Advances in Rheumatoid Arthritis (RA) treatment

Advances in RA treatment

魏正宗James C. WEI, MD, PhD.

中山醫學大學附設醫院過敏免疫風濕科

James Cheng-Chung Wei, M.D.,PhD.

Chief, Division of Allergy, Immunology and Rheumatology

Director, Chinese Medicine Clinical Trial CenterAssociate professor, Institute of Medicine, Chung Shan Medical University.

Clinical Trials Experience

2010.Oct. FDA GCP SITE INSPECTION PASSED

2012.Aug. TFDA (Taiwan) GCP SITE INSPECTION PASSED

**World top one enroller in

-Norvatis RHAK study in ankylosing spondylitis.

-Pfizer Etanercept study in non-radiographic axial spondyloarthritis.

*

*Taiwan top one enroller in

-BMS abatacept study in rheumatoid arthritis

-UCB anti-IL6 in rheumatoid arthritis

-MSD Etoricoxib in ankylosing spondylitis

-TWi Biotechnology, Inc. IL-1 receptor antagonist in gouty arthritis

Outline

Pathogenesis of RA Traditional therapies Immune target therapies

Biological agents Small molecules

Summary & Take home message

Outline




RA Overview

Prevalence: 0.4~1% A prototype of autoimmune chronic

inflammatory arthritis. Lifelong, progressive damage to

joints and bone. Market of Humira & Enbrel are top 1

and 2 in the world.

Courtesy of J. Cush, 2002.

類風濕性關節炎的後遺症

類風濕性關節炎的併發症

Overview of Immunity -Cellular -Humoral

-InnateMacrophageMonocyteNeutrophilEosinophil…

-Acquired

B cellT cellDendritic cell…

Pathogenesis of Rheumatoid Arthritis

Outline




非類固醇消炎藥（ NSAID）新的消炎止痛藥 --COX-2 抑制劑 -- 如

meloxicam (Mobic 骨敏捷 ), celecoxib (Celebrex 希樂葆 ), etoricoxib (Arcoxia 萬克適 ) 已證實效果與傳統的消炎藥相當且較不傷胃。

消炎藥併用止痛劑（如 acetamenophen, tramadol, ultracet 及通安）及肌肉鬆弛劑，有很好的加成效果。

免疫調節劑 (DMARDs)1. Hydroxyclhoroquine (Plaquenil, Genuquine)

奎寧、必賴克廔2. Methotrexate (MTX) 滅殺除癌 , 治善錠3. Sulfasalazine (Salazopyrin) 斯樂 , 撒樂4. Leflunomide (Arava, Arheuma) 亞努麻5. Cyclosporin (Neoral) 環孢靈，新體睦

奎寧 Hydroxychloroquine,

必賴克廔 Plaguenil

足夠劑量（一般每天 400 毫克）的奎寧是治療紅斑狼瘡最基本的藥

最沒有副作用的免疫調節劑還有降血脂、抗血栓、增加骨質、降

血糖等附帶好處。

MTX (methotrexate) 滅殺除癌 , 治善錠適應症：風濕性關節炎、牛皮癬或其他自

體免疫相關疾病。亦可治療癌症。每周 4-6 顆 : 使用方式為每周固定一日早餐

後服用 2 顆，晚餐後再服 2 顆，隔日早餐後再服 2 顆。

副作用：口腔炎、白血球減少、血小板缺少、噁心、肝炎

用藥期間須特別監測血液功能。

Sulfasalazine (Salazopyrin)斯樂 , 撒樂

主治：潰瘍性結腸炎，僵直性脊椎炎，類風濕性關節炎。

副作用：頭痛、食慾不振、腹痛、皮膚紅疹、蕁痲疹。多於停藥後可恢復。

早晚各兩顆

Leflunomide (Arheuma) 亞努麻

治療類風濕性關節炎、乾癬關節炎用於 Methotrexate 治療無效，或無法忍

受 Methotrexate 副作用時使用。可能副作用：腹痛、噁心、腹瀉、影

響肝功能、貧血、白血球減少、皮膚疹、高血壓、感染、掉髮。

Outline




免疫標靶療法Immune target therapy

Aiming molecular target

Receptor / Ligand

Signaling pathway

Complex biotechnology

Biological agent生物製劑

Small molecule小分子藥物

Choy EHS, Panayi GS. N Engl J Med. 2001;344:907–916.

免疫標靶療法的原理Inflammatory Cytokine

Normal Interaction Neutralization of Cytokines

Receptor BlockadeActivation of

Anti-inflammatory Pathways

Cytokine Receptor

Soluble Receptor

Monoclonal Antibody

Monoclonal Antibody

Receptor Antagonist

Anti-inflammatoryCytokine

Block signaling

No Signal

No Signal

Inflammatory Signal

Nomenclature -cept : fusion of a receptor -mab : a monoclonal antibody (mAb) -ximab: a chimeric mAb -zumab : a humanized mAb -tinib: tyrosine kinase inhibitors

Biological agents

T cell modulationCTLA4/CD28anti-CD2anti-CD11a

B cell modulationanti-CD20anti-BAFF

Cytokines inhibitionanti-TNFanti-IL6anti-IL1anti-IL12/23anti-RANKL

抗腫瘤壞死因子生物製劑（ TNF抑制劑）

Etanercept （商品名 Enbrel 恩博）是一種由中國倉鼠卵巢細胞組織培養而來的對抗腫瘤壞死因子的融合蛋白，需皮下注射，每周兩次。

Adalimumab （商品名 Humira 復邁）是一種全人的腫瘤壞死因子的單株抗體，皮下注射，每兩周一次。

Golimumab （商品名 Simponi辛普尼），是一種全人的腫瘤壞死因子的單株抗體，皮下注射每四週一次即可。

Etacercept in RA

Adalimumab in RA

目前第一線生物製劑目前健保給付於嚴重頑固型之類風溼

性關節炎、僵直性脊椎炎、乾癬、乾癬關節炎、發炎性大腸疾病。

需事先報健保局審查。 70-90% 的病患可以有明顯的進步。

抗腫瘤壞死因子生物製劑（ TNF抑制劑）

TNF抑制劑副作用發燒、倦怠、頭痛、背痛，輕微上呼吸道感染，打針處發生皮膚疹或細菌感染。

最需要注意是可能造成肺結核的復發或擴散。發生率大約是每 100,000的病人當中 24個，相當於正常人的 3倍左右。 Baseline screening for TB Monitor Quantiferon q6m

B肝復發機率 15-60%。 Close monitor or Preemptive anti-viral agents

長期使用，人體會產生對抗該藥物之抗體。

Outer cellular

Cell membrane

Intra cellular

IL-6

Signal transduction

gp130

[soluble IL-6 receptor (sIL-6R)]

[membrane bound IL-6 receptor (IL-6R)]Tocilizumab

×

Mode of Action of Tocilizumab

Actemra 安挺樂 , IL6R MoAb

疼痛的關節數量

個

週

疼痛關節數逐漸減少 CRP, C反應蛋白

Tocilizumab（ Actemra安挺樂）

是一種 IL-6單株抗體適應症為類風濕性關節炎靜脈輸注，每月一次。可以幫助 60-80% 的患者症狀進步及減少關

節破壞， 30%以上的患者達成疾病緩解，也能改善患者的貧血及疲倦症狀及生活品質。

是目前唯一單一療法與合併 DMARD 或MTX 治療臨床療效相當生物製劑

Th17-- Key player in autoimmune diseases-- IL12, 17, 22, 23

IL-17單株抗體 IL-17 為更專一性造成發炎的細胞激素之ㄧ

為學術研究的熱門主題每四週皮下注射一次目前正進行類風濕性關節炎及僵直

性脊椎炎臨床試驗。

Biological agents




B cell modulation targets

B cell development

Antigen-independent phase Antigen-dependent phase

Activated B cell

Plasmacell

SecretedIgG, IgA,

IgE, or IgM

Mature B cell

Pro-B cell Pre-B cell Immature B cell

Surrogate light chain IgM IgM IgD

IgM, IgD, IgA, or IgE

Adapted from Sell et al. Immunology, Immunopathology, and Immunity. 6th ed. 2001; Roitt et al. Immunology. 6th ed. 2001;Tedder et al. J Immunol 1985;135:973.

Stem cell

CD19CD20

Rituximab(anti-CD20) in RAEdwards et al. Engl J Med. 2004 Jun 17;350(25):2572-81.

• 1000 mg at Day 1&15, q6m

• Better response in RF+ or CCP+ pts

• TNF-IR RA• Combine with MTX

http://www.ncbi.nlm.nih.gov/pubmed?term=Edwards%202004%202572

Rituxtimab (MabTheRa莫須瘤 )

是一種抗 CD20單株抗体之抗 B 細胞療法用來治療淋巴瘤；類風溼性關節炎，也對紅斑

狼瘡、乾燥症、血管炎等有效。使用方法為靜脈輸注，劑量為每次 500-1000 毫

克，間隔 14 天再次輸注 , 共 2 次為一個療程。通常治療效果於靜脈注射後二個月出現，療效

可以持續 6到 9個月。健保給付：限 TNF 抑制劑無效之類風濕性關節

炎。費用約需每年 16-32 萬元。

Potential use of Rituximab• Systemic lupus erythematosus • Idiopathic thrombocytopenic purpura • Multiple sclerosis • Cold agglutinin disease • Autoimmune hemolytic anemia • Antineutrophil cytoplasmic antibody—associated vasculiti

s

• Cryoglobulinemia

• Thrombotic thrombocytopenic purpura • Sjögren's syndrome • IgM mediated neuropathy • Pemphigus vulgaris • Grave's disease• Dermatomyositis • Neuromyelitis optica • Idiopathic membranous nephropathy

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6W7N-4TW528B-2&_user=1565457&_coverDate=01/31/2009&_rdoc=1&_fmt=full&_orig=search&_cdi=6631&_sort=d&_docanchor=&view=c&_acct=C000053757&_version=1&_urlVersion=0&_userid=1565457&md5=5e2a5fc4c084358d36ddfd1391f1fa28%23secx9
















Safety of Rituximab

Infusion-related reactions Anaphylaxis/angioedema More severe

Lymphopenia (40%) Neutropenia (6%) Leukopenia (4%)

Hepatitis B! Sepsis (2%)

Belimumab, BenlystaHuman genomic science, GSK

First biologics for SLE

MoAb of soluble BLyS

Belimumab（商品名 Benlysta）

是一種『 B淋巴球刺激因子單株抗體』(anti-BLyS)

已經在歐美上市，適應症是紅斑狼瘡(SLE)

50年來第一個核可治療紅斑狼瘡的新藥。另兩個類似機轉的藥正進行紅斑狼瘡臨床試驗中。

Biological agents




Co-stimulatory Pathways

APC

T cell

++ –

–

There are several co-stimulatory and co-inhibitory pathways; signals through these pathways can either upregulate or downregulate T-cell activation

CTLA4Ig (Abatacept, Orencia)

Reduction of joint inflammation

0

10

20

30

40

50

60

70

80

90

100

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

ACR 20 ACR 50 ACR 70

Sustained ACR Responses Through 5 Years

Year 0.5 (n) Year 1 (n) Year 1.5 (n) Year 2 (n) Year 2.5 (n) Year 3 (n) Year 3.5 (n) Year 4 (n) Year 4.5 (n) Year 5 (n)

ACR 20 371 373 353 337 311 303 289 288 273 268

ACR 50 373 372 348 338 314 306 289 288 274 270

ACR 70 374 374 350 340 314 309 289 288 278 270

% o

f P

atie

nts

Ach

ievi

ng

A

CR

Res

po

nse

As-observed analysis for patients initiated on ORENCIA® (abatacept) during the double-blind period.

Kremer JM, et al. EULAR 2009. Poster #FRI0263.

Years

84%

61%

40%

Double-blind

82%

54%

32%

Open-label LTE

Abatacept（商品名 Orencia 恩瑞舒）

機轉是透過 T 細胞活化的抑制因子 CTLA4 適應症為類風濕性關節炎第一線生物製劑即使對 TNF 抑制劑無效的 RA 病人，此藥仍有 50% 的有效率

靜脈輸注，每月一次 10 mg/kg

免疫標靶藥物英文藥名台灣商品名作用機轉適應症健保給付

Etanercept（ Enbrel ）

恩博抗腫瘤壞死因子

類風溼性關節炎 , 僵直性脊椎炎 , 乾癬 , 乾癬關節炎 ,幼年型關節炎

有

Adalimumab（ Humira ）

復邁抗腫瘤壞死因子

類風溼性關節炎 , 僵直性脊椎炎 , 乾癬 , 乾癬關節炎 , 潰瘍性大腸炎

有

Golimumab（ Simponi

）

辛普尼抗腫瘤壞死因子

類風溼性關節炎 , 僵直性脊椎炎 , 乾癬 , 乾癬關節炎 ,

有

Rituxtimab（ Mabthera

）

莫須瘤 B 細胞CD20 抗原

類風溼性關節炎有

Denosumab (Prolia)

保骼麗抗RANKL

骨質疏鬆症有

Abatacept（ Orencia ）

恩瑞舒 T 細胞因子 CTLA4


Tocilizumab（ Actemra

）

安挺樂細胞激素IL-6


Systemic review of all biologics efficacy and safety in RA. PLoS One. 2012;7(1):e30275.

Outline

Pathogenesis of immune system Immune target therapies


Take home message

The MAPK, Syk kinase, NF-κB and JAK/STAT intracellular signalling pathways

Bonilla-Hernán M G et al. Rheumatology 2011;50:1542-1550

The majority of cytokine receptors use three JAK combinations

Shown are well-studied cases where JAK usage by each cytokine receptor has been established by genetic and biochemical studies. Exceptions shown are the G-CSFR (*) where it is currently unclear whether both JAK1 and JAK2 are required together. Additionally, the IL-12R (†) and IL-23R (†) require TYK2 but the requirement for JAK2 has not been definitively determined. Receptors that use JAK2 and JAK3, JAK3 alone, TYK2 alone, or JAK3 and TYK2 have not been described.

ORAL Standard – MTX-IR RA

ORAL Standard – MTX-IR RA

ACR 50 response rates over time

Xeljanz (tofacitinib)

FDA approved on Nov. 6, 2012

5 mg twice dailyadults with moderately to

severely active rheumatoid arthritis (RA) who have had an inadequate response to, or who are intolerant of, methotrexate.

Cost: 90% of TNFi biologics

63

『小分子標靶藥物』 Tofacitinib

機轉是抑制細胞內訊息傳遞分子 JAK-3 用於治療類風濕性關節炎 ; 目前也針對中重度

乾癬及僵直性脊椎炎進行臨床試驗中 Apremilast

機轉是抑制細胞內訊息傳遞分子 PDE-4 目前正針對中重度乾癬及僵直性脊椎炎進行臨床試驗

Fostamatinib Syk inhibitors, phase II clinical trial

Biosimilars

Affordability created by entry of biosimilar

Biosimilar -- It’s the trend!

• Biosimilar TuNEX® completes Phase I/II clinical trial in Taiwan, Phase I in Korea ( 2009/10/20 )

• The first biosimilar drug, Inflectra, was approved by the EMA on September 10, 2013.

Outline

Pathogenesis of immune system Immune target therapies



107 ongoing Phase 2 & 3 trial in RA @ clinicaltrial.gov, 2013-Oct-12

Selected potential trials in RA

IL6 MoAb: Sirukumab IL17 MoAb: Secukinumab B cell: BAFF, CD22 JAKi: JNJ, VX-509 (Vertex). Masitinib ,a tyrosine-kinase inhibitor Mesenchymal Stem Cells

Future Trends in RA therapies

Small Molecules Target therapy JAK SYK PGE4 Tyrosine kinase inhibitor, TKI Histamin-4

Future of immune target therapy?

Take home message

Chronic inflammation and immune-related diseases markets arising.

Immune-target therapies is the trend! Questions to be answered

What is the most important target? Personalized medicine

Key to success: Sustained efficacy Long-term safety Availability

Health & Medicine

Advances in Rheumatoid Arthritis (RA) treatment