ABCs of Immune Modifiers. Relevant Disclosures

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1 ABCs of Immune Modifiers Dennis K. Ledford, MD Ellsworth and Simmons Professor of Allergy/Immunology University of South Florida Morsani College of Medicine Tampa, FL USA Relevant Disclosures Research Investigator Funds to University employer Genentech MedImmune/Astra Zeneca Legal opinion Asthma death Latex allergy Corticosteroid allergy Metal allergy Consultant Novartis Genentech Astra Zeneca Boehringer Ingelheim Speaker Astra Zeneca Genentech Meda Merck TEVA The Pharmacogenetics of Asthma Therapies 1

2 Objectives Review the therapeutic potential of biologics or monoclonal antibodies and immune modifiers in asthma and allergic disease Discuss strategies to optimize treatment with monoclonal antibodies and immune modifiers Discuss patient-specific features that can influence monoclonal antibodies efficacy Biology and Biomarkers The Mother of All Biologic Modifiers The Pharmacogenetics of Asthma Therapies 2

3 The Mother of All Biologic Modifiers Corticosteroids Small Molecule Biololgic Modifiers Hydroxychloroquine Toll receptor inhibitor (TLR9, TLR3,7) Dapsone Neutrophil myeloperoxidase inhibitor Methotrexate Antimetabolite Adenosine inhibitor for neutrophils H1 or H2 inhibitors High dose Questionable effects The Pharmacogenetics of Asthma Therapies 3

4 Small Molecule Biololgic Modifiers Phosphodiesterase inhibitors Increased cyclic AMP Possible adenosine inhibitors Asthma and atopic dermatitis Mycophenalate mofetil Interfers with inosine metabolism Targets B and T cells Colchicine Interfers with microtubules PMN chemokinesis and phagocytosis Small Molecule Biololgic Modifiers Antimetabolites Inhibit cell division without long term toxicity Cytotoxic therapies Inhibit cell division with potential of DNA modification and long term cancer risk CRTH2 inhibitors Inhibits T cell and eosinophil migration Calcineurin inibitors Select T cell inhibitors The Pharmacogenetics of Asthma Therapies 4

5 Annals Allergy Asthma Immunol 2102;109:365 Efficacy Of A CXCR2 (IL-8R) Antagonist In Severe Asthma With Sputum Neutrophils Blood Sputum Nair P, et al. Clin Exp Allergy Jul;42(7): The Pharmacogenetics of Asthma Therapies 5

6 Monoclonal Antibodies Engineered specificity Typically animal antibody due to limited ability of human immune system to respond to human antigens Targets usually molecules or receptors Humanized Reduced animal determinants by grafting genetic segments into human Monoclonal Antibodies The Pharmacogenetics of Asthma Therapies 6

7 Monoclonal Antibodies Murine (-omab) Short half-life with resistance Side-effects Chimeric (-ximab) Grafting of variable region or receptor Humanized (-zumab) 95% human Mouse hypervariable region Human (-umab) Transgenic mice or phage libraries Monoclonals To Be Discussed Anti-IgE Omalizumab Ligelizumab Anti-IL-5 Mepolizumab Reslizumab Anti-IL-5Rα Benralizumab Anti-IL4/13Rα Dupilumab Anti-IL-13 Lebrikizumab Tralokinumab Others TNF-α inhibitors Rituximab The Pharmacogenetics of Asthma Therapies 7

8 Therapeutic Response Variability Due to the heterogeneity of asthma, it is inevitable that distinct dominant pathogenic mechanisms exist (e.g. Th2/eosinophil dominant inflammation) Finding which pathogenic factor(s) are important in individual patients is a challenge in treating severe asthma Pathogenic pathways may vary with time A broad spectrum immunomodulator approach for all patients is problematic due to potential adverse consequences, cost and lack of efficacy in all patients Journal of Allergy and Clinical Immunology , DOI: ( /j.jaci ) Copyright 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions The Pharmacogenetics of Asthma Therapies 8

9 Asthma Targets Neutrophilic inflammation Type 2 Low Asthma Paucigranulocytic inflammation ILC1/3? Epithelium Neutrophil Th1 Th17 IL 8 IL 23 Barrier dysfunction Proteases ROS IFN γ TNF α Airway hyperreactivity and remodeling IL 17 IL 22 IL 23 CXCR2 P H E N O T Y P E E N D O T Y P E Approved treatment targets Under investigation treatment targets Potential treatment targets The Pharmacogenetics of Asthma Therapies 9

10 Eosinophilic inflammation IL 5 Type 2 Hi Asthma Ag specific IgE Airway hyperreactivity and remodeling ILC2 Epithelium Mast cell NKT Th2 IL 13 IL 9 CRTH2/PGD2 TSLP IL 33 Barrier dysfunction IL 4 IL 13 IL 9 CRTH2/PGD2 IL 4 IL 13 IL 4 IL 13 IL 5 CRTH2/PGD2 P H E N O T Y P E E N D O T Y P E Approved treatment targets Under investigation treatment targets Potential treatment targets Biomarker BLOOD Eosinophil Specific IgE Periostin Dipeptidyl peptidase 4 (DPP 4) INDUCED SPUTUM Eosinophils Treatment expected to produce a response Anti IL5 Anti IgE Anti IL 4/IL 13 Corticosteroids (CS) CRTH2 antagonists Anti IgE AIT Anti IL13 Anti IL 5 ICS Associations Exacerbations LF decline Fixed airway obstruction Exacerbations AHR (AIT) LF decline Exacerbations Exacerbations Comments (point of care, variability/fluctuation) Easily available Significant fluctuation Research type Assay dependent (ref) Research type Significant fluctuation (ref) IL 13 Anti IL 13? Research type EXHALED BREATH FeNO Anti IL 5 Anti IgE Anti IL 13 Exacerbations, LF decline Easily available Point of care Significant fluctuation (ref) ICS Metabolomics (VOC) ICS? Research type The Pharmacogenetics of Asthma Therapies 10

11 Monoclonals To Be Discussed Anti-IgE Omalizumab Ligelizumab Anti-IL-5 Mepolizumab Reslizumab Anti-IL-5Rα Benralizumab Anti-IL4/13Rα Dupliumab Anti-IL-13 Lebrikizumab Tralokinumab Anti-IL-33 APC TSLP Targeting Th2 Cytokines IL-5 GMCSF Tcell FcεRII IL-2Rα CD40 CD40L B cell IL-4Rα Plasma Cell IgE FcεRI Anti-IL-5 IL-4 IL-13 IL-9 Mediators/PGD2 Cytokines Bone Marrow CCR Eosinophil TNF-α VLA-4 VCAM-1 ICAM Blood Vessel Airway Inflammation Remodelleing The Pharmacogenetics of Asthma Therapies 11

12 The Targets: IL-5 or Eosinophils/Basophils (IL-5Rα) Mepolizumab Reslizumab IL 5 Enhanced ADCC resulting in eosinophil/basophil depletion by apoptosis Benralizumab Eosinophil Basophil Mepolizumab Phase III Studies Phase (trial name(s)) Phase III (SIRIUS, MENSA), PhIIb/III (DREAM), plus extensions (MEA115666, MEA115661) 12 years and older Target Patient Population HD ICS/LABA (>880 µg/day fluticasone or equivalent) +/- chronic OCS (5-35mg/d) Blood eosinophil count 150 cells/µl at screening OR 300 cells/µl in the past 12 months H/O Exacerbations Admin and Frequency 100 mg SC or 75 mg IV Q4W Ortega et al. N Engl J Med 2014; 371: ; Bel et al. N Engl J Med 2014; 371: The Pharmacogenetics of Asthma Therapies 12

13 The MENSA Study 50% reduction in exacerbations ~100 ml improvement in FEV1 Significant improvements in ACQ-5 ( ) and SGRQ ( ) Ortega et al. N Engl J Med 2014; 371: Subgroup analysis of 177 patients with blood eosinophils 500 cells/μl from MENSA population 80% reduction in exacerbation Source: Ortega et al. N Engl J Med 2014; 371: The Pharmacogenetics of Asthma Therapies 13

14 Cluster and Response Analyses of DREAM Study Ortega H, et al. Ann Am Thorac Soc Sep;11(7):1011. What Happens When Mepo is Stopped? Haldar et al, JACI, 3/2014 The Pharmacogenetics of Asthma Therapies 14

15 Reslizumab IV Program Overview Blood eosinophils 400 cells/μl Two 52-week studies (n = 489) Primary endpoint: exacerbations Two 16-week studies (n = 315) Primary endpoint: lung function Ages Medium doses of ICS ± other controller Inadequately controlled (ACQ 1.5) Reversible to SABA (12%) during screening Exacerbation studies: Required 1 asthma exacerbation in prior year OCS-dependent asthma allowed Reslizumab Effects on Exacerbations and Lung Function Placebo; n= Reslizumab 3.0 mg/kg; n= HR (95% CI ) p< Placebo Reslizumab Number at risk Placebo Probability of not having CAE (%) Reslizumab LS mean change from baseline in FEV 1 (L) * Placebo Reslizumab 3.0 mg/kg Endpoint Visit (week) * Castro et al. Lancet Respir Med, May 2015 The Pharmacogenetics of Asthma Therapies 15

16 Benralizumab and Airway Eosinophils J Allergy Clin Immunol 2013;132:1086 Benralizumab: Phase IIb Study In Patients With Uncontrolled Eosinophilic Asthma Benralizumab 2 mg SC Stratification by eosinophil phenotype* and ICS dose (high/medium) Eosinophilic Noneosinophilic Benralizumab 20 mg SC Benralizumab 100 mg SC Placebo SC Benralizumab 100 mg SC Placebo SC Study medication administered Primary endpoint analysis Screening/ Run in Treatment period Follow up Eosinophil recovery period Week *ELEN Index positive and/or FE NO 50 ppb. ICS, inhaled corticosteroid; SC, subcutaneous Castro M et al. Lancet Resp Med 2014; S The Pharmacogenetics of Asthma Therapies 16

17 Benralizumab s Effects on Annual Exacerbation Rate By Eosinophil Level 0.9 Placebo Benralizumab 2 mg Benralizumab 20 mg Benralizumab 100 mg 0.8 Annual exacerbation rate RR= 30% p=0.327 RR=24% p=0.362 RR=30% p=0.131 RR= 7% p=0.822 RR=57% p=0.015 RR=43% p=0.049 RR=6% p=0.844 RR=57% p=0.024 RR=70% p= cells/μl 300 cells/μl 400 cells/μl RR, rate ratio Castro et al. Lancet Resp Med 2014; 2: Benralizumab s Effects on Change in FEV 1 By Baseline Eosinophil Level 0.4 Placebo Benralizumab 2 mg Benralizumab 20 mg Benralizumab 100 mg Mean FEV 1 change from baseline (L) p = p = p = p = p = p = p = p = p = cells/μl 300 cells/μl 400 cells/μl FEV 1, forced expiratory volume in 1 second Castro et al. Lancet Resp Med 2014; 2: The Pharmacogenetics of Asthma Therapies 17

18 Relapse at 12 weeks after acute exacerbation is 40-50% despite systemic steroids Patients treated according to guidelines in ED and received ICS + ~40mg/d prednisone Does benralizumab (single IV dose) reduce recurrence of exacerbations? Benralizumab Primary Outcomes Proportion of subjects with > 1 exacerbation at 12 weeks was not different between placebo and combined benralizumab groups (38.9% vs 33.3%; P=.67). Compared with placebo, exacerbation rates reduced by 49% (3.59 vs 1.82; P=.01) and exacerbations resulting in hospitalization by 60% (1.62 vs 0.65; P=.02) in the combined groups The Pharmacogenetics of Asthma Therapies 18

19 APC TSLP Targeting Th2 Cytokines IL-5 GMCSF IL-2Rα Tcell CD40 CD40L B cell IL-4Rα IL-4 IL-13 IL-9 FcεRII Anti-IL-13 Anti-IL-4Rα Anti-IL-4 Plasma Cell IgE FcεRI Mediators/PGD2 Cytokines Bone Marrow Anti-IL-9 CCR Eosinophil TNF-α VLA-4 VCAM-1 ICAM Blood Vessel Airway Inflammation Remodelleing DPP-4 And Periostin Stimulated By IL-13 in Asthma Periostin and DPP-4 expression Fold change induced by IL-13 (compared with unstimulated control) Bronchial epithelium (n=2) Normal EpiAirway (n=3) Asthma EpiAirway (n=4) Unstimulated DPP-4 Periostin DPP-4, dipeptidyl peptidase-4; IL, interleukin Brightling CE, et al. Presented at the Annual Meeting of the American Thoracic Society, San Diego, USA, May 16 21, 2014 The Pharmacogenetics of Asthma Therapies 19

20 Serum DPP-4 And Periostin Elevated In A Subset Of Patients With Asthma DPP-4 Periostin DPP-4 (ng/ml) Periostin (ng/ml) Normal Moderate Severe Normal Moderate Severe 52-Week Replicate Lebrikizumab Trials in Adults with Asthma Hanania NA, et al. Th.orax Aug;70(8):748 The Pharmacogenetics of Asthma Therapies 20

21 52-Week Replicate Lebrikizumab Trials in Adults with Asthma Hanania NA, et al. Thorax Aug;70(8):748. Lavolta I and II Two phase 3 multicenter trials with more than 2100 subjects in 28 countries Endpoint: asthma exacerbations over 52 wk Lavolta I: reductions in exacerbations in subjects with increased eosinophils and periostin with minimal increase in FEV1 Lavolta II: NO statistical reduction in exacerbations American Thoracic Society, A1318-A1318. The Pharmacogenetics of Asthma Therapies 21

22 Asthma Exacerbation Rates in Subgroups Treated with Tralokinumab for 52 Weeks * * High and low biomarker levels defined by median values Plot created from data presented in: Brightling CE, et al. Lancet Respir Med 2015;DOI: /S (15) Changes In FEV 1 In Subgroups Treated With Tralokinumab for 52 Weeks FEV 1 increased significantly from baseline to week 52 in patients with high DPP-4 receiving Tralokinumab q2w Placebo FEV 1 % change from baseline Serum periostin subgroups Periostin-high; p=0.057 n= Periostin-low; p=0.028 n= Time (weeks) Serum DPP-4 subgroups DPP-4-high; p=0.005 n= DPP-4-low; p=0.244 n= Time (weeks) Brightling CE, et al. Lancet Respir Med 2015;DOI: /S (15) The Pharmacogenetics of Asthma Therapies 22

23 Dupilumab: Fully human mab to IL-4Rα IL-4 JAK/ STAT IL-13 JAK/ STAT Blocker No Signal Blocker No Signal Signal Signal Phase II study: assess efficacy in adults with persistent, moderate-to-severe asthma and symptoms not well controlled with medium- to high-dose ICS + LABA and elevated eosinophil levels: blood eos 300 or sputum eos level 3% Wenzel et al. NEJM: 05/2013 Dupilumab Study Design Wenzel et al. NEJM: 05/2013 The Pharmacogenetics of Asthma Therapies 23

24 Dupilumab s Effects On Exacerbations Wenzel etl al NEJM 05/2013 Dupilumab Improved Secondary Endpoints FEV1 and PEF ACQ Sx Scores SABA use Nocturnal awakenings SNOT-22 score Wenzel et al. NEJM: 05/2013 The Pharmacogenetics of Asthma Therapies 24

25 Phase 2B Study Results Every 2 weeks works well If Eos >300: Decreased exacerbations Improved FEV1 Causes an initial increase in blood Eos which declines towards baseline with further treatment. Well tolerated Presented at ERS 2015 APC IL-5 GMCSF IL-2Rα TSLP Tcell CD40 CD40L B cell IL-4Rα FcεRII Quilizumab Plasma Cell Omalizumab Ligelizumab IgE Targeting Th2 Pathway FcεRI IL-4 IL-13 IL-9 Mediators Cytokines CRTH2 Antagonists Bone Marrow CCR Eosinophil TNF-α IL-17 Neutrophil VLA-4 VCAM-1 ICAM Blood Vessel Airway Inflammation Remodelleing The Pharmacogenetics of Asthma Therapies 25

26 How Does Omalizumab Compare to New Biologics In Similar Patients? Omalizumab s Effects Based on Th2 Biomarkers Hanania et al, AJRCCM, 2013 Asthma Exacerbation Reductions in Omalizumab Clinical Trials by Eosinophil Strata 10% Asthma Exacerbation Reduction 0% -10% -20% -30% -40% -50% -60% -70% < < < < < Eosinophils per L Sources: Hanania et al. AJRCCM 2013; Busse et al. JACI 2013; Genentech and Novartis Data on File The Pharmacogenetics of Asthma Therapies 26

27 Effects of QGE031 (Ligelizumab) on Ag Induced Wheal Arm JP, et al. Clin Exp Allergy Nov;44(11):1371. Anti-TSLP APC Daclizumab Anti-IL-5 IL-5 GMCSF Anti- GMCSF OX40L MAb Keliximab Bone Marrow TPI ASM8 IL-2Rα Suplatast AVP Abatacept Tcell IL-4 IL-13 Anti-IL-13 Anti-IL-4Rα AIR645 Lumiliximab FcεRII Plasma Cell CD40 CD40L B cell IL-4Rα IDEC 131 BAFF anatgonists IL-9 MEDI-528 ISS PPAR Anti-IL-4 STAT NF B Antagonists Quilizumab 2 nd Gen Anti-IgE IgE Immunomodulators for Asthma Omalizumab FcεRI Mediators Cytokines R112/343 CRTH2 Antagonists Chemokine Receptor Blockers TNF-α TNF Blockers IL-17 Anti-IL-17 Neutrophil VLA-4 VCAM-1 ICAM Blood Vessel Airway Inflammation Remodelling The Pharmacogenetics of Asthma Therapies 27

28 Critical Issues /Questions for Th2 Blockers Many options for similar patient populations. Phenotype/Endotype (Biomarker) driven choices overlap: No specific biomarkers Optimal treatment goals have not yet been met: True Immunomodulation: prevent/alter disease course Th2 blockers likely have favorable risk/benefit ratio Too Weak Very Specific Too Powerful Broad-spectrum Non-Th2 High Asthma Heterogeneous group Primary targets not well defined Likely treatment population size smaller, incentive for development is reduced May be our most challenging patient population The Pharmacogenetics of Asthma Therapies 28

29 Other Potential Applications Asthma TNF-α inhibitors Rituximab Atopic dermatitis Calcineurin inhibitors Antimetabolites including mycophenalate mofetil Omalizumab, dupilumab, rituximab Phosphodiesterase 4 inhibitor (apremilast) Other Potential Applications Nasal polyps Omalizumab, dupilumab, mepolizumab Urticaria Omalizumab Antimetabolites Dapsone Hydroxychloroquine Rituximab Colchicine The Pharmacogenetics of Asthma Therapies 29

30 Conclusions Immune mechanism modification offers the possibility of treating asthma and allergic disease at a basic and not symptomatic level Understanding of the immune mechanism of the disease is critical to intentional application of biologic modifiers Targets that are limited to one disease or organ system are unusual resulting in side effects, Th2 mechanisms tend to be less risky Small molecules cannot be easily designed but offer oral therapy Monoclonal therapies offer designed target development but will be SQ or IV The Pharmacogenetics of Asthma Therapies 30