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