BIOLOGICS IN ALLERGY 101 DR CLAUDIA GRAY ALLSA 2017

Transcription

1 BIOLOGICS IN ALLERGY 101 DR CLAUDIA GRAY ALLSA 2017

2 DR CLAUDIA GRAY MBChB, FRCPCH (London), MSc (Surrey), Dip Allergy (Southampton), DipPaedNutrition(UK), PhD (UCT) Paediatrician and Allergologist, UCT Lung Institute Red Cross Children s Hospital Allergy and Asthma Department claudia@kidsallergy.co.za

3 WHAT IS A BIOLOGIC? Biological agents, also known as biologics, are manufactured in, extracted from or semi-synthesised from biological sources. antibodies, vaccines or interleukins used to treat disease

4 WHAT IS A BIOLOGIC? Biological agents, also known as biologics, are manufactured in, extracted from or semi-synthesised from biological sources. antibodies, vaccines or interleukins used to treat disease Monoclonal antibodies are antibodies that are made by identical immune cells that are all clones of a unique parent cell. Traditionally manufactured in an animal host to target specific cell type or block disease mechanisms in the body.

5

6 HISTORY OF BIOLOGICS The field of biologic immune modulators is currently mushrooming at a dizzying pace (Davis et al JACI May 2017) Long been used in cancer and rheumatology therapy, some approved for allergic and respiratory disorders, many currently in development Many abandoned : lack of efficacy or intolerable side effects

7 HISTORY OF BIOLOGICS Both success and failure stories in biologics have facilitated our ability to better understand what molecules and pathways are important in the pathogenesis of allergic diseases and in the development of symptoms in individual patients. (Casale et al JACI May 2017)

8 NOMENCLATURE Monoclonal antibodies are often manufactured in mouse, hamster, rabbit or horse. Those agents that contain a large amount of host protein are more allergenic than the more humanised and fully humanised biologic agents. The suffix allergenicity

9 NOMENCLATURE -momab (eg are fully host agents and the most potentially allergenic) -ximab chimeric and contain approximately 30% host protein (eg infliximab and rituximab) -zumab humanised agent, contains approximately 5% host protein (eg trastuzumab, omalizumab) -umab fully humanised agent and the least allergenic (eg golimumab, dupilumab) (transgenic mice/phage display)

10

11

12 WHY THE NEED FOR BIOLOGICS? Many patients with allergic diseases have poorly controlled symptoms despite several existing pharmacological options Bell-shaped curve for pharmacotherapies.. non responders vs responders..? distinct mechanisms of disease.

13 BIOLOGICS: CONCEPT OF PRECISION MEDICINE Biologics target specific and critical pathways in disease which addresses lack of response to pharmacological agents. Identification of biomarkers that characterise a patient and their response to treatment Ability to phenotype and endotype patients Allow picking a specific biologic agent for a specific patient Patient X Biomarker Y Anti-Y Antibody

14 BIOLOGICS: CONCEPT OF PRECISION MEDICINE Biologics target specific and critical pathways in disease which addresses lack of response to pharmacological agents. Identification of biomarkers that characterise a patient and their response to treatment Ability to phenotype and endotype patients Allow picking a specific biologic agent for a specific patient Patient X Biomarker Y Anti-Y Antibody

15

16 WHAT ARE THE PROBLEMS WITH BIOLOGICS? Heterogeneity in response: not all patients respond High cost Potential for significant adverse events : broader the spectrum of biologic reactions great chance of clinical response greater chance of adverse Biomarkers not always available/difficult to obtain to pick the best biologic for each patient

17 BIOLOGICS IN ALLERGY MANAGEMENT: BASICS

18

19

20

21 IgE, IgE Gives the mast cell liberty

22

23 IL4, IL4 Stimulates B cells and much more

24

25 IL5, IL5 Keeps the eosinophil alive

26 BIOLOGICS IN ALLERGY MANAGEMENT: WHAT IS AVAILABLE?

27 LANDMARKS: APPROVED BIOLOGICS IN ALLERGY Omalizumab Omalizumab Mepolizumab Dupilumab Xolair ( asthma) CSU Nucala (asthma) Dupixent (AD)

28 BIOLOGICS IN ASTHMA MANAGEMENT Asthma the most prominent disease likely to be treated by allergists with biologics. 2 major inflammatory phenotypes for asthma: - type 2 high (eosinophilic inflammation) and - type 2 low (neutrophilic or paucigranulocytic inflammation) Most of biologics appropriate for type 2 high asthma Typical biomarkers for type 2 high asthma: blood and sputum eosinophils, FeNO, periostin and DPP-4 (dipeptidyl peptidase-4)

29 BIOLOGICS IN ASTHMA MANAGEMENT Indications Mechanism of action Biomarkers Dosing Clinical efficacy Side effects (briefly)

30 OMALIZUMAB A recombinant humanised anti-ige monoclonal antibody (anti-ige mab) with a molecular weight of 150 kda; 95% of the antibody is derived from human kappa IgG1 Bind selectively and with high affinity to the Fc of IgE, preventing binding of this domain to the high-affinity IgE receptors (Fc ε RI) of mast cells and basophils Binding to the low-affinity receptors (Fc ε RII) of dendritic cells, T cells, eosinophils and other cells related to allergic inflammation is also inhibited.

31

32 OMALIZUMAB: INDICATIONS Indications: moderate to severe perennial allergic asthma in patients over 6 years US moderate to severe asthma; total IgE IU/L UK severe persistent asthma; total IgE IU/L. Uncontrolled despite high-dose inhaled corticosteroids (ICS) 800 mcg beclomethasone equivalent plus long-acting β-agonists, with or without other controllers. Omalizumab approved Paediatric use approved 2009 (EMA) and 2016 (FDA)

33 OMALIZUMAB: MECHANISMS OF ACTION Binds free IgE in blood and interstitial fluid: reducing free allergen-specific IgE downregulates FCεR1 and FCεR2 expression decreased mediator release from mast cells and basophils circulating anti-ige/ige complexes are able to capture antigens from the bloodstream preventing them from reaching the specific IgE already bound to the cells. decreased antigen uptake by dendritic cells

34

35

36 OMALIZUMAB: BIOMARKERS Antigen specific IgE Works better in those asthmatics with high periostin levels High eosinophil count (the higher the count, the greater the reduction in exacerbations) Higher FeNO values.

37 OMALIZUMAB: DOSING Dosage is mg/kg body weight per international unit of IgE at 2 4 weekly intervals subcutaneously. There are published tables for dosage according to weight and pre-treatment total IgE level mg SC 2-4 weekly based on body weight and IgE levels

38

39 OMALIZUMAB: EFFICACY The effects in asthma include: Decreased use of inhaled corticosteroids (ICS) Decreased use of rescue medication Relative reduction in exacerbations requiring systemic steroids by 55% compared with placebo (Casale TB et al JACI 2015) Decreased frequency of exacerbations Decreased emergency visits and hospitalisations Improved asthma-related QoL.

40 OMALIZUMAB: EFFICACY Appears that effects depend on the degree to which IgE levels are reduced, with better clinical efficacy if IgE reduced by 90% or more (Castale, JAMA 2001)

41 OMALIZUMAB: SIDE EFFECTS Precautions: Black box warning for anaphylaxis. Post marketing surveillance suggests 0.2% prevalence of anaphylaxis Usually within first 3 doses; within 1 hour of dosing. Malignancy: pooled analysis of Phase 1-4 clinical trials: no difference in malignancy rates between omalizumab and control arms (Busse W JACI 2012, 129: 983-9)

42 OMALIZUMAB: SIDE EFFECTS/PRECAUTIONS: Written informed consent must be obtained. Patients should receive education on anaphylaxis, both immediate and delayed reactions. A clinical examination +lung-function tests is required prior to treatment to ensure the patient is well enough to receive the biologic. Administration in area equipped to manage severe adverse reactions and anaphylaxis

43 IL5-BLOCKERS Mepolizumab and Reslizumab are humanised anti IL5 mabs approved by the FDA for treatment of patients with severe persistent asthma with eosinophilic prototype. Mepolizumab licensed over 12 years, Reslizumab > 18 years

44 IL5-BLOCKERS: MECHANISM OF ACTION IL5 is important cytokine in eosinophil biology, promoting eosinophil differentiation, chemotaxis, activation, survival IL5 blockage prove useful in asthmatic patients with eosinophilia

45

46

47 ANTI-IL5: BIOMARKERS Blood eosinophil count >150/microL at initiation or 300 cell/microlitre in past year. Better response from patients with higher eosinophil counts (500 cells/microl had 80% reductions)

48 ANTI-IL5: DOSING Mepolizumab given 100 mg SC 4 weekly Reslizumab IV monthly

49 ANTI-IL5: EFFICACY EFFECTS: Asthma exacerbation reduction by about 53% (Ortega et al NEJM 2014) Improved FEV1 by 100 L/min Better asthma related QoL Decreased ER visits Steroid sparing (by 50%: Nair P et al, NEJM 2009; Bel EH et al, NEJM 2014)

50 ANTI-IL5: EFFICACY ISSUES: Studied > 12 years age. Do not seem to induce remission; efficacious only whilst being given monthly

51 ANTI-IL5: SIDE EFFECTS Reslizumab: black box warning for anaphylaxis Consider shingles vaccine before administration

52 AGENTS IN CLINICAL TRIALS FOR ASTHMA Dupilumab: Fully human recombinant monoclonal antibody against Anti-IL4 receptor alpha chain

53

54 IL4, IL4 Stimulates B cells and much more

55 DUPILUMAB: MECHANISM OF ACTION IL4 and IL13=prototypical Th2 cytokines Dupilumab binds to the IL4R-alpha chain or IL13 from binding and signalling prohibits either IL4 Decreases IgE levels by about 40% Additional actions blocking pathophysiological events mediated by IL4 and 13 independent of IgE production

56

57

58 DUPILUMAB Clinical effects in asthma, eczema and nasal polyposis Initial trials in asthma have shown reduced exacerbation and improvements in pulmonary function ; now phase III Given 2 weekly subcut mg; good safety profile means home dosing possible

59 MORE AGENTS IN CLINICAL TRIALS FOR ASTHMA IL13 blocking 2 antibodies have been trialled: Lebrikizumab- lack of efficacy has led to its being abandoned Tralokinumab variable results and in phase 2 of clinical trials.

60

61 MORE AGENTS IN CLINICAL TRIALS FOR ASTHMA Anti-alarmins Airway epithelium derived cytokine thymic stromal lymphopoeitin (TSLP) promotes type 2 inflammation and eosinophilic inflammation Clinical trials mab to TSLP, AMG157, currently in early clinical trials.

62

63 BIOLOGICS IN URTICARIA MANAGEMENT CSU intense pruritis, hives, poor QoL Certain monoclonal Abs have been used with success

64 OMALIZUMAB IN CSU Licensed as adjunctive therapy in CSU in patients > 12 years, refractory to high dose anti-histamines. No IgE limit FDA approved 2014 Studied in CSU, physical urticaria, urticarial vasculitis and recent meta-analysies have proven its efficacy (Zhao et al. J Allergy Clin Immunol 2016, 137:

65 Graph

66 OMALIZUMAB IN CSU Used in Step 3 or 4 in urticarial pathway Dosing: 300 mg subcut monthly for 6 months

67 OMALIZUMAB IN CHRONIC URTICARIA How does it work? Generally reduced binding of IgE to its receptor -- mediator release reduced Downregulation of high affinity IgE receptor---decreased IgE binding, Decreased binding of autoantibodies to IgE receptors.

68

69 ANTI-TNF ANTIBODIES IN CSU TNF alpha antagonists : - etanercept (soluble TNF alpha receptor bound to IgG Fc) - infliximab (chimeric monoclonal antibody) - adalimumab (humanised monoclonal antibody)

70 ANTI-TNF ANTIBODIES IN CSU How do they work? Possible upregulation of TNF alpha expression in the skins of patients with chronic urticaria

71

72 ANTI-TNF ANTIBODIES IN CSU Studied in CSU and physical urticaria; Small studies have shown promise Trial 118 patients 75% response Not yet licensed

73 RITUXIMAB IN CHRONIC URTICARIA Anti CD 20 chimeric mab Causes antibody-dependent cell mediated cytotoxicity of immature, mature and memory B cells that express CD 20 Primarily used to treat B-cell tumours

74

75 RITUXIMAB IN CSU Possible role in urticaria: Targets B cells that produce IgE and autoantibodies against FceRI Promising results in case reports but not yet in controlled trials

76 ANTI-IL1 AGENTS IN CSU IL1 antagonists- Anakira: IL1-alpha Receptor antagonist Canakinumab: Anti-IL1beta mab Rilonacept: IL1 receptor fusion protein

77 ANTI-IL1 AGENTS IN CSU Subset of urticarial patients with the autoinflammatory condition cryopyrin-associated periodic syndromes- associated with overproduction of cryopyrin and overproduction of IL 1 Also of possible use in urticarial vasculitis In clinical trials

78 IV IMMUNOGLOBULINS IN CSU Postulated role of autoimmunity and autoantibodies in CSU IV IG used for CSU and physical urticarias Small case series of monthly doses for at least 6 months leading to complete remission (0.15g/kg)

79 BIOLOGICS IN ECZEMA Most common chronic inflammatory pruritic skin disease Genetic dysfunction of epithelial barrier + local immune dysfunction in the skin

80 BIOLOGICS IN ECZEMA Most common chronic inflammatory pruritic skin disease Genetic dysfunction of epithelial barrier + local immune dysfunction in the skin Recent insights demonstrate Th2 driven inflammation (NB IL4 and IL13)

81

82 BIOLOGICS IN ECZEMA Dupilumab now FDA approved for treatment of severe unresponsive eczema in adults in clinical trials: SOLO 1 and SOLO 2 ( adult patients) with eczema inadequately controlled on topical treatment: superior to placebo in skin clearance (40% v 10%) (Simpson EL et al. NEJM 2016) Trial results so impressive that given fast-track FDA review Further trial in patients 6-18 years in progress

83 Placebo Dupilumab every 2 weeks Dupilumab once weekly P value vs placebo IGA (SOLO 1) 10% 38% 37% <.0001 IGA (SOLO 2) 9% 36% 36% <.0001 EASI-75 (SOLO 1) 15% 51% 53% <.0001 EASI-75 (SOLO 2) 12% 44% 48% <.0001

84 DUPILUMAB IN ECZEMA Side effects include serious allergic reactions (rare), conjunctivitis, and keratitis. Injection site reactions, cold sores around the mouth, and inflammation of the eye and eyelid. $ per annum!!!

85 OMALIZUMAB IN ECZEMA? Case reports and small studies Severe refractory AD with elevated serum IgE treated with omalizumab Must always be combined with conventional treatment? Correct dose (high IgE s),? Frequency and duration Not yet licensed for this indication (Belloni JACI 2007; Park Ann Dermatol 2010)

86 BIOLOGICS IN NASAL POLYPOSIS Eosinophilia at tissue level (rarely, neutrophilia) Increased IgE concentrations in nasal polyp tissue and secretions resulting from local polyclonal IgE production

87 BIOLOGICS IN NASAL POLYPOSIS Therefore: proof of concept studies beginning for: Omalizumab (IgE) Mepolizumab Reslizumab(IL5) Dupilumab (IL4, IL13)

88 BIOLOGICS IN NASAL POLYPOSIS Effects in early studies: Decreased polyps Decreased symptoms Decreased sinus opacification Decreased need for surgery Gevaert P JACI 2006, 2011, 2013; Schneider JS et al. JAMA Otolaryngol Head Neck Surg 2016

89 BIOLOGICS IN EOSINOPHILIC OESOPHAGITIS Eosinophil haven-?anti IL5?

90 ANTI-IL5 IN EOSINOPHILIC OESOPHAGITIS 1. Stein ML, Collins MH, Villanueva JM, et al. Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis. J Allergy Clin Immunol 2006; 118: Straumann A, Conus S, Grzonka P, et al. Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, doubleblind trial. Gut 2010; 59: Assa'ad AH, Gupta SK, Collins MH, et al. An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology 2011; 141:1593.

91 ANTI-IL5 IN EOSINOPHILIC OESOPHAGITIS 1. Stein ML, Collins MH, Villanueva JM, et al. Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis. J Allergy Clin Immunol 2006; 118:1312. Showed benefit 2. Straumann A, Conus S, Grzonka P, et al. Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial. Gut 2010; 59: Assa'ad AH, Gupta SK, Collins MH, et al. An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology 2011; 141:1593.

92 ANTI-IL5 IN EOSINOPHILIC OESOPHAGITIS 1. Stein ML, Collins MH, Villanueva JM, et al. Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis. J Allergy Clin Immunol 2006; 118: Straumann A, Conus S, Grzonka P, et al. Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind Marginal trial. Gut 2010; 59:21. benefit 3. Assa'ad AH, Gupta SK, Collins MH, et al. An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology 2011; 141:1593.

93 ANTI-IL5 IN EOSINOPHILIC OESOPHAGITIS 1. Stein ML, Collins MH, Villanueva JM, et al. Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis. J Allergy Clin Immunol 2006; 118: Straumann A, Conus S, Grzonka P, et al. Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind Marginal trial. Gut 2010; 59:21. benefit 3. Assa'ad AH, Gupta SK, Collins MH, et al. An antibody against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology 2011; 141:1593. No clear benefit

94 CONCLUSION: BIOLOGICS IN EOE Not licensed Results disappointing Use is off-label

95 OMALIZUMAB IN FOOD ALLERGIES/ DESENSITISATION Used in conjunction with SOTI Allows quicker dose escalation, but does not seem to affect tolerance rates.

96 OMALIZUMAB IN FOOD ALLERGIES/ DESENSITISATION Nadeau KC JACI 2011 (milk) Bedoret D Mucosal Immunol 2012 (milk) Schneider LC JACI 2013 (peanut) Begin P JACI 2014 (multiple foods)

97 BIOLOGICS: ADVERSE EFFECTS Biological agents target specific sites which play key roles in normal physiology. Disruption of these normal processes can lead to targetrelated adverse events. Biologics are often large, peptide-based molecules that can result in hypersensitivity reactions. These lead to agent-related hypersensitivity reactions.

98 BIOLOGICS: ADVERSE EFFECTS As biologics is usually the last step in a long line of treatment options, subjects with adverse drug reactions often need to continue these medications and therefore may require premedication and desensitisation procedures.

99 s Type of adverse reaction High dose Hypersensitivity Secondary immunodeficiency Examples Cytokine-release syndrome Infusion reactions (non-immune) Anaphylaxis (immune) Tuberculosis with the TNF inhibitors Opportunistic infections (fungal and MOTS) in patients treated with TNF inhibitors Serious infections TNF inhibitors, anakinra, rituximab, combination TNF antagonists and abatacept Herpes infections with TNF inhibitors and rituximab Hepatitis B and C reactivation TNF antagonists and rituximab Decreased primary immune response to vaccination in patients on rituximab and abatacept Autoimmunity Atopic disorders Cross reactivity Non-immunologic Antinuclear antibodies (ANAs) and anti-double-stranded DNA antibodies (antidsdna) with TNF inhibitors. Clinical manifestations lupus-like syndrome, vasculitis, sarcoidosis and antiphospholipid syndrome Psoriasis with TNF inhibitors Atopic dermatitis Acne from anti-epidermal growth factor receptor Depression from interferons

100 BIOLOGICS IN ALLERGY: CONCLUSION Emerging role of biologics in allergy treatment NB anti-ige, anti IL5, anti IL4/13 Use of biologics have helped us to understand pathophysiology of diseases NB concept of precision medicine

101 FUTURE NEEDS Inexpensive point of care biomarkers Induction of true immunomodulation (more permanent effect) Biologics with favourable risk/benefit ratio Affordable biologics

102 THANK YOU!