gaps in the treatment of psoriasis and psa for systemic ... in the treatment of psoriasis and psa...

Gaps in the Treatment of

Psoriasis and PsA for Systemic

Therapy

Mark Lebwohl, MD Sol and Clara Kest Professor

And Chairman

Department of Dermatology

Icahn School of Medicine at Mount Sinai

Mark Lebwohl is an employee of Mount Sinai which receives research

funds from: Abbvie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly,

Janssen / Johnson & Johnson, Kadmon, Medimmune/Astra Zeneca,

Novartis, Pfizer, Valeant and ViDac.

Dr. Lebwohl is also a consultant for Allergan, Aqua Leo-pharma,and

Promius.

Disclosure

Research gaps in psoriasis: opportunities for future studies

Ryan C, Korman NJ, Gelfand JM, Lim HW, Elmets CA, Feldman SR, Gottlieb AB, Koo JY, Lebwohl M, Leonardi CL, Van Voorhees AS, Bhushan R, Menter A.

J Am Acad Dermatol. 2014;70:146-67

Psoriasis outcome measures: a report from the GRAPPA 2012 annual meeting

Gottlieb AB, Armstrong AW.

J Rheumatol. 2013;40:1428-33

Research Gaps

• Can we predict who’ll develop PsA and can we prevent it?

• Can we predict who’ll develop other comorbidities (cardiac, renal, etc) and can we prevent them?

• Can we predict who’ll respond to which therapy?

Can we predict who’ll develop PsA?

(Can we treat to prevent joint disease?)

Patient perspectives in the management of

psoriasis: Results from the population-

based Multinational Assessment of

Psoriasis and Psoriatic Arthritis Survey.

Lebwohl MG, Bachelez H, Barker J, Girolomoni

G, Kavanaugh A, Langley RG, Paul CF, Puig L,

Reich K, van de Kerkhof PC.

J Am Acad Dermatol. 2014 Feb 24. [Epub ahead

of print]

• 139,948 households were screened and

3426 patients

• prevalence of psoriasis/PsA ranged from

1.4% to 3.3%

• 79% had psoriasis alone and 21% had

PsA

• 27% (psoriasis) and 53% (PsA ± psoriasis)

of patients rated it as severe

• 45% had not seen a physician in a year;

Psoriasis and Psoriatic Arthritis: Timing of

Onset

Psoriasis 1st

Arthritis 1st

concurrent

72%

Psoriasis 1st

21%

Arthritis 1st

7% concurrent

Subclinical Joint Involvement in Patients With Psoriasis

• Joint structural damage can occur before the appearance of clinical symptoms of PsA

• In a study by Offidani and colleagues, which used MRI rather than conventional radiography to assess joint involvement, 68% of patients with psoriasis were found to have 1 or more arthritic signs

– Appeared before patients experienced clinically evident joint symptoms

– Joint damage was only detected by X-ray imaging in 32% of these patients

Source: Offidani A, et al. Acta Derm Venereol (Stockh). 1998;78:463-465.

Biannual radiographic assessments of hands and feet

in a three-year prospective followup of patients with early

rheumatoid arthritis.

van der Heijde DM, et al

Arthritis Rheum. 1992 Jan;35(1):26-34.

Sharp score or van der Heijde

score measures joint damage

on x-ray: narrowing and erosions

12†

**

Etanercept for Psoriatic Arthritis: Radiographic Improvement

*X-rays of hands and wrists (includes DIP joints); **P = .0001 vs placebo (stratified rank test). †Start of OLE.

Source: Mease P, et al. Arth Rheum. 2004;50:2264-2272.

Lebwohl M, et al. Presented at: 63rd Annual Meeting of AAD; February 18-22, 2005; New Orleans, La. (Abstract P2753).

Placebo (n=104)

Etanercept

25 mg biw (n=101)

OLE completers

originally randomized

to etanercept (n=71)

OLE completers

originally randomized

to placebo (n=70) -0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

6 18 24

Study Month

Me

an

Ch

an

ge

in

mT

SS

*

Fro

m B

ase

lin

e

Adalimumab for Psoriatic Arthritis: Radiographic Results

Weeks

24

N Baseline 24 Wk Mean Change 48 Wk Mean Change

Placebo 152 21.8 0.9 1.0

Adalimumab 144 23.7 – 0.1* 0.1

*P≤.001 vs placebo for ranked ANCOVA.

Sources: Mease P, et al. Arth Rheum. 2005;52:3279-3289.

Mease P, et al. Presented at: EULAR Annual Meeting; June 8-11, 2005; Vienna, Austria.

Me

an

Ch

an

ge

in

mT

SS

*

Mean Change in mTSS Through Week 48

48

−0.5

0

0.5

1.0

1.5 Placebo Adalimumab

Total vdH-S Score – Mean Change from Baseline at Week 24*

*Median Change in

both groups was 0.0

-1.0

-0.5

0.0

0.5

1.0

Placebo (n=100) Infliximab 5 mg/kg (n=100)

To

tal vd

H-S

Sco

re

p<0.001

-0.70

0.82

Van der Heijde D, et al. Ann Rheum Dis. 2005;64 (Supplement III):109.

Treatment of psoriatic arthritis with

tumor necrosis factor inhibitors: longer-

term outcomes including enthesitis and

dactylitis with golimumab treatment in

the Long term Extension of a

Randomized, Placebo-controlled Study

(GO-REVEAL).

Kavanaugh A, Mease P.

J Rheumatol Suppl. 2012 Jul;89:90-3.

Effect of certolizumab pegol on signs

and symptoms in patients with

psoriatic arthritis: 24-week results of a

Phase 3 double-blind randomised

placebo-controlled study (RAPID-PsA)

Mease PJ, Fleischmann R, Deodhar AA,

Wollenhaupt J, Khraishi M, Kielar D,

Woltering F, Stach C, Hoepken B, Arledge

T, van der Heijde D.

Ann Rheum Dis. 2014;73:48-55.

*

PALACE 1: Apremilast in PsA (Phase 3)

• Apremilast, oral phosphodiesterase 4 (PDE4) inhibitor

• RDBPC trial stratified for DMARD use, N=489, 1:1:1 randomization

• Major adverse events diarrhea and nausea, resolve over time

Kavanaugh A et al, ACR 2012, Washington, #L13

Apremilast 30mg BID Apremilast 20mg BID

ACR20 ACR70

45

% a

ch

ievin

g r

esp

on

se

Placebo

*P<0.05; §P<0.0001

§

ACR50

Week 16 Week 24

ACR20

§

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Week 0 Week 24 Week 52

Placebo (n=310) Placebo→45 mg at Wk 24 (n=269)*

UST 45 mg (n=308) UST 90 mg (n=309)

PSUMMIT I and II

Change From Baseline in Modified Total vdhS Score Over Time (ITT)

*Patients who did not receive UST are excluded

Mean

Ch

an

ge f

rom

Baselin

e

USTEKINUMAB

FUTURE 1: Radiographic progression in PsA patients stratified by MTX use

Gottlieb AB, et al. EADV 2015, P0348 Sponsored by Novartis Pharma AG

0.08 0.04 0.13

0.57 0.57 0.58

0

0.2

0.4

0.6

0.8

1

Overallpopulation

MTX: Yes MTX: No

Me

an

ch

an

ge

in

vd

H-m

TS

S

Pooled SKB doses PBO

Baseline to Week 24 (full analysis set)

366 179 216

114 150 65 344 206

98

138 54

*P<0.05 vs PBO

Change in mTSS >0.5 considered progression of radiographic disease

* *

SECUKINUMAB

Ixekizumab, an interleukin-17A specific

monoclonal antibody, for the treatment of

biologic-naive patients with active psoriatic

arthritis: results from the 24-week randomised,

double-blind, placebo-controlled and active

(adalimumab)-controlled period of the phase

III trial SPIRIT-P1.

Mease PJ, et al

Ann Rheum Dis. 2017;76:79-87.

IXEKIZUMAB

Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active

(adalimumab)-controlled period of the phase III trial SPIRIT-P1. Mease PJ, et al; Ann Rheum Dis. 2017;76:79-87.

IXEKIZUMAB

Brodalumab Phase 2 PsA study: Clinical response and improvement in psoriasis in subjects with PsA

Mease P, et al. AAD 2014, P7605

ACR20 response rate at Week 24

PBO (n=55) BRO 140 mg q2w (n=57) BRO 280 mg q2w (n=56)

Indicates time point at which all subjects began receiving BRO 280 mg q2w

80

20

0

Pa

tie

nts

(%

± S

E)

2 Week

60

40

4 8 12 16 24

43.5

51.1

64.4

*

*

*

* †

†

ACR20 Open label

2 Week

4 8 12 16 24

19.6

32.7

33.3

*

*

ACR50 Open label

Pa

tie

nts

(%

± S

E)

Number of subjects

PBO 54 52 51 52 49 46

140 mg 56 56 51 53 51 47

280 mg 50 55 53 50 49 45

Number of subjects

PBO 54 53 51 52 50 46

140 mg 56 56 53 53 51 49

280 mg 50 55 53 51 50 45

80

20

0

60

40

BRODALUMAB

We don’t have a serologic marker

that predicts psoriatic arthritis or

its severity

Research Gaps




Risk of myocardial infarction in patients with

psoriasis.

Gelfand JM, Neimann AL, Shin DB, Wang X,

Margolis DJ, Troxel AB.

JAMA 2006;296:1735-41

Does treatment of psoriasis reduce the risk of cardiovascular disease?

Churton S, Brown L, Shin TM, Korman NJ.

Drugs. 2014;74:169-82

Reduction in the incidence of

myocardial infarction in patients with

rheumatoid arthritis who respond to anti-

tumor necrosis factor alpha therapy:

results from the British Society for

Rheumatology Biologics Register.

Dixon WG, Watson KD, Lunt M, Hyrich KL; British Society for Rheumatology Biologics Register Control Centre Consortium, Silman AJ, Symmons DP; British Society for Rheumatology Biologics Register. Arthritis Rheum. 2007;56(9):2905-12.

Association between tumor necrosis

factor inhibitor therapy and

myocardial infarction risk in patients

with psoriasis.

Wu JJ, Poon KY, Channual JC, Shen AY

Arch Dermatol. 2012;148:1244-50

Risk of moderate to advanced kidney disease in patients with psoriasis: population based cohort study.

Wan J, Wang S, Haynes K, Denburg MR, Shin DB, Gelfand JM.

BMJ. 2013;347:f5961

Research Gaps




Cost of Biologics: Year 1

• Etanercept: ~$79,623

• Adalimumab: ~ $69,670

• Ustekinumab: ~$52,525-105,015

• Infliximab: ~$22,995-80,482 (50-100 kg q4-

8w. at 5mg/kg)

• Secukinumab: ~$75,007

• Ixekizumab:~$82,891

• Brodalumab:~$31,395

• Guselkumab: ~$71,237

www.goodrx.com 1/21/18

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

ERASURE study results: Secukinumab rapidly improved plaque Ps, and sustained high responses through 52 weeks

Elewski B, et al. EADV 2013: P1501. Sponsored by Novartis Pharma AG

Patients

(%

)

PASI 75 Response

Weeks

* *

*p<0.0001 vs placebo at Wk 12. Grey arrows indicate peak response

aIGA score of 0 (clear) or 1 (almost clear) and an improvement of at least 2 points on the IGA scale compared with baseline; bOne subject did not sign informed consent before starting study procedures and was excluded from analyses

SEK 150 mg (n=245) SEK 300 mg (n=245) Placebo (n=247)b

ERASURE

87.8% SECUKINUMAB

ERASURE study results: Secukinumab rapidly improved plaque Ps, and sustained high responses through 52 weeks

Elewski B, et al. EADV 2013: P1501. Sponsored by Novartis Pharma AG

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

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

PASI 100 Response

*

*

*

*

SEK 150 mg (n=245) SEK 300 mg (n=245) Placebo (n=247)b

*p<0.0001 vs placebo at Wk 12

aIGA score of 0 (clear) or 1 (almost clear) and an improvement of at least 2 points on the IGA scale compared with baseline; bOne subject did not sign informed consent before starting study procedures and was excluded from analyses

PASI 90 Response

Weeks

Patients

(%

)

Weeks

ERASURE

PASI 75 Response Rate (NRI) by Week in the Induction Phase

34

Data on file, Amgen.

140 mg

Q2W Ustekinumab

Placeb

o Weight-Based 210 mg Q2W

0%

80

%

60

%

40

%

20

%

12 1 2 4 6 8 10

Visit Week

8.09%

86.3%

77.0%

66.6% 70.0%

Per

cen

t o

f R

esp

on

der

s

100% AMAGINE-2

BRODALUMAB


35


140 mg

Q2W Ustekinumab

Placeb


0%

60

%

40

%

20

%

12 1 2 4 6 8 10

Visit Week

Per

cen

t o

f R

esp

on

der

s

3.24%

70.3%

58.7%

49.3% 47.0%

80% AMAGINE-2

BRODALUMAB

50% AMAGINE-2


36


140 mg

Q2W Ustekinumab

Placeb


0%

30

%

20

%

10

%

12 1 2 4 6 8 10

Visit Week

Per

cen

t o

f R

esp

on

der

s

0.65%

44.4%

33.6%

25.7%

21.7%

40

%

BRODALUMAB

IXEKIZUMAB

PASI 50 at Wk 4 optimal for predicting PASI 75 at Wk 12

• Good overall sensitivity (83%), specificity (87%), positive predictive value (90%),

and negative predictive value (77%)

• Combining results for 75 and 150 mg groups showed similar results

• PASI 50 responders at Wk 4 were called early responders

Predictability for PASI 75 at Wk 12 at different percentages of

PASI improvement at Wk 4 (combined groups)

Zhu B, et al. EADV 2012: P952

Sensitiv

ity / S

pecific

ity

PASI improvement at Week 4

10 20 30 40 50 60 70 90 100 0.0

0.4

0.6

0.8

0.2

1.0

80 -10 -20 0

*Optimal threshold at PASI48;

PASI 50 selected for practicality Optimal

threshold*

Sensitivity

Specificity

IXEKIZUMAB

Early responders had significantly higher improvement in PASI 75 and 100 than non-responders

*p<0.05; **p<0.01; ***p<0.001 vs

non-responder group

Zhu B, et al. EADV 2012: P952

Weeks

% P

atients

Weeks

*** *** ***

*** **

*

PASI 75 PASI 10S0

IXEKIZUMAB

Week 16 Partial Responders (50 ≤ PASI < 75) and Nonresponders (25 ≤ PASI < 50) That Achieved PASI 50, 75, or 90 at Week 28

UST Combined*

50 ≤ PASI < 75 at Week 16 25 ≤ PASI < 50 at Week 16

Patients at Week 16, n 98 48

Achieve PASI 50 at Week 28 98% 71%



*Combined data for PHOENIX 1 and 2 patients ≤100kg

receiving 45 mg UST and >100kg receiving 90 mg UST. Sobell J, et al. Poster Presentation at FCD 2010.

USTEKINUMAB

Successful treatment of recalcitrant

palmoplantar psoriasis with

etanercept. Weinberg JM.

Cutis. 2003;72:396-8.

Successful treatment of hand and foot psoriasis

with infliximab.

Di Lernia V, Guareschi E.

Dermatol Online J. 2010 ;16:8.

Severe psoriasis pustulosa palmaris et plantaris

(Barber-Königsbeck) treated successfully with

soluble tumour necrosis factor receptor fusion

protein (etanercept).

Kasche A, et al

J Eur Acad Dermatol Venereol.2007;21:255-7.

Safety and efficacy of Adalimumab in

the treatment of moderate to severe

palmo-plantar psoriasis: an open label

study.

Clin Ter. 2012;163(2):e61-6.

Richetta AG, et al

4/11→clear

5/11→50% improvement

Increased expression of IL-17A and limited

involvement of IL-23 in patients with palmo-plantar

(PP) pustular psoriasis of PP pustulosis; results from a

randomized controlled trial. Bissonnette R et al.

JEADV 2013 DOI: 10.1111/jdv.12272.

• UST 45mg doesn’t work

Investigator-initiated, open-label trial of

ustekinumab for the treatment of moderate-to-

severe palmoplantar psoriasis.

J Dermatolog Treat. 2012 May 8. [Epub ahead of print]

Au SC, Goldminz AM, Kim N, Dumont N, Michelon M, Volf E,

Hession M, Lizzul PF, Andrews ID, Kerensky T, Wang A, Yaniv S,

Gottlieb AB.

7/20 → clear (90 mg:6/9; 45mg:1/11)

12/20 → >2point PGA approval

An investigator-initiated, open-label study evaluating the efficacy and safety of UST in patients with moderate-to- severe palmar/plantar psoriasis

• 24 subjects with palmar/plantar psoriasis with PGA ≥3 treated with FDA-approved dose of UST using weight-based dosing

• Report of 20/24 subjects, 11 in 45-mg dose, 9 in 90-mg dose. Mean weight of subjects not reported

Shimrat Y, et al. AAD 2012: P4733; Study sponsored by Centocor

Apremilast, an oral phosphodiesterase-4 inhibitor, in

the treatment of palmoplantar psoriasis: Results of a

pooled analysis from phase II PSOR-005 and phase

III Efficacy and Safety Trial Evaluating the Effects

of Apremilast in Psoriasis (ESTEEM) clinical trials

in patients with moderate to severe psoriasis.

Bissonnette R, et al.

J Am Acad Dermatol. 2016 Mar 24. pii: S0190-

9622(16)01400-6. doi: 10.1016/j.jaad.2016.02.1164.

[Epub ahead of print]

PPPGA 0 or 1 Achievement at Week 16 in Patients

With Baseline PPPGA ≥3

20.0

30.8 31.3

66.7

38.6

65.4

0

10

20

30

40

50

60

70

80*

ESTEEM 2

Pa

tien

ts A

ch

ievin

g P

PP

GA

0 o

r 1

(%

)

ESTEEM 1 *P<0.05 vs. placebo.

Includes patients with Palmoplantar Psoriasis Physician Global Assessment (PPPGA) ≥3, indicating moderate or severe

palmoplantar psoriasis, at baseline; all data are last observation carried forward. n/m=number of patients with response/number

of patients with sufficient data for evaluation.

*

PSOR-005

6/

9

n/m = 8/26 22/57 5/16 17/2

6

2/10

Placebo

Apremilast 30 mg BID

Clinical and patient-reported improvements of hand and/or foot psoriasis with ADA 40 mg qow: Subanalysis of REACH

• Subanalysis of REACH study looking at elements of erythema, scaling, induration and fissuring (ESIF) score along with DLQI

0102030405060708090

100

Week 16 Week 28% P

ati

en

ts A

ch

iev

ing

Ch

an

ge

fro

m

Ba

se

lin

e in

ES

IF S

co

re o

f >

4.9

8

Patients achieving a change from baseline in ESIF score of >4.98

PBO

ADA

Non-responder

imputation.

ESIF: Erythema,

scaling, induration,

fissuring.

Menter A, et al. AAD 2012: P5061; Study sponsored by Abbott Laboratories

Secukinumab shows significant efficacy in palmoplantar

psoriasis: results from GESTURE, a randomized

controlled trial.

Gottlieb A, Sullivan J, van Doorn M, Kubanov A, You

R, Parneix A, Hugot S, Milutinovic M.

J Am Acad Dermatol. 2016 Oct (epub ahead of print)

Journal of the American Academy of Dermatology DOI: (10.1016/j.jaad.2016.07.058)

More than Half of All Subjects on Secukinumab

300 mg Achieved Clear/Almost Clear Palms and

Soles at 1.5 Years

Palmoplantar disease improved by approximately 70% at 1.5 years

in subjects receiving secukinumab 300 mg

ppIGA 0/1†Response Out to 1.5 Years ppPASI Change Out to 1.5 Years

39.4%**

23.1%*

1.5%

–54.6%***

–35.3%***

34.9%

57.2%

–69.5%

–52.4%***

UNCOVER-3: Ixekizumab in patients with palmoplantar involvement: ppPASI 75 response rates

Menter A, et. al. EADV 2016, FC03.08; Sponsored by Eli Lilly and Company

• These patients have plaque psoriasis of the hands and feet, this does not address efficacy in

pustular disease nor patients with predominantly palmoplantar disease

0 2 4 8 12 16 20 24 28 32

Weeks

36 40 44 48 52 56 60

100 Induction

dosing period

Open label, long term extension period (IXE q4w)

78.1*

68.4*†

44.0

20.0

80.0

80.0

71.1

68.8

0

Pa

tie

nts

(%

)

ETN/IXE q4w (n=25) Placebo washout

IXE q4w/IXE q4w (n=32) IXE q2w/IXE q4w (n=38)

Placebo/IXE q4w (n=20)

*†

*

40

20

80

60

gaps in the treatment of psoriasis and psa for systemic ... in the treatment of psoriasis and psa...

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