Jamie Lee Memorial Lecture ( ) Targets and Outcomes: Mepolizumab, Benralizumab, Reslizumab

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1 Jamie Lee Memorial Lecture ( ) Targets and Outcomes: Mepolizumab, Benralizumab, Reslizumab Larry Borish, M.D. Professor of Medicine and Microbiology University of Virginia Conflict of Interest Grant Support: NIH Consulting: Allakos, PluriStem Clinical Trial: Cumberland

2 Learning Objectives To describe the different phenotypes of asthma and the requirement for disease-specific therapeutics To know the distinct behaviors of the different IL- 5/IL-5R targeting therapeutics Jamie (minus baseball cap)

3 James (Jamie) J. Lee, Ph.D. Barbara Woodward Lips Professor Department of Biochemistry and Molecular Biology Mayo Medical School State University of New York at Stony Brook (Class Valedictorain), B.S California Institute of Technology (sea urchins and RNA ; Eric Davidson), PhD Columbia University, (Frank D. Constantini) Post-doc out in Mayo Clinic 24 Years at Mayo Clinic Arizona: collaborated and/or provided Lee Laboratories materials to 1292 investigators (>64 colleagues/year) in 371 different institutions from 35 countries and published ~200 articles EPX / MBP, antibodies, assays for human and mice IL-5 Tg (NJ.1638, NJ.1726) MBP and EPX knockout mice, PHIL, iphil,eocre Eosinophils just destructive cells or innocent bystanders? Local Immunity And/or Remodeling/Repair in health and disease- The LIAR Hypothesis

4 We Will Miss You

5 I DON T ALWAYS STUDY EOSINOPHILS BUT WHEN I DO I FIRST TALK WITH JAMIE LEE! Distinct asthma phenotypes Non-eosinophilic Eosinophilic Allergen-Exacerbated Eosinophilic

6 Expression of Th2 cytokine gene signature defines subgroups of asthmatic patients: Expression of IL-4, IL-5, and IL-13 in bronchial biopsy homogenates from asthmatics: cluster 1: Th2-high asthma, red bars cluster 2: control subjects, gray bars cluster 3: Th2-low asthma, blue bars Woodruff, PG et al. Am. J. Respir. Crit. Care Med. 2009;180: Th2 High Signature Reflects Eosinophil (and Allergic (IgE)) Phenotype: Control Th2 Low Signature Th2 High Signature IgE, IU/ml 27 (3-287) 125 (19-1,194) 244 (32-2,627) Absolute Eosinophil Count, x 10 9 /L 0.10± ± ±0.22 BAL eos % 0.26± ± ±1.9 Woodruff, PG et al. Am. J. Respir. Crit. Care Med. 2009;180:

7 Non-Eosinophilic Asthma Physiology: associated with severe / remodeling-prone asthma and irreversible obstruction Immunology: often associated with increased PMN may be a Th17 disease (IL-17 + predominant T helper cells) Therapeutic implications: CCS resistant CCS inhibit PMN apoptosis and thereby exacerbate PMN-mediated inflammation CCS are less effective for and may paradoxically worsen non-eosinophilic asthma Macrolide antibiotics, MTX, LAMAs, theophylline Th17/IL-17 antagonists? Eosinophilic Asthma Immunology +/- allergic component non-allergic may be Th5 asthma (IL-5 hi /IL-4 +/- ) T cells Definition Eosinophilic infiltration of the airway Therapeutic Implications Corticosteroids effective in large part through their ability to induce eosinophil apoptosis CCS (inhaled or oral) are largely ineffective in noneosinophilic disease and are also ineffective when the disease becomes steroid resistant Anti-IL-5 / Anti-IL-5R

8 Biological Activities of IL-5 in Asthma IL-5 is the most important eosinophil hematopoietin TSLP and IL-33 may also have a role IL-5 is an important survival factor for eosinophils although in the airway autocrine production of GM-CSF may take on a more important role (eosinophils do not make IL-5) IL-5 is chemotactic for mature eosinophils and a priming factor for enhanced functional activities Anti-IL-5 (Mepolizumab) in Eosinophilic Asthma: Reduction in Exacerbations Haldar P et al. New Engl J Med 2009;360:973 Nair P et al. New Engl J Med 2009;360:985 Severe (CCS-dependent) asthma Sputum eosinophilia required for enrollment No improvement in FEV 1, control, symptoms

9 Mepolizumab: DREAM study Randomization to placebo, or mepolizumab 75 mg, 150 mg, or 750 mg IV Primary outcome parameter: Exacerbation Secondary outcome parameters AEC Induced sputum eosinophils FEV1, ACQ, QOL And no significant effect on lung function or control Pavord, ID, et al. Lancet 2012;380:651-9 MENSA study RCTx of 576 patients with frequent exacerbations and evidence of eosinophilic inflammation on high dose inhaled CCS Randomized to placebo 75 mg IV or 100 mg SQ mepolizumab Primary outcome: exacerbations Secondary outcomes: FEV1, ACQ-5, qol With significant improvement in QOL Ortega, HG et al. New Engl J Med 2014;371:1198

10 Exacerbation reduction is based on baseline AEC Pooled analysis of DREAM and MENSA studies Ortega, HG et al. Lancet Respir Med 2016;4: Things the keep me up the long winter nights in Charlottesville Why only a 50% reduction in exacerbation? Why not 100%? Omalizumab, dupilumab, mepolizumab, reslizumab, whateveramab all reduce exacerbations by ~50%. Are they the same 50%? And what is the cause of the other 50%?

11 Inadequately dosed? Why only 50% IL-5-independent eosinophil activation Maybe we left behind some of those pesky neutrophils, basophils, mast cells, whatever Inadequately dosed? Why only 50% IL-5-independent eosinophil activation Maybe we left behind some of those pesky neutrophils, basophils, mast cells, whatever

12 Would a higher dose help? Effect of mepolizumab on induced sputum eosinophils Pavord, ID, et al. Lancet 2012;380:651-9 Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts Blood eosinophils 400/µL Ages Inadequately controlled asthma Frequent exacerbations RCTx of placebo v. reslizumab at 3mg/kg Also significant improvement in ACQ6, qol, etc. Mean AEC: /µL Castro M et al. Lancet Respir Med 2015;3:355-66

13 Effect of reslizumab on eosinophils Reslizumab Placebo p-value Induced sputum Median, % Change Blood AEC Median (x 10 3 cells/µl) Baseline Change from baseline 10.7 (1.7, 67.6) -95.4% (-100.0, 315.9) Baseline Change from baseline 8.5 (3.0, 77.0) -38.7% (-96.0, 1,480) (0.1, 1.50) (-1.50, 0.0) 0.5 (0.0, 1.20) 0.0 (-0.80, 0.80) < Castro M et al. Lancet Respir Med 2015;3: Use of reslizumab where mepolizumab failed 10 prednisone-dependent asthmatics with induced sputum >3% and blood AEC >300/µL Failed mepolizumab (100 mg SQ q4 weekly for >1 yr) Single blind, RCTx of reslizumab (3 mg/kg q 4weekly) Primary outcomes: Reduction in sputum and blood eosinophils Secondary outcomes: FEV1, ACQ, EPO, etc. Mukherjee, M et al. Am J Respir Crit Care Med 2018;197:38-46

14 Use of reslizumab where mepolizumab failed Decreased in sputum eosinophils and EPX was greater with reslizumab (91.2%) compared with mepolizumab (5%) Reslizumab a/w improved ACQ5 Greater improvement associated with: - Extent in drop in IS eos a/w greater improvement in ACQ - Changes in sputum IL-5 a/w greater response An increase in sputum eos (despite drug administration) predicted exacerbations Mukherjee, M et al. Am J Respir Crit Care Med 2018;197:38-46 Inadequately dosed? Why only 50% IL-5-independent eosinophil activation Maybe we left behind some of those pesky neutrophils, basophils, mast cells, whatever

15 Incomplete attenuation of airway eosinophils IL-5 essential for eosinophil maturation possible role for IL-33, TSLP IL-5 less important for eosinophil persistence and activation in the tissue increasingly important role for GM-CSF (± IL-3) including autologous eosinophil-derived GMCSF airway eosinophils express high levels of GMCSFR and IL-3R and downregulate IL-5R (in part in response to IL-5) eosinophils may survive for month(s) in tissue! eosinophils do not produce IL-5 Preservation of activated tissue eosinophils despite mepolizumab Endobronchial allergen challenge model before and after mepolizumab (750 mg IV) Blood and BAL eosinophils examined Mepolizumab eliminated rise in blood eos after allergen challenge Mepolizumab only attenuated the rise in BAL/tissue eos after allergen challenge Kelly, EA et al. Am J Respir Crit Care Med 2017;196:

16 . and these challenges are associated with increased airway eosinophil expression of IL-3R mrna transcripts and perhaps by extension: - IL-3R surface protein - And GM-CSFR protein Kelly, EA et al. Am J Respir Crit Care Med 2017;196: Inadequately dosed? Why only 50% IL-5-independent eosinophil activation but those eos do still express the IL-5R Maybe we left behind some of those pesky neutrophils, basophils, mast cells, whatever

17 Anti-IL-5R (Benralizumab) Binds anti-il-5r acting as a competitive inhibitor of IL-5 binding (largely similar biological activity of anti-il-5) Afucosylated IgG1 antibody acufosylation promotes binding to FcgRIII thereby promotes NK-mediated ADCC / apoptosis of opsonized cells including IL-5-independent eosinophils, basophils and perhaps mast cells, PMNs, mononuclear phagocytes Benralizumab for severe asthma RCTx of benralizumab sc (30 mg q 4 weeks and q 8 weeks) v. placebo 1306 subjects Primary outcome: exacerbations Secondary outcome: FEV1, etc. And perhaps a hint (?) that it works in subjects with lower AECs - enough of a hint to convince the FDA, anyway FitzGerald, JM et al. Lancet 2016; 388:

18 Oral CCS-Sparing Effect of Benralizumab RCTx of benralizumab (30 mg q4 v. q8 weekly) v. placebo 220 subjects on oral prednisone Primary outcome: Reduction in prednisone dose Unclear why ~20% of subjects had no reduction or oral CCS dose - Baseline AEC who did not respond were similar to those who did - Suggesting that: circulating AEC has little predictive value regarding tissue eosinophils AND/OR benralizumab works by targeting something (some cell) other than eosinophils Inadequately dosed? Why only 50% IL-5-independent eosinophil activation Maybe we left behind some of those pesky neutrophils, basophils, mast cells, whatever

19 The severe asthma research program at UVA* *Gerry Teague, MD - director Distribution of BAL Fluid Granulocyte Patterns in 189 Children and Adolescents with Treatment-Resistant Asthma Absolute eosinophil count (cells/µl; median (25 th -75 th percentile) by granulocytic pattern Isolated Eosinophila 305 ( ) Isolated Neutrophilia Mixed Granulocytic Pauci-Granulocytic 320 ( ) 380 ( ) 200 ( )* *p=0.01 versed mixed granulocytic

20 Summary: Targeting IL-5 in Treatment Resistant Asthma IL-5 targeting biologics have been a game changer in treatment-resistant asthma Although they only attenuate ~50-80% of exacerbations and have variable effect on lung function, symptoms, qol, etc. And many patients are non-responders Summary: Targeting IL-5 in Treatment Resistant Asthma (II) Non-responsiveness may reflect: - inadequate dosing - conversion of an IL-5-dependent response to a GM-CSF (±IL-3, TSLP, IL- 33, etc., etc., etc) dependent response - mixed inflammatory response in treatment-resistant asthma: PMNs, basophils, mast cells, etc.

21 How I Choose Which Biologic to Use: Coin flip Eenie, meenie, miny, mo A Few Specific Reasons I Might Use a Given Biologic Mepolizumab - EGPA or mixed (undifferentiated) HES/EGPA (at 300 mg SQ) Reslizumab - Obesity (where weight-based dosing is important) Benralizumab - Lower AEC (no specific FDA requirement for high AEC) - Concern for non-eosinophilic inflammation that could be response to a-il-5r-mediated ADCC: IL-5 non-responding/ IL-5R + eosinophils, PMNs, mast cells, basophils, others

22 Phenotype (Endotype) -Specific Approaches Phenotype (Endotype) Severe allergic Eosinophilic Non-Eosinophilic AERD Severe obstruction Treatment anti-ige, perhaps IL-4/IL-13/IL-4R, allergen avoidance, IT anti-il-5/il-5r macrolide antibiotics, LAMAs, MTX, Anti-IL-8, CXCR2 antagonists, PDEIV inhibitors/theophylline, LTB4 antagonists, anti-il-17, desperately TBD. zileuton, aspirin desensitization, thromboxane/pgd2/lte4 antagonists anti-il-13, anti-il-4r, bronchial thermoplasty