psoriatic arthritis: new and emergent therapies s041... · psoriatic arthritis: new and emergent...
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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