JAK Inhibitors
and Safety
Kevin L. Winthrop, MD, MPH Associate Professor, Divisions of Infectious
Diseases, Public Health, and
Preventive Medicine
Oregon Health & Science University
Learning Objectives
• Discuss recent clinical trial and real world data
from approved and investigational JAK inhibitors
• Review safety profiles of approved and
investigational JAK inhibitors across the
spectrum of rheumatoid arthritis
Clark JD, et al. J Med Chem. 2014.
Winthrop KL. Nat Rheum Rev. 2017.
Clark JD, et al. J Med Chem. 2014.
Winthrop KL. Nat Rheum Rev. 2017.
Tofacitinib (Tofa) and Lipids
Charle-Schoeman C, et al. ACR Abstract. 2014 #487.
Malignancy and Tofa
Curtis J, et al. ARD. 2015.
0
1
2
3
4
5
6
0 to 6 6 to 12 12 to 18 18 to 24 24 to 30 30 to 36 36 to 42 >42
IR (
even
ts/1
00 p
t-yrs
[95%
CI]
)
Months
• Overall rate of serious infection
reported with tofacitinib:
– 3.1 events/100 patient-years
• Rates previously reported in clinical
trial safety analyses of other RA drugs:
– Adalimumab 3.9–5.1 events/
100 patient-years
– Rituximab 3.9–4.3 events/
100 patient-years
– Tocilizumab 3.8–5.1 events/
100 patient-years
– Etanercept 3.8 events/100
patient-years
– Abatacept 2.0–3.1 events/100
patient-years
– Golimumab 5.09 events/100
patient-yearsReproduced with permission.
Incidence Rates of Serious Infections by 6-Month Intervals
Cohen S, Radominski SC, Gomez-Reino JJ, et al. Arthritis Rheumatol. 2014 Jul 21. [Epub ahead of print]. Slide prepared by CSF.
Risk Factors for Serious Infection
Cohen S, et al. Arthritis Rheumatol. 2014.
• 60 OIs reported (IR 0.46/100 pys [0.36-0.59])
– TB (n=26)
– PCP (n=4)
– CMV (n=6)
– Candida Esophagitis (n=9)
– Cryptococcus (n=3)
– NTM (n=2)
– HZ, multi-dermatomal (n=8)
– BK encephalopathy (n=1)
– Toxoplasmosis (n=1)
Tofa and “Opportunistic” Infections (P2P3LTE)
Winthrop K, et al. ARD. 2015.
Winthrop, et al. Arth and Rheumatol. 2014.
Herpes Zoster and JAK Inihibition
Winthrop K, et al. EULAR. 2015.
Real World HZ with Tofa and Biologics
Curtis J, et al. ARD. 2016.
Real World HZ and HSV with Tofa and Biologics
Curtis J, et al. ARD. 2016.
HZ in Tofa-treated PsO
Tofacitinib 10mg BID dose is not approved
Winthrop KL, et al. Fall Clinical Derm Congress. (abstract) 2015.
Polymorphism for HZ
Bing N, et al. ACR. abstract 2015.
• 5,246 Tofa-treated RA patients
• Genome-wide screen
– Adjusted for age, baseline lymphocyte, and
MTX use
• Outcome modeled
– Time to HZ and HZ incidence
• CD83, OR 3.7, p=2.1 X 10-8
– (allelle freq only 3% whites, <0.1% Japanese)
• IL-17RB, HR 3.6, p = 7.6 X 10-10
– (allelle freq only <0.2% whites, 17% Japanese)
Xie F, et al. ARD. 2016; Smolen JS, et al. EULAR 2016.
• Other JAKi
– Baricitinib
development
program with 2
GI perforations
(5/1,000
patient-years)
JAKi and GI Perforation: Tofa in Real World
Tofa Diminishes NK Cell Activation
Nocturne G, et al. ACR Abstract. 2016.
Tofa Decreases B Cell Activation
Wang S-P, et al. ARD. 2014.
Tofa Inhibits CD4 Proliferation in RA Patients
Maeshima, et al. Arth Rheum. 2012.
Baricitinib
• JAK 1,2
• Approved in Europe for RA
– 2mg and 4mg once daily doses
Lymphocyte Decline
Wollenhaupt J, et al. J Rheum. 2014.
Emery P, et al. ACR. 2015.
Emery P, et al. ACR. 2015.
SIE and Baricitinib
Smolen JS, et al. EULAR. 2016.
HZ and Baricitinib
Smolen JS, et al. EULAR. 2016.
HZ and Bari by Region
Winthrop KL, et al. ACR. 2016 abstract
TNFi and Baricitinib: A Look During the Overlap
Tayler PC, et al. ACR. 2016 abstract.
Malignancy and Baricitinib
(Excluding NMSC)
Smolen JS, et al. EULAR. 2016.
Ruxolitinib---JAK1/JAK2 Inhibitor
(Asia)
Wong Jun C, et al. Leukemia and Lympoma. 2014.
PML
Wathes R, et al. NEJM. 2013.
JAK 1 Race
• Filgotinib
• ABT-494 (“Upa”)
IC50 values for inhibition of recombinant JAK1, JAK2, JAK3, and TYK2 by GLPG0634 were determined by
measuring the incorporation of phosphate into an ULight-JAK-1(Tyr1023) peptide using an europium-labelled anti-
phosphotyrosine Ab. The Kd values of GLPG0634 on JAK1, JAK2, and JAK3 were determined by measuring the
competition of GLPG0634 with a fluorescently labelled ATP mimetic. IC50 values corresponding to 50% probe
displacement were obtained and Kd values calculated according to the Cheng–Prusoff equation.
Recombinant
human kinase
IC50 (nM, ± SEM; n = 2–
4)Kd (nM)
JAK1 10 ± 0.8 11
JAK2 28 ± 5.4 32
JAK3 810 ± 180 300
TYK2 116 ± 39 ND
GLPG0634 preferentially inhibits JAK/STAT signalling involving JAK1
than JAK2 kinase in a cellular context
CIA, collagen-induced arthritis; QD, once daily
Reproduced with permission from Van Rompaey, et al. J Immunol. 2013;191:3568–577. slide prepared by CSF.
Potency and Selectivity of Filgotinib in JAK Biochemical Assays
Vanhoutte F, et al. ACR. 2012-2489; Namopur F, et al. ACR Abstract. #1481, 2014; Galien R, et al. ACR. 2015 abstract 2781.
• Dose ranging study (phase 2b), 285 RA patients
– No increase in LDL-cholesterol
– No LFT rise
– Modest decrease in neutrophils and platelets
– No change in CD8, NK, or RBC counts
– Small increase in creatinine, hemoglobin
• In vitro, GLPG0634 and main metabolite
– No induction of CYP1A2, CYP2B6 and CYP3A4 enzymes
– No difference in midazolam pharmacokinetics
• Little clinical data yet reported
GLPG0634-JAK 1 “Selective”
Number of pts, n (%) PBO (n=56)
ABT-494
3 mg BID
(n=55)
6 mg BID
(n=55)
12 mg BID
(n=55)
18 mg BID
(n=55)
Serious AE 1 (2) 2 (4) 2 (4) 0 1 (2)
Infections 13 (23) 11 (20) 12 (22) 22 (40) 21 (38)
Serious infection 1 (2) 0 0 0 0
Anemia 0 0 0 0 1 (2)
Herpes zoster 2 (4) 1 (2) 0 1 (2) 1 (2)
Hepatic disorder 1 (2) 0 0 0 2 (4)
Neutropenia 0 0 0 1 (2) 1 (2)
Malignancy 0 0 1 (2) 0 0
ABT-494 in RA TNF-IR (Phase 2b)
JAK 1 inhibitor
Kremer J, et al. ACR. Later-breaker 2015.
Vaccination prior to JAK Inhibition
Winthrop KL, et al. ACR. 2015 late breaker poster #12L.
Winthrop KL, et al. ACR. 2015 late breaker poster #12L.
Disseminated Vaccine
Winthrop KL, et al. ACR. 2015 late breaker poster #12L.
Tofacitinib and PPSV-23
0
2
4
6
8
10
12
14
16
18
20
1 3 4 5 6B 7F 9V 14 18C 19A 19F 23F
PBO PBO + MTX
Tofacitinib 10 mg BID Tofacitinib 10 mg BID + MTX
Pn
eu
mo
co
ccal
an
tib
od
y G
MF
R
(95%
CI)
Pneumococcal Antigen Serotype
Winthrop K, et al. EULAR. abstract 2013.
Tofacitinib and Trivalaent Influenza Vaccine
41
62.2
67.4
58.256.9
64.4
50.9
0
20
40
60
80
100PBO Tofacitinib 10 mg BID
Overall Without
Methotrexate
With
Methotrexate
Resp
on
ders
(%
)
Response defined by ≥4-fold increase in antibody titers
in ≥2 of 3 influenza antigensWinthrop K, et al. EULAR. abstract 2013.
Tofacitinib and Ruxolitinib Inhibit HIV Replication
Gavegnano, et al. Antimicrobial Agents and Chemotherapy. 2014.
Acknowledgements
• UAB colleagues
• ACR and EULAR colleagues
• Oregon Health Authority colleagues
• CDC colleagues