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EULAR conference, 13 June 2019
Efficacy of filgotinib vs placebo in active psoriatic arthritis: patient-level data from EQUATOR, a randomized phase 2 study
P. Mease1, D. Gladman2, F. Van den Bosch3, M. Stanislavchuk4, A. Rychlewska-Hanczewska5, C. Tasset6, L. Meuleners6, R. Besuyen7, J. Gao8, M. Trivedi8, L. Coates9, P. Helliwell10
1Swedish Medical Center/Providence St Joseph Health and University of Washington, Seattle, United States of America; 2University of Toronto and Krembil Research Institute, Toronto Western Hospital, Toronto, Canada; 3University of Ghent, Department of
Rheumatology, Ghent, Belgium; 4National Pirogov Memorial Medical University, Vinnytsya, Ukraine; 5Ai Centrum Medyczne sp. z o.o. sp.k., Poznan, Poland; 6Galapagos NV, Mechelen, Belgium; 7Galapagos BV, Leiden, Netherlands; 8Gilead Sciences Inc, Foster City,
United States of America; 9University of Oxford, Oxford, United Kingdom; 9Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, United Kingdom
http://dx.doi.org/10.1016/S0140-6736(18)32483-8
Disclosures
♦ PJ Mease: Abbvie, Amgen, BMS, Boehringer Ingelheim, Celgene, Galapagos, Genentech, Gilead, Janssen, Eli Lilly, Novartis, Pfizer, SUN, UCB
♦ D Gladman: Abbvie, Amgen, BMS, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, UCB
♦ F Van den Bosch: Abbvie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Janssen, Merck, Novartis, Pfizer, UCB
♦ M Stanislavchuk: no conflicts of interest♦ A Rychlewska-Hanczewska: national study coordinator, Galapagos, Gilead Sciences♦ C Tasset, L Meuleners, R Besuyen: Galapagos employees♦ J Gao, M Trivedi: Gilead Sciences employees♦ LC Coates: Abbvie, Amgen, Celgene, Galapagos, Janssen, Lilly, Novartis, Pfizer, Prothena, Sun
pharma, UCB♦ PS Helliwell: Abbvie, Amgen, Celgene, Galapagos, Janssen, Novartis, Pfizer, UCB
2
Filgotinib Background
3
Janus kinases (JAKs) play a key role in cytokine signalling— JAK1 is involved in numerous (pro)inflammatory cytokine signaling
— JAK2 mediates GM-CSF, EPO, TPO, GH, PRL signaling
— JAK3 has an effect on γ-chain cytokines critical for lymphocyte function
— TYK2 mediates Type1 IFN and IL-12/IL-23 signaling
Yamaoka K et al., Genome Biology 2004; 5(12):253
FILGOTINIB
Filgotinib, oral JAK1 selective inhibitor— 30-fold selective over JAK2 in whole blood assay
— t1/2 = 5–11h
— In addition, there is an active metabolite with t1/2 = 21–27h
— Both block cytokine signaling through inhibition of STAT phosphorylation
— Demonstrated efficacy and consistent safety profile in CD and RA
GM-CSF = Granulocyte-macrophage colony-stimulating factor; EPO = erythropoietin; TPO = thrombopoietin; GH = growth hormone; PRL = prolactin
Study ObjectivesPh2 EQUATOR study with filgotinib in PsA
4
♦ Primary objective of this analysis– Evaluate time to first response on patient-
level and individual duration of response, comparing filgotinib to placebo on signs and symptoms of psoriatic arthritis
♦ Secondary objectives– Evaluate effect of filgotinib compared to
placebo on signs and symptoms of psoriatic arthritis, psoriasis, enthesitis, physical function, fatigue, quality of life
– Evaluate safety and tolerability of filgotinib
♦ Inclusion Criteria – PsA for at least 12 weeks prior to screening (CASPAR)
– Active PsA: ≥5 tender and ≥5 swollen joints
– Active or documented history of plaque psoriasis
– Insufficient response or intolerance to ≥1 csDMARD• csDMARDs could be continued during the study provided
patient received this treatment for ≥12 weeks prior to screening and was on stable dose for 4 weeks prior to baseline
♦ Exclusion Criteria – Prior treatment with
• bDMARDs, except prior use of 1 anti-TNF agent• tsDMARDs
– Systemic steroids of ≥10 mg/day prednisone or equivalent
Study DesignPh2 EQUATOR study with filgotinib in PsA
5
♦ Mixed population – Anti-TNF naive and anti-TNF previously-exposed– Monotherapy and add-on to csDMARDs
Week 16Baseline
Primary endpoint
Screening Randomization OLE(N=122)D-28 1:1
filgotinib 200 mg qd (N=65)
placebo (N=66)
qd= once daily; OLE= open label extension study
Total N=131
Demographics Ph2 EQUATOR study with filgotinib in PsA
6
Filgotinib (N=65) Placebo (N=66)
Female, n (%) 36 (55.4) 30 (45.5)
Age, mean, years 49 50
Weight, mean, kg 81 87
BMI, mean, kg/m² 28.6 30.1
Duration of PsA, mean, years (since diagnosis) 7 7
Prior aTNF use, n (%) 11 (16.9) 9 (13.6)
Concurrent csDMARD use, n (%) 47 (72.3) 50 (75.8)
Concurrent steroid use, n (%) 17 (26.2) 16 (24.2)
Baseline disease characteristicsPh2 EQUATOR study with filgotinib in PsA
7
Filgotinib (N=65) Placebo (N=66)
TJC68, mean 18.3 21.6
SJC66, mean 11.6 12.7
HAQ-DI, mean 1.43 1.36
DAS28(CRP), mean 4.9 5.1
hsCRP, mean, mg/L 13.9 10.9
hsCRP ≥ULN, n (%) 25 (38.5) 17 (25.8)
Enthesitis, n (%) 38 (58.5) 49 (74.2)
SPARCC enthesitis (1) 4.9 5.5
LEI (enthesitis), mean (2) 2.8 2.6
≥3% BSA of psoriasis, n (%) 42 (64.6) 40 (60.6)
PASI, mean (3) 10.9 11.7
ULN hsCRP = 10 mg/L(1) full analysis set with enthesitis at baseline (SPARCC Enthesitis Index >0); (2) full analysis set with enthesitis at baseline (LEI >0) ;(3) full analysis set with baseline BSA ≥3%
ACR20 (primary endpoint), ACR50 and ACR70 at Week 16Ph2 EQUATOR study with filgotinib in PsA
80.0
80.0
33.3
47.7
15.223.1
6.1
**
***
***
0
10
20
30
40
50
60
70
80
90
100
ACR20 ACR50 ACR70
**: p<0.01; ***: p<0.001 PlaceboN=66
FilgotinibN=65
Primary endpoint
ACR responses, NRI% responders
NRI=non-responder imputation
ACR20Ph2 EQUATOR study with filgotinib in PsA
9
9
ACR20, response over timeACR20, time to first response, OC
ACR50Ph2 EQUATOR study with filgotinib in PsA
10
10
ACR50, time to first response, OC ACR50, response over time
ACR70Ph2 EQUATOR study with filgotinib in PsA
11
ACR70, time to first response, OC ACR70, response over time
MDA at Week 16Ph2 EQUATOR study with filgotinib in PsA
12
% responders
MDA = minimal disease activity (at least 5 out of 7: TJC68 ≤1, SJC66 ≤1, PASI ≤1 or BSA ≤3%, pain ≤15, PtGADA ≤20, HAQ-DI ≤0.5, SPARCC enthesitis ≤1); NRI=non-responder imputation
23.1
9.10
10
20
30
40
50
60
70
80
90
100
FIL N=65 PBO N=66
MDA, NRI
*
*: p<0.05
MDAPh2 EQUATOR study with filgotinib in PsA
13
13
MDA, time to first response, OC MDA, response over time
MDA = minimal disease activity (at least 5 out of 7: TJC68 ≤1, SJC66 ≤1, PASI ≤1 or BSA ≤3%, pain ≤15, PtGADA ≤20, HAQ-DI ≤0.5, SPARCC enthesitis ≤1); NRI=non-responder imputation
DAPSA low disease activity at Week 16Ph2 EQUATOR study with filgotinib in PsA
14
% responders
DAPSA = Disease Activity Index for Psoriatic Arthritis = TJC68 + SJC66 + PtGADA + Pain VAS + CRP (mg/dL); LDA = Low Disease Activity = DAPSA ≤ 14; NRI=non-responder imputation
49.2
15.2
0
10
20
30
40
50
60
70
80
90
100
FIL N=65 PBO N=66
DAPSA low disease activity, NRI
***
***: p<0.001
DAPSA Low Disease ActivityPh2 EQUATOR study with filgotinib in PsA
15
15
DAPSA LDA, time to first response, OC DAPSA LDA, response over time
DAPSA = Disease Activity Index for Psoriatic Arthritis = TJC68 + SJC66 + PtGADA + Pain VAS + CRP (mg/dL); LDA = Low Disease Activity = DAPSA ≤ 14; NRI=non-responder imputation
HAQ-DI response at Week 16 Ph2 EQUATOR study with filgotinib in PsA
16
% responders
HAQ-DI = health assessment questionnaire disease severity index, FAS with baseline value ≥0.35 (FIL N=63; PBO N=62); MCID = minimal clinically important difference = change from baseline ≤ -0.35; NRI = non-responder imputation
65.1
41.9
0
10
20
30
40
50
60
70
80
90
100
FIL N=63 PBO N=66
HAQ-DI MCID, NRI
**
**: p<0.01
HAQ-DI responsePh2 EQUATOR study with filgotinib in PsA
17
HAQ-DI MCID, time to first response, OC HAQ-DI MCID, response over time
HAQ-DI = health assessment questionnaire disease severity index, FAS with baseline value ≥0.35 (FIL N=63; PBO N=62); MCID = minimal clinically important difference = change from baseline ≤ -0.35; OC = observed case
PASI75 at Week 16Ph2 EQUATOR study with filgotinib in PsA
18
% responders
**: p<0.01
PASI75=Psoriasis Area and Severity Index 75%; Full Analysis Set with ≥ 3% BSA at baseline (FIL N=42; PBO N=40); BSA=body surface area; NRI=non-responder imputation
45.2
15
0
10
20
30
40
50
60
70
80
90
100
% change from baseline ≤-75%FIL N=42 PBO N=40
PASI75, NRI
**
PASI75Ph2 EQUATOR study with filgotinib in PsA
PASI75, time to first response, OC PASI75, response over time
PASI75=Psoriasis Area and Severity Index 75%; Full Analysis Set with ≥ 3% BSA at baseline; BSA=body surface area; OC=observed case;
Pruritus at Week 16Ph2 EQUATOR study with filgotinib in PsA
20
% respondersPruritus, NRI
**: p<0.01
Pruritus responder=Pruritus NRS score change from baseline ≤-3; Full Analysis Set with pruritus NRS ≥ 3% at baseline (FIL N=36, PBO N=36); NRI=non-responder imputation
58.3
22.2
0
10
20
30
40
50
60
70
80
90
100
change from baseline ≤-3FIL N=42 PBO N=40
**
PruritusPh2 EQUATOR study with filgotinib in PsA
21Pruritus responder=Pruritus NRS score change from baseline ≤-3; Full Analysis Set with pruritus NRS ≥ 3% at baseline (FIL N=36, PBO N=36); OC=observed case;
Pruritus, time to first response, OC Pruritus, response over time
LEI activity at Week 16Ph2 EQUATOR study with filgotinib in PsA
22
% responders
**: p<0.01
LEI = Leeds Enthesitis Index; FAS with baseline enthesitis (LEI >0); NRI=non-responder imputation
51.5
25.6
0
10
20
30
40
50
60
70
80
90
100
FIL N=33 PBO N=43
**
LEI=0, NRI
LEI activityPh2 EQUATOR study with filgotinib in PsA
23
23
LEI, time to first response, OC LEI, response over time
LEI = Leeds Enthesitis Index; FAS with baseline enthesitis (LEI >0); NRI=non-responder imputation
SafetyPh2 EQUATOR study with filgotinib in PsA
*1 patient died following pneumonia infection24
n (%) Filgotinib(N=65)
Placebo(N=66)
TE AE 37 (56.9) 39 (59.1)
Serious TE AE 1 (1.5) 1 (1.5)
Leading to temporary study drug interruption 5 (7.7) 8 (12.1)
Leading to permanent study drug discontinuation 1 (1.5) 0
Infections 14 (21.5) 14 (21.2)
All serious infections 1 (1.5)* 0
Opportunistic infections 0 0
Herpes zoster 1 (1.5) 0
Active tuberculosis 0 0
Pneumonia 1 (1.5)* 0
Malignancies, incl. lymphoma 0 0
Deep venous thrombosis, pulmonary embolism 0 0
Adjudicated Major Adverse Cardiac Events (MACE) 0 0
Death 1 (1.5)* 0
Safety - key hematology parametersPh2 EQUATOR study with filgotinib in PsA
25
200220240260280300
FIL PBO
Platelets, mean (109/L)
13
13.5
14
14.5
15
FIL PBO
Hemoglobin, mean (g/dL)
0
2
4
6
FIL PBO
Neutrophils, mean (109/L)
11.21.41.61.8
2
FIL PBO
Lymphocytes, mean (109/L)
150175200225250275300
FIL PBO
NK cells (/µL)
Baseline Week 16
FIL PBOGrade 2 3 (4.6%) -Grade 3-4 - -
FIL PBOGrade 2 3 (4.6%) 2 (3.0%)Grade 3 - 1 (1.5%)Grade 4 - -
FIL PBOWorstcase decrease <LLN 6 (9.2%) 1 (1.6%)Worstcase increase >ULN 1 (1.5%) -
Toxicity grades were defined by modified Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Worst case CTCAE grades for each subject are reported
FIL PBOGrade 2-4 - -
FIL PBOGrade 2-4 - -
Safety - key chemistry parametersPh2 EQUATOR study with filgotinib in PsA
26Baseline Week 16
100
120
140
FIL PBO
Creatinine clearance, mean (mL/min)
0.6
0.7
0.8
0.9
FIL PBO
Creatinine, mean (mg/dL)
0
10
20
30
FIL PBO
AST, mean (U/L)
FIL PBOGrade 2 1 (1.5%) 1 (1.5%)
Grade 3-4 - -
FIL PBOGrade 2 7 (10.8) 3 (4.1)
Grade 3 1 (1.5%) -
Grade 4 - -
FIL PBOGrade 2 10 (15.4%) 4 (6.0%)
Grade 3-4 - -
Toxicity grades were defined by modified Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Worst case CTCAE grades for each subject are reported
050
100150200250
FIL PBO
Total Cholesterol (mg/dL)
0255075
100125150
FIL PBO FIL PBO
LDL, mean (mg/dL)
3.53.73.94.14.34.5
FIL PBO
Total Cholesterol / HDL
FIL PBOGrade 2 4 (6.2%) 1 (1.6%)
Grade 3-4 - -HDL and LDL are not part of CTCAE grading system
ConclusionsPh2 EQUATOR study with filgotinib in PsA
♦ Selective JAK1 inhibition by filgotinib significantly improved signs and symptoms of PsAin patients with active disease vs placebo
– Primary and key secondary endpoints achieved
♦ Patients treated with filgotinib achieved ACR20 response earlier and responses over time appear to be more stable
– Patients on PBO had more occurrences of response being lost over time and fewer cases of regaining a lost response
– Similar trends were observed for other efficacy endpoints
♦ Safety profile of filgotinib after 16 weeks of treatment in line with previous reports, without new safety signals
♦ Positive proof-of-concept study with filgotinib in patients with active psoriatic arthritis
27http://dx.doi.org/10.1016/S0140-6736(18)32483-8
Acknowledgments
We extend our thanks to the patients, their families, and all participating investigators– Belgium: Leon M, Malaise M, Margaux J, Van den Bosch F– Bulgaria: Marinova N, Penev D, Rashkov R, Spasov Y, Stoilov R, Vladeva S, Velkova M– Czech Republic: Dokoupilova E, Hala T, Urbanova Z– Estonia: Raussi E, Tälli S, Valter I– Poland: Dudek A, Glowacka-Kulesz M, Gruszecka K, Jeka S, Miakisz M, Nowak N,
Rychlewska-Hanczewska A, Swierkocka K– Spain: Fernandez Nebro A, Gratacos Masmitja J, Mera Varela A, Navarro Sarabia F, Perez Venegas J,
Povedano Gomez J, Veiga Cabello R– Ukraine: Garmish O, Golovchenko O, Nadashkevych O, Shevchuk S, Smiyan S, Stanislavchuk M,
Trubina S, Tseluyko V, Turyanytsya S, Zhdan V
This study was funded by Gilead Sciences, Inc. and Galapagos NV
28