atopic dermatitis - dermatology updatedermatologyupdate.com/docs/pdf/2017/melinda-gooderham-atopic...

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

https://investor.lilly.com/releasedetail.cfm?ReleaseID=1040434

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

https://investor.lilly.com/releasedetail.cfm?ReleaseID=1040434

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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


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)

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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



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

http://newsroom.regeneron.com/releasedetail.cfm?ReleaseID=974316

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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