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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
• AbbVieA,C,RI,S
• ActelionS
• AmgenA,C,RI,S
• Celgene A,C,RI,S
• CoherusRI
• DermiraRI
• Eli Lilly A,C,RI,S
• GaldermaA,RI,S
• GSKRI
• JanssenA, C, RI,S
• Kyowa Kirin PharmaC,RI
• Leo Pharma Inc.A,C,RI,S
• MedimmuneRI
• MerckRI
• NovartisRI,S
• PfizerA,RI
• RegeneronRI
• RocheRI
• Sanofi GenzymeA,RI,S
• UCBRI
• ValeantA,S
Speaker Disclosures
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
Systemic Therapy (10%)
Topical Treatment
Atopic DermatitisEscalating Treatment Approaches to Meet Patient Needs
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.
Nonpharmacologic Therapy
Off-Label biologics investigated for AD
Agent Study, N Benefits Drawback
Infliximab(anti-TNF)
Open label, N=9 2/9 experienced long term benefit
Initial clinical response was not maintained over time
Ustekinumab(anti-IL 12/23)
Case series and RCT N=37 (USA)RCT N=79 (Japan)
RCT – benefit did not reach statistical significance
Safe drug, further study is needed
Rituximab(anti-CD20)
OL, N=6 Results were inconclusive
Lack of data
Omalizumab(anti-IgE)
OL, RCT, case seriesN = 103
Conflicting data on efficacy
Safe drug; cost may outweighclinical benefit
Mepolizumab(anti-IL5)
RCT, N=43 No clinical improvement at d14
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
7
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.
Targeted biologics currently under investigation
Target Agent Details Sponsor
IL-5 Mepolizumab RCT N=43Phase 2 trial ongoing
GSK
IL-31RA Nemolizumab Phase 2, N=264Published NEJM
Galderma /Chugai
IL-13 Tralokinumab Phase 2 RCT, N=204 +TCS MedImmune/ LEO
Lebrikizumab Phase 2 RCT, N=209 +TCS(TREBLE)
Genentech/Roche
IL-4RA(IL-4, -13)
Dupilumab (Dupixent®) Phase 3, N > 2000approved US, EMAPublished Lancet, NEJM
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
Target Drug AD studies Results to date
JAK 1 PF-04698542 Phase 2 completed
• 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)
JAK 1 Upadacitinib(ABT-494)
Phase 2 completed
• IGA 0/1 (30 mg) 50% vs. 2% (PBO) at 12 wks
• 74% reduction (30mg) in EASI score vs. 23% (PBO)
JAK 1/2 Baricitinib Phase 2 completed (+ TCS)
• EASI 50 (4mg) 61% vs. 37% with TCS alone (p<0.05) at 16 wks
Small molecules: JAK Inhibitors
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, SwitzerlandPress releases: Baricitinib, https://investor.lilly.com/releasedetail.cfm?ReleaseID=1040434, Upadacitinib, https://news.abbvie.com/news/abbvies-upadacitinib-abt-494-meets-primary-endpoint-in-phase-2b-study-in-atopic-dermatitis.htm
Image: Gooderham, M. Skin Therapy Letter 2013
Target Drug AD studies Results to date
JAK 1 PF-04698542 Phase 2 completed
• 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)
JAK 1 Upatacitinib(ABT-494)
Phase 2 completed
• IGA 0/1 (30 mg) 50% vs. 2% (PBO) at 16 wks
• 74% reduction (30mg) in EASI score vs. 23% (PBO)
JAK 1/2 Baricitinib Phase 2 completed (+ TCS)
• EASI 50 (4mg) 61% vs. 37% with TCS alone (p<0.05) at 16 wks
Small molecules: JAK Inhibitors
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, SwitzerlandPress releases: Baricitinib, https://investor.lilly.com/releasedetail.cfm?ReleaseID=1040434, Upadacitinib, https://news.abbvie.com/news/abbvies-upadacitinib-abt-494-meets-primary-endpoint-in-phase-2b-study-in-atopic-dermatitis.htm
11
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
Targeting IL-5
Mepolizumab
- Blocks IL-5- Phase 2 trials in AD underway- Approved in asthma (high eos)
12
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
Nemolizumab
- Blocks IL-31RA- Completed
phase 2- Phase 3 trials
ongoing- Effective for
control of itch
Targeting IL-31
Ruzicka T. et al. N Engl J Med 2017;376:826-35. DOI: 10.1056/NEJMoa1606490
-50
-40
-30
-20
-10
0
10
20
30
40
50
. . Improvement IGA .
Secondary Outcome Measures Wk 16
Placebo 0.1 mg/kg 0.5 mg/kg 2.0 mg/kg
% change EASI % change SCORAD % change BSA
Ruzicka T. et al. N Engl J Med 2017;376:826-35. DOI: 10.1056/NEJMoa1606490
Part A0
20
30
40
10
50
Results Up to Week 64:
Ruzicka T, et al. Presented at EADV 2017; Presentation #FC03.08.
Part A Part B
EASI-50
0
Weeks
20
30
40
60
10
Pro
po
rtio
n o
f p
atie
nts
wit
h a
chie
vem
ent
(%)
0 20 28 32 36 40 44 48 52 56 60 644 8 12 2416
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 population50
Part B
EASI-75
Weeks
60
0 20 28 32 36 40 44 48 52 56 60 644 8 12 2416
Part A Part B
Part A Part B
Absolute DLQI
Pruritus VAS: % Change from Baseline
20 28
-90
-80
-70
-60
-50
-100
0 32 36 40 44 48 52 56 60 644 8 12 2416
-30
-20
-10
0
-40
Ch
ange
fro
m b
asel
ine
(%)
0.1 mg/kg q4w (n=53)
0.5 mg/kg q4w (n=54)
2.0 mg/kg q4w (n=52)
20 28
2
4
6
8
10
0
0 32 36 40Weeks
44 48 52 56 60 644 8 12 2416
14
16
18
20
12
DLQ
I sco
re
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)
2.0 mg/kg q8w (n=52)
18
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.
Tralokinumab,Lebrikizumab
- Blocks IL-13- Currently in Phase 3
Targeting IL-13
Tralokinumab Phase 2: Primary/Secondary Endpoints at Wk 12
0
10
20
30
40
50
60
70
80
IGA 0/1 EASI 50
Primary Endpoints
Placebo Tralo 300 mg
• 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.
* p=0.025
*
NS
+ TCS
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-atopic-dermatitis.aspx#
Tralokinumab Phase 2b Primary Efficacy Data
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
Weeks
Change in EASI score at week 12
PL + TCS
45mg + TCS
150mg+ TCS
300mg + TCS
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
10
20
30
40
50
60
70
80
90
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
23
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.
Targeting IL-4, -13
Dupilumab (Dupixent)
- Blocks IL-4R- Approved for use in US,EU and awaiting approvalin Canada (2017 Q4)
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.
Adult patients
Dupilumab AD Clinical Development Program1
Phase 1 Phase 3Phase 2
4-week monotherapy (×2)1
Drug-drug interactions2
4-week concomitant TCS1
12-week monotherapy1
16-week monotherapy dose-ranging3
EXPLORE: 16-week monotherapy biopsy/biomarkers4
(serum CCL17, CCL18, periostin, and IgE; S. aureus abundance)
EVALUATE: 16-week vaccine interaction5,6 (Tdap and MPSV4)
CHRONOS: 52-week concomitant TCS8
SOLO-CONTINUE: 36-week monotherapy9
CAFÉ: 16-week concomitant TCS in cyclosporine-experienced
patients6,10
Open-label extension11
SOLO 1 & 2: 16-week monotherapy7
The Canadian Regulatory Submission includes data from a total of 2526 patients with AD treated with dupilumab in clinical trials6
SOLO -1, 2: Efficacy of Dupilumab for Moderate-to-Severe AD
aP<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.
Pat
ien
ts A
chie
vin
g P
rim
ary
End
po
int
Bas
ed
o
n IG
A S
core
, %a
108
383637 36
0
10
20
30
40
50
60
SOLO 1 SOLO 2
Placebo Dupilumab Q2W Dupilumab QW
n=224 n=224 n=223 n=236 n=233 n=239 Pat
ien
ts W
ith
EA
SI-7
5, %
a
1512
51
44
5248
0
10
20
30
40
50
60
SOLO 1 SOLO 2
n=224 n=224 n=223 n=236 n=233 n=239
IGA 0/1 EASI 75
Dupilumab Safety
aAdverse 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.
Adverse EventSOLO 1, % of patients SOLO 2, % of patients
Placebo (n=222)
Dupilumab Q2W (n=229)
Dupilumab QW (n=218)
Placebo (n=234)
Dupilumab Q2W (n=236)
Dupilumab QW (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 Eventa
• 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 Eventa
• 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
23.2%
68.9%63.9%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Placebo + TCS (n=315)
Dupilumab 300 mg q2w + TCS (n=106)
Dupilumab 300 mg qw + TCS (n=319)
*P<0.0001
EASI
-75
Pat
ien
ts (
%)
**
EASI-75 at Week 16
12.4%
38.7% 39.2%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
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.
CHRONOS: Both Primary Endpoints Met at wk 16
*P<0.0001
IGA
(0
,1)
Pat
ien
ts (
%)
* *
IGA (0,1) and ≥2-Point Improvement FromBaseline at Week 16
• 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
CHRONOS: Efficacy and Safety Over 52 wks With Concomitant TCS
aP<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
12.5
3640
0
10
20
30
40
50
60
70Placebo Dupilumab Q2W Dupilumab QW
EASI-75a
Pat
ien
ts, %
21.6
65.2 64.1
0
10
20
30
40
50
60
70
IGA 0 /1 and ≥2-point Reduction From Baselinea
Peak Pruritus NRS 4-point Improvementa
12.9
51.2
39
0
10
20
30
40
50
60
70
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 efficacybased on Phase 3 data
Thank you!
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