Psoriatic Arthritis: New and Emergent Therapies

Alice Bendix Gottlieb MD, PhD

Professor of Dermatology

New York Medical College

Metropolitan Hospital

New York, NY, USA

DISCLOSURE OF RELEVANTRELATIONSHIPS WITH INDUSTRY

Current Consulting/Advisory Board Agreements/or Speakers Bureau:

Janssen Inc.; Celgene Corp., Bristol Myers Squibb

Co., Beiersdorf, Inc., Abbvie, UCB, Novartis, Incyte,

Lilly, Reddy Labs, Valeant, Dermira, Allergan, Sun

Pharmaceutical Industries

Research/Educational Grants :

Janssen, Incyte

Agenda

• Skin Matters• IL-17 Blockade

• Ixekizumab• Secukinumab

• IL-23 Blockade• Guselkumab

• Abatacept

• Tofacitinib• TNF Blockade

Data shown will be from only PSA studies except for certolizumab

Skin Matters

Arthur Kavanaugh, Alice Gottlieb, Akimichi Morita, Joseph Merola, Julie Birt, Chen-Yen Lin, Catherine Shuler, Diamant Thaçi ACR, 2017

GRAPPA PsA Treatment Recommendations 2015

CS: corticosteroid; csDMARD: conventional synthetic disease-modifying antirheumatic drug; IA: intra-articular; IL: interleukin; NSAID: nonsteroidal anti-inflammatory drug; PDE-4i: phosphodiesterase-4 inhibitor; PsA: psoriatic arthritis; SpA: spondyloarthropathy; TNFi: tumor necrosis factor inhibitor.

Assess which domains are involved

csDMARDs, TNFi,

or PDE-4i

NSA

IDs

and

IA c

ort

ico

ster

oid

s as

ind

icat

ed

Ass

ess

act

ivit

y, im

pac

t, a

nd

pro

gno

stic

fact

ors

Biologics (TNFi,

IL12/23i, IL17i)

or PDE-4i

IA=intraarticular; i=inhibitor. Yellow text=conditional recommendations (no current regulatory approval or based on abstract data only.Coates LC et al. Arthritis Rheum. 2016;68(5):1060-1071.Consider previous therapy, patient preference, other disease involvement & comorbidities

NSAIDs only

Ph

ysio

ther

apy

and

NSA

IDs

TNFi, IL17i or IL12/23i

Switch biologic

(TNFi, IL17i or IL12/23i)

NSAIDs

Ph

ysio

ther

apy Biologics

(TNFi, IL12/23i,

IL17i) or PDE-4i

Switch biologic (TNFi, IL12/23i, IL17i) or PDE-4i

NSAIDS

Co

rtic

ost

ero

id in

ject

ion

s as

ind

icat

ed

Biologics (TNFi,

IL12/23i)

Switch biologic,

(TNFi, IL12/23i, IL17i) or PDE-4i

Topicals

Top

ical

sas

ind

icat

ed

Biologics, (TNFi,

IL12/23i, IL17i)

or PDE-4i

Topical or procedural

or csDMARDs

Biologics, (TNFi,

IL12/23i, IL17i)

or PDE-4i

Switch biologic, (TNFi, IL12/23i, IL17i)

or PDE-4i

Enthesitis Dactylitis Skin NailsPeripheral

arthritis Axial disease

Expedited therapeutic routeTreat, periodically re-evaluate & modify therapy as needed

No direct evidence for therapies in axial PsA; recommendations based on SpAliterature

CS injections: consider on individual basis due to potential for serious side effects; no clear evidence for efficacy

csDMARDs, or PDE-4i

Phototx or csDMARDsor PDE-4i

Switch biologic (TNFi, IL12/23i, IL17i) or PDE-4i

Switch biologic (TNFi,

IL12/23i, or IL17i)

Ixekizumab is FDA Approved forPsoriasis

INDICATIONS AND USAGE

• TALTZ™ is a humanized interleukin-17A antagonist indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy

DOSAGE AND ADMINISTRATION

• Administered by subcutaneous injection

• Recommended dose is 160 mg (two 80 mg injections) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks

• 90% PASI 75, 70% PASI 90, 40% PASI 100 at week 16

FDA: Food and Drug Administration; PASI: Psoriasis Area Severity Index.

Ixekizumab is FDA approved for adults with active psoriatic arthritis

DOSAGE AND ADMINISTRATION

• Plaque Psoriasis TALTZ is administered by subcutaneous injection. The recommended dose is 160mg (two 80 mg injections) at Week 0, followed by 80mg at Weeks 2, 4, 6, 8, 10, and 12, then 80mg every 4weeks.

• Psoriatic Arthritis The recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at week 0, followed by 80 mg every 4 weeks. For psoriatic arthritis patients with coexistent moderate-to-severe plaque psoriasis, use the dosing regimen for plaque psoriasis

Clinical Studies Cited in the PSA Package Insert

• Signs and Symptoms Control at weeks 12 and 24

• Inhibition of Radiographic Progression at week 16

• Improved Health Related Outcomes and Physical Function at weeks 12 and 16

• Decreased CRP at weeks 12 and 16

• Improved Dactylitis and Enthesitis (no data shown)

At wk 24 PeripheralArthritis

AxialDisease

EnthesitisLEI 0%

DactylitisLDI-B%0

Skin %PASI 90

Nails% NAPSI 0

Bio Naïve*

-Ixe q 4wks

57.9% ACR20mTSS 0.17

42.6 (NS) 79.5 56.2 25.7 (NS)

-Placebo 31.1%ACR20%mTSS 0.49

19.3 25 6 18.9

-ADAActive control

57.4%ACR 20mTSS 0.10

33.3 77.8 38.6 39.4

Bio Exp.**

-Ixe q 4wks

53%ACR20

35 (NS) 75 44 20

-Placebo 19%ACR20

22 21 12 7

*Mease et alAnn Rheum Dis 2016;0:1–9. doi:10.1136/annrheumdis-2016-209709, **Nash et al Lancet 2017; 389: 2317–27

Secukinumab is FDA Approved for Psoriasis

• Indication: for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy

• Dosage: Recommended dose is 300 mg by subcutaneous injection at weeks 0, 1, 2, 3, and 4, followed by 300 mg every 4 weeks. For some patients, a dose of 150 mg may be acceptable

FDA: Food and Drug Administration.

Secukinumab is Indicated for PsA in the United States

2.2 Psoriatic Arthritis

• For psoriatic arthritis patients with coexistent moderate to severe plaque psoriasis, use the dosing and administration recommendations for plaque psoriasis [see Dosage and Administration (2.1)]

• For other psoriatic arthritis patients, administer secukinumab with or without a loading dosage by subcutaneous injection. The recommended dosage:

o With loading dosage is 150 mg at weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter

o Without a loading dosage is 150 mg every 4 weeks

o If a patient continues to have active psoriatic arthritis, consider a dosage of 300 mg

• Secukinumab may be administered with or without methotrexate

Package Insert. PsA: psoriatic arthritis.

IL-23 Blockade: GuselkumabPSA Phase 2 Clinical Trial

Guselkumab is FDA-approved for Psoriasis

• Indicated for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy

• Dosing: 100 mg sq at weeks 1,4 and every 8 weeks

Efficacy and Safety Results of Guselkumab, an Anti-IL23 Monoclonal

Antibody, in Patients with Active Psoriatic Arthritis over 24 Weeks: A Phase 2a, Randomized, Double-Blind, Placebo-

Controlled Study

Atul A. Deodhar1, Alice B Gottlieb2, Wolf-Henning Boehncke3, Bin Dong4,Yuhua Wang4, William Barchuk5, Xie Xu5, Elizabeth

C. Hsia4

1Oregon Health & Science University, Portland, OR, USA; 2Department of Dermatology, New York Medical College, Valhalla, NY, USA; 3Department of Dermatology, Geneva University Hospital, Geneva, Switzerland, 4Janssen Research & Development, LLC, Spring

House, PA, USA; 5Janssen Research & Development, LLC, San Diego, CA, USA, ACR,2016

Originally presented at ACR 2016 This presentation was supported by Janssen Research & Development, LLC

Presentation number:

Abatacept in the Treatment of Active Psoriatic Arthritis: 1-year Results From a Phase III Study

P Mease,1 AB Gottlieb,2 D van der Heijde,3 O FitzGerald,4 A Johnsen,5 M Nys,6 S Banerjee,5 D Gladman7

1Swedish Medical Center and University of Washington, Seattle, WA, USA; 2New York Medical College, Valhalla, NY, USA; 3Leiden University Medical Center, Leiden, Netherlands; 4St Vincent’s University Hospital and University College Dublin, Dublin, Ireland; 5Bristol-Myers Squibb, Princeton, NJ, USA; 6Bristol-Myers Squibb, Braine-l’Alleud, Belgium; 7University of Toronto and Toronto Western Hospital, Toronto, ON, Canada

OP0223

EULAR Annual European Congress of Rheumatology14–17 June 2017 ● Madrid, Spain

Introduction

• Unmet need exists for new targeted therapies for PsA

• PsA susceptibility is associated with Class I MHC molecules that are involved in antigen presentation to T cells1

• T cells are implicated in disease pathogenesis

• Abatacept, a selective T-cell co-stimulation modulator,2 is a potential therapy for PsA with a distinct mechanism of action upstream of currently available agents3

• Abatacept is an approved treatment for RA with >10 years post-marketingexperience

APC=antigen-presenting cell; MHC=major histocompatibility complex; PsA=psoriatic arthritis1. FitzGerald O, et al. Arthritis Res Ther 2009;11:214; 2. Cutolo M, et al. Autoimmun Rev 2013;12:758–67; 3. Ramiro S, et al. Ann Rheum Dis 2016;75:490–8. Figure adapted from Kremer JM. J Clin Rheumatol2005;11:S55–62

APC

CD80/86

Co-stimulatorypathway

CD28

T-cell receptor

MHC

Abatacept• Fully human solublefusion protein

• Works early in the inflammatoryprocess to reduce T-cell activation

T cell

Study Design

BSA=body surface area; SHS=Sharp/van der Heijde score; TNFi=tumour necrosis factor inhibitor 1. Mease P, et al. Arthritis Rheum 2011;63:939–48

Week 44 End of early escapeopen-label phase

Placebo SC weekly

Abatacept 125 mg SC weekly

Screening

(7–42 days)

Double-blind

phase

Open-label

phase

Week 24

1° Endpoint:

ACR20

Week 52

Abatacept 125 mg SC weekly

Day 1

Randomization stratified by:

• MTX use

• prior TNFi use

• plaque psoriasis

≥3% BSA

Week 16Early escape to open-label if <20% improvement in joint

counts

Eligibility criteria• Age ≥18 years

• Met CASPAR criteria

• Active arthritis (≥3 swollen and ≥3 tender joints)

• Active plaque psoriasis with ≥1 qualifying target lesion ≥2 cm in diameter

• Inadequate response or intolerance to ≥1 non-biologic DMARD

• May have failed TNFi agents

Sample size calculation assumptions• Estimates based on results of Phase

II study of abatacept in PsA1

Baseline Patient Characteristics

Abatacept (n=213) Placebo (n=211)

Age, years 51.0 (10.7) 49.8 (11.3)

Female, n (%) 121 (56.8) 112 (53.1)

Region, n (%)South AmericaEuropeNorth AmericaRest of World

95 (44.6)53 (24.9)44 (20.7)21 (9.9)

80 (37.9)59 (28.0)40 (19.0)32 (15.2)

Prior TNFi, n (%) 129 (60.6) 130 (61.6)

Concomitant MTX, n (%) 129 (60.6) 127 (60.2)

MTX weekly dose, mg 17.1 (7.0)* 17.1 (9.2)†

Concomitant oral corticosteroid, n (%) 56 (26.3) 51 (24.2)

PsA duration, years 8.3 (8.1) 8.8 (8.3)

Psoriasis ≥3% BSA, n (%) 146 (68.5) 148 (70.1)

Enthesitis, n (%) 140 (65.7) 132 (62.6)

Dactylitis, n (%) 61 (28.6) 50 (23.7)

Data are mean (SD) unless indicated otherwise*n=124; †n=123

Baseline Disease Characteristics

Abatacept (n=213) Placebo (n=211)

TJC 68 21.0 (13.4) 19.3 (13.1)

SJC 66 12.1 (7.8) 11.1 (7.2)

DAS28 (CRP) 5.0 (1.1) 4.9 (1.1)

Leeds Enthesitis Index (range: 0–6) 2.1 (2.0) 1.9 (2.0)

Leeds Dactylitis Index – Basic 20.3 (56.0) 16.9 (45.7)

PASI in patients with psoriasis ≥3% BSA 7.4 (8.0) 7.2 (7.8)

HAQ-DI 1.3 (0.7) 1.3 (0.7)

Total SHS, PsA-modified 20.0 (46.8) 17.7 (39.6)

CRP, mg/L 14.0 (20.9) 14.3 (30.3)

Elevated CRP >ULN (3 mg/L), n (%) 146 (68.9) 131 (62.7)

Data are mean (SD) unless indicated otherwisePatient numbers in the abatacept and placebo arms were 210 and 208 for DAS28 (CRP), 145 and 148 for PASI, 212 and 211 for HAQ-DI, 205 and 202 for PsA-modified total SHS, and212 and 209 for elevated CRP PASI=Psoriasis Area and Severity Index; ULN=upper limit of normal

Abatacept

At week 24 Peripheral Arthritis

AxialDisease

Enthesitis- % Complete Resolution

Dactylitis-%CompleteResolution

Skin%PASI75

Nails

Abatacept 39.4 % ACR20; %non progression xray 42.7%

32.9% complete resolution

44.3% complete resolution

16.4%

PBO % 22.3 ACR 20; %non progression xray 32.7%

21.7% complete resolution

34.0% complete resolution

10.1%

Peripheral Arthritis p <0.001; All others could not be analyzed because in hierarchy they were below HAQ-DI which did not meet statistical significance.

Philip Mease, Alice B Gottlieb, Désirée van der Heijde, Oliver FitzGerald, Alyssa Johnsen,Marleen Nys,Subhashis Banerjee, Dafna Gladman:ARD Online First, published on May 4, 2017 as 10.1136/annrheumdis-2016-210724.

TofacitinibJAK kinase inhibitor FDA approved for rheumatoid

arthritis

Tofacitinib@ 3 monthsExcept xraydata

Peripheral Arthritis: % ACR 20/% Non progression on mTSS at 12 months

Axial ND EnthesitisChange in LEI Index

DactylitisChange in dactylitis score

Skin % PASI 75

Nails ND

Biologics Naive

5 mg BID 50/96 -0.4+0.2 NS -3.5+1.0 43

10 mg BID 61/95 -0.8+0.2 -5.5+0.9 44

Adalimumab 55/98 -1.1+0.2 -4.0+1.0 39

Placebo (x 3 months)

33 /xrays not done for placebo at 12 months

-0.4+0.2 -2.0+1.1 15

Mease et al NEJM 377:16 15371550 , 2017; Inhibition of radiographic progression at 12 months; all patients on a cDMARD; adalimumab = active control; no stats on dactylitis and xray non progression

TNF- Blockers

Comparative Data at Primary Endpoint

Adalimumab Etanercept Infliximab Golimumab/Certolizumab

% PASI 75 75 49 80 58 (tested in only PSA)/80 (PSO)

% ACR 20 58 59 58 51/58

Safety (Perceived)

4+ 4+ 2+ 3+

Adalimumab (A), Etanercept (E), Certolizumab and Infliximab (I) are FDA approved for controllingsigns and symptoms, inhibition of radiographic progression and improvement of qualityof life in PSA; A, E, I also for moderate to severe psoriasis. Golimumab is FDA

approved for controlling signs and symptoms in PSA

Conclusion

Class Peripheral Arthritis:Signs/Symptoms

Inhibition of XRAY Progression

Enthesitis Dactylitis Skin Nails

IL-17 Mabs yes yes yes yes 4+ Yes

IL-23 Mab yes ? yes yes 4+ Probably yes

Tofacitinib yes ? ?yes ?yes 1-2+ ?yes

Abatacept yes ? ? ? no ?

TNF inhibitors yes yes yes yes 2-3.5+ yes