Rheumatoid Arthritis treatment with biologics

APLAR 2014, Cebu, April 3, 2014 Rheumatoid Arthritis treatment with biologics Tsutomu Takeuchi, MD.PhD. Professor and Chief of Rheumatology, Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University

Keio University Hospital and Medical School 2nd wing of Keio University Hospital 3rd wing of Keio University Hospital Keio Immunotherapy Center at 3rd wing of Keio University Hospital Research Park

Rheumatoid Arthritis ~ points to be reminded ~ Rheumatoid Arthritis is a common disease, leading to disability

Japan in Asia and western countries - Similarities and dissimilarities - Smoking rate Japan Male:41%, Female:12% US and EU US Male:19%, US Female 15% Prevalence of Tuberculosis (/100,000) 19 4-9 Anti-HBc sero-positivity 14% US 5% Body weight of RA pts in clinical trials 53-55kg 75-80kg MTX mean dose in clinical trials 6-8mg/week 15-20mg/week The effectiveness and safety of biologics in Japanese patients with RA could be influenced by the unique genetic, environmental and medical backgrounds. Takeuchi T et al. Nature Rev Rheum 6:644-52, 2010

% of the patients Clinical trials for MTX in Japan - multi-center RCT for 12 weeks - * P<0.001 * P<0.005 * P<0.005 * P<0.005 (AST, ALT greater than 100IU/ml) Kashiwazaki inflammation (Japanese) 1996, 16: 437 MTX was approved in 1999 in Japan and maximum dose was 8mg/ week. Since February 2011, we can use MTX as first DMARD and the maximum dose up to 16mg/week.

Appropriate Targets and Targeted Therapy in RA ~ which pro-inflammatory cytokines are the targets ~ Conditional knock-out experiments in human diseases such as RA

Target molecules in RA? new blood formation anti-icam-1 ECM (collagen, fibronectin) B cells New Targets! antigen presenting cells (APC) VEGF adhesion molecules Failed! T cells anti-cd4 pro-inflammatory cytokines (TNFα, IL-6) CD20 activated T cells CD80/86 CD28/CTLA4 synovial proliferation prostaglandins Bone/Caltilage Highly successful! osteoclasts MMP Apoptosis joint pain

Structure and targets of Biologics in RA antibody mouse human chimeric anti-tnfαab infliximab Recptor-Ig fusion, etc chimeric anti-cd20ab rituximab humanized anti-il-6rab tocilizumab human anti-tnfαab adalimumab golimumab humanized anti-tnfαfab Certolizumab Biologics are used in about 20-30% of RA patients in Japan TNFR2(p75)- IgGFc fusion Etanercept CTLA-4- IgGFc fusion Abatacept IL-1ra anakinra underline: marketed in Japan (March 2014

Appropriate targets are distinct among autoimmune/inflammatory diseases RA Crohn/UC AS PS/PsA CAPS Gout SLE anti-tnf IFX, ETN, ADA GLM, CZP IFX ADA IFX, ADA,GLM IFX, ADA,GLM? anti-il-6r TCZ X sarilumab, TCZ? anti-il-6 sirukumab olokizumab clazakizumab anti-il-1β canakinumab anti-il-12/23 (p40) anti-il-17 anti-il-17r ixekizumab secukinumab X brodalimumab ustekinumab O ixekizumab secukinumab O brodalimumab anti-baff X belimumab, tabalumab belimumab

Rationale for the use of biologics in RA ~ clinical point of view ~

ACR response (%) Effectiveness of anti-tnf treatment 100 Smolen JS, et al. Lancet 370:1861, 2007 ACR20 ACR50 ACR70 100 However, be careful for high disease activity! 100 80 80 80 70 60 60 60 60 40 50 40 40 40 50 20 30 20 20 20 30 15 0 0 0 MTX naive/ DMARD-IR anti-tnf+mtx MTX-inadequate responders (MTX-IR) anti-tnf failures As a group level, no clear difference in effectiveness and safety among different anti-tnfs. As an individual level it can be better for one to others.

Switch or Adding-on when you start anti-tnf in MTX-IR patients? Fisher s exact test 40 35 ETN ETN+MTX P=0.010 P=0.038 30 Patient (%) 25 20 15 10 5 0 2 4 8 12 24 52 When you start anti-tnf in MTX-IR patients Treatment Period(W) you should add anti-tnf on MTX! Kameda et al. J Rheum 38:1581-92 2011

MUSICA study 309 MTX-IR patients randomized to ADA 40 mg eow and either MTX 7.5 mg/week or 20 mg/week. Non-inferiority design; ultrasound assessment every 4 weeks When you start anti-tnf in higher dose of MTX-IR patients you may decrease the dose of MTX down to 7.5mg/ week! Kaeley GS, et al. ACR 2013, San Diego, #2686

CONCERTO study Burmester G, et al. Ann Rheum Dis, Feb 18, online 2014 AAA: 2.5mg-21% 5mg-13% 10mg-6% 20mg-6% When you start anti-tnf and MTX in MTX-naive patients you should use MTX greater than 10mg/ week!

Comparison of TCZ/ADA mono on MTX-IR or intolerant RA :ADACTA study Superiority trial design Randomised Drug Treatment 8 Weeks Safety Follow-up MTX-IR or intolerant RA Treated (N=326) age 54.4y, duration 7.3y tocilizumab 8 mg/kg IV Q4w + SC Placebo Q2 weeks adalimumab 40 mg SC Q2w + IV Placebo Q4 weeks age 53.3y, duration 6.3y 1:1 randomisation Week 16+: Escape 24 weeks; primary endpoint: ΔDAS28 Criteria for escape: <20% improvement from baseline in SJC and TJC at week 16 or later Escape therapy: Weekly SC(ADA/placebo) injections; study medication remained blinded C Gabay, P Emery, R van Vollenhoven et al. Lancet 381:1451-50, 2013.

ADACTA study: Change in DAS28 C Gabay, P Emery, R van Vollenhoven et al. Lancet 381:1451-50, 2013. When you start biologics as mono in MTX-IR or intolerant efficacy of TCZ may be better than that of ADA!

Results of Signs and Symptoms (%) 80% 60% Remission Rate at 24wk (superiority analysis) 72.2% P=0.0181 Δ15.4 (95%CI; 2.4~28.2) (%) 87.5 70. ACR response ACR20 Add-on ACR20 Switch ACR50 Add-on ACR50 Switch ACR70 Add-on ACR70 Switch 56.8% 52.5 40% 35. 20% 17.5 When you start tocilizumab in MTX-IR 0% 0. you should add TCZ on MTX at least in initial 3 to 6 months. Add-on Switch 4wk 8wk 12wk 16wk 20wk 24wk LOCF method #OP0043. Takeuchi T, et al. EULAR 2013, Madrid

Rationale for antibody-based targeted therapy ~ basic point of view ~

Factors determining the efficacy of biologics appropriate target(tnfα, IL-6R, CD80/86, CD20?) trough concentration>minimum efiicacious conc trough concentration amount of target molecules dose and intervals of biogics affinity of Fc receptors for clearing antibody anti-biologics antibody adverse drug reaction(infusion reaction, etc) transfer to the site of inflammation

IFX trough level (ug/ml) dose and serum concentration of infliximab 18 16 14 12 10 10mg/kg 6mg/kg TNF CRP IFX Minimum Effective Dose 8 6 4 dose of IFX 3mg/kg ligand concentration (TNF ) clearance of IFX and IC 2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 (w)

Response rate at week 54 (%) RISING: Clinical response at 54 w 100 80 78.8 83.7 87.5 * 3 mg/kg/8w (n=99) 6 mg/kg/8w (n=104) 10 mg/kg/8w (n=104) 60 40 41.4 49.0 53.8 * 41.4 49.0 53.8 * 30.3 39.4 45.2 * 20 0 moderate response good response Takeuchi T, et al. Ann Rheum Dis, 70:1208-15, 11 Low Disease Activity (DAS28-CRP<2.7) Remission (DAS28-CRP<2.3)

Serum IFX level at week 54 Serum IFX level at week 54 in 3, 6, and 10 mg/kg groups (µg/ml) 100 10 35% 2.3 67% 5.5 78% 1 0.4 0.1 <0.1* 40% 24% 11% Anti-IFX antibodies: 27.3% 23.1% 12.5% 3mg/kg (n=86) 6mg/kg (n=91) 10mg/kg (n=95) EULAR no-response: 21.2% 16.3% 12.5%

Numbers of patients (%) Distribution of baseline TNFα concentration in RA patients Circulating levels of TNFα were measured for plasma samples From RA patients using ELISA (RD systems) 40 25% 60% 15% 30 20 10 0 0 1.1 2.2 2.75 3.3 3.85 4.4 4.95 >5.5 (pg/ml) 0.55 1.65 TNF-low TNF-int TNF-high Baseline plasma TNF-alpha level Detection limit 3xlimit Takeuchi et al. Ann Rheum Dis, 70:1208-15, 2011

patients (%) at week 54 Disease activity at 54w in RA patients with different baseline TNFα B 100 80 60 40 p=0.786 p=0.081 p=0.025 * Kendall s rank test secondary failure other targets HDA MDA LDA Remission 20 0 IFX dose n= 3mg 6mg 10mg (28) (22) (37) 3mg 6mg 10mg (57) (66) (57) 3mg 6mg 10mg (14) (16) (10) TNF-low:<0.55 TNF-int:0.55-<1.65 TNF-high:1.65- Takeuchi et al. Ann Rheum Dis, 70:1208-15, 2011

proportion of the patients proportion of the patients Baseline sil-6r levels can predict remission at 24 wk with tocilizumab (8mg/kg, e4w) in KEIO cohort (n=61) DAS28-ESR remission 1.00 0.75 p<0.01 nonremission 100% 75% p<0.01 0.50 50% 85% 0.25 remission 25% 48% 0.00 100 200 300 400 0% sil-6r<72.6 sil-6r<1556 ng/ml sil-6r 72.6 sil-6r 1556 ng/ml The target sil-6r levels at baseline at baseline (ng/ml) are also important for tocilizumab, which is directing against sil-6r. non-remission at week 24 (n=20) remission at week 24 (n=41) Nishina N, et al. Ann Rheum Dis in press, 2014.

What happened in vivo during Tx? - how different among biologics with different targets -

Cytokine Network in Rheumatoid Arthritis Feldmann & Maini Immune System TNF IL-1 IL-6 clinical sign & symptom joint destruction

Change in circulating cytokine levels during MTX treatment in early RA Nishina N, et al Clin Rheum 32:1661, 2013 IL-6 (pg/ml) TNF (pg/ml) 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 baseline during MTX baseline during MTX 4.72 [<0.30-307] 1.04 [<0.30-35.9] 0.87 [<0.55-7.16] 78% suppress 5% suppress 0.83 [<0.55-13] Inhibition of plasma cytokine is IL-6, but not TNF during MTX Tx. median [range] is expressed. red: p<0.001 Wilcoxon log rank

Median (IQR) plasma IL-6 level (pg/ml) RISING study:plasma IL-6 concentration 3 mg/kg therapy (at weeks 0, 2, and 6) 3 mg/kg/8 weeks (from week 14 to 54) 6 mg/kg/8 weeks (from week 14 to 54) 10 mg/kg/8 weeks (from week 14 to 54) 80 70 60 50 40 37 30 20 27 28 10 0 week 0 (n=307) 2.8 3.4 3.2 3.8 week 10 (n=307) 6.6 6.1 5.6 5.4 week 14 (n=307) week 30 (n=287) 2.2 3.0 1.6 1.4 week 50 (n=274) 4.3 2.5 1.5 week 54 (n=272) Takeuchi et al. Ann Rheum Dis, 70:1208-15, 2011

Efficacy of infliximab based on the plasma concentration of IFX and IL-6 levels 81% vs 19% Takeuchi et al. Ann Rheum Dis, 71:1583-85, 2012 High IFX: >1μg/mL Low IL-6: <10pg/mL group 1 group 2 group 3 group 4 HighIFX LowIL-6 HighIFX HighIL-6 LowIFX LowIL-6 LowIFX HighIL-6 number n=134 n=31 n=48 n=58 proportion 49.4% 11.4% 17.7% 21.4% TNF inhibition IL-6 inhibition 100 SDAI (54w) 80 HDA 60 MDA LDA 40 Remission 20 Remission rate is maximized when both TNF and IL-6 are inhibited 0 G1 G2 G3 G4 ALL

Cytokine Network in Rheumatoid Arthritis and the targets by biologics Feldmann & Maini TNF-IL-6 pathway is playing a significant role in majority of RA patients anti-tnf Y sicam-1 Immune System in A patient TNF anti-il-6r? MTX sicam-1 IL-6 IL-6R VEGF Immune System in B patient IFNγ IL-17 X Osteonectin Osteopontin Osteocalcin TNF independent IL-6 or other independent pathways are working in a subset of RA

Inhibition of TNFαvs IL-6receptor signaling Answer:Those responding to blockade against TNFα and IL-6R may be overlapping. RA anti-tnfα anti-tnfα anti-il-6r

Safety of the biologics in RA ~ Japanese Post-Marketing Survey (PMS) ~

Post Marketing Surveillance (PMS) for Biologics in Japan n=5,000 Infliximab July 2003 July 2005 N=13,894 Etanercept March 2005 March 2007 N=12,799 Tocilizumab April 2008 August 2010 N=7,913 Adalimumab June 2008 May 2011 September 2010 Abatacept 0 1 2 3 4 5 6 7 8 9 Time duration(years) Takeuchi T et al. Nature Rev Rheum 6:644-52, 2010

INH prophylaxis (%) number of the TB patients Infliximab PMS: tuberculosis 10 5 0 6 5 0 2 1 30 25 20 13.5 14.5 15 19.5 21.9 25.3 10 5 Caution of prophylactic INH use for the patients at risk 0 register 1-1000 register 1001-2000 register 2001-3000 register 3001-4000 register 4001-5000

Adverse drug reactions in PMS infliximab etanercept tocilizumab adalimumab abatacept (n=5000) (n=13894) (n=7901)& (n=3000)* (3985) Adverse drug reactions (%) 28.0 26.7 38 27.3 15.3 severe ADR (%) 6.2 4.6 7.5 4.1 2.5 severe infections(%) n.d. 2.4 3.6 2.4 0.8 pneumonia 2.16% (n=108) 1.25% (n=174) 1.49% (n=118) 1.20% (n=35) 0.73% (n=29) important infection (%) tuberculosis 0.28% (n=14) 0.07% (n=10) 0.06% (n=4) 0.13% (n=4) 0.03% (n=1) PCP 0.44% (n=22) 0.18% (n=25) 0.18% (n=14) 0.29% (n=9) 0.10% (n=4) interstitial pneumonitis 0.50% (n=25) 0.58% (n=81) 0.44% (n=35) 0.57% (n=17) 0.30% (n=12) ; T Takeuchi et al., ARD 2008 67: 189-194. ; T Koike et al., JR 2009 36: 898-906. &;T Koike, JR 2013, in press, T Koike, ARD 2012 70:2148-52. *; T Koike et al,. MR 2012 22:498-508.

Treatment algorithm aiming for remission in RA MHLW study group Use of biologics in RA PI:Takeuchi MTX+anti-TNF combination: HDA+Poor prognosis factor HOPEFUL-1 study MTX+anti-TNF Early RA (<1-3y) indication for MTX Stop joint destruction within 1-3 years after onset, when aiming for functional remission SAMURAI study RISING study GO-FORTH study GO-MONO stduy ETN-315 study HOPEFUL-1 study J-RAPID study HIKARI study Japanese guideline for MTX:First line for RA with poor prognosis factor yes no Personalization of 1st biologics: dose, intervals, co-medication Efficacy:baseline ligand level, drug level monitoring Safety:infusion reaction & high affinity FcgRIIIB steroids, pts backgrounds and infection remission non-remission remission MTX+/- anti-il-6r anti-tnf MTX+ anti-tnf MTX+/- anti-t cell anti-tnf remission non-remission remission anti-tnf anti-il-6r anti-t cell anti-b cell anti-tnf RECONFIRM study RECONFIRM-2 study RECONFIRM-2J study RISING study JESMR study ENRICH study HARMONY study SAMURAI study SATORI study STREAM study REACTION study ORBIT study Biologics-free can be achieved in 20-40% of RA with low/remission for 6months to 1 year Sustained remission Discontinue Biologics RRR study HONOR study BRIGHT study ORION study