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Emerging therapeutics for rheumatoid arthritis.

Abstract

Therapeutics options for rheumatoid arthritis (RA) have increased tremendously in the past decade with the introduction of biological agents in 1999. Several different cellular and cytokine targets have been identified, with specific inhibitors now approved to treat RA, including the tumor necrosis factor (TNF) antagonists (adalimumab, etanercept, infliximab), an interleukin 1 (IL1) antagonist (anakinra), an inhibitor of T cell co-stimulation (abatacept), and a selective depleter of B cells (rituximab). As research has progressed, additional promising targets have been identified. Results from RA studies using several new agents have been reported in the last year. Some of these compounds are similar to agents already available, with additional TNF inhibitors (certolizumab pegol, golimumab) and agents targeting CD20 (ocrelizumab, ofatumumab, TRU-015) in development. Other agents are directed toward new cytokine targets, including IL-6 (tocilizumab), and lymphotoxin pathways (briobacept), as well as other B-cell targets, to include BLyS and APRIL (belimumab, atacicept). Additional small molecule therapies have been studied that are directed against intracellular kinases, including JAK-3 and Syk. This article provides a brief update of data from selected clinical trials in RA, highlighting efficacy, and mechanism-based safety concerns.

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In the last decade, the agents available to treat rheumatoid arthritis (RA) have moved from broad immunomodulatory agents to molecules targeting specific cytokines and cells involved in the pathogenesis of RA. Along with the recognition of the importance of early, aggressive definitive disease-modifying antirheumatic drugs (DMARDs) grounded in the use of methotrexate, the introduction of these agents has provided significantly improved outcomes to patients with RA, with a goal of true remission or at least a state of very low disease activity, now possible in large numbers of patients. The rheumatology community has become increasingly comfortable using these agents across the spectrum of disease. While these agents have all proven to be effective, with improvement in symptoms, physical function, quality of life, and the slowing of radiographic progression, a substantial proportion of patients remain that do not receive adequate responses, even with these agents. Fortunately, this unmet need has been recognized, with additional compounds moving forward in development that are aimed at currently available targets [e.g., tumor necrosis factor (TNF) and CD20-expressing cells], as well as toward new targets [e.g., IL-6, lymphotoxin, RANKL (receptor activator of nuclear factor kappa B ligand), and intracellular kinases]. As the development of targeted therapies moves forward, it is increasingly important to understand the mechanisms of action of these compounds, the role of the target in RA disease pathogenesis, as well as in normal host defense.

Targets in RA

There are a number of methods to inhibit cytokines, cellular receptors, and pathways of signal transduction that have been used thus far and are in development (Fig. 1). These have included monoclonal antibodies and soluble receptors to inhibit cytokines, and receptor antagonists, but now also include small molecules that directly interfere with signal transduction pathways and enzymes that convert cytokines from an inactive to an active form. Other methods of interrupting pathways are also under exploration, and new methods to inhibit existing targets are now in the final stages of development.

[FIGURE 1 OMITTED]

TNF Antagonists

Three TNF antagonists are currently approved for the treatment of RA: a fully human monoclonal antibody, adalimumab (ADA); the TNF receptor (p75):FcIgG construct, etanercept (ETN); and the chimeric monoclonal antibody, infliximab (IFX). ADA, ETN, and IFX have similar efficacy demonstrated across a number of clinical trials at all stages of disease. The safety and potential toxicities of these agents have been well described and recognized, with more than 12 years of human treatment experience in RA and other diseases. (1) The major differences in the available compounds have been their methods of delivery and frequency of administration. Two new compounds that also inhibit TNF are presently in the late stages of clinical development, certolizumab pegol (CZP) and golimumab (GLM).

Certolizumab pegol, previously known as CDP870, is a novel construct composed of the Fab' antigen binding domain of a humanized monoclonal anti-TNF antibody, site-specifically bound to two 20-kDa molecules of polyethylene glycol (PEG) that do not interfere with TNF binding properties. PEG is a bulky hydrophilic inert molecule that increases the pharmacokinetic half-life. Another PEG TNF antagonist, pegsunercept [TNFRII (p55)-PEG], was previously developed and proved effective in early RA clinical trials. PEG molecules have also been developed for multiple sclerosis (PEG-Interferon) with a long track record in this disease. Though CZP binds to TNF, it has several properties that are distinct from monoclonal antibodies and soluble receptors. Because the molecule does not have an Fc portion, it does not form immune complexes with TNF, does not activate complement, or initiate complement-dependent cell lysis or antibody-dependent cytotoxicity in vitro, or kill cells with membrane-bound TNF.

Three recent studies in RA were presented at EULAR (European League against Rheumatology) and ACR (American College of Rheumatology) in 2007 using CZP, a monotherapy study (2) in comparison to true placebo and two studies using CZP RAPID-I (3,4) and RAPID-II (5) in combination with methotrexate (MTX) in MTX-inadequate responders. The first is a 24-week monotherapy study of CZP, 400 mg administered subcutaneously every 4 weeks, compared to placebo. (2) In this study, all background DMARDs (including MTX) were discontinued. ACR20 responses were achieved by 46% of patients receiving CZP versus 9% of placebo; ACR50 by 23% with CZP versus 4% placebo; and ACR70 by 6% with CZP versus 0% placebo. In two studies of CZP with MTX, RAPID 1, (3,4) and RAPID 2, (5) RA patients were randomized 2:1 to drug versus placebo, all on background MTX. One group received CZP, 400 mg every 2 weeks. The second group received CZP, 400 mg every 2 weeks for 4 weeks, with dose reduction to 200 mg every 2 weeks. The differences between RAPID 1 and 2 were: numbers of subjects (982 in RAPID1, 619 in RAPID 2); drug formulations (RAPID 1 lyophilized, RAPID 2 liquid). While primary endpoints were slightly different, the efficacy data at 24 weeks was remarkably similar (Table 1). It is notable that the placebo responses in both studies were quite low. Six-month radiographic outcomes demonstrated a reduction in both erosions and overall radiographic progression with both doses of CZP. (4,6)

In terms of safety, there was an increase in serious infections in the groups receiving CZP versus MTX alone. In both studies, cases of tuberculosis were seen, but using an agent that is not known to cause cell lysis, highlighting the importance of screening for latent tuberculosis regardless of the agent used.

Golimumab (GLM) is a fully human monoclonal antibody to TNF. This agent has been studied in RA, (7) psoriatic arthritis. (8) and ankylosing spondylitis. (9) The results from a Phase II study of GLM administered subcutaneously with background MTX have recently been published. (7) Patients were randomized for the first 16 weeks to the following for the primary endpoint determination: placebo, GLM 50 mg every 4 weeks; GLM 50 mg every 2 weeks; GLM 100 mg every 4 weeks; and GLM 100 mg every 2 weeks. At all doses and response levels, higher responses were seen with GLM (Fig. 2). After 16 weeks, patients on placebo received IFX, 3 mg/kg every 8 weeks. Patients on every 2-week injection of GLM had the frequency decreased to every 4 weeks, while patients on every 4 weeks were continued with this dose through 52 weeks. There were additional increases in ACR responses (ACR20/50/70) at the week 52 endpoint in all groups on active GLM.

The data we have seen thus far indicate that these two new TNF antagonists show efficacy in patients with RA. As we have learned from multiple switch studies among currently available TNF antagonists, some patients who do not respond to one agent will respond to another of the same class, and patients who lose response to one agent may also respond to another. The mechanisms remain unclear but may include acquired "resistance," due to neutralizing antibodies, differences in tissue penetration, or altered pharmacokinetics. These new TNF antagonists will add to the available choices for patients. The data thus far do not suggest that these are "better mousetraps" but rather that they are likely to be similarly efficacious. Longer term studies and additional radiographic data are needed.

B-Cell Targets

Several additional compounds are in development that target B cells. Rituximab, a chimeric monoclonal antibody targeting the CD20 molecule expressed on developing B cells, was the first B-cell agent approved for RA. Recent studies in RA have been presented of additional B-cell agents that also bind to CD20, as well as other compounds that affect cytokines important in the later stages of B cell maturation: the B-lymphocyte stimulator (BLyS), also known as B-cell-activating factor of the TNF family (BAFF), and the related molecule A proliferation-inducing ligand (APRIL).

Ocrelizumab is a humanized monoclonal antibody against CD20. In a large Phase II study, 237 patients, all rheumatoid factor (RF)-positive with incomplete responses to MTX, were randomized to one of several doses of ocrelizumab. (10) The primary efficacy endpoints were ACR responses at 24 weeks (Table 2). In this study, there was an expected dose-dependent B-cell depletion. The most frequent adverse events were infusion-associated reactions, in spite of a humanized molecule. Ofatumumab is a fully human anti-CD20 antibody that binds to different epitope on CD20 than rituximab or ocrelizumab. In a Phase II study of about 200 patients, most of whom were RF-positive, two infusions with three different doses or placebo were given with corticosteroid premedication. (11) Efficacy at 24 weeks was seen with all doses when compared to placebo (Table 2). With this molecule, infusion-related events, some significant, were also seen, suggesting that infusion-related events with anti-CD20 therapy are not dependent on the molecule structure, but rather on rapid cell depletion common with all these molecules. TRU015 is another molecule that targets CD20 on the B cells. A small module immunopharmaceutical (SMIP), this drug has also been studied in a Phase II study of patients with RA. (12) In this study, more patients reached ACR 20 responses than with the other compounds but also with higher placebo responses at this level, while few reached an ACR70 (Table 2).

Other molecules that target B cells have also been studied in RA. These agents target the cytokines BLyS and APRIL or their receptors BCMA, BR3/BAFFR, and TACI. (13) Belimumab is a fully human monoclonal antibody that specifically targets BLyS. Atacicept is a fusion construct of the extracellular domain of the receptor TACI, with the Fc portion of IgG that binds both BLyS and APRIL. Another Fc fusion construct has been developed with BR3, briobacept, which only binds BLyS. The results of a Phase II study of belimumab in RA have been reported: 283 patients with RA were randomized to 3 different doses of belimumab or placebo. (14,15) There was a reduction in B cells, and in rheumatoid factors, but the ACR responses were quite low, with an ACR20 achieved in only 29% of all active treatment groups versus 16% of placebo, with more efficacy in RF-positive patients. The results of a small study of atacicept in RA were recently reported, (16) with only a small proportion (32%) reaching an ACR20 at an early time point and more patients achieving this endpoint over time. With both of these compounds there was a reduction in B-cell numbers, reduction in rheumatoid factors, and reductions in total immunoglobulin levels, but efficacy in these studies was not as robust as that seen with compounds targeting CD20.

Additional Cytokine Antagonists

A number of cytokines are targets for RA therapy, including IL-6, IL-15, and RANKL. Tocilizumab is a humanized monoclonal antibody targeting the IL6-receptor, with a number of recent publications demonstrating its efficacy in RA, and is now approved for the treatment of RA in Japan. (17-19) Excellent recent reviews have summarized the mechanism of action of this compound, the roles of IL6 in inflammation, and the efficacy of the drug in RA. (20,21) Other compounds targeting IL6 are also in clinical development.

Another group of cytokines from the lymphotoxin family have been implicated in inflammatory diseases. Lymphotoxins are members of the TNF superfamily encoded in the MHC region with receptors that are also in the same family as TNF receptors. (22-28) There are [alpha] and [beta] forms of lymphotoxin that form soluble or cell bound homotrimers as LT[alpha] ([alpha]3), and a cell-bound heterotrimer [alpha]1[beta]2 found on T cells, B cells, NK cells and follicular B cells. A related cytokine, LIGHT (lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells) is cell-bound or secreted from activated T cells and immature dendritic cells. Both lymphotoxin [alpha]1[beta]2 and LIGHT, but not TNF, bind to the lymphotoxin-[beta] receptor found on dendritic cells, mononuclear cells, and high endothelial venules (Fig. 3). The lymphotoxin-[beta] receptor has been implicated in the organization of lymphoid microarchitecture, forming tertiary lymphoid structures, and in cell trafficking. Knockout mouse models have indicated that these are important in protection from tuberculosis, listeria, and some herpes viruses. Baminercept is a lymphotoxin-[beta] receptor-FcIgG fusion construct that binds cell-bound lymphotoxin [alpha]1[beta]2, and cell-bound or secreted LIGHT. A small study of 31 RA patients was recently reported. (29) Patients received placebo or four doses of baminercept weekly for 4 weeks and were followed for an additional 8 weeks. At 12 weeks, with the highest dose of baminercept, 3 mg/kg, the ACR20/50/70 responses were 67%/50%/33% with baminercept, compared with 30%/0%/0% with placebo. With all doses, 17% to 33% achieved an ACR70 response even with the lowest dose studied (0.1 mg/kg). Additional studies in larger numbers of patients are anticipated. The potential for mechanism-based side effects of infection risk will need to be carefully studied over longer time periods.

[FIGURE 3 OMITTED]

Kinase Inhibitors

The agents discussed above are all biological therapies produced using recombinant technology, and all require injection or infusion for administration. As pathways are better understood, downstream molecules through various cell surface receptors provide additional targets of therapy. A large class of these intracellular molecules are known as kinases and are involved in various aspects of signal transduction, with small molecule orally available inhibitors developed that inhibit these enzymes. Information regarding two different kinases, JAK-3 and Syk, has been recently reported, with additional kinases being studied, including other JAKs and the p38 MAP kinase.

JAK-3 is a cytoplasmic protein tyrosine kinase (involved in signaling through the common gamma chain of several cytokine receptors: IL2, IL4, IL7, IL9, IL15, and IL21) in many hematopoietic cells, including B cells, T cells, and NK cells. Through a series of steps, JAK3 phosphorylates downstream molecules, ultimately resulting in gene transcription. An oral inhibitor of JAK-3 has been used in a study of 254 RA patients randomized to placebo or three doses of the drug (5 mg, 15 mg, or 30 mg) administered twice daily. (30,31) At 6 weeks, the ACR responses to this drug were quite high at all doses and all levels of response. At the highest dose, the ACR20/50/70 were 77/51/28%, compared with 29/6/3% in placebo. Neutropenia, increased HDL (high-density lipoprotein) and LDL (low-density lipoprotein), and reversible increases in creatinine were seen. There were slightly more infections in the treatment groups than those taking placebo, but only short-term results have been reported thus far. Given the association of mutations in JAK-3 with a phenotype of severe, combined immunodeficiency in humans, increased infections, potentially opportunistic, would not be unanticipated with this compound.

Syk is another protein tyrosine kinase that is involved in signaling through multiple receptors which have immuno-receptor tyrosine-based activation motifs. The Fc gamma receptor is one of the important receptors with which Syk is linked. After immunoglobulin binding to its receptor, Syk phosphorylation leads to downstream generation of lipid mediators, cytoskeletal changes, cytokine production, and degranulation of various cells. Potential sites for Syk in RA include: Fc receptors on mast cells, dendritic cells, macrophages, and neutrophils; the B-cell receptor; and potentially sites through osteoclast receptors. (32) A 12-week Phase II study in 189 RA patients on background methotrexate randomized to placebo or 3 doses of the Syk inhibitor, tamatinib fosdium, given orally twice daily (50, 100, 150 mg) has been reported. (33) With this compound there was a dose-dependent increase in efficacy compared with placebo. At 12 weeks with the highest dose studied, 150 mg b.i.d., the ACR20/50/70 were 72/57/40% compared with 38/19/4% in the placebo group. Ten percent of patients experienced neutropenia (21% of patients at the highest dose), and diarrhea and gastrointestinal side effects occurred in between 4% and 20% of the patients in the different treatment groups. Additional small molecules under study in RA include p38 MAP kinase inhibitors, an adenosine A3 receptor antagonist, and oral chemokine inhibitors.

Conclusion

The continued study of agents in RA with new compounds offers tremendous opportunities to further improve patient outcomes with this disease. New molecules that target existing targets such as TNF and CD20 show similar efficacy to existing agents, but without any new toxicities demonstrated thus far. Studies with other agents targeting B cells through the BLyS/APRIL system in RA have not been as successful as agents targeting CD20, suggesting that the means of inhibiting a particular cell population (in this case, B cells) in a particular disease may be of relevance. Newly described cytokine targets such as the lymphotoxin/LIGHT pathway provide additional areas for examination. Recent studies have demonstrated that intracellular kinases are attractive targets in RA, with agents bioavailable orally and with impressive short-term responses. Given the multiple cell types and receptors, however, with which these kinases are associated, and because of their roles in both homeostasis and disease, toxicities may be anticipated and may emerge only as additional patients are studied for longer periods of time.

The current pathway to drug approval, with clinical trials in relatively homogenous patients with severely active disease and study designs that were developed to demonstrate changes at a group level, may not be adequately informative for individual decision-making in clinical practice. The promise of these new therapies, some showing extremely impressive short-term responses, should hasten our consideration of new study designs that will test induction, remission, and maintenance; head-to-head studies of different drug classes and strategies; and studies incorporating patient phenotyping from the earliest stages of clinical development. By anticipating these future needs, we will be best equipped to effect the greatest changes for our patients with RA.

Disclosure Statement

The author has no financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony.

References

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Clifton O. Bingham III, M.D.

Clifton O. Bingham III, M.D., is Associate Director, Johns Hopkins Arthritis Center, and Assistant Professor of Medicine, Divisions of Rheumatology and Allergy and Clinical Immunology, Johns Hopkins University, Baltimore, Maryland.

Correspondence: Clifton O. Bingham III, M.D., 5200 Eastern Avenue, Mason F. Lord Building, Center Tower Room 404, Baltimore, Maryland 21224; clifton.bingham@jhmi.edu.
Table 1 24-month Results from CZP Studies in MTX Inadequate Responders

 RAPID 1 RAPID 2

 Placebo 200 mg 400 mg Placebo 200 mg 400 mg

ACR20 14 59 61 9 57 58
ACR50 8 37 40 3 32 33
ACR70 3 21 21 1 16 11
Erosion 0.7 0.1 -0.3
JSN 0.5 0.1 -0.1

Total Sham 1.2 0.2 -0.4
 score

CZP, certolizumab pegol; MTX, methotrexate.

Table 2 24-Week Efficacy Results from Ocrelizumab, Ofatumumab, and
TRU015 Studies

 Placebo Ocrelizumab
 10 mg 50 mg 200 mg 500 mg 1000 mg
ACR20 22 42 35 45 50 50
ACR50 7 31 13 25 20 28
ACR70 2 8 3 13 8 18
 Placebo Ofatumumab
 300 mg 700 mg 1000 mg
ACR20 15 41 49 46
ACR50 5 19 26 26
ACR70 0 9 4 6
 Placebo TRU015
 800 mg 1600 mg
ACR20 33 65 61
ACR50 9 26 13
ACR70 2 0 4

Figure 2 Golimumab Phase II study in methodrexate (MTX)
incomplete responders: 16-week primary efficacy.

 ACR20 ACR050 ACR70
PBO +MTX 37 6 0
50 q 4wk 60 37 9
50 q 2w 50 24 15
100 q 4 wk 56 29 18
100 q 2 wk 79 32 9

Note: Table made from bar graph.
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Author:Bingham, Clifton O., III
Publication:Bulletin of the NYU Hospital for Joint Diseases
Geographic Code:1USA
Date:Sep 1, 2008
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