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CME

Selective Costimulation Modulators: Addressing Unmet Needs in Rheumatoid Arthritis Management

  • Authors: Larry W. Moreland, MD
  • THIS ACTIVITY HAS EXPIRED
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Target Audience and Goal Statement

This activity is intended for rheumatologists and primary care physicians who specialize in the management and treatment of patients with rheumatoid arthritis.

Author:

Larry W. Moreland, MD

Anna Lois Waters Professor of Medicine, Associate Dean for Clinical Research, University of Alabama at Birmingham.

Disclosure
Consultant: Abbott Laboratories, Almirall, Amgen, Bristol-Myers Squibb Company, Centocor, Eli Lilly, Genzyme, Genentech, Novartis, Pfizer Inc, Regeneron, Wyeth; Grants/Research Support: Abbott Laboratories, Amgen, Bristol-Myers Squibb Company, Centocor, GlaxoSmithKline, Genentech, Regeneron, Wyeth; Honoraria: Abbott Laboratories, Almirall, Amgen, Bristol-Myers Squibb Company, Centocor, Genentech, Genzyme, Novartis, Pfizer Inc, Wyeth; Speakers' Bureau: Amgen, Abbott Laboratories, Wyeth

For complete author disclosure information, please click the "Authors and Disclosures" link at right.

At the conclusion of this activity, the participant should be better able to

  1. Outline the clinical and scientific foundations for which rheumatoid arthritis is defined as an autoimmune disease
  2. Assess recent efficacy and safety data of targeted anti-TNF-α biologic therapies and identify their limitations in the treatment of rheumatoid arthritis
  3. Discuss the advantages of targeting T cells in the treatment of rheumatoid arthritis using the novel costimulation modulators and evaluate recent clinical trial data


Disclosures

In accordance with ACCME Standards for Commercial Support of Continuing Medical Education and the Health Science Center for Continuing Medical Education Disclosure Policy for CME Activities, faculty members have been asked to disclose any relationship they may have with commercial supporters of this CME activity or with companies providing drugs, medical equipment, etc, that may have relevance to the content of their presentations. Such disclosure is intended to provide participants with sufficient information to evaluate whether any given presentation has been influenced by the faculty's relationship(s) or financial interests with said companies.

The following faculty have reported receiving something of value from the commercial supporter(s) of this activity or from a corporate organization whose product(s) may have relevance to the content of their presentations:


Author(s)

  • Larry W. Moreland, MD

    Anna Lois Waters Professor of Medicine, Associate Dean for Clinical Research, University of Alabama at Birmingham

    Disclosures

    Disclosure: Consultant: Abbott Laboratories, Almirall, Amgen, Bristol-Myers Squibb Company, Centocor, Eli Lilly, Genzyme, Genentech, Novartis, Pfizer, Regeneron, Wyeth; Grants/Research Support: Abbott Laboratories, Amgen, Bristol-Myers Squibb Company, Centocor, GlaxoSmithKline, Genentech, Regeneron, Wyeth; Honoraria: Abbott Laboratories, Almirall, Amgen, Bristol-Myers Squibb Company, Centocor, Genentech, Genzyme, Novartis, Pfizer, Wyeth; Speakers Bureau: Amgen, Abbott Laboratories, Wyeth.

    Rituximab and Abatacept are being investigated for therapies for rheumatoid arthritis; they will be reviewed in this presentation.


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CME

Selective Costimulation Modulators: Addressing Unmet Needs in Rheumatoid Arthritis Management

Authors: Larry W. Moreland, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

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Targeted Biologic Therapies for Rheumatoid Arthritis , Presented by Larry W. Moreland, MD

Introduction

  • The goal of this program is to give a review of the targeted biological therapies for rheumatoid arthritis (RA), including the currently available tumor necrosis factor (TNF) and interleukin (IL)-1 therapies as well as a new costimulatory blocker called abatacept. A detailed review of the basic immunology involved in the pathogenesis of RA was included in this program.

  • Targeted Biologic Therapies for Rheumatoid Arthritis

    Slide 1.

    Targeted Biologic Therapies for Rheumatoid Arthritis

    (Enlarge Slide)
  • Rheumatoid arthritis is an immune-mediated, autoimmune disease that affects roughly 2 million people in the United States. Its peak age of onset is usually between 20 to 45 years, and several studies have documented that it results in a decrease of 5 to 10 years in life expectancy, on average. In addition, in data obtained in 2001, the direct annual cost to treat RA in the United States was approximately $10,000 per patient.

  • Overview of RA

    Slide 2.

    Overview of RA

    (Enlarge Slide)

Treating Rheumatoid Arthritis: What Are the Options?

  • The current treatment options for RA are multifocal. First, nonsteroidal anti-inflammatory drugs are commonly used. In addition, we often use corticosteroids, such as low-dose prednisone, which are often used as bridge therapy or to allow treatment for acute flares. In addition, there are a variety of other more potent, so-called disease-modifying drugs including methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, and others. In the past 5 to 6 years, there have been biologic modifiers, or biologic disease-modifying drugs, approved. Moreover, in the past few years, clinicians have learned that the combination of biologic disease-modifying drugs with some of the synthetic disease-modifying drugs has added benefit and may provide more complete response than either synthetic disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs when used as monotherapy.

  • Current Treatment Options for RA

    Slide 3.

    Current Treatment Options for RA

    (Enlarge Slide)
  • At the present time, there are 4 biologic response modifiers that have been approved by the US Food and Drug Administration (FDA) for the treatment of RA. Three of these inhibit TNF and are thus called TNF inhibitors. These include adalimumab, or Humira; etanercept, or Enbrel; and infliximab, or Remicade. In addition, one biologic response modifier that inhibits IL-1 is called anakinra, or Kineret.

  • Current Biologic Therapies for Treatment of RA

    Slide 4.

    Current Biologic Therapies for Treatment of RA

    (Enlarge Slide)
  • The biologic therapies that have been approved have different potential structures, half-lives, and routes of administration. For example, infliximab is a chimeric, monoclonal antibody aimed at targeting TNF. Adalimumab is a human IgG anti-TNF monoclonal antibody, and etanercept is a soluble TNF receptor linked to the IgG Fc receptor fusion protein. Finally, anakinra is a recombinant IL-1 receptor antagonist. These agents can be given intravenously (IV), in the case of infliximab, or subcutaneously (SC), in the cases of etanercept, adalimumab, and anakinra.

  • Biologic Therapies for RA

    Slide 5.

    Biologic Therapies for RA

    (Enlarge Slide)

Pathophysiology of Rheumatoid Arthritis: The Role of T Cells

  • For reasons that are unclear â€' the etiology of RA is still not understood â€' the synovial tissue, which is normally 1 to 2 layers thick in patients with normal joints, starts to grow; with biopsy of this tissue, one can see a variety of different cells. First, one can see T cells, B cells, or neutrophils and a variety of other inflammatory mediators. With time, these inflammatory cells secrete a variety of different mediators such as TNF, IL-1, and IL-6 that result in the degradation of the underlying cartilage and bone.

  • RA Pathophysiology

    Slide 6.

    RA Pathophysiology

    (Enlarge Slide)
  • It has been learned in the last decade or so that the T cells may play a pivotal role in the immunopathology of RA. First, one can detect the localization of T cells within the synovial tissue. It is believed that these T cells play an active role in causing the other cells to become activated and proinflammatory. According to this view, one can find activated B cells and T cells, macrophages, neutrophils, and fibroblast-like synoviocytes. Each of these cells may be contributing to the pathophysiology seen in RA through underlying destruction of cartilage and bone.

  • Immunopathology of RA

    Slide 7.

    Immunopathology of RA

    (Enlarge Slide)
  • This section will now review in more basic terms some of the data that underlie the known immunologic basis of RA.

  • Immunologic Basis of RA

    Slide 8.

    Immunologic Basis of RA

    (Enlarge Slide)
  • The current model for the etiopathogenesis of RA is illustrated on this slide. First, in the context of a genetically susceptible individual, the immune system is activated by an unknown antigen; antigen-presenting cells take this antigen to the T cells and stimulate them. The T cells then proliferate, secrete a variety of proinflammatory cytokines, and migrate to the synovial tissue, resulting in tissue proliferation and growth and the creation of what is called the pannus. This is made up of a variety of different cells, including T and B cells as well as macrophages. These cells then secrete a variety of proinflammatory mediators, such as TNF, IL-1, and other cytokines such as IL-6, resulting in the underlying joint damage and destruction that are seen as the signature for patients with long-standing RA.

  • Model for the Etiology of RA

    Slide 9.

    Model for the Etiology of RA

    (Enlarge Slide)
  • T cells are key initiators of the immune response involved in the pathogenesis of RA. Antigen-presenting cells take up the antigen or antigens that are responsible for the pathology seen in RA, and in the context of the major histocompatibility complex (MHC) molecules deliver this antigen to T cells, which then become activated. The T cell receptor binds to the MHC/antigen complex and activates these T cells. The T cells then migrate to the synovial tissue and orchestrate the immune responses seen in the clinical picture of RA.

  • T Cells Are Key Initiators of Immune Responses

    Slide 10.

    T Cells Are Key Initiators of Immune Responses

    (Enlarge Slide)

Pathophysiology of Rheumatoid Arthritis: The Role of T Cells (cont'd)

  • There is a tremendous amount of information available from work done over the last decade or more with the association of MHC Class II alleles with RA. Specifically, in certain ethnic groups -- Caucasians in particular -- 80% or more of patients carry the MHC Class II risk alleles. In particular, they may contain the so-called shared epitope, the RA epitope called QKRAA. More aggressive disease and a worse outcome have been associated with patients with this particular shared epitope.

  • Association of MHC Class II Alleles With RA

    Slide 11.

    Association of MHC Class II Alleles With RA

    (Enlarge Slide)
  • Once the T cells become activated through a variety of mechanisms including costimulatory molecules, which will be covered shortly, the T cells secrete a variety of different cytokines such as IL-2, which results in a further perpetuation of T cells. This results in the production of more T cells, which produce effective cytokines or chemokines, which, in the case of an infectious process, destroy the infection. However, in a case of RA, these cytokines or chemokines cause a chronic immune-mediated inflammatory response that results in the clinical picture seen as RA.

  • Activated T Cells Proliferate and Differentiate

    Slide 12.

    Activated T Cells Proliferate and Differentiate

    (Enlarge Slide)
  • As covered previously, it is believed that T cells are a key initiator of the RA pathogenesis. The left side of this slide illustrates the interaction between dendritic cells and T cells in the lymph node, which then can activate further T cells and cause proliferation of the T cell population as well as activate B cells. These cells migrate to the synovial tissue, where there is further activation of T cells, perpetuation of additional T cells, and activation of B cells, which can then produce autoantibodies such as rheumatoid factor and anticyclic citrullinated peptide (CCP) antibodies. In addition, the T cells activate fibroblasts and macrophages, which then secrete a variety of different proinflammatory cytokines such as TNF-alpha, IL-1, and other mediators including matrix metalloproteinases, prostaglandins, and nitric oxide (NO).

  • T Cells Are Key Initiators of RA Pathogenesis

    Slide 13.

    T Cells Are Key Initiators of RA Pathogenesis

    (Enlarge Slide)
  • This scheme for the pathogenesis of RA represents a reasonable objective for biologically targeted therapies. As illustrated on the right side of this slide, the current TNF inhibitors adalimumab, etanercept, and infliximab inhibit the production or the activity of TNF; anakinra inhibits IL-1. The next part of this program will address the role that T cells play and possible ways to inhibit T cell function and provide an effective therapy for RA.

  • Targets of Biologic Therapies for RA

    Slide 14.

    Targets of Biologic Therapies for RA

    (Enlarge Slide)

Clinical Studies: Adalimumab and Etanercept

  • Before focusing on the specific new therapy, the costimulation molecule, this section will review the clinical data for the currently available biologic therapies.

  • Review of Clinical Data for Current Biologic Therapies

    Slide 15.

    Review of Clinical Data for Current Biologic Therapies

    (Enlarge Slide)
  • The first of these biologic therapies is adalimumab. This is a study that was published in 2004 in Arthritis and Rheumatism called the Anti-TNF Research Study Program of the Monoclonal Antibody D2E7 in Rheumatoid Arthritis (ARMADA) trial, in which patients who were taking background methotrexate therapy were randomized to placebo or 2 different doses of SC adalimumab 20 mg every week or 40 mg SC every 2 weeks. What is seen here is that an American College of Rheumatology 20% (ACR20) response was achieved by 59% in the 40-mg group every 2 weeks and by 55% in the 20-mg group every week. In addition, 42% and 38% attained an ACR50 response in the 40-mg group every 2 weeks and in the 20-mg group every week, respectively; and 23% and 21% attained an ACR70 response in the 40-mg group every 2 weeks and in the 20-mg group every week, respectively. These results are striking compared with the left side of the slide, which shows the responses seen in those who received methotrexate plus placebo. This was one of the pivotal studies that resulted in the FDA approval of adalimumab for the treatment of RA.

  • Adalimumab + MTX in Active RA: ACR Responses at 52 Weeks

    Slide 16.

    Adalimumab + MTX in Active RA: ACR Responses at 52 Weeks

    (Enlarge Slide)
  • These are the results of the X-ray data from this same study, in which patients were randomized to receive placebo or adalimumab at 2 different doses. Patients who were randomized to receive just methotrexate plus placebo had a worsening of their X-ray changes as measured by the Sharp score. Patients who received the highest doses of adalimumab, 40 mg every 2 weeks (shown in the last line on the graph), basically experienced a significant reduction or halting of the progression of the disease. This is consistent with data seen with the other TNF inhibitors such as etanercept and infliximab.

  • Adalimumab + MTX in Active RA: Mean Change From Baseline in Total Sharp Score

    Slide 17.

    Adalimumab + MTX in Active RA: Mean Change From Baseline in Total Sharp Score

    (Enlarge Slide)
  • This is a recent study published in the Lancet called the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO). This study, which was carried out in Europe and Australia, looked at the combination of a TNF inhibitor plus methotrexate. Patients who were methotrexate naive or had not taken methotrexate in the past few months were randomized to receive either methotrexate alone, methotrexate plus etanercept, or etanercept alone. The primary results to highlight in this study are those on the far right of this slide, which show that 85% of the patients who received the combination of etanercept plus methotrexate had an ACR20 response, 69% had an ACR50 response, and 43% had an ACR70 response.

  • Etanercept in Active RA (TEMPO Trial): ACR Responses at 52 Weeks

    Slide 18.

    Etanercept in Active RA (TEMPO Trial): ACR Responses at 52 Weeks

    (Enlarge Slide)
  • In addition to the clinical benefit that has been found with etanercept in terms of improved signs and symptoms, one of the major advantages seen with the Lancet study is the decrease in radiographic damage. Patients who received just methotrexate as monotherapy continued to have radiographic damage, as illustrated by a 2.8 mean worsening of Sharp scores. However, in patients who received a combination of etanercept plus methotrexate there was a negative score of 0.5 in patients at week 52, suggesting that there was a marked decrease or inhibition of radiographic progression in patients who received this combination.

  • Etanercept in Active RA (TEMPO Trial): Mean Change From Baseline in Total Sharp Score

    Slide 19.

    Etanercept in Active RA (TEMPO Trial): Mean Change From Baseline in Total Sharp Score

    (Enlarge Slide)

Clinical Studies: Infliximab and Anakinra

  • Finally, this section will review the infliximab studies. The Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) was the pivotal study for which infliximab was approved by the FDA; the most recent data -- the 102-week results -- were published by Maini and colleagues in Arthritis and Rheumatism in 2004. The previous data from the 30-week and the 52-week results were published in the Lancet and the New England Journal of Medicine in 1999 and 2000, respectively. The study by Maini and colleagues was the follow-up of patients who were originally randomized to the ATTRACT trial. This slide illustrates that there was continued sustained response to infliximab at 102 weeks in patients who were receiving various doses of infliximab while taking background methotrexate.

  • Infliximab in Active RA (ATTRACT Trial): ACR Responses at 102 Weeks

    Slide 20.

    Infliximab in Active RA (ATTRACT Trial): ACR Responses at 102 Weeks

    (Enlarge Slide)
  • This slide presents the radiographic data from this study, showing again that there was a marked decrease in the rate of progression in patients who received methotrexate plus infliximab compared with those who received only methotrexate plus placebo infusions.

  • Infliximab in Active RA (ATTRACT Trial): Mean Change From Baseline in Total Sharp Score

    Slide 21.

    Infliximab in Active RA (ATTRACT Trial): Mean Change From Baseline in Total Sharp Score

    (Enlarge Slide)
  • In general, the TNF inhibitors have been shown to be fairly safe in clinical trials. However, some issues have developed at the postmarketing stage that clinicians need to be aware of as they see patients and advise them about these drugs. Infliximab is an agent that is given IV, and infusion reactions have been reported. Although they have been rare, serious, life-threatening anaphylactic reactions may occur. Injection-site reactions, again, are not a serious problem, but they are commonly reported with adalimumab and etanercept; they usually do not result in the need to discontinue the use of the drug. Common infectious complications, such as upper respiratory tract infections, sinus congestion, or infections, have been reported and are easily managed in those patients; however, there have been data published with postmarketing information that opportunistic infections and tuberculosis can be an issue with the TNF inhibitors. It is thus important to carefully screen patients by performing a purified protein derivative (PPD) skin test and chest X-ray prior to starting these drugs to make sure there is no active infection. Less common are drug-induced lupus-like syndrome, demyelinating disorders, and malignancies. These issues continue to be an area of research and need to be resolved with appropriate databases to determine if they are problems that may be part of the RA clinical spectrum or if the TNF inhibitors actually increase the risk of these side effects. Finally, some of these agents may be associated with the appearance of human antichimeric antibodies (HACAs), antibodies that develop against the TNF protein that has been administered. To date, there is very little data published about the clinical significance of these antibodies. There are several issues associated with how these agents are measured in clinical trials and in clinical practice.

  • TNF Inhibitors: Safety

    Slide 22.

    TNF Inhibitors: Safety

    (Enlarge Slide)
  • The final approved biologic response modifier to be reviewed in this section is the IL-1 inhibitor anakinra. This study, published in Arthritis and Rheumatism in 2002, was one of the pivotal studies in which patients taking background methotrexate were randomized to receive a variety of different doses of anakinra, from a low dose of 0.04 mg/kg up to a dose of 2 mg/kg. As seen on this slide, the ACR20, ACR50, and ACR70 responses were statistically superior to the responses seen with placebo. The highest response was seen in the 1-mg/kg dose group, in which 42% of the patients had an ACR20 response, 24% had an ACR50 response, and 10% had an ACR70 response.

  • Anakinra + MTX in Active RA: ACR Responses at 24 Weeks

    Slide 23.

    Anakinra + MTX in Active RA: ACR Responses at 24 Weeks

    (Enlarge Slide)
  • The safety profile with anakinra has been generally positive. Some patients develop injection site reactions. Infectious complications, although not severe, have been reported, including upper respiratory tract infections. More recently, a study published in Arthritis and Rheumatism by Genovese and colleagues has shown that anakinra, when used in combination with etanercept, increases the risk for serious adverse events, and the combination of anakinra with a TNF inhibitor is no longer indicated based on the safety profile as well as data demonstrating that the combination was not more effective in suppressing the disease activity. Although not a major issue, neutropenia has been reported in the clinical trials, especially in combination with the TNF inhibitors. This has been reversible when the TNF inhibitor and the IL-1 blockers were stopped. As with the TNF inhibitors, there is also the potential of developing antibodies to anakinra, but again, these are felt not to be of major clinical significance. Of course, much more work needs to be done in order to understand the true significance and clinical consequences of antibodies to all of the biologic response modifiers.

  • Anakinra Therapy: Safety

    Slide 24.

    Anakinra Therapy: Safety

    (Enlarge Slide)
  • In summary, the currently available targeted biologic therapies are directed at proinflammatory cytokines such as TNF-alpha and IL-1. They have been found to be effective in many patients with RA not only in reducing the signs and symptoms but also in preventing or halting joint progression and improving the activities of daily living and quality of life. However, not all patients with RA who have been treated with these agents have a response; 30% to 40% of patients who receive anti-TNF therapies do not have clinical responses as measured by ACR20 criteria. In addition, many patients who receive these agents have initial positive responses but do not maintain them over time. Moreover, few patients are in what would be called true remission; there remains active disease in many patients who have had a good response to these agents. There is a need for new therapies that are targeted at the immune-mediated inflammatory response seen in RA.

  • Targeted Biologic Therapies: Summary

    Slide 25.

    Targeted Biologic Therapies: Summary

    (Enlarge Slide)

Costimulation Modulators: Targeting the T Cell

  • The next section will cover a new targeted therapy known as costimulation modulators. As previously mentioned, T cells are important in the immunopathogenesis of RA. What follows is a review of current data that support selectively targeting the costimulation molecules.

  • Emerging Strategy: Targeting T Cells

    Slide 26.

    Emerging Strategy: Targeting T Cells

    (Enlarge Slide)
  • The rationale for T cell–targeted therapy is that T cells are important in the immune process, as illustrated by points made earlier in this presentation. There is a clear genetic link with MHC Class II genes. T cells are present in the synovium; they express activation markers, suggesting that they are not just present but activated. They secrete a variety of proinflammatory cytokines such as IL-2, interferon, and TNF, among others. Moreover, they stimulate the macrophages to produce the same cytokines that are driving the immune-mediated inflammatory response seen in this disease. In addition, arthritis can be transferred in some animals by moving activated T cells from one animal to an animal that does not have RA. Finally, RA is a typical autoimmune disease; it is very similar to many of the other autoimmune diseases in which T cells have been shown to be important in their pathogeneses.

  • Rationale for T Cell–Targeted Therapy in RA

    Slide 27.

    Rationale for T Cell–Targeted Therapy in RA

    (Enlarge Slide)
  • To summarize again, it is currently thought that, based on current basic scientific data analysis that will be presented in the next few slides and on some clinical data, is that T cells are important in the perpetuation of the synovium inflammation. It is shown here that T cells are activating macrophages and B cells and also stimulating fibroblast-like cells to produce not only rheumatoid factor and other autoantibodies but proinflammatory cytokines; matrix metalloproteinases such as elastase and cathepsin, which destroy underlying cartilage and bone; and prostaglandins and NO, to name just a few of the proinflammatory mediators. This leads to the synovium inflammation seen clinically as swelling of the joints, which results in joint damage over several months or years.

  • Central Role of Effector T Cells in RA Pathogenesis

    Slide 28.

    Central Role of Effector T Cells in RA Pathogenesis

    (Enlarge Slide)

T Cell Activation

  • This slide will review the interaction between T cells and antigen-presenting cells to give a simple view of this costimulatory pathway, or the so-called second signal. The left side of this slide has already been covered in this presentation, but it will set the stage to illustrate the second signal and costimulatory pathway. T cells become involved in this process by being activated by antigen-presenting cells, which present antigens in the context of the MHC Class II. In that context, the T cell receptor responds to specific MHC Class II molecules and the antigen, and the T cell becomes activated. However, in order for the T cells to become fully activated and have an immune response that can really result in ameliorating the infectious process or making the autoimmune disease or inflammatory response worse, they become activated through a process called costimulatory activation, or the second signal. On the right side of this slide, the expression of CD28 on T cells and CD80/CD86 on antigen-presenting cells is illustrated. The result of this activation of the second signal is that the T cells become more activated; more T cells are produced, causing them to secrete a variety of mediators and that results in a more robust immune response.

  • T Cell Activation Requires 2 Signals

    Slide 29.

    T Cell Activation Requires 2 Signals

    (Enlarge Slide)
  • The consequences of this second signal or costimulation are summarized here. First, T cells are activated and differentiated, and more are produced. Second, it prevents T cell anergy; and third, T cell migration to the periphery occurs; it alters adhesion molecule expression, adherence to endothelial cells, and migration into tissues from the blood vessels. These activated T cells are taken from the peripheral circulation to the synovial tissue, where they are able to continue this activation process and cause the synovial tissue proliferation.

  • Consequences of Costimulation

    Slide 30.

    Consequences of Costimulation

    (Enlarge Slide)
  • This slide is somewhat complex, but it illustrates several points. What will be reviewed in the next several slides is one particular second signal or costimulatory pathway, the CD28-CD80/CD86. As illustrated here, there are multiple interactions between T cells and the antigen-presenting cells, which involve costimulatory pathways. Some of these are positive, as illustrated in the interaction of MHC plus T cell receptors. This causes a positive interaction in which the T cells are more activated. The CD80/CD86 and CD28 pathways function in the same way. However, there are several pathways involved that tend to turn down the T cell response; an example is the CD80/CD86 in the context of cytotoxic T lymphocyte–antigen 4 (CTLA4). This is a complex system, so this section will concentrate primarily on the interactions at the CD80/86 and CD28 and CTLA4 pathways.

  • Multiple Costimulation Pathways Modulate T Cell Activity

    Slide 31.

    Multiple Costimulation Pathways Modulate T Cell Activity

    (Enlarge Slide)
  • To summarize what was briefly reviewed in the previous slide, the CTLA4 pathway, the costimulatory pathway, attenuates or downregulates T cell activation. CTLA4 is expressed by T cells early after activation; there is shared homology to CD28 within the CD80/CD86 binding region. CTLA4 binds CD80/86 500 to 2500 times more avidly than CD28 does. Thus, this has become an important area of investigation and has been shown to be important for T cell regulation. It is felt that the CTLA4 serves as a natural inhibitor -- that once T cells become activated by whatever disease process is turning them on, the body has a natural process to turn down the T cell pathways so that it does not get too much out of control.

  • CTLA4 Attenuates T Cell Activation

    Slide 32.

    CTLA4 Attenuates T Cell Activation

    (Enlarge Slide)
  • The control of T cell activation prevents stimulation of T cells that may lead to chronic activation. This will inhibit production of cytokines such as TNF, IL-1, and interferon gamma. In addition, if activation of T cells is blocked after they have been activated by a CTLA4 pathway, there will be a decrease in cell survival, proliferation, and turnover. Thus, there will be an attenuation in the immune response, dampening it so that the T cell activation that has taken place will not get out of control but will be attenuated or brought to an end.

  • Control of T Cell Activation

    Slide 33.

    Control of T Cell Activation

    (Enlarge Slide)

Costimulation Modulators: Abatacept

  • To illustrate the costimulatory pathway and how it has evolved into a new biologic response modifier, a novel, selective costimulation molecule called abatacept will now be reviewed.

  • Abatacept: A Novel, Selective Costimulation Modulator

    Slide 34.

    Abatacept: A Novel, Selective Costimulation Modulator

    (Enlarge Slide)
  • Abatacept is a human immunoglobulin receptor fusion protein made up of the extracellular domain part of CTLA4 plus the heavy chain constant region of an IgG1 molecule.

  • A Human Immunoglobin Receptor Fusion Protein

    Slide 35.

    A Human Immunoglobin Receptor Fusion Protein

    (Enlarge Slide)
  • Abatacept selectively modulates T cell activation by blocking the interaction between CD80/CD86 and CD28. Shown on this slide on the left is the T cell response with antigen-presenting cells without abatacept present, where there is full activation of T cells. On the right it can be seen that abatacept binds selectively to CD80/CD86, preventing the costimulatory pathway that binds CD28 to CD80/CD86.

  • Abatacept Selectively Modulates T Cell Activation

    Slide 36.

    Abatacept Selectively Modulates T Cell Activation

    (Enlarge Slide)
  • This slide will clarify the differences between abatacept and CTLA4. As seen on the right side of this slide, CTLA4 is a naturally occurring cell-surface protein. It naturally attenuates activated T cells, competes for CD28 binding to CD80/86 on antigen-presenting cells, and naturally sends a negative signal to T cells. It is an important molecule for the regulation of T cell-mediated immune responses. In order to help this process along, the biologic response modifier called abatacept, a CTLA4Ig fusion protein, has been formed. It is a recombinant human fusion protein that is given to attenuate the activation of native T cells. It also competes for CD28 binding to CD80/86 on antigen-presenting cells, prevents positive costimulation signal to T cells, and has no negative signal to the T cells. It may attenuate T cell–mediated autoimmunity, which will be illustrated in subsequent slides with a pivotal phase 2 study in patients with RA.

  • Abatacept and CTLA4

    Slide 37.

    Abatacept and CTLA4

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  • This is a slide that was seen earlier, and it illustrates how abatacept is working in RA to attenuate the immune-mediated inflammatory response. As seen here at the bottom left, antigen-presenting cells in the context of MHC molecules deliver an antigen to T cells, and the costimulatory molecules are involved where T cells become activated. Abatacept blocks that costimulatory pathway; this will prevent the activation or proliferation of T cells and the downstream effects that occur with B cell activation, rheumatoid factor production, activation of macrophages and monocytes, and production of other proinflammatory molecules such as TNF and IL-1.

  • Upstream Action of Abatacept May Decrease Multiple Inflammatory Events

    Slide 38.

    Upstream Action of Abatacept May Decrease Multiple Inflammatory Events

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Abatacept: Clinical Data

  • Several clinical trials have been performed with abatacept, some in psoriatic arthritis. More recently, a phase 1 study in patients with RA showed the most effective dose that should be used. Based on these phase 1 studies, a pivotal phase 2 study has been carried out and published in the New England Journal of Medicine in 2003. This is the abatacept-methotrexate clinical trial, a double-blind, randomized, placebo-controlled efficacy and safety trial in which 339 patients with refractory RA were enrolled. Patients had to be taking methotrexate and have had an inadequate response to it; in other words, they had to still have active disease. They were then randomized to receive either abatacept or placebo for a 6-month trial. If they were on other disease-modifying drugs, such as hydroxychloroquine or sulfasalazine, these were discontinued prior to entry into this clinical trial.

  • Abatacept-MTX Clinical Trial

    Slide 39.

    Abatacept-MTX Clinical Trial

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  • The clinical responses as measured by ACR criteria are illustrated here for the patients who were involved in the abatacept-methotrexate combined study. Patients who had received abatacept 10 mg/kg plus methotrexate had a 60% ACR20 response criteria as opposed to those who received a lower dose (2 mg/kg), vs placebo, where 35% of patients who received placebo had an ACR20 response. The clinical benefit occurred as early as day 30, with the maximum benefit appearing on day 60, and this was sustained to day 180 of therapy.

  • Abatacept-MTX Clinical Trial: ACR20 Response Over 6 Months

    Slide 40.

    Abatacept-MTX Clinical Trial: ACR20 Response Over 6 Months

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  • This graph presents the data a little differently, showing the ACR20 responses in the highest dose of abatacept to be 60% ACR20, 37% ACR50, and 17% ACR70, compared with 35, 12, and 2 placebo responses, respectively.

  • Abatacept-MTX Clinical Trial: ACR Responses at 6 Months

    Slide 41.

    Abatacept-MTX Clinical Trial: ACR Responses at 6 Months

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  • In addition to improving the signs and symptoms as measured by the ACR20, ACR50, and ACR70 responses, patients were evaluated with the 36-Item Short-Form Health Survey (SF-36) questionnaire to determine whether it improved their quality of life, and as illustrated here, the patients who received the highest dose -- or 10 mg/kg -- of abatacept plus methotrexate all had significant improvements in their SF-36 domains, from physical function to mental function.

  • Abatacept-MTX Clinical Trial: Health-Related QOL at 6 Months

    Slide 42.

    Abatacept-MTX Clinical Trial: Health-Related QOL at 6 Months

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  • More recent abatacept data looked at whether patients who entered into this clinical trial were in remission, with remission rates defined as a disease activity score (DAS28) of less than 2.6 (on this slide, this was attained at day 180). The patients in the group that was treated with 10 mg/kg of abatacept plus methotrexate had a statistically significantly higher rate of remission than those who received just methotrexate plus placebo. This data was presented at the recent European League Against Rheumatism meeting in 2004.

  • Abatacept-MTX Clinical Trial: Increased Remission Rate

    Slide 43.

    Abatacept-MTX Clinical Trial: Increased Remission Rate

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Abatacept: A Well-Tolerated and Effective Treatment

  • The data from the pivotal phase 2 study was also analyzed to look at any potential adverse events. Thus far, no significant adverse events have been seen more commonly in the abatacept group than in the placebo group. This slide looks at the most common adverse events reported in the pivotal phase 2 study; these included headache, upper respiratory tract infection, musculoskeletal pain, nausea, vomiting, fatigue, cough, diarrhea, and pharyngitis. In all cases, there was no difference between the placebo and abatacept groups.

  • Abatacept-MTX Clinical Trial: Adverse Events at 6 Months

    Slide 44.

    Abatacept-MTX Clinical Trial: Adverse Events at 6 Months

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  • This slide looks at the reasons why patients withdrew from this study. As seen here, the primary reason patients left was lack of efficacy, and this was more common in the placebo-treated group than in the abatacept groups. Other reasons for withdrawal, such as adverse events, were uncommon, and there was no difference between the abatacept groups and the placebo group.

  • Abatacept-MTX Clinical Trial: Reasons for Trial Withdrawal

    Slide 45.

    Abatacept-MTX Clinical Trial: Reasons for Trial Withdrawal

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  • The current development plan for abatacept is illustrated on this slide, where it can be seen that 3 pivotal studies are being completed at this time. These are the Abatacept in Inadequate responders to MTX (AIM) study, the Abatacept Trial in Treatment of Anti-TNF INadequate responders (ATTAIN), and the Abatacept Study of Safety in Use with other RA thErapies (ASSURE). The objective of each of these studies is to determine the clinical benefit as well as the safety profile in different patient populations. The AIM study is looking at the safety and efficacy of the combination of abatacept plus methotrexate with 12 months of therapy. The ATTAIN study is looking at a different patient population, in which patients who have been previously treated with anti-TNF therapies but had an inadequate response are now being randomized to receive abatacept or placebo for 6 months. Finally, in an effort to get a handle on the safety of coadministration of abatacept with other disease-modifying drugs and/or biologic combinations, the ASSURE study is looking at several hundred patients who will receive abatacept plus different disease-modifying drugs other than methotrexate or anti-TNF therapy. Radiographic progression will be measured in the AIM and ATTAIN studies to get a picture of the results of inhibition of radiographic damage with abatacept.

  • Abatacept Phase III Clinical Development in Treatment of RA

    Slide 46.

    Abatacept Phase III Clinical Development in Treatment of RA

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  • Targeting costimulatory activation of T cells is an attractive approach to the treatment of RA. A phase 1 and a phase 2 study have been completed, illustrating that blocking the costimulatory pathway CD80/86 or CD28 can be effective and safe in patients with RA. Abatacept is a novel, selective costimulatory modulator that selects just one costimulatory pathway and leaves the others largely intact. In the studies presented to date, abatacept has brought about significant improvement in clinical responses as measured by the ACR response criteria, quality of life, and remission rate. Studies completed to date have also found abatacept to be well tolerated.

  • Conclusion

    Slide 47.

    Conclusion

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