New Therapeutics in Rheumatoid Arthritis Eulji University Seung-cheol Shim M.D., Ph.D. Division of Rheumatology Eulji University Hospital

How to take care of these ?

보건의료 환경의 변화 의료소비자의 서비스 질에 대한 기대 증대 의료소비자의 의식수준, 생활수준향상 건강정보의 대중화로 매스컴, 인터넷을 통해 의료정보 습득용이 건강, 질병에 대한 관심고조 양질의 서비스요구 의료기관에서 환자 건의 사례 및 의료분쟁증가 의료소비자 욕구의 다양화 의료수혜자로써의 의식변화

Treat what?

a systemic disorder characterized predominately by a chronic inflammatory polyarthritis, with frequent progression to joint destruction and disability. Rheumatoid arthritis (RA) is

Eicosonoid pathway

류마티스 질환의 치료제 Radiographic joint damage develops in 75% of patients within the first 2 years of disease Pyramid therapy Dimaryp therapy

류마티스관절염의 진행 Severity (arbitrary units) RA Duration of Disease (years) Kirwan et al, J rheumatol, 2001

Combined use of MTX and a TNF-a inhibitor is among the most potent of treatment regimens, Methotrexate (MTX) remains the first-choice DMARD for the treatment of moderate to severe RA, and is often the anchor drug for combination regimens. Yet clinical trials of early RA show that this combination produces ACR70 responses of only 35% to 45% Needs for developing novel therapy

Cell types and cytokines involved in RA pathogenesis as potential targets for treatment with biologic drugs.

Cytokine targeting

류마티스관절염에서 싸이토카인의 불균형

TNF 란 ?

생물학적제제 TNF-α Inflixmab(Remicade) Etanercept(Enbrel) Adalimumab(Humira) APC TB

Apoptotic Pathways within the Cell

Should be balanced

Comparison of ACR20, ACR50, ACR70, and ACR90 responses.

Change in radiographic scores*

Serious infections observed in 0.5% of patients who received at least 1 dose of study drug*

pegylated form of an antibody fragment (certolizumab pegol [CDP-870]) and human anti–TNF-a monoclonal antibody (CNTO 148). Pharmaceutical companies are developing other TNF-a inhibitors

IL-

Although the results of randomized, placebo-controlled trials have shown anakinra (recombinant human IL-1 receptor antagonist) to be effective in treating RA, the reduction in signs and symptoms is modest compared with TNF-a blockade. Moreover, IL-1 blockade may not be a useful strategy for treating patients who fail therapy with a TNF-a antagonist. Anakinra

developed to create a more potent IL-1 blocker. high-affinity inhibitor of IL-1 consisting of the Fc portion of human IgG1 and the extracellular domains of both IL-1 receptor components. However, the results from a phase 2 trial involving 201 patients who had RA show that weekly subcutaneous administration of IL-1 TRAP produces only modest clinical improvements compared with placebo. IL-1-TRAP

Efficacy of combined biologic agents

Serious adverse events that occurred during the study*

Anakinra in adult-onset Still’s disease who are refractory to corticosteroids, methotrexate, and TNF-a blockade Anakinra in AOSD

Proposed cytokine cascades in AOSD.

IL-

Pleiotropic action of IL-6

Role of interleukin-6 (IL-6) in murine models of arthritis*

recombinant,humanized, monoclonal antibody against the IL-6 receptor (MRA, tocilizumab).

Adverse events observed in at least 3% of patients*

Increase level of cholesterol in the patients on tocilizumab

IL-

is a proinflammatory cytokine produced in rheumatoid synovium by macrophages, fibroblasts, and endothelial cells. essential for the development of natural killer (NK) cells, NK T cells, and intraepithelial lymphocytes, and the proliferation and maintenance of CD8+ memory T cells IL-15

Clinical responses to anti–IL-15 antibody in RA patients* human IgG1 anti–IL-15 monoclonal antibody (HuMax-IL-15, AMG714)

IL-15 binds to the heterotrimeric, high-affinity IL-15 receptor (IL-15R), which consists of the α-subunit (IL- 15R α ), IL-2/IL-15β-subunit, and common γ -chain (γc). IL-15 alone binds with high affinity to IL-15R α ; it shares the common γ c-subunit with IL-2, IL-4, IL-7, IL-9, and IL-21

IL-

A heterodimer consisting of a p40 and p35 subunit, critically involved in the development of Th1 immune responses. RA is often assumed to be a Th1-mediated disease process. IL-12

Signals that Influence Th Cell Differentiation

Currently, a monoclonal antibody to human IL-12 p40 subunit is in early clinical development. Results are available from a phase 1 study using this antibody in patients who had psoriasis, but not yet for studies of RA.

IL-

a member of the IL-1 family of cytokines, was initially discovered based on its interferon-γ–inducing activity, and is produced by macrophages and dendritic cells. IL-18 is a Th1 cytokine, and can induce the synthesis of proinflammatory cytokines and chemokines IL-18

Phylogenetic tree of IL-1 family amino acid sequences.

release of IL-18 is processed by the IL-1 β – converting enzyme (ICE) (caspase-1), then the production of IL-18 and IL-1 may be simultaneously downregulated by an ICE inhibitor. oral ICE development program was terminated because animal toxicology studies found significant drug-related liver abnormalities. IL-1β–converting enzyme (ICE)

Inhibition of leukocyte migration

Chemokine family classification.

natalizumab, a monoclonal antibody to the a4 integrin subunit In multiple sclerosis, one who had Crohn’s disease No RA clinical data Adhesion molecule

approves rituximab for moderate to severe RA Cell targeting

T cell targeting

Anti-CD4, anti-CD5, and anti-CD52 antibodies have failed to produce significant clinical benefits in RA, indicating that merely killing T cells is not the answer for treating this disease.

Too easy……

Woooooooops!!!

IL-10 afforded little or no clinical efficacy Inhibitory T-cell cytokine

T-cell costimulatory blockade

T 임파구의 활성화 물질

is a fusion protein consisting of cytotoxic T- lymphocyte–associated antigen 4 (CTLA4) covalently linked to the Fc region of a human IgG1. Abatacept

Efficacy of Abatacept

AEs and discontinuations at 1 year in the intent-to-treat population*

B-cell targeting

The B cell, the other major arm of the adaptive immune response, has emerged as a therapeutic target success of rituximab therapy for RA Because of

1.was approved in for use in relapsed or refractory, low-grade or follicular, CD20+ B-cell non-Hodgkin’s lymphoma. 3.CD20 is expressed on the cell surface of B cells from the pre–B-cell stage through the mature stage, but is absent on stem cells and plasma cells. 4.eliminates B cells by a mechanism of antibody- dependent cellular cytotoxicity, leading to transient depletion of CD20+ B cells. Rituximab, a chimeric anti-CD20 monoclonal antibody

Median Levels of Peripheral CD19+ B Cells and Median Changes in Levels of Total Rheumatoid Factor during the 24-Week Study Period.

Summary of adverse events

Osteoclast inhibitors

The most potent form of the aminobisphosphonates, protects against bone erosion, although these studies also suggest that the aminobisphosphonates may increase the systemic inflammatory response in animal study. zoledronic acid

small, randomized, placebo-controlled study, two infusions of zoledronic acid Larger trials are required administered 12 weeks apart did not seem to exacerbate the signs and symptoms of RA, while decreasing the mean change in the progression of bone erosions and bone edema over 26 weeks, as measured by MRI

Receptor activator of nuclear factor-κB ligand inhibitors

A schematic representation of osteoclast differentiation

a critical mediator of osteoclast differentiation and bone resorption. RANKL-positive cells line the synovium of patients who have RA. Studies have shown that TNF-a enhances RANKL-induced osteoclast activity in the rheumatoid synovium. Soluble RANKL levels are elevated in patients who have RA, and decrease following anti–TNF-a treatment. receptor activator of nuclear factor-kB/receptor activator of nuclear factorkB ligand (RANK/RANKL)

Researchers hypothesize that inhibition of RANKL protects against structural bone damage in RA. Preliminary studies have found that a fully human anti-RANKL monoclonal antibody (AMG162) inhibits bone loss in postmenopausal women who have osteoporosis; it has not yet been tested in RA.

Small molecules

p38 mitogen-activated protein kinase inhibitors

The p38 mitogen-activated protein kinase (MAPK) signaling cascade in T cells.

p38 mitogen-activated protein kinase (MAP) Since the identification of the p38 as a key signal-transducing molecule in the expression of the TNF more than 10 years ago huge efforts have been made to develop inhibitors of p38 with the intent to modulate unwanted TNF activity

The effectiveness and safety of, is currently being explored in a large phase 2 trial involving patients who have RA. Phase 2 trials in RA using BIRB 796, another inhibitor of p38 MAP kinase, have also begun. An earlier phase 1 trial showed that BIRB 796 was well tolerated by patients who had this disease. SCIOS 469 is another p38 MAP kinase inhibitor under development. VX-702 (Vertex Pharmaceuticals), an oral p38 MAP kinase

Three-hydroxy-3-methylglutaryl-CoA reductase inhibitors

The cholesterol synthesis pathway and protein prenylation

reduce anti-CD3/anti-CD28–stimulated T-cell proliferation and interferon-gamma release from mononuclear cells in synovial fluid and peripheral blood Simvastatin, a HMGCoA reductase inhibitor

randomized, double-blind, placebo-controlled trial of atorvastatin in RA However, the clinical benefits of atorvastatin are modest compared with those of MTX, most other traditional DMARDs, and the TNF-a antagonists.

With potent induction regimens, drug-free holidays may be a realistic goal to mitigate the potential risks associated with the long-term use of immunosuppressive drugs. In the BEST study, a randomized trial comparing four different treatment strategies in early RA, 56% of 120 patients who started treatment with infliximab, 3 mg/kg, in combination with MTX were able to maintain a low disease activity score even after stopping infliximab. These encouraging results will provide impetus for further studies of drug withdrawal in the context of induction therapy for early RA. Summary

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