UPDATE ON ASTHMA THERAPY: MATCHING PHENOTYPE TO TREATMENT Sally E. Wenzel, MD Professor of Medicine University of Pittsburgh Asthma Institute@UPMC Subsection Chief of Allergy 1234567 891234 567891 2345678 Distinguishing Type-2 Asthma Asthma Blood eos Periostin FeNO Type-2 inflammation No/less Type-2 inflammation
Blockade of IL-4/-13 receptor decreased allergen induced exacerbation Wenzel, Lancet, October 27 11 1 1 Placebo inhaled Pitrakinra nhaled 9 8 % f 7 Screening Day 27 Screening Day 27 Allergen 2 4 6 8 1 Hours Mean ± SEM (n = 14 placebo, 15 AEROVANT) Allergen 2 4 6 8 1 Hours Similar efficacy of Anti-IL-13 antibodies, with no effect on sputum eos Gauverau Am J Resp Crit Care Med 211 Suggests early onset allergic asthma should respond to IL-4/13 targeted therapy Anti-IL-5 did not impact allergen induced responses Leckie NEJM 2 3 What are the best biomarkers? Is there gold standard and how do you define? Previous studies defined gold standard as lung/sputum eosinophils but no proof that best defines a Type-2 phenotype Is it more important to use biomarkers to predict response to treatments, either non-specific (CSs) or targeted biologics Likely to have modest to good predictability Blood (sputum) eos, FeNO and serum periostin Not likely to be helpful Atopy/specific IgE
Predicting lung eosinophils In moderate to severe asthma, serum periostin related to lung eosinophils Jia JACI 212 In relation to FeNO, blood eosinophils or IgE periostin best predicted lung eos But not better than FeNO in predicting response to anti-il- 13 Corren NEJM 211 Cannot be used <18 years old Sputum eosinophils predict response to inhaled CS No response Good response Patients from ACRN clinical trials with at least 3 sputum samples Divided into those with eosinophils on 2 or 3, eosinophils on at least 1 or no eosinophils ever (about 3% in each) Not yet clear whether blood eos can be substituted McGrath AJRCCM 212
Type-2 targeted therapies: Anti-IL-13 2+ pts with moderate to severe asthma on mid to high dose ICS±LABA randomized to Rx with anti-il-13 vs placebo Anti-IL-13 modestly effective in improving FEV1 in all comers Dividing pts into serum periostin Hi/Lo (Th2-Hi/Lo) identified responder population FeNO worked similarly well Corren, et al N Engl J Med 211 Blockade of IL-13 also decreased Fe NO confirming bioresponse marker inos 13 kd -actin 42 kd CON IL-13 CON IL-13 CON IL-13 Normal Mild-Mod Severe inos/ -actin*1 1 9 8 7 6 5 4 3 2 1 P<.5 N=15 Control IL-13 1 ng/ml Chibana, K Clin Exp Allergy 28
Current targeted Rxs (anti-ige) may be more efficacious in Type-2 Hi Lo Th2 Hi Lo Th2 Hi Lo Th2 Hi Hanania, AJRCCM May 213 Does broader blockade of Type 2 cytokines further improve outcomes?
Blockade of both IL-4/13: Targeted Hi Eos subgroup (>3/ul) Screening/ run in period Treatment period Post treatment period Background therapy stable phase Background therapy withdrawal phase monotherapy Fluticasone/salmeterol DPI: 25/5 µg BID 5/5 µg BID MDI: 23/42 µg BID 46/42 µg BID Fluticasone 25 µg BID 5 µg BID 22 µg BID 44 µg BID 1 µg BID 25 µg BID 11 µg BID 22 µg BID 5 µg BID 1 µg BID 44 µg BID 11 µg BID µg BID 5 µg BID µg BID 44 µg BID µg BID µg BID Fluticasone/salmeterol 25/5 µg BID 5/5 µg BID 23/42 µg BID 46/42 µg BID SC = subcutaneous; BID = twice daily dosing; DPI = dry powder inhalation; MDI = metered dose inhalation Wenzel S, et al. N Engl J Med. 213;368:2455 66. IL4R inhibition decreased time to 1 st exacerbation Cumulative Exacerbation Rate (%) 55 5 45 4 35 3 25 2 15 1 5 Stable ICS/LABA LABA discontinuation ICS Taper or placebo monotherapy 1 2 3 4 5 6 7 8 9 1 11 12 13 Number at Risk Week Placebo 52 52 5 5 48 44 43 41 37 35 32 28 24 52 51 51 51 5 5 5 5 47 45 44 43 42 Placebo Hazard ratio.1 (95% CI.3,.34) P <.1 Wenzel S, et al. N Engl J Med. 213;368:2455 66.
Improves lung function Mean Change from Baseline (± SE).3. Stable ICS/LABA LABA discontinuation ICS Taper or placebo monotherapy P <.1 P <.1 Placebo -.3 1 2 3 4 5 6 7 8 9 1 11 12 No. subjects Week Placebo 52 52 51 51 5 49 47 46 45 43 41 4 36 52 51 52 52 5 49 52 52 47 46 46 45 45 Wenzel S, et al. N Engl J Med. 213;368:2455 66. And Asthma Control Mean Change from Baseline (± SE). -.1 -.2 -.3 -.4 -.5 -.6 -.7 -.8 -.9-1. -1.1-1.2-1.3 Stable ICS/LABA LABA discontinuation ICS Taper or placebo monotherapy 1 2 3 4 5 6 7 8 9 1 11 12 Week No. subjects Placebo 52 49 5 51 48 47 46 45 44 4 41 4 36 52 49 5 49 5 48 52 51 46 45 46 45 44 Wenzel S, et al. N Engl J Med. 213;368:2455 66. Placebo P P = = <.1.1.1
Clinical Response correlates with biologic response Mean Percent Change from Baseline (± SE) 5 4 3 2 1-1 -2-3 -4 Stable ICS/LABA LABA discontinuation ICS Taper or placebo monotherapy Correlation of FeNO with FEV 1 at Week 12: r =.48 P =.9 Placebo P <.1 P <.1 4 Week 8 12 No. subjects Placebo 52 51 47 44 51 48 5 4 also impacted upper airway: SNOT-22 SNOT22 subscales Total change from placebo -8.49 (MCS -8.99)
Phase 2b: What will define Type-2 asthma and how well will it respond? Multinational, randomized, placebo-controlled study in patients with uncontrolled asthma despite background therapy with medium- to high-dose ICS and LABA Patients stratified by blood eosinophil (Eos) count Hi Eos defined as >3/ul, Lo Eos all others n = 15 3 mg q2w with loading dose (6 mg) n = 15 3 mg q4w with loading dose (6 mg) Screening period (14 21 days) Randomization (1:1:1:1:1) was used as add-on therapy to ICS and LABA n = 15 2 mg q2w with loading dose (4 mg) n = 15 2 mg q4w with loading dose (4 mg) n = 15 Placebo 24-week treatment period q2w, every 2 weeks; q4w, every 4 weeks. Study Endpoints Primary endpoint: Change from baseline in FEV 1 (L) at Week 12 in the high Eos (HEos) population Secondary endpoints included: Change from baseline in FEV 1 (L and %) at Week 12 Annualized rate of severe exacerbation* during treatment period Safety and tolerability data Secondary outcomes reported for: HEos, defined as 3 cells/µl Low Eos (LEos), defined as < 3 cells/µl Overall *A severe exacerbation event during the study defined as deterioration of asthma requiring use of systemic corticosteroids for 3 days or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids.
Baseline Demographics and Clinical Characteristics: Overall Population Placebo (n = 158) 2 mg q4w (n = 154) 3 mg q4w (n = 157) 2 mg q2w (n = 15) 3 mg q2w (n = 157) Mean age, years 49. 47.9 47.9 51. 47.5 Male, % 34.2 43.5 36.3 36. 34.4 BMI > 3 kg/m 2,% 38. 39.9 39.5 43.3 4.1 Baseline FEV 1, L 1.82 1.88 1.86 1.79 1.85 Baseline FEV 1, % predicted 61. 6.3 6.7 61.3 6.8 Mean asthma exacerbations in past year 1.94 1.78 1.9 1.75 1.96 High dose ICS/LABA use, % 49.4 47. 54.2 5.7 51. Atopic medical history, % 77.3 76.2 8.6 79.2 73.4 Atopic dermatitis 1.4 11.3 12.9 6.7 1.4 Allergic rhinitis 66.2 66.2 63.9 66.4 61. Nasal polyposis 11.7 13.9 2. 16.8 19.5 ACQ5 score 2.69 2.78 2.7 2.73 2.8 Mean FeNO, ppb 38.9 42. 38.1 39.2 37.1 BMI, body mass index; FeNO, fractional exhaled nitric oxide; ppb, parts per billion. Baseline Blood Eosinophil Counts Placebo 2 mg q4w 3 mg q4w 2 mg q2w 3 mg q2w Baseline Eosinophil counts (cells/µl) Mean (SD) n Mean (SD) n Mean (SD) n Mean (SD) n Mean (SD) n Overall population 34 (3) 158 38 (76) 154 33 (27) 157 36 (35) 15 32 (25) 157 HEos population 56 (34) 68 7 (112) 62 56 (28) 66 61 (41) 65 53 (27) 64 LEos population 17 (7) 9 17 (7) 92 17 (8) 91 17 (6) 85 18 (7) 93 SD, standard deviation
Primary Endpoint: Absolute Change in FEV1 In HEos Population Placebo (n = 62) Dup 2q4w (n = 62) Dup 3q4w (n = 66) Dup 2q2w (n = 65) Dup 3q2w (n = 64) HEos population FEV 1 liter change.5 LS mean change (± SE).4.3.2 *** ** *.1 2 4 Week 8 12 Statistically significant improvement in FEV 1 at Week 12 in patients with HEos versus placebo at all doses explored except 2 mg q4w ; *P <.5, **P <.1, ***P <.1 vs placebo; Dup, dupilumab; LS, least squares; SE, standard error BUT FEV1 improves in those with <3 eos/ul too Placebo Dup 2q4w Dup 3q4w Dup 2q2w Dup 3q2w LS mean % change (± SE) LS mean % change (± SE) 3 2 1 3 2 1 HEos population 2 4 8 12 Week Overall population *** ** * 2 4 6 8 1 12 Week *** *** ** * LS mean % change (± SE) 3 2 1 LEos population 2 4 8 12 Week ** * In the overall population, significant improvement was observed for all dupilumab dose regimens versus placebo In the LEos population, significant improvement was observed for the q2w regimens versus placebo, but not for the q4w regimens ; *P <.5, **P <.1, ***P <.1 vs placebo; Dup, dupilumab; LS, least squares; SE, standard error
And, no difference in effect on exacerbations Adjusted annualized severe exacerbation rate - estimate (95% CI) 1.8 1.6 1.4 1.2 1..8.6.4.2. HEos population * Placebo 2 mg (N = 68) q4w (N = 59) 74% 26% 64% 75% 3 mg q4w (N = 66) * 2 mg q2w (N = 64) * 3 mg q2w (N = 64) Adjusted annualized severe exacerbation rate - estimate (95% CI) 1.8 1.6 1.4 1.2 1..8.6.4.2. LEos population 46% 51% 68% 62% Placebo (N = 9) 2 mg q4w 3 mg q4w 2 mg q2w 3 mg q2w (N = 91) (N = 91) (N = 84) (N = 92) ** * Adjusted annualized severe exacerbation rate - estimate (95% CI) 1.8 1.6 1.4 1.2 1..8.6.4.2. Placebo (N = 158) Overall population 57% 38% 67% 68% ** 2 mg q4w (N = 15) 3 mg q4w (N = 157) ** *** 2 mg q2w (N = 148) 3 mg q2w (N = 156) In the HEos and overall populations, significant decreases in severe asthma exacerbation rates were observed for all dupilumab regimens versus placebo, except the 3 mg q4w In the LEos population, significant decreases in severe asthma exacerbation rates were observed for the dupilumab q2w regimens versus placebo However, BETTER response seen in those with higher blood eos Anti-IL-5 approaches: Directly targeting eosinophils Haldar P et al. N Engl J Med 29;36:973-984 Anti IL-5 not effective in unselected pts Flood-Paige 27 Targeted Anti-IL-5 approach to eosinophilic asthma led to 4% reduction in asthma exacerbations Eosinophils nearly gone in blood Is there phenotype that responds best?
Mepolizumab consistently effective in 3 large trials of eosinophilic patients Targeted patients with blood eosinophils >~28/ml Reductions in exacerbations of 4-5% Recent studies show some impact on FEV1/ACQ as well Responses improve with increasing eosinophils Similar data with benralizumab Castro Lancet Res Med 214 Ortega HG et al. N Engl J Med 214;371:1198-127. Will anti-il-5 approach do best in Adult onset Eosinophilic asthma? Wu, JACI 214 BAL Eosinophil %
Anti-IL-5 Receptor antibody approach (benralizumab) NCT1238861 (CP22) Eosinophilic phenotype: ELEN Index positive and/or Fe NO 5 ppb Non-eosinophilic phenotype: ELEN Index negative and Fe NO <5 ppb ELEN Index: mathematical algorithm to predict elevated sputum eosinophils 1 Primary endpoint: AER Secondary endpoints: FEV 1, ACQ-6 27 Demographics: High % of patients with nasal polyps Eosinophilic Non-eosinophilic Placebo Benralizumab Placebo Benralizumab n=8 2 mg n=81 2 mg n=81 1 mg n=82 n=142 1 mg n=14 Age, years 45.6 (11.7) 47.1 (12.8) 46.6 (13.2) 47.8 (12.9) 5. (12.3) 5. (11.5) Female, n (%) 53 (66.3) 58 (71.6) 48 (59.3) 6 (73.2) 1 (7.4) 98 (7.) White, n (%) 53 (66.3) 59 (72.8) 5 (61.7) 62 (75.6) 16 (74.6) 99 (7.7) BMI, kg/m 2 28.8 (6.) 29.2 (6.5) 28. (5.2) 28. (6.1) 29.6 (5.) 29.5 (6.) ACQ-6 score 2.7 (1.) 2.6 (1.) 2.5 (.9) 2.5 (1.) 2.5 (.8) 2.6 (.8) Nasal polyps, n (%) 15 (18.8) 13 (16.) 21 (25.9) 17 (2.7) 12 (8.5) 12 (8.6) Exacerbations in past year 2.2 (.5) 2.3 (.7) 2.5 (.7) 2.3 (.6) 2.2 (.5) 2.3 (.7) FE NO, ppb 37.9 (31.9) 39.5 (32.7) 4.8 (31.) 37.8 (31.7) 2.7 (13.9) 2.2 (12.1) FEV 1, % predicted 65. (15.3) 65.1 (15.2) 64.8 (14.8) 66.1 (15.9) 69.1 (14.5) 66.8 (15.1) FEV 1 reversibility, % 18.3 (15.1) 18.7 (22.) 19.8 (2.3) 18. (13.3) 12.8 (13.) 15.3 (15.3) Blood eosinophil count, 1 3 /µl.53 (.3).53 (.33).54 (.28).56 (.36).16 (.9).19 (.12) Baseline ICS dose (fluticasone equivalent), µg 739.1 691. 724.9 697. 673.7 75.2 *Data are expressed as mean (standard deviation) unless otherwise specified. ACQ-6; Asthma Control Questionnaire-6; BMI, body mass index; FE NO, fractional exhaled nitric oxide; FEV 1, forced expiratory volume in 1 second; ICS, inhaled corticosteroids; mitt, modified intent-to-treat; ppb, parts per billion 28 Castro, Lancet Resp Med 214
Only reduced exacerbations in Hi-Eos Benralizumab 1 mg significantly reduced AER relative to placebo - In eosinophilic subjects - In subjects with baseline blood eosinophils 3 and 4 cells/µl *Statistically significant (p<.169). Data are expressed as mean (8% confidence interval). AER, annual exacerbation rate; AERR, annual exacerbation rate reduction; mitt, modified intent-to-treat; RR, rate reduction 29 While some FEV1 improvement in low eos, greater in those with Hi eos In subgroups with blood eosinophil counts 2, 3 and 4 cells/μl, all doses of benralizumab showed significant improvements in FEV 1 vs placebo *Statistically significant (p<.169). FEV 1, forced expiratory volume in 1 second; mitt, modified intent-to-treat 3
Anti-IL-5 as CS sparing agent in VSA Investigational Product SC every 4 weeks Primary Efficacy Endpoint assessed at week 24 (Exit Visit) Visit 1 Visit 2 Week Visit 3 4 8 12 16 4 5 6 7 2 8 24 9 OCS Optimisation Phase Induction Phase OCS Reduction Phase Maintenance Phase 8 to 3 weeks Mepolizumab 1mg SC Placebo SC Bel E, et al, N Engl J Med Sept 214 Baseline Characteristics Characteristic Placebo N=66 Mepolizumab N=69 Age (yr), mean (range) 49.9 (28 7) 49.8 (16 74) Female, n (%) 3 (45) 44 (64) BMI (kg/m 2 ) 29.5 (6.) 27.8 (5.9) Duration of asthma, yr 2.1 (14.4) 17.4 (11.8) Screening OCS dose (mg) median 15 12.5 Optimized OCS dose (mg), median 12.5 1 Duration of OCS 5 years at baseline, (%) 31 (47) 34 (49) Percent reversibility FEV 1 24.7 (18.1) 27.3 (17.4) ACQ score 2. (1.2) 2.2 (1.3) SGRQ score 45 (18) 5 (18) Blood eosinophil count (cells/µl), geometric mean (SD on log e scale) 23 (1,1) 25 (1,245)
4% of patients able to decrease OCS by >75% % study population % Reduction Strata 4% vs 18% OR= 2.39 (95% CI, 1.25 4.56) P=.8 BUT, 3-4% with no/minimal reduction despite starting eosinophilia Other: no decrease in OCS dose, or lack of control during weeks 2 24 or withdrawal from treatment Improvement in asthma control despite reduction in corticosteroids Mean ACQ-5 Score p=.4
Will there be phenotypic differences in IL-4/13 vs IL-5 responders? Anti-IL-4/13 effective in allergen challenge Anti-IL-5 no effect Sources differ: IL-4 more likely from Th2 cells More mature Th2 cells produce IL-5 Upadhaya J Immunol 211 IL-5/-13 produced by ILC2 cells, lesser amounts of IL-4 IL-4/13 approaches MAY be better in early onset allergic, IL-5 in late onset, neither (or combined) in complicated Type-2 In CS dependent asthma, IL-4/13 efficacy not yet confirmed (de Boever JACI 214), while anti-il-5 effective What about non-type-2 approaches? Overview IL-17A IL-17F IL-17A/F heterodimer IL-17C IL-25 (IL-17E) IL-17B IL-17D Ligands Source of Ligand Receptors T H 17 cells CD8+ T cells γδ T cells NK cells Epithelial cells (trachea, colon, skin) T cells Intraepithelial lymphocytes Cells of the GI tract and uterus Unknown Unknown Note: IL-17 ligands are expressed as dimers NKT cells LTi cells Neutrophils Eosinophils Basophils Mast cells Alveolar MФs IL-17RA IL-17RC IL-17RA IL-17RE IL-17RA IL-17RB IL-17RB Unknown 1. Gaffen SL. Nat Rev Immunol. 29;9:556-568. 2. Chang SH, et al. Cell Res. 27;17:435-44. 3. Garley M, et al. Adv Med Sci. 28;53:326-33. 4. Pappu R, et al. Immunology. 211;134:8-16. 5. Ramirez-Carrozzi V, et al. Nat Immunol. 211;12:1159-1166. 6. Song X, et al. Nat Immunol.. 211;12:1151-1158. 7. Moseley TA, et al. Cytokine Growth Factor Rev. 23;14:155-174. 8. Ge D, et al. Int Arch Med. 28;1:1-19. 9. Lee J, et al. J Biol Chem. 21;276:166-1664.
Brodalumab Is an Anti IL-17RA mab That Blocks the Activities of IL-17A, IL-17F, IL-17A/F, and IL-25 Overview IL-17A IL-17A/F IL-25 (IL-17E) IL-17A/F IL-17F IL-17A IL-17F IL-25 IL-17C Brodalumab Brodalumab? Brodalumab IL-17RB IL-17RA IL-17RC IL-17RA IL-17RE IL-17RA Brodalumab is a human IgG2 antibody It binds to IL-17RA (K D =239 pm) to block IL-17A, IL-17F, IL-17A/F, and IL-25 activities 1. Toy D, et al. J Immunol. 26;177:36-39. 2. Wright JF, et al. J Immunol. 28;181:2799-285. 3. Rickel EA, et al. J Immunol. 28;181:4299-431. 4. Chang SH, et al. Cell Res. 27;17:435-44. 5. Claudio E, et al. J Immunol. 29;182:1617-163. 6. Kuestner RE, et al. J Immunol. 27;179:5462-5473. 7. Ramirez-Carrozzi V, et al. Nat Immunol. 211;12:1159-1166. 8. Amgen data on file. Primary Endpoint: Overall Population ACQ Change From Baseline Line Graph of ACQ Change From Baseline LOCF Phase 2: Efficacy. -.2 -.4 Mean (SE) -.6 -.8-1. -1.2-1.4 BL 1 2 4 6 8 1 12 Study Week N=76 N=73 N=74 N=76 N=76 N=76 N=76 N=76 N=74 N=73 N=73 N=73 N=73 N=73 N=73 N=73 N=76 N=74 N=74 N=74 N=75 N=75 N=75 N=75 N=76 N=74 N=74 N=74 N=74 N=74 N=74 N=74 Placebo AMG 827 14 mg Q2W AMG 827 21 mg Q2W AMG 827 28 mg Q2W Although identified responder group related to high reversibility, 2 nd larger study targeting high reversibility subgroup completely negative
Bronchial Thermoplasty: More likely to be efficacious in Type-2 Lo asthma? Castro, M AJRCCM 21; 181:116-24 No studies of BT to date have tried to identify responder group Data slowly emerging on reduction in airway smooth muscle although without control groups No evidence for reduction in inflammatory markers Should do better in those with less overall inflammation Conclusions Multiple drugs in development have clinically and biologically meaningful effects in Type-2 Hi asthma Which Type-2 subphenotype will respond best to which biologic still unclear Considerable progress likely to be made with use of biomarkers New approaches for Type-2 Lo asthma remain elusive