idiopathic urticaria; DLQI, Dermatology Life Quality Index; HRQoL, health-related quality of life; LSM, least squares mean; mITT, modified intention to treat; NS, not significant 1. Maurer M, et al. N Engl J Med. 2013;368:924−35; 2. Saini S, et al. J Invest Dermatol. 2015;135:67–75; 3. Kaplan A, et al. J Allergy Clin Immunol. 2013;132:101–9; 4. Casale T, et al. Allergy. 2014;69(S99):580‒1 QGE031C2201 was a Phase IIb randomized, double-blind dose-finding study for ligelizumab

Core study Screening Treatment Follow-up

Wk -2 R Wk 12 Wk 20 Wk 32 Wk 44

Ligelizumab 240 mg q4w (n=85) Ligelizumab 72 mg q4w (n=84) Eligible to enroll in the Ligelizumab 24 mg q4w (n=43) extension study from Wk 32 b Omalizumab 300 mg q4w (n=85) onwards, if UAS7 ≥12

Ligelizumab a 120 mg SD Placebo q4w (n=42) Placebo (n=43)

R = Randomization Wk 12 = Primary endpoint = Treatment visit in the core study aThe 120 mg single-dose (SD) arm was chosen to characterize the PK/PD. Data from this arm assesses the duration of response and correlates this with the concentration of drug in serum at the time when symptoms reappear; bPatients who remained in the follow-up period for at least 12 weeks and had active disease (UAS7 ≥12), could enter the extension study from Week 32 onwards n, number of patients; q4w, every 4 weeks; UAS7, weekly Urticaria Activity Score; Wk, week Bernstein JA, et al. AAD 2019 (Abs 11224); Clinicaltrials.gov. NCT02649218 A higher proportion of patients achieved well-controlled CSU and complete hives control with ligelizumab vs omalizumab The mean change in UAS7 from baseline to Week 32 The proportion of patients achieving HSS7=0 at Week 12

Weeks 100 0 4 8 12 16 20 24 28 32 0 80

-4 51.2 -8 60 42.4 -12 30.2 -16 40 25.9 -20 -24 20 Patients with HSS7 = 0(%) = HSS7 with Patients 0 -28 Mean change from BL in UAS7 0 Placebo Omalizumab Ligelizumab Ligelizumab Ligelizumab (n=43) 24 mg q4w 72 mg q4w 240 mg q4w Ligelizumab 24 mg q4w (n=43) Ligelizumab 72 mg q4w (n=84) 300 mg q4w (n=85) (n=43) (n=84) (n=85) Ligelizumab 120 mg SD (n=42) Ligelizumab 240 mg q4w (n=85) Omalizumab 300 mg q4w (n=85) Placebo (n=43) Treatment Visit

BL, baseline; HSS7, weekly Hives Severity Score; n, number of patients; q4w, every 4 weeks; SD, single dose; UAS7; weekly Urticaria Activity Score Maurer M, et al. EAACI 2018 Ligelizumab provided rapid disease control

UAS7=0 48.8 60 UAS7≤6 60.5 70 (N=84) 45.7 43.4 (N=81) 29.8 (N=81) (N=83) 43.9 50 60 (N=84) (N=82) 52.6 20.5 43.6 36.1 30.5 (N=78) 40 (N=83) (N=78) 50 (N=83) (N=82) 18.1 51.9 40 (N=77) 30 (N=83) 28.6

(N=77) controlled urticaria (%) 30 - 32.5 20 (N=83) 20 28.6 20.5 (N=84) 10 (N=83) 10.7 10 (N=84) 0 0

Patients with complete response (%) 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 Patients with well

Ligelizumab 72 mg q4w Ligelizumab 240 mg q4w Omalizumab 300 mg q4w

*Analysis performed on as observed data. N, total number of patients in each arm at that time point. q4w, every 4 weeks; UAS7, weekly Urticaria Activity Score, complete response: UAS7=0 Maurer M, et al. EADV 2020 Virtual congress The proportion of patients with completely controlled CSU was higher with ligelizumab vs omalizumab

Patients considered completely controlled Patients considered CSU free (HSS7=0, ISS7=0, AAS7=0) (HSS7=0, ISS7=0, AAS7=0, DLQI=0–1)

60 Treatment period Treatment-free period 60 Treatment period Treatment-free period ) ) % % ( ( 50 50 44.1

40 40 38.1

34.1 patients patients 40.0 32.1

29.8 of

of 29.4 30 33.3 29.0 30 35.3 31.8 29.4 26.2 25.0 28.6 22.8 18.8 22.8 20 20.5 20 15.3 23.5 20.0 Proportion Proportion 10 9.3 10 4.7 4.7 5.3 4.8 4.9 0 0 0 4 12 20 28 0 4 12 20 28

Ligelizumab 72mg Ligelizumab 240mg Omalizumab 300mg Placebo

DLQI, Dermatology Life Quality Index; HSS7, weekly Hives Severity Score; ISS7, weekly Itch Severity Score Giménez-Arnau A, et al. EAACI 2021 (Abs 278) Patients with active disease after the core study could enter an extension study

Core study Extension study Screening Treatment Follow-up Treatment Follow-up

Wk -2 R Wk 12 Wk 20 Wk 32 Wk 44 Wk 0 Wk 52 Wk 104 End of Ligelizumab 240 mg q4w (n=85) Ligelizumab 240 mg q4w study

Ligelizumab 72 mg q4w (n=84)

Ligelizumab 24 mg q4w (n=43)

Omalizumab 300 mg q4w (n=85)

Ligelizumab 120 mg SD Placebo q4w (n=42) R = Randomization Wk 12 = Primary endpoint = Treatment visit in Placebo (n=43) the core study

n, number of patients; q4w, every 4 weeks; SD, single dose; UAS7, weekly Urticaria Activity Score; Wk, week Bernstein JA, et al. AAD 2019 (Abs 11224); Clinicaltrials.gov; NCT02649218 Patients treated with ligelizumab 240 mg achieved symptom control up to 1 year

% of patients who achieved UAS7=0 up to 1 year % of patients who achieved UAS7≤6 up to 1 year 100 100

80 80 67.3% 60 53.1% 60 61.1% 40 51.8% 40 54.4% after 1st dose of Patients (%) Patients (%) Patients ligelizumab 20 20 35.4% after 1st dose of ligelizumab 0 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks Weeks

UAS7, 7-day urticaria activity score Bernstein JA, et al. EAACI 2019 (Abs 1214) Long-term treatment with ligelizumab 240 mg achieved prolonged symptom control

Core study Extension study 100 Kaplan-Meier plot 100 Kaplan-Meier plot Time to loss of UAS7=0 Time to loss of UAS7=0 90 90

80 with 80 ) 70 ) 70 % %

10.5 weeks ( 11 weeks 60 4 weeks 60 Median (n=26) (n=34) Median (n=120) 50 patients 50

4 weeks of 40 (n=33) 40 3 weeks response (

response 30 30 (n=8) 20 20

Proportion of patients with 10 10 Proportion 0 0

20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 Study week Study week

Ligelizumab 24 mg q4w Ligelizumab 72 mg q4w Ligelizumab 240 mg q4w Omalizumab 300 mg q4w Placebo

X represents all the censored patients who left the study without a loss of response observed n, number of patients; q4w, every 4 weeks; UAS7, weekly Urticaria Activity Score Soong W, et al. AAAI 2020 (Poster L20) All ligelizumab doses were well tolerated, with a safety profile similar to omalizumab Phase IIb core study Extension

Ligelizumab q4w Omalizumab Ligelizumab Ligelizumab Placebo Total Category 300 mg q4w 120 mg SD 240 mg q4w 24 mg 72 mg 240 mg (n=43) (N=382) (n=43) (n=84) (n=85) (n=85) (n=42) (n=226) At least one AE 36 (83.7) 63 (75.0) 63 (74.1) 62 (72.9) 34 (79.1) 37 (88.1) 295 (77.2) 190 (84.1) Mild 16 (37.2) 31 (36.9) 32 (37.6) 36 (42.4) 15 (34.9) 22 (52.4) 152 (39.8) 100 (44.2) Moderate 16 (37.2) 27 (32.1) 28 (32.9) 21 (24.7) 12 (27.9) 13 (31.0) 117 (30.6) 77 (34.1) Severe 4 (9.3) 5 (6.0) 3 (3.5) 5 (5.9) 7 (16.3) 2 (4.8) 26 (6.8) 13 (5.8) At least one serious 3 (7.0) 2 (2.4) 2 (2.4) 3 (3.5) 4 (9.3) 4 (9.5) 18 (4.7) 13 (5.8) AE AEs leading to 0 (0.0) 1 (1.2) 1 (1.2) 2 (2.4) 2 (4.7) 2 (4.8) 8 (2.1) 8 (3.5) discontinuation ≥1 AE possibly related to 5 (11.6) 18 (21.4) 24 (28.2) 7 (8.2) 12 (27.9) 6 (14.3) 72 (18.8) 54 (23.9) treatment

AE, Adverse event; SD, Single dose; q4w, every 4 weeks. Data presented as n (%) Sussman G, et al. EADV 2019 (Abs 1178). Ligelizumab is now in Phase III of clinical development

CQGE031C23021 (PEARL 1) & CQGE031C2302E13 CQGE031C23032 (PEARL 2) Phase III double-blind and Phase III double-blind active- and open-label extension study to placebo- controlled efficacy and evaluate the efficacy and safety of safety study of ligelizumab in adult ligelizumab as retreatment, and adolescent patients with CSU self-administered therapy and monotherapy in patients with CSU

CSU, chronic, spontaneous urticaria 1. https://clinicaltrials.gov/ct2/show/NCT03580369 [Accessed May 2021]; 2. https://clinicaltrials.gov/ct2/show/NCT03580356 [Accessed May 2021]; 3. https://clinicaltrials.gov/ct2/show/NCT04210843 [Accessed May 2021] Summary Summary

Many patients are misdiagnosed/experience a delay in diagnosis or do not receive optimal treatment despite the recommended treatment algorithm for CSU

Quick and complete symptom control to improve patient QoL is an important treatment goal for CSU

UCARE centers can help to improve the management of CSU, as well as increasing our understanding and management options

IgE-associated mast cell activation is a key driver of CSU

Ligelizumab and omalizumab bind to different IgE epitopes, resulting in different pathophysiology and disease modification

Treatment with ligelizumab results in rapid and sustained control of CSU

CSU, chronic, spontaneous urticaria; IgE, immunoglobulin E; QoL, quality of life Thank you for your participation

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