Atopic Dermatitis: Emerging therapies Melinda Gooderham MSc MD FRCPC SKiN Centre for Dermatology, Peterborough Assistant Professor, Queen s University, Kingston ON Investigator, Probity Medical Research, Waterloo ON
Speaker Disclosures AbbVie A,C,RI,S Actelion S Amgen A,C,RI,S Celgene A,C,RI,S Coherus RI Dermira RI Eli Lilly A,C,RI,S Galderma A,RI,S GSK RI JanssenA, C, RI,S Kyowa Kirin Pharma C,RI Leo Pharma Inc. A,C,RI,S Medimmune RI Merck RI Novartis RI,S Pfizer A,RI Regeneron RI Roche RI Sanofi Genzyme A,RI,S UCB RI Valeant A,S A Advisory Board, C Consultant, RI Research Investigator, S Speaker
Objectives Review current biologic therapies for atopic dermatitis (AD) Explore our understanding of AD pathophysiology Recognize newly identified targets for AD therapy that are under development to provide safe and effective treatment for this chronic condition
Atopic Dermatitis Escalating Treatment Approaches to Meet Patient Needs Systemic Therapy (10%) Topical Treatment Nonpharmacologic Therapy Eichenfield LF, et al. J Am Acad Dermatol. 2014;71(1):116-132; Sidbury R, et al. J Am Acad Dermatol. 2014;71(2):327-349.
Off-Label biologics investigated for AD Agent Study, N Benefits Drawback Infliximab (anti-tnf) Ustekinumab (anti-il 12/23) Rituximab (anti-cd20) Omalizumab (anti-ige) Mepolizumab (anti-il5) Open label, N=9 Case series and RCT N=37 (USA) RCT N=79 (Japan) OL, N=6 OL, RCT, case series N = 103 RCT, N=43 2/9 experienced long term benefit RCT benefit did not reach statistical significance Results were inconclusive Conflicting data on efficacy No clinical improvement at d14 Initial clinical response was not maintained over time Safe drug, further study is needed Lack of data Safe drug; cost may outweigh clinical benefit No significant safety concerns Adapted from Gooderham M, et al. JCMS 2016 (9):1-9 DOI: 10.1177/1203475416670364, Saeki, H. et al. BJD 2017 doi: 10.1111/bjd.15493
AD, atopic dermatitis; AMPs, antimicrobial proteins; IgE, immunoglobulin E; IL, interleukin; DC, dendritic cell; IDEC, Inflammatory dendritic epidermal cells; ddc, dermal dendritic cell; TSLP, thymic stromal lymphopoietin; IFN, interferon Gooderham M, et al. JCMS 2016 (9):1-9. 7
Targeted biologics currently under investigation Target Agent Details Sponsor IL-5 Mepolizumab RCT N=43 Phase 2 trial ongoing IL-31RA Nemolizumab Phase 2, N=264 Published NEJM GSK Galderma /Chugai IL-13 Tralokinumab Phase 2 RCT, N=204 +TCS MedImmune/ LEO IL-4RA (IL-4, -13) Lebrikizumab Phase 2 RCT, N=209 +TCS (TREBLE) Dupilumab (Dupixent ) Phase 3, N > 2000 approved US, EMA Published Lancet, NEJM Genentech/ Roche Regeneron/ Sanofi Genzyme Reference: Dermatology News March 13, 2016 (AAD report); Dermatology News October 15, 2016; Beck L,, et al. N Engl J Med. 2014 Jul 10;371(2):130-9; Thaci D et al. Lancet 2016; 387: 40 52; Blauvelt A, et al. Presented AAD 2017, Orlando. Florida
Small molecules: JAK Inhibitors Target Drug AD studies Results to date JAK 1 PF-04698542 Phase 2 completed JAK 1 Upadacitinib (ABT-494) Phase 2 completed JAK 1/2 Baricitinib Phase 2 completed (+ TCS) IGA 0/1 (200 mg) 44.5% at 12 wks vs. 6.3% (PBO) (p<0.003) 82% reduction (200 mg) in EASI score vs. 35% (PBO) IGA 0/1 (30 mg) 50% vs. 2% (PBO) at 12 wks 74% reduction (30mg) in EASI score vs. 23% (PBO) EASI 50 (4mg) 61% vs. 37% with TCS alone (p<0.05) at 16 wks Image: Gooderham, M. Skin Therapy Letter 2013 Gooderham M et al. PF-04965842, a JAK1 inhibitor, for treatment of atopic dermatitis: a 12-week, randomised, double-blind, placebo-controlled phase 2 clinical trial. Presented at EADV 2017, Geneva, Switzerland Press releases: Baricitinib, https://investor.lilly.com/releasedetail.cfm?releaseid=1040434, Upadacitinib, https://news.abbvie.com/news/abbvies-upadacitinibabt-494-meets-primary-endpoint-in-phase-2b-study-in-atopic-dermatitis.htm
Small molecules: JAK Inhibitors Target Drug AD studies Results to date JAK 1 PF-04698542 Phase 2 completed JAK 1 Upatacitinib (ABT-494) Phase 2 completed JAK 1/2 Baricitinib Phase 2 completed (+ TCS) IGA 0/1 (200 mg) 44.5% at 12 wks vs. 6.3% (PBO) (p<0.003) 82% reduction (200 mg) in EASI score vs. 35% (PBO) IGA 0/1 (30 mg) 50% vs. 2% (PBO) at 16 wks 74% reduction (30mg) in EASI score vs. 23% (PBO) EASI 50 (4mg) 61% vs. 37% with TCS alone (p<0.05) at 16 wks Gooderham M et al. PF-04965842, a JAK1 inhibitor, for treatment of atopic dermatitis: a 12-week, randomised, double-blind, placebo-controlled phase 2 clinical trial. Presented at EADV 2017, Geneva, Switzerland Press releases: Baricitinib, https://investor.lilly.com/releasedetail.cfm?releaseid=1040434, Upadacitinib, https://news.abbvie.com/news/abbvies-upadacitinibabt-494-meets-primary-endpoint-in-phase-2b-study-in-atopic-dermatitis.htm
Targeting IL-5 Mepolizumab - Blocks IL-5 - Phase 2 trials in AD underway - Approved in asthma (high eos) AD, atopic dermatitis; AMPs, antimicrobial proteins; IgE, immunoglobulin E; IL, interleukin; DC, dendritic cell; IDEC, Inflammatory dendritic epidermal cells; ddc, dermal dendritic cell; TSLP, thymic stromal lymphopoietin; IFN, interferon Gooderham M, et al. JCMS 2016 (9):1-9; Ruzicka T. et al. N Engl J Med 2017;376:826-35. DOI: 10.1056/NEJMoa1606490 11
Targeting IL-31 Nemolizumab - Blocks IL-31RA - Completed phase 2 - Phase 3 trials ongoing - Effective for control of itch AD, atopic dermatitis; AMPs, antimicrobial proteins; IgE, immunoglobulin E; IL, interleukin; DC, dendritic cell; IDEC, Inflammatory dendritic epidermal cells; ddc, dermal dendritic cell; TSLP, thymic stromal lymphopoietin; IFN, interferon Gooderham M, et al. JCMS 2016 (9):1-9; Ruzicka T. et al. N Engl J Med 2017;376:826-35. DOI: 10.1056/NEJMoa1606490 12
Ruzicka T. et al. N Engl J Med 2017;376:826-35. DOI: 10.1056/NEJMoa1606490
50 Secondary Outcome Measures Wk 16 40 30 20 10 0-10 % change EASI % change SCORAD % change BSA.. Improvement IGA. -20-30 -40-50 Placebo 0.1 mg/kg 0.5 mg/kg 2.0 mg/kg Ruzicka T. et al. N Engl J Med 2017;376:826-35. DOI: 10.1056/NEJMoa1606490
Proportion of patients with achievement (%) Change from baseline (%) DLQI score EASI-50 60 50 40 30 20 10 0 Results Up to Week 64: Part A Part B 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 Weeks EASI-75 50 40 30 20 10 0 Part A Ruzicka T, et al. Presented at EADV 2017; Presentation #FC03.08. 60 Part B 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 Weeks 0.1 mg/kg q4w (n=53) 0.5 mg/kg q4w (n=54) 2.0 mg/kg q4w (n=52) 2.0 mg/kg q8w (n=52) ITT population Absolute DLQI 20 18 16 14 12 10 8 6 4 2 0 Part A Part A Part B Pruritus VAS: % Change from Baseline 0-10 -20-30 -40-50 -60-70 -80-90 -100 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 Weeks Part B 0.1 mg/kg q4w (n=53) 0.5 mg/kg q4w (n=54) 2.0 mg/kg q4w (n=52) 2.0 mg/kg q8w (n=52) 0.1 mg/kg q4w (n=53) 0.5 mg/kg q4w (n=54) 2.0 mg/kg q4w (n=52) 2.0 mg/kg q8w (n=52) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64
Targeting IL-13 Tralokinumab, Lebrikizumab - Blocks IL-13 - Currently in Phase 3 AD, atopic dermatitis; AMPs, antimicrobial proteins; IgE, immunoglobulin E; IL, interleukin; DC, dendritic cell; IDEC, Inflammatory dendritic epidermal cells; ddc, dermal dendritic cell; TSLP, thymic stromal lymphopoietin; IFN, interferon Gooderham M, et al. JCMS 2016 (9):1-9. 18
Tralokinumab Phase 2: Primary/Secondary Endpoints at Wk 12 + TCS 80 70 60 50 40 30 20 10 0 NS Primary Endpoints IGA 0/1 EASI 50 Placebo Tralo 300 mg * p=0.025 * At wk 12, tralokinumab 150 mg/ 300 mg, reduced total EASI from baseline: 4.4 (p=0.027) and 4.9 (p=0.011), respectively, compared with PBO Secondary endpoints showed significant reduction in SCORAD, DLQI in the tralokinumab arm (150mg/ 300 mg) compared with PBO. Reduction in pruritus NRS in the tralokinumab 300 mg group was greater than PBO. http://www.leo-pharma.com/home/leo-pharma/media-centre/news/news-2017/leo-pharma-announces-positive-results-from-phase-2b-clinical-study-for-tralokinumab-in-atopicdermatitis.aspx#
Tralokinumab Phase 2b Primary Efficacy Data Change in EASI score at week 12 PL + TCS 45mg + TCS 150mg+ TCS 300mg + TCS Weeks EASI, Eczema Area and Severity Index; SE, standard error; TCS, topical corticosteroids. *P 0.05 vs. placebo (intent-to-treat population). Wollenberg et al. AAD 2017
Lebrikizumab Phase 2 (TREBLE): Primary/Secondary endpoints at wk 12 + TCS EASI 50 and EASI 75 was only significant with monthly dosing of 125 mg lebrikizumab SCORAD 50 was significant at monthly 125 mg and 250 mg x 1 dose Adverse events more herpes infections and conjunctivitis in the treatment group 0 90 80 70 60 50 40 30 20 10 * * * EASI 50 SCORAD 50 placebo 125 mg x 1 250 mg x 1 125 mg 0/4/8/12 http://www.mdedge.com/edermatologynews/article/115736
Targeting IL-4, -13 Dupilumab (Dupixent) - Blocks IL-4R - Approved for use in US, EU and awaiting approval in Canada (2017 Q4) AD, atopic dermatitis; AMPs, antimicrobial proteins; IgE, immunoglobulin E; IL, interleukin; DC, dendritic cell; IDEC, Inflammatory dendritic epidermal cells; ddc, dermal dendritic cell; TSLP, thymic stromal lymphopoietin; IFN, interferon Gooderham M, et al. JCMS 2016 (9):1-9. 23
Dupilumab AD Clinical Development Program 1 Adult patients Phase 1 Phase 2 Phase 3 4-week monotherapy ( 2) 1 Drug-drug interactions 2 4-week concomitant TCS 1 12-week monotherapy 1 16-week monotherapy dose-ranging 3 EXPLORE: 16-week monotherapy biopsy/biomarkers 4 (serum CCL17, CCL18, periostin, and IgE; S. aureus abundance) SOLO 1 & 2: 16-week monotherapy 7 CHRONOS: 52-week concomitant TCS 8 SOLO-CONTINUE: 36-week monotherapy 9 CAFÉ: 16-week concomitant TCS in cyclosporine-experienced patients 6,10 The Canadian Regulatory Submission includes data from a total of 2526 patients with AD treated with dupilumab in clinical trials 6 EVALUATE: 16-week vaccine interaction 5,6 (Tdap and MPSV4) Open-label extension 11 1. Beck LA et al. N Engl J Med 2014; 371:130 139. 2. ClinicalTrials.gov (NCT02647086). Accessed February 2017. 3. Thaçi D et al. Lancet 2016;387:40 52. 4. Guttman-Yassky E et al. J Invest Dermatol 2016;136:S224 abstract 373. 5. ClinicalTrials.gov (NCT02210780). Accessed February 2017. 6. Sanofi Genzyme, Regeneron. Data on file. 2016. 7. Simpson EL et al. N Engl J Med 2016;375:2335 2348. 8. Sanofi Genzyme, Regeneron. 2016. [Press Release]. Available at: http://newsroom.regeneron.com/releasedetail.cfm?releaseid=974316. Accessed February 2017. 9. ClinicalTrials.gov (NCT02395133). Accessed February 2017. 10. ClinicalTrials.gov (NCT02755649). Accessed February 2017. 11. ClinicalTrials.gov (NCT01949311). Accessed February 2017.
Patients Achieving Primary Endpoint Based SOLO -1, 2: Efficacy of Dupilumab for Moderate-to-Severe AD IGA 0/1 EASI 75 on IGA Score, % a 60 50 40 30 20 10 0 Placebo Dupilumab Q2W Dupilumab QW 10 38 37 36 36 n=224 n=224 n=223 n=236 n=233 n=239 SOLO 1 SOLO 2 8 Patients With EASI-75, % a 60 50 40 30 20 10 0 51 52 48 44 15 12 n=224 n=224 n=223 n=236 n=233 n=239 SOLO 1 SOLO 2 a P<0.001 for all comparisons of dupilumab vs placebo. EASI-75, improvement from baseline of 75% on the EASI; IL-4Rα, IL-4 receptor α; QW, every week. Patients 18 years of age with moderate-to-severe atopic dermatitis inadequately controlled with topical therapy were randomized to dupilumab 300 mg QW, dupilumab 300 mg Q2W, or placebo for 16 weeks (dupilumab-treated patients received a 600-mg loading dose on day 1). Simpson EL, et al. N Engl J Med. 2016;375(24):2335-2348.
Dupilumab Safety Adverse Event SOLO 1, % of patients a Adverse events occurring in 5% of patients in at least 1 dupilumab arm and more frequently than in the corresponding placebo arm. One death occurred in each dupilumab treatment group in SOLO 2 (one from an asthma attack and one from suicide). Simpson EL, et al. N Engl J Med. 2016;375(24):2335-2348. SOLO 2, % of patients Placebo Dupilumab Q2W Dupilumab QW Placebo Dupilumab Q2W Dupilumab QW (n=222) (n=229) (n=218) (n=234) (n=236) (n=237) At least 1 adverse event 65 73 69 72 65 66 Adverse event leading to discontinuation 1 2 2 2 1 1 Noninfectious Adverse Event a Injection-site reaction 6 8 19 6 14 13 Headache 6 9 5 5 8 9 Allergic conjunctivitis 1 5 3 1 1 1 Infectious Adverse Event a Infections and infestations 28 35 34 32 28 29 Nasopharyngitis 8 10 11 9 8 8 Upper respiratory tract infection 2 3 5 2 3 4 Conjunctivitis 1 5 3 <1 4 4 Any herpes viral infection 4 7 4 3 4 5 Nonskin infection 22 30 31 24 25 26
IGA (0,1) Patients (%) EASI-75 Patients (%) CHRONOS: Both Primary Endpoints Met at wk 16 100% 90% IGA (0,1) and 2-Point Improvement From Baseline at Week 16 100% 90% EASI-75 at Week 16 *P<0.0001 80% 70% 60% *P<0.0001 80% 70% 60% 68.9% * 63.9% * 50% 40% * * 38.7% 39.2% 50% 40% 30% 20% 10% 12.4% 30% 20% 10% 23.2% 0% Placebo + TCS (n=315) Dupilumab 300 mg q2w + TCS (n=106) Dupilumab 300 mg qw + TCS (n=319) 0% Placebo + TCS (n=315) Dupilumab 300 mg q2w + TCS (n=106) Dupilumab 300 mg qw + TCS (n=319) Blauvelt A et al. Lancet 2017 May 4. doi: 10.1016/S0140-6736(17)31191-1.
Patients, % a P<0.0001 for all comparisons of dupilumab vs placebo; TCS, topical corticosteroids. N=623 patients treated with dupilumab 300 mg QW, dupilumab 300 mg Q2W, or placebo for 52 weeks weeks (dupilumab-treated patients received a 600-mg loading dose on day 1). Blauvelt A, Lancet 2017 CHRONOS: Efficacy and Safety Over 52 wks With Concomitant TCS IGA 0 /1 and 2-point Reduction From Baseline a EASI-75 a Peak Pruritus NRS 4-point Improvement a 70 60 50 40 Placebo Dupilumab Q2W Dupilumab QW 36 40 70 60 50 40 65.2 64.1 70 60 50 40 51.2 39 30 30 30 21.6 20 12.5 20 20 12.9 10 10 10 0 0 0 Fewer patients experienced disease flares in DUP QW (12.7%) and DUP Q2W (13.6%) compared to PBO (41.3%) Conjunctivitis and injection-site reactions were more common in DUP-treated patients
Conclusions Increased understanding of the pathophysiology of AD has led to new targets in development for treatment JAK 1 inhibitors, IL-5, IL-31RA, IL-13 mab are in development and are promising targets for AD therapy IL-4RA mab (IL-4, IL-13) is the furthest in development and has proven safety and efficacy based on Phase 3 data
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