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.
IR (events/100 pt-yrs [95% CI]) Incidence Rates of Serious Infections by 6-Month Intervals 6 5 4 3 2 1 0 0 to 6 6 to 12 12 to 18 18 to 24 24 to 30 30 to 36 36 to 42 >42 Reproduced with permission. 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-years 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.
Tofa and Opportunistic Infections (P2P3LTE) 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) Winthrop K, et al. ARD. 2015.
Herpes Zoster and JAK Inihibition Winthrop, et al. Arth and Rheumatol. 2014.
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 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) Bing N, et al. ACR. abstract 2015.
JAKi and GI Perforation: Tofa in Real World Other JAKi Baricitinib development program with 2 GI perforations (5/1,000 patient-years) Xie F, et al. ARD. 2016; Smolen JS, et al. EULAR 2016.
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 )
Potency and Selectivity of Filgotinib in JAK Biochemical Assays 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 IC 50 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 antiphosphotyrosine 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. IC 50 values corresponding to 50% probe displacement were obtained and Kd values calculated according to the Cheng Prusoff equation. 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.
GLPG0634-JAK 1 Selective 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 Vanhoutte F, et al. ACR. 2012-2489; Namopur F, et al. ACR Abstract. #1481, 2014; Galien R, et al. ACR. 2015 abstract 2781.
ABT-494 in RA TNF-IR (Phase 2b) JAK 1 inhibitor ABT-494 Number of pts, n (%) PBO (n=56) 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 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.
Pneumococcal antibody GMFR (95% CI) Tofacitinib and PPSV-23 20 18 PBO PBO + MTX 16 Tofacitinib 10 mg BID Tofacitinib 10 mg BID + MTX 14 12 10 8 6 4 2 0 1 3 4 5 6B 7F 9V 14 18C 19A 19F 23F Pneumococcal Antigen Serotype Winthrop K, et al. EULAR. abstract 2013.
Responders (%) Tofacitinib and Trivalaent Influenza Vaccine 100 PBO Tofacitinib 10 mg BID 80 60 62.2 56.9 67.4 64.4 58.2 50.9 40 20 0 Winthrop K, et al. EULAR. abstract 2013. Overall Without Methotrexate 41 With Methotrexate Response defined by 4-fold increase in antibody titers in 2 of 3 influenza antigens
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