Health and Pills » Arthritis http://healthandpills.com Guide To Good Health and Drugs: Tablets, Gels, Capsules Tue, 07 Feb 2012 09:49:47 +0000 en hourly 1 http://wordpress.org/?v=3.3.1 Rheumatoid Arthritis: Emerging Therapies http://healthandpills.com/disorders-and-conditions/arthritis/rheumatoid-arthritis-emerging-therapies http://healthandpills.com/disorders-and-conditions/arthritis/rheumatoid-arthritis-emerging-therapies#comments Wed, 11 May 2011 10:30:17 +0000 admin http://healthandpills.com/?p=908
Contents


      The launch of highly effective biological therapies in the late 1990s — in particular, the tumor necrosis factor-alpha (tumor necrosis factor-alpha) inhibitors — has dramatically improved the therapeutic options available for the treatment of rheumatoid arthritis (rheumatoid arthritis). The availability of these effective, albeit expensive, agents has significantly raised the bar for emerging therapies in the rheumatoid arthritis market. Despite the steep competition in developing therapies for this market, a vast number of agents, many of them biologies, are under development for the treatment of rheumatoid arthritis.

      This discussion focuses on emerging therapies that have mLed comparatively late-stage development for rheumatoid arthritis (i.e., Phase II or later trials, for which clinical results are available). TABLE . Emerging Therapies in Development for Rheumatoid Arthritis summarizes emerging therapies in late-stage development for rheumatoid arthritis. The discussion of emerging therapies is organized in this section according to their mechanisms of action.

      Tumor Necrosis Factor-a Inhibitors

      Overview

      Inhibitors of tumor necrosis factor-alpha represent the most recent and significant advance in the treatment of rheumatoid arthritis. The first anti-tumor necrosis factor-alpha agent approved for rheumatoid arthritis, etanercept (Amgen/Wyeth/Takeda’s Enbrel), was launched in the United States in 1998. Since then, two other agents have entered the market — infliximab (Centocor [a Johnson&Johnson subsidiary]/Schering-Plough/Tanabe Seiyaku’s Remicade) and adalimumab (Abbott/Eisai’s Humira). Because of the relatively high cost and risk of immunomodulatory side effects associated with these agents, researchers have directed their attention toward the development of improved anti-tumor necrosis factor-alpha therapies for the treatment of rheumatoid arthritis. Different approaches to targeting and blocking tumor necrosis factor-alpha include monoclonal antibodies, tumor necrosis factor-alpha receptors, TNF-binding proteins, and antisense technology. Two new tumor necrosis factor-alpha inhibitors that have progressed into Phase II clinical trials or beyond are discussed here.

      Currently available products are administered parenterally, and various companies have sought to develop orally active agents as a means of reducing cost and broadening the market scope for anti-tumor necrosis factor-alpha therapy. Oral delivery of tumor necrosis factor-alpha inhibition is seen as a particularly desirable goal by many rheumatologists. In practice, however, the development of orally active agents has proven difficult. Work on a number of apparently promising oral agents, such as AtheroGenics’ AGIX-4207, Bristol-Myers Squibb’s BMS-561392, and Isis’s ISIS-104838, has been discontinued. The most promising oral tumor necrosis factor-alpha inhibitor remaining in the pipeline is apratastat. This agent, however, is in early Phase II development and is not discussed because of a lack of clinical trial data.

      Mechanism Of Action

      The role of tumor necrosis factor-alpha in rheumatoid arthritis has been demonstrated in transgenic mouse models in which tumor necrosis factor-alpha overexpression led to joint destruction and aggressive synovitis. Among rheumatoid arthritis patients, the degree of synovial tumor necrosis factor-alpha expression correlates with the degree of synovitis and bone erosion. Further investigations have shown increased expression of tumor necrosis factor-alpha receptors in synovial tissues of patients with rheumatoid arthritis but not in some other forms of arthritis.

      Receptors for tumor necrosis factor-alpha are found on the surface of most cells, including mononuclear cells and cells in the synovium. Cleavage of membrane-bound tumor necrosis factor-alpha receptors yields soluble tumor necrosis factor-alpha receptors that retain ligand-binding ability but cannot activate cells. Two distinct types of tumor necrosis factor-alpha receptors have been identified: type I (p55) and type II (p75). tumor necrosis factor-alpha inhibitors reduce free, bioactive tumor necrosis factor-alpha by emulating the physiological role played by soluble tumor necrosis factor-alpha receptors.

      TABLE . Emerging Therapies in Development for Rheumatoid Arthritis

      Compound Development

      Phase

      		 Marketing Company
      tumor necrosis factor-alpha inhibitors
      CDP-870
      United States III UCB
      Europe III UCB
      Japan — —
      Pegsunercept
      United States II Amgen
      Europe - -
      Japan — —
      Interleukin-based therapies
      Atlizumab
      United States Ill Chugai/Roche
      Europe III Chugai/Roche
      Japan III Chugai/Roche
      AMG-714
      United States II Amgen
      Europe - -
      Japan — —
      Lymphocyte modulators
      Abatacept
      United States PR Bristol-Myers Squibb
      Europe - -
      Japan — —
      Rituximab
      United States Ill Roche/Biogen Idec/Genentech
      Europe III Roche/Biogen Idec/Genentech
      Japan — —
      Conventional Disease-modifying antirheumatic drugs
      Iguratimod
      United States Ila Toyoma Chemical/Eisai
      Europe I la Toyoma Chemical/Eisai
      Japan PR Toyoma Chemical/Eisai/Taisho
      Selective COX-2 inhibitors
      Lumiracoxib
      United States III Novartis
      Europe PR Novartis
      Japan II Novartis
      Immunosuppressants
      Tacrolimus
      United States III Astellas
      Europe II Astellas
      Japan PR Astellas
      MAP kinase inhibitore
      SCIO-469 Scios
      United States II Scios
      Europe II
      Japan -
      Doramapimod

      United States

      Europe

      Japan

      		 II

      II

      -

      		 Boehringer Ingelheim Boehringer Ingelheim

      -

      COX-2 = Cyclooxygenase-2; Disease-modifying antirheumatic drugs = Disease-modifying antirheumatic drugs; IL = Interleukin; MAP = Mitogen-activated protein; PR = Preregistered; tumor necrosis factor-alpha = TNF-α.

      This action modulates the amount of circulating, bioactive tumor necrosis factor-alpha by binding to the cytokine before it can activate cell-surface receptors on mononuclear cells. Because tumor necrosis factor-alpha plays an important role in the eradication of neoplastic cells, its suppression is not without hazard — particularly as a long-term therapeutic strategy. Concerns have been raised as to whether chronic immunosuppression leads to opportunistic infection, malignancies, or other complications.

      CDP-870

      UCB is developing CDP-870, a pegylated anti-tumor necrosis factor-alpha antibody fragment, for the treatment of rheumatoid arthritis and other inflammatory disorders such as Crohn’s disease in the United States and Europe. The agent was originally under development with Celltech, which was acquired by UCB in mid 2004, and is currently in Phase III trials. Celltech had previously been developing the agent in collaboration with Pfizer under an agreement terminated in December 2003. Regulatory filings are expected in 2006. No development has been reported in Japan.

      CDP-870 binds tumor necrosis factor-alpha with high affinity, thereby blocking its ability to activate the inflammatory cascade. Unlike infliximab, which is a chimeric monoclonal antibody (mAb) composed of 75% human and 25% mouse protein, CDP-870 is a humanized anti-tumor necrosis factor-alpha mAb fragment conjugated to two polyethylene glycol (PEG) subunits. The agent is being developed as an injectable formulation with a once-monthly subcutaneous (SC) dosing regimen. UCB can manufacture CDP-870 in Escherichia coli at very low cost using proprietary technology. The production cost may be as little as 10% of that for creating an antibody or receptor fusion product using mammalian cell culture.

      In a Phase II, double-blind, placebo-controlled study involving 203 patients, CDP-870 significantly reduced the signs and symptoms of rheumatoid arthritis (Keystone E, 2001). In the study, patients were randomized to receive CDP-870 (50, 100, 200, or 400 mg) once monthly as an SC injection or placebo for 12 weeks. Clinical response was assessed using American College of Rheumatology (ACR) criteria. The percentages of patients achieving an ACR 20, ACR 50, or ACR 70 response

      at week 12 after treatment with the most-effective dose (400 mg) of CDP-870 were 72%, 48%, and 32%, respectively, compared with 15%, 0%, and 0% for placebo. The most common adverse events reported in this trial were headache, nausea, and upper respiratory tract infection.

      In October 2002, Celltech presented data from a Phase II clinical trial involving approximately 600 rheumatoid arthritis patients. Of the patients receiving CDP-870 (400 mg once monthly), 75% achieved an ACR 20 response seven days after initial administration. The company reported no significant differences in adverse events between CDP-870 (400 mg or 800 mg once monthly) and placebo, and no significant occurrences of injection-site reaction or urinary tract infection. In 2004 press releases, Celltech announced preliminary results from two Phase III studies in rheumatoid arthritis, in which CDP-870 was used both in combination with methotrexate (Stada’s Rheumatrex, generics) and as monotherapy. Again, the agent met the primary end point: a significant ACR 20 response at 24 weeks. A further trial required for registration, designed to assess the impact of CDP-870 on disease progression, was scheduled to commence in the second half of 2004. Additional information on the drug’s safety or efficacy were not announced in the press releases, but UCB stated that full results will be released after conclusion of the entire Phase III program in rheumatoid arthritis.

      CDP-870 treatment was considered to be well tolerated in a Phase II study in 36 rheumatoid arthritis patients. The most common adverse event reported was headache, and there was a higher incidence of mild or moderate lower respiratory tract infections and urinary tract infections in the treatment group as compared with placebo. Overall, CDP-870 appears to have a similar safety profile to the other tumor necrosis factor-alpha inhibitors, with the most common side effects being headache, nausea, and respiratory and urinary tract infections.

      Pegsunercept

      Amgen has been evaluating the pegylated monomeric soluble TNF receptor type I inhibitor pegsunercept (PEG-sTNF-RI) in Phase II clinical trials in the United States. Although the product remains in the corporate portfolio, no clinical development has been reported since 2003, and Amgen appears to be pursuing other opportunities in rheumatoid arthritis. Despite the lack of recent development, pegsunercept is cited here as an emerging therapy because Amgen may decide to revive the product for use in combination regimens or as a defensive posture against market encroachment by CDP-870.

      Pegsunercept is a second-generation TNF-binding protein (TNF-bp) that comprises a soluble TNF-receptor type I (TNF-RI) subunit joined by a pegylated (PEG) linker. Like other tumor necrosis factor-alpha inhibitors, pegsunercept binds tumor necrosis factor-alpha with high affinity, thereby blocking its ability to activate the inflammatory cascade. As with CDP-870, pegsunercept is manufactured in Escherichia coli at a very low cost.

      At the 67th annual ACR meeting in October 2003, researchers presented results of a Phase II trial in which 309 patients with active rheumatoid arthritis were randomized to receive an SC injection of pegsunercept (400, 800, or 1,100 µg/kg) twice weekly or placebo for 24 weeks. All patients received concomitant methotrexate, and the primary end point was improvement in ACR response.

      At the end of the study period, all doses of pegsunercept significantly improved ACR 20, ACR 50, and ACR 70 responses, but the most significant response was seen for pegsunercept at 800 µg/kg. The ACR 20, 50, and 70 responses for pegsunercept 800 µg/kg in combination with methotrexate were 68%, 35%, and 25%, respectively, compared with 26%, 10%, and 3% for placebo. The results indicate that pegsunercept may reduce disease activity when administered concomitantly with methotrexate. The overall incidence of adverse events was similar between treatment groups, but injection site reactions were more frequent in patients receiving pegsunercept (38%, 36%, and 50% for 400, 800, and 1,100 µg/kg) than in those given placebo (30%).

      Pegsunercept has been evaluated in combination with other agents in clinical trials, suggesting that its efficacy as a monotherapy cannot compete with that of currently available drugs. Additionally, the ACR 20, 50, and 70 response rates for pegsunercept in combination with methotrexate are lower than those demonstrated by etanercept in combination with methotrexate in the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) study: 85%, 69%, and 43%, respectively.

      Interleukin-Based Therapies

      Lymphocyte Modulators

      Conventional Disease-Modifying Antirheumatic Drugs

      Selective Cyclooxgenase-2 Inhibitors

      Immunosuppressants

      MAP Kinase Inhibitors

      ]]> http://healthandpills.com/disorders-and-conditions/arthritis/rheumatoid-arthritis-emerging-therapies/feed 0 Interleukin-Based Therapies http://healthandpills.com/disorders-and-conditions/arthritis/interleukin-based-therapies http://healthandpills.com/disorders-and-conditions/arthritis/interleukin-based-therapies#comments Wed, 11 May 2011 10:26:46 +0000 admin http://healthandpills.com/?p=906
      Contents

          Overview

          Despite the relatively low efficacy of the interleukin (IL)-lβ antagonist anakinra and the relative lack of success of this agent in the rheumatoid arthritis market, companies continue to study IL-1 and other interleukins in the hope of finding a novel drug for rheumatoid arthritis. Three interleukin-based therapies that have advanced to comparatively late-stage development are discussed here, including Chugai/Roche’s atlizumab (MRA) and Amgen’s AMG-714 (HuMax IL-15), which target IL-6 and IL-15 respectively. Abbott’s ABT-874, an anti-IL-12 mAb currently in Phase II studies, is not discussed owing to a lack of clinical data in rheumatoid arthritis. Regen-eron’s IL-1 inhibitor RGN 303 was also in clinical trials for rheumatoid arthritis, but development was discontinued in September 2005.

          Mechanism Of Action

          The inflammatory cascade involves many proinflammatory cytokines in addition to tumor necrosis factor-alpha — notably, IL-1, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, IL-18, and IL-23. Dysregulated expression of these cytokines has been observed in rheumatoid arthritis patients and likely contributes to progressive joint degradation. Therefore, suppressing other inflammatory pathways may be an effective way to control rheumatoid arthritis, and blocking multiple pathways in the inflammatory cascade may act synergistically to block disease progression.

          Atlizumab

          Chugai and its parent company Roche are developing atlizumab (MRA), a humanized anti-IL-6 receptor mAb for the treatment of rheumatoid arthritis, Crohn’s disease, multiple myeloma, and Castleman’s disease (giant lymph node hyperplasia).

          In February 2003, the companies announced their intention to copromote the drug in the United Kingdom, France, and Germany. Roche will codevelop and promote atlizumab worldwide, except in Japan, South Korea, and Taiwan. Chugai also retained copromotion rights in the United States, Italy, and Spain. Phase III trials are ongoing in Japan and a Phase III preparation program is under way in Europe and the United States.

          Atlizumab inhibits the proinflammatory cytokine IL-6, which has a wide range of effects, including stimulating B cells to differentiate into plasma cells to produce immunoglobulin and stimulating T lymphocytes to differentiate into cytotoxic T cells. IL-6 is implicated in the pathogenesis of rheumatoid arthritis and stimulates chondrocytes, synoviocytes, and osteoblasts to secrete prostaglandins, plasmino-gen activator, collagenases, and other proteases. These substances promote the breakdown of extracellular matrix and cause extensive tissue destruction. Unlike the situation with the other cytokines, increased serum levels of IL-6 appear to correlate with increased levels of acute-phase reactant proteins (such as C-reactive protein and fibrinogen) in arthritic patients.

          Results presented at the 66th annual ACR meeting in October 2002 demonstrate atlizumab’s efficacy and tolerability. In a multicenter, double-blind, placebo-controlled Phase II study, 164 patients with active rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs (Disease-modifying antirheumatic drugs) were randomized to receive a monthly infusion of atlizumab (4 or 8 mg/kg) or placebo for three months. Patients were permitted to take prednisolone (10 mg/day or less). The primary end point was the ACR 20 response at week 12, at which point both doses of atlizumab demonstrated successful outcomes. ACR 20 responses for atlizumab 4 mg/kg and 8 mg/kg were 57.42% and 78.2%, respectively, compared with 11.3% for placebo; ACR 50 responses were 25.9%, 40.0%, and 1.9% and ACR 70 responses were 20.4%, 16.4%, and 0% of patients taking atlizumab 4 mg/kg, 8 mg/kg, and placebo, respectively. Patients receiving the 8 mg/kg dose also displayed 63.1% and 63.4% reductions, respectively, in the number of tender and swollen joints, compared with 7.7% and 2.6% reductions for placebo. Open-label extension study data were presented at the ACR 2003 meeting that confirmed the long-term safety of atlizumab. Subsequent to the original study, 142 patients were treated with 8 mg/kg of atlizumab intravenously every four weeks. Blood cholesterol increase was frequently observed, but stabilized at 3 months (185 mg/dL at base line; 224 mg/dL at 3 months; 225 mg/dL at 12 months). No cardiovascular events were observed.

          AMG-714

          Amgen is developing AMG-714 (HuMax IL-15) under an agreement with Genmab of Denmark for the treatment of inflammatory conditions. The lead indication is rheumatoid arthritis, in which AMG-714 is currently being evaluated in U.S. Phase II trials. In July 2003, Genmab announced that Amgen had exercised its commercial option to AMG-714 and would be responsible for all further development costs for the product. In addition to the ongoing studies in the United States, Amgen is expected to initiate clinical studies for AMG-714 in Europe.

          AMG-714 is a fully human monoclonal IgGl antibody that binds to human IL-15, a pro-inflammatory cytokine present in rheumatoid arthritis synovium, and inhibits IL-15-induced effector functions.

          Data from an interim analysis of a Phase II study were presented at the ACR Annual Scientific Meeting in October 2004. In this study, 110 patients naive to therapy with biologies and with active disease despite treatment with at least one conventional Disease-modifying antirheumatic drug were randomized to receive one of four doses of AMG-714 (40, 80, 160, or 280 mg injected subcutaneously) or placebo every two weeks for 12 weeks. Stable background methotrexate, NSAIDs, and low-dose corticosteroids were continued. Clinical and safety assessments were performed at 2-week intervals for 16 weeks and monthly over the subsequent 8 weeks. The primary efficacy outcome measured was ACR 20 response at 12 weeks. At this time point, those patients receiving the highest dose (280 mg) demonstrated a 62% ACR 20 response compared with 26% for placebo. The other active treatment groups demonstrated higher ACR responses compared with placebo, but the differences were not statistically significant. The total incidence of adverse events in all four AMG-714 groups (60.9%) was similar to placebo (56.5%). The incidence of infectious adverse events was also similar between the 280 mg AMG-714 group (33.3%) and placebo (34.8%).

          RGN-303

          Regeneron’s RGN-303 (IL-1 Trap) is in Phase lib development in the United States for the treatment of rheumatoid arthritis. In March 2003, Regeneron signed an agreement with Novartis concerning its development and commercialization. However, in February 2004, after reviewing Phase II trial results, Novartis informed Regeneron that it would no longer continue development of the agent unless the terms of the collaboration were revised. Regeneron rejected Novartis’s proposed revisions and proceeded with clinical development alone. In September 2005, Regeneron discontinued development for the rheumatoid arthritis indication.

          RGN-303 is a fully human IL-1 inhibitor consisting of the Fc portion of IgGl fused to the extracellular domains of both IL-1 receptor components, thereby mimicking the cell surface receptor for IL-1. RGN-303 binds to both IL-1α and IL-1β with high affinity, trapping the cytokine to block its activity.

          Results of a 12-week, placebo-controlled Phase II study in 201 patients with moderate to severe rheumatoid arthritis who had failed at least one prior Disease-modifying antirheumatic drug were presented at the ACR Annual Scientific Meeting in October 2004. Patients were randomized to receive weekly SC injections of placebo or 25, 50, or 100 mg of RGN-303. Stable doses of background conventional Disease-modifying antirheumatic drugs, but not other biologies, were permitted. The primary end point was improvement in ACR 20 response at 12 weeks. At the end of the study period, 46.0% of the patients receiving 100 mg RGN-303 achieved an ACR 20 response compared with 30.9% in the placebo group; these results were not statistically significant. However, significant improvements in the Disease Activity Score (DAS28) of the 100 mg RGN-303 group over placebo were apparent by one week ( — 0.55 versus  — 0.29) and continued through the end of the study ( — 1.121 versus  — 0.702). The percentage of rheumatoid arthritis patients with a moderate or good response to treatment with 100 mg RGN-303 as assessed by the DAS28 was also significantly greater than placebo (46% versus 26%). The authors of this study concluded that further evaluation of the efficacy of the drug at higher doses is warranted. No significant infectious complications were seen, with the most common adverse event being injection site reactions.

          Although the agent failed to meet its primary end points in this study, Regeneron considered it possible that the optimal dose level for RGN-303 had not yet been achieved. In April 2004, the company announced its intention of initiating a Phase lib trial with RGN-303 in the second half of 2004, following the recommendation of an independent advisory panel of medical experts. The panel recommended that the new Phase lib trial examine higher doses of RGN-303 in a larger patient population for a longer period of time compared with previous Phase II trial protocols.

          ]]> http://healthandpills.com/disorders-and-conditions/arthritis/interleukin-based-therapies/feed 0 Lymphocyte Modulators http://healthandpills.com/disorders-and-conditions/arthritis/lymphocyte-modulators http://healthandpills.com/disorders-and-conditions/arthritis/lymphocyte-modulators#comments Wed, 11 May 2011 10:25:49 +0000 admin http://healthandpills.com/?p=904
          Contents

              Overview

              A new class of biological agents has emerged that specifically target T and B lymphocytes, the main cells involved in an adaptive immune response. Most currently available biological agents target the products of activated macrophages, cytokines. However, T cells help activate macrophages, and both types of lymphocytes have been implicated in the inflammation and joint destruction found in rheumatoid arthritis. The rheumatoid synovium contains activated T and B cells, and immunoglobulin produced by B cells, such as rheumatoid factor and antinuclear or anticytoplasmic autoantibodies, serve as diagnostic markers for rheumatoid arthritis that may also be involved in the disease process. This section discusses one emerging therapy that targets T cells and one that targets B cells.

              Excluded from this analysis are lymphocyte modulators in Phase II clinical trials for which large-scale trial data are currently lacking, such as Human Genome Sciences/Cambridge Antibody Technology’s belimumab.

              Mechanism Of Action

              Lymphocyte modulators target T and B cells, which are immune cells known to be involved in the rheumatoid arthritis disease process. Agents in this class can act in a variety of ways, but the main mechanisms of action for therapies in late-stage development are interfering with lymphocyte activation or the actual depletion of the specific cell population. Either way, the lymphocytes cannot carry out their effector functions, which contribute to the inflammatory state and the production of autoantibodies.

              Abatacept

              Bristol-Myers Squibb is developing the CD28 antagonist abatacept (CTLA4-Ig BMS-188667) for the treatment of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), and other autoimmune disorders. Abatacept will be the first of a new class of agents termed T-cell costimulation modulators. The FDA has granted fast-track status for rheumatoid arthritis in the United States, and a rolling bio-logics license application (BLA) submission was initiated in November 2004.The drug received FDA approval in December 2005, and a launch is expected in the first half of 2006. No development has been reported elsewhere, but BMS is likely to submit further new product applications in European markets.

              Abatacept is a genetically engineered fusion protein that consists of the extracellular domain of human CTLA-4 and a fragment of the Fc portion of human IgGl. Abatacept binds to CD80 and CD86 molecules on antigen-presenting cells, blocking their engagement with CD28 on T cells. The blockade of this costim-ulatory signal prevents T-cell activation and the consequent proinflammatory cytokine release and acquisition of effector functions that contribute to the rheumatoid arthritis disease process.

              Published clinical trial results demonstrate that abatacept improves physical function in patients with active rheumatoid arthritis. In this Phase lib study, 339 patients refractory to methotrexate were randomized to receive intravenous administrations of abatacept (2 mg/kg or 10 mg/kg) or placebo on days 1, 15 and 30, and monthly thereafter for six months. All patients received concomitant methotrexate. At the end of the study period, the most significant ACR responses were seen with abatacept 10 mg/kg. The percentages of patients in the 10 mg group who achieved ACR 20, ACR 50, and ACR 70 responses were 60%, 37%, and 17%, respectively, compared with 35%, 12%, and 2% for placebo. The incidence of adverse events was similar for abatacept and placebo. The most frequent adverse events were headache, upper respiratory tract infection, musculoskeletal pain, and nausea. Further clinical response results over two years incorporating a one-year open-label extension study were presented at the 2004 ACR scientific meeting. Of those patients randomized to the abatacept treatment arm, 75 (89%) completed two years of treatment. At two years, ACR 20, 50, and 70 responses were 77.3%, 54.7%, and 29.3%, respectively. Furthermore, 15% of patients demonstrated a 90% improvement in ACR criteria at two years.

              The company is also pursuing development of abatacept in patients refractory to tumor necrosis factor-alpha inhibitors. Data from the Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN) were presented at the ACR 68th Annual Scientific Meeting in October 2004 (Genovese MC, 2004). In this placebo-controlled study, 391 patients with active rheumatoid arthritis were treated with at least one conventional Disease-modifying antirheumatic drug and abatacept at a fixed dose of 10 mg/kg (258 patients) or placebo (133 patients). All patients had discontinued tumor necrosis factor-alpha therapy. After six months of treatment, significant differences were observed in the ACR response rates: 50.4% of abatacept-treated patients achieved an ACR 20 response compared with 19.5% on placebo; 20.3% of abatacept-treated patients achieved an ACR 50 response versus 3.8% on placebo; and 10.2% of abatacept-treated patients achieved an ACR 70 response versus 1.5% on placebo. The incidence of adverse events was similar between abatacept and placebo, with the most common side effects being headache and nasopharyngitis. The incidence of serious infections was the same in each group (2.3%).

              Rituximab

              Rituximab is being developed by Roche as MabThera and codeveloped by Biogen Idee and Genentech as Rituxan as a potential treatment for rheumatoid arthritis. Both compounds have already launched their respective products worldwide for the treatment of relapsed or refractory, low-grade, CD20-positive, B-cell non-Hodgkin’s lymphoma. Rituximab is being evaluated across a range of immunological indications, including multiple sclerosis, vasculitis, SLE, and rheumatoid arthritis. It is in Phase III clinical trials for anti-tumor necrosis factor-alpha refractory rheumatoid arthritis and Phase lib clinical trials for moderate to severe rheumatoid arthritis in the United States and Europe. No development has been reported in Japan for rheumatoid arthritis, but rituximab is marketed there for B-cell lymphoma by Zenyaku Kogyo.

              This mouse/human chimeric mAb targets CD20 on the surface of B lymphocytes and recruits the body’s natural defenses to attack and kill the marked B cells. The labeling for rituximab indicates that the drug is associated with serious adverse events, including fatal infusion reactions, tumor lysis syndrome, mucocutaneous reactions, hypersensitivity reactions, cardiac arrhythmias and angina, and renal failure. The product label includes black box warnings for the first three of these adverse events.

              Rituximab demonstrated efficacy for the treatment of rheumatoid arthritis in a Phase II trial of 161 partial methotrexate responders with long-standing disease. Study participants were randomized to receive methotrexate alone (>10 mg per week), rituximab alone (1 g administered intravenously on days 1 and 15), rituximab plus cyclophosphamide (750 mg administered intravenously on days 3 and 17), or rituximab plus methotrexate. All groups also received a 17-day course of corticosteroids (100 mg intravenous methlyprednisolone on days 1, 3, 15, and 17; 30 mg oral methlyprednisolone on days 2 and 4 through 7; and 60 mg oral methlyprednisolone on days 8 to 14). Rituximab treatment resulted in nearly complete depletion of peripheral B cells, but peripheral blood immunoglobulin concentrations remained within normal ranges throughout the study period. At week 24, 43% of patients taking rituximab plus methotrexate achieved an ACR 50 response compared with 41% of patients taking rituximab plus cyclophosphamide, 33% of patients taking rituximab alone, and 13% of patients taking methotrexate alone. All ACR 50 responses for the patients treated with a combination of rituximab and methotrexate were maintained at 48 weeks. The majority of adverse events occurred with the first rituximab infusion. At 24 weeks, serious infections occurred in 2.5% of the control group and in 3.3% of the rituximab groups.

              Subsequent data from the study were presented at the 68th annual ACR meeting in October 2004. Results demonstrated that a single course of rituximab in combination with methotrexate produced a substantial duration of response over two years. At week 104, ACR 20 and 50 responses were achieved by 34% and 21% of the rituximab plus methotrexate group compared with 14% and 11% on methotrexate alone, while 13% of the former group achieved a major clinical response (ACR 70 maintained for >6 months). The authors concluded that all three rituximab treatment arms were well tolerated with no significant differences observed in rates of infection.

              Many rheumatologists have employed rituximab off-label on a compassionate basis for patients refractory to currently available therapies. This agent is considered a highly exciting development in the field of rheumatoid arthritis because it has the potential to induce long-term remission — up to two years, in some patients.

              Initially, rituximab is likely to be reserved for rheumatoid arthritis patients who are refractory to other Disease-modifying antirheumatic drugs, conventional and biologic, although it is unclear what dosing strategy would be used. In clinical trials, rituximab has been administered intravenously weekly or every two weeks, but if the agent can truly induce long-term remission, dosing could be much less frequent. Excitement for the potential of the drug is tempered with serious concerns over the adverse events associated with rituximab. Administration of rituximab is linked to a high rate of infusion reactions, with up to 77% incidence for the first infusion. Some of these infusion reactions have proved fatal, prompting the black box warnings discussed previously.

              ]]> http://healthandpills.com/disorders-and-conditions/arthritis/lymphocyte-modulators/feed 0 Conventional Disease-Modifying Antirheumatic Drugs http://healthandpills.com/disorders-and-conditions/arthritis/conventional-disease-modifying-antirheumatic-drugs-2 http://healthandpills.com/disorders-and-conditions/arthritis/conventional-disease-modifying-antirheumatic-drugs-2#comments Wed, 11 May 2011 10:24:55 +0000 admin http://healthandpills.com/?p=902
              Contents

                  Overview

                  The conventional Disease-modifying antirheumatic drug class includes a wide range of agents as diverse as antimalarials, cytotoxics, and immunosuppressants. Unlike anti-inflammatories, which provide symptomatic relief without altering the natural course of the disease, Disease-modifying antirheumatic drugs typically lack a direct analgesic effect but have the potential to slow or prevent joint damage in rheumatoid arthritis patients. In 2002, the ACR published revised guidelines for the treatment of rheumatoid arthritis advocating more aggressive use of conventional Disease-modifying antirheumatic drugs earlier in the rheumatoid arthritis treatment regimen in an effort to limit joint damage and minimize loss of joint function and disability. As a result, the use of conventional Disease-modifying antirheumatic drugs, which were once reserved for treating severe or late-stage rheumatoid arthritis, has become widespread and is now the cornerstone of rheumatoid arthritis treatment.

                  The development of new Disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis has focused primarily on biological agents. Biological agents, particularly the tumor necrosis factor-alpha inhibitors, have the best efficacy of all drugs used for the treatment of rheumatoid arthritis, but their high cost limits their widespread use. The production costs of synthetic compounds are much lower than those of biological agents, allowing them to be priced competitively and therefore used as first-line Disease-modifying antirheumatic drug therapy. Synthetic agents are also usually available in oral formulations that offer an additional advantage over the parenteral biological agents. Emerging conventional Disease-modifying antirheumatic drugs, however, must contend with methotrexate, which is firmly established as the favored Disease-modifying antirheumatic drug because it offers the best balance of efficacy, cost, and safety.

                  Mechanism Of Action

                  Conventional Disease-modifying antirheumatic drugs include a wide range of agents, such as antimalarials, cytotoxics, and immunosuppressants, each with a distinct mechanism of action. In general, agents in this class are anti-inflammatory and/or antiproliferative, inhibiting various molecules and cell types that play a role in the inflammatory cascade. Most have demonstrated the ability to slow the rate of progression of joint erosion and disability to varying degrees.

                  Iguratimod

                  Toyama Chemical is developing a chromone derivative, igurati-mod (T-614), as a potential therapy for rheumatoid arthritis. As of November 2004, iguratimod was preregistered in Japan, while a Phase Ha program had been completed in the United States and Europe. Toyama has a codevelopment and comarketing agreement with Eisai, and Toyoma licensed Japanese marketing rights to Taisho Pharmaceuticals in 2003. We anticipate iguratimod will launch in Japan in 2006. Iguratimod was discovered in a program to develop novel anti-inflammatory compounds that preferentially inhibit cyclooxygenase (COX)-2 activity. The drug is now recognized as a Disease-modifying antirheumatic drug, reflecting its ability to block the synthesis of proinflammatory cytokines and immunoglobulin production in addition to inhibiting COX-2 enzyme activity and COX-2 mRNA induction. Unlike most other conventional Disease-modifying antirheumatic drugs, iguratimod has direct analgesic properties that should help the drug provide symptomatic relief in addition to its disease-modifying ability.

                  Iguratimod has demonstrated efficacy at least comparable to that of sul-fasalazine. In a Japanese multicenter, double-blind trial presented at the 2004 European League Against Rheumatism (EULAR) meeting, 375 patients with active rheumatoid arthritis were randomly allocated to receive either iguratimod 50 mg/day (n = 146), sulfasalazine 1,000 mg/day (n = 156), or placebo (n = 73). The efficacy end point was ACR 20 response at 28 weeks. The ACR 20 response of the iguratimod group was 62.5%, which was comparable to the sulfasalazine group (58.1%). The presenters also stated that iguratimod was significantly superior to placebo, although the percentage of ACR 20 respondents in the placebo group was not shown. Elevated plasma enzyme levels (e.g., aspartate aminotransferase and alanine aminotransferase) were relatively frequent in the iguratimod group but were transient and improved after discontinuation.

                  The failure to provide placebo data in the study results hinders determination of the true efficacy of this agent. If it proves to have efficacy comparable to that of sulfasalazine, an agent widely considered to be a comparatively ineffective Disease-modifying antirheumatic drug, iguratimod’s use will be limited. Furthermore, concerns over the cardiovascular safety of selective COX-2 inhibitors may limit uptake of this agent, since it does preferentially inhibit COX-2 in addition to its immunosuppression. Therefore, iguratimod is likely to be used in milder forms of rheumatoid arthritis or in combination with other Disease-modifying antirheumatic drugs in European and U.S. markets, although the agent may become an alternative to salazosulfapyridine (sulfasalazine) in Japan.

                  ]]> http://healthandpills.com/disorders-and-conditions/arthritis/conventional-disease-modifying-antirheumatic-drugs-2/feed 0 Selective Cyclooxgenase-2 Inhibitors http://healthandpills.com/disorders-and-conditions/arthritis/selective-cyclooxgenase-2-inhibitors-2 http://healthandpills.com/disorders-and-conditions/arthritis/selective-cyclooxgenase-2-inhibitors-2#comments Wed, 11 May 2011 10:24:05 +0000 admin http://healthandpills.com/?p=900
                  Contents

                      Overview

                      The first generation of selective COX-2 inhibitors, such as rofecoxib (Merck’s Vioxx) and celecoxib (Pfizer’s Celebrex), demonstrated their ability to reduce gastrointestinal (GI) side effects in comparison with traditional nons-teroidal anti-inflammatory drugs (NSAIDs), which suppress the isoforms of COX, COX-1 and COX-2, less discriminately. These agents still cause some degree of GI upset, however, so R&D efforts have been focused on developing a second generation of inhibitors that have an even higher degree of selectivity for COX-2. Valdecoxib (Pfizer’s Bextra) and etoricoxib (Merck’s Arcoxia) were the first of this second generation of selective COX-2 inhibitors to be launched; they are reviewed in “Current Therapies.”

                      Concerns regarding the cardiovascular safety of COX-2 inhibitors have drastically lowered expectations for new selective COX-2 agents. It remains unclear whether current selective COX-2 inhibitors will remain on the market and whether agents in the pipeline will launch. Although development of earlier-stage drugs in this class may be abandoned as a consequence of their significantly lowered sales potential, development for etoricoxib in new markets and for lumiracoxib (Novartis’s Prexige) will likely continue. Therefore, the discussion of emerging therapies in this drug class is limited to lumiracoxib.

                      Mechanism Of Action

                      COX-1 (also called constitutive cyclooxygenase) is present in cells under normal physiological conditions and stimulates the synthesis of prostaglandins that help regulate renal function, blood flow, platelet activity, and protection of the mucous membrane along the GI tract. COX-2 (also known as inducible cyclooxygenase) occurs only under pathological conditions. Its production is induced by proinflammatory cytokines, mitogens, or endotox-ins, and it stimulates the production of prostaglandins that drive the inflammatory process. Selective COX-2 inhibitors predominantly inhibit COX-2 while minimizing inhibition of COX-1. As a result, COX-2 inhibitors act specifically to reduce pathological inflammation caused by prostaglandins, without disrupting their beneficial effects.

                      Lumiracoxib

                      Lumiracoxib (Novartis’ Prexige, COX-189), at a dose of 100-200 mg daily, was approved by the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) in September 2003 for the treatment of osteoarthritis (OA). In addition, lumiracoxib at a dose of 400 mg daily was approved for the short-term relief of moderate to severe acute pain associated with primary dysmenorrhea and dental and orthopedic surgery. With these approvals, the United Kingdom was acting as the reference member state for the European mutual recognition procedure. However, Novartis temporarily withdrew its European Union mutual recognition procedure application in November 2004 pending European Agency for the Evaluation of Medicinal Products (EMEA) review of the selective COX-2 inhibitor class in 2005. The U.K. approval of lumiracoxib came on the heels of news that the FDA had requested additional clinical data on lumiracoxib for OA and acute pain. The FDA also denied the registrational filing for rheumatoid arthritis. By January 2003, Novartis had initiated an additional clinical trial for rheumatoid arthritis. In October 2004, the company revised its anticipated U.S. resubmission date for all indications to 2007.

                      Similar to other agents in its class, lumiracoxib predominantly inhibits COX-2 while minimizing inhibition of COX-1. As a result, lumiracoxib acts specifically to reduce pathological inflammation caused by prostaglandins without disrupting their beneficial effects.

                      Data from a Phase III study demonstrated that the efficacy of lumiracoxib is significantly better than placebo and similar to naproxen in the reduction of rheumatoid arthritis symptoms. In the study, 1,124 patients with symptomatic rheumatoid arthritis were randomized to receive lumiracoxib 200 mg once daily, lumiracoxib 400 mg once daily, naproxen 500 mg twice daily, or placebo for 26 weeks. The primary end point was ACR 20 response at week 13, and secondary end points included ACR 20 response at weeks 4, 20, and 26. After 13 weeks of treatment, an ACR 20 response was achieved by 41.1% and 42.7% for lumiracoxib 200 and 400 mg, respectively, compared with 39.1% and 32.4% for naproxen and placebo. Similar response levels were observed after 26 weeks of treatment. The rate of discontinuation due to adverse events was similar in all treatment groups. However, incidence of GI events was 15.7% and 16.4%, respectively, for lumiracoxib 200 mg and 400 mg, compared with 19.7% and 10.9% for naproxen and placebo.

                      A meta-analysis presented at the annual meeting of the American Society for Gastrointestinal Endoscopy in May 2003 suggests that lumiracoxib’s GI safety profile is superior to that of traditional NSAIDs and comparable to that of cele-coxib and rofecoxib. This analysis, which included 6,295 patients and data from nine OA studies, showed that the overall incidence of GI events was 22% for lumiracoxib (200 and 400 mg daily), 22% for celecoxib (200 mg daily), 29% for rofecoxib (25 mg daily), and 47% for ibuprofen (2,400 mg daily).

                      Further evidence of an improved GI safety profile for lumiracoxib as compared with traditional NSAIDs came from the large-scale Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET). In this study, 18,325 OA patients were randomized to receive lumiracoxib 400 mg once daily (n = 9, 156), naproxen 500 mg twice daily (n = 4, 754), or ibuprofen 800 mg three times daily (n = 4, 415) for 52 weeks in two substudies of identical design. The primary gastrointestinal end point was the one-year incidence of upper GI ulcer complications: bleeding, perforation, or obstruction. Lumiracoxib demonstrated a significantly lower incidence of ulcers than the traditional NSAIDs in the overall population and in patients not taking aspirin, but the difference was not significant for the group taking aspirin. Thus, lumiracoxib demonstrated a three- to fourfold decrease in ulcer complications compared to traditional NSAIDs, although concomitant aspirin appears to negate lumiracoxib’s improved GI safety profile.

                      The critical question of lumiracoxib’s cardiovascular safety was also addressed in TARGET. The primary cardiovascular end point in that study was defined as the incidence of major adverse cardiovascular events — nonfatal and silent myocardial infarction, stroke, or cardiovascular death. At one year, incidence of the primary end point was low with both lumiracoxib (59 events [0.65%]) and the NSAIDs (50 events [0.55%]). No significant differences were observed between lumiracoxib and the comparator NSAIDs in the overall population or in the subpopulations investigated separately (patients taking or not taking low-dose aspirin). Furthermore, no significant differences were observed in the incidence of myocardial infarctions, congestive heart failure, and other thrombotic events in the overall population groups studied.

                      The fate of this agent is inextricably linked with that of the other members of this class, currently under review by regulatory agencies in the United States and Europe. While the results of the TARGET study provide some encouragement, increased cardiovascular risk associated with rofecoxib therapy did not become apparent until 18 months.

                      ]]> http://healthandpills.com/disorders-and-conditions/arthritis/selective-cyclooxgenase-2-inhibitors-2/feed 0 Immunosuppressants http://healthandpills.com/disorders-and-conditions/arthritis/immunosuppressants http://healthandpills.com/disorders-and-conditions/arthritis/immunosuppressants#comments Wed, 11 May 2011 10:23:17 +0000 admin http://healthandpills.com/?p=898
                      Contents

                          Overview

                          Even though immunosuppressive agents such as azathioprine (Glax-oSmithKline’s   Imuran,   generics)  and  cyclosporine   (Novartis’   Sandimmune/Neoral, generics) have been used for decades to treat the signs and symptoms of rheumatoid arthritis, development of novel agents in this class for rheumatoid arthritis has been sluggish because of efficacy and safety concerns that have arisen in clinical trials of agents under development. Nonetheless, companies are pursuing development of immunosuppressive therapies.

                          Excluded from this analysis are immunomodulators currently in Phase II trial programs but for which large-scale trial data are currently lacking, including Androclus Therapeutics’ AT-001 and Wyeth’s temsirolimus.

                          Mechanism Of Action

                          Immunosuppressants function through a variety of mechanisms, but they generally target key immunologic processes and molecules. In general, these agents exert their effects by blocking the activation of T-helper and cytotoxic T lymphocytes, promoting the accumulation of anti-inflammatory molecules, and decreasing the formation of antibodies.

                          Tacrolimus

                          Tacrolimus, or FK-506 (Astellas’s Prograf), has been launched for atopic dermatitis and for the prophylaxis of liver and kidney allograft rejection. A supplementary new drug application (NDA) was filed in Japan for rheumatoid arthritis in November 2002, and in April 2005 the drug was approved for the treatment of rheumatoid arthritis in patients who responded insufficiently to conventional treatments. The drug will be marketed in Japan by Astellas, formed from the merger of Fujisawa and Yamanouchi. The agent is in Phase III trials in the United States and in Phase II in Europe.

                          Tacrolimus is a microbial product isolated from the bacterium Streptomyces tsukubaensis. The drug binds to a T-cell-specific FK-binding protein, preventing T-cell activation, proliferation, and survival. As an immunosuppressant, tacrolimus is 50-100 times more potent than cyclosporine, as measured by inhibition of lymphocyte activation in vitro.

                          The safety and efficacy profiles of tacrolimus appear to be favorable both as monotherapy and in combination with methotrexate. A six-month, randomized, double-blind, placebo-controlled Phase III trial that enrolled 464 patients with active rheumatoid arthritis who were intolerant of or refractory to one or more Disease-modifying antirheumatic drugs, including methotrexate, found that 18.8% and 26.8% of patients receiving 2 mg and 3 mg, respectively, of tacrolimus daily achieved an ACR 20 response compared with 10.2% of patients receiving placebo. Of the patients receiving 2 mg and 3 mg of tacrolimus, 11.7% and 11.8%, respectively, achieved ACR 50 responses compared with 4.5% of patients in the placebo group.

                          A 12-month, open-label extension of this trial, which enrolled 896 patients, sought to establish the long-term safety of tacrolimus. This study involved patients who chose to enroll in the extension trial, together with an additional 685 patients who either had never received tacrolimus or had not received it in 11 months or more. All patients received 3 mg of tacrolimus daily; 38.4% achieved ACR 20, 18.6% achieved ACR 50, and 9.0% achieved ACR 70. The drug was found to be generally well tolerated in this study; minor side effects included diarrhea (14.6%), nausea (10.3%), tremor (9.0%), and headache (8.7%).

                          Tacrolimus is occasionally used off-label in rheumatoid arthritis patients who are refractory to methotrexate and other marketed Disease-modifying antirheumatic drugs, a practice that may be indicative of the limited patient population to whom this agent will be prescribed when it is approved for rheumatoid arthritis.

                          ]]> http://healthandpills.com/disorders-and-conditions/arthritis/immunosuppressants/feed 0 MAP Kinase Inhibitors http://healthandpills.com/disorders-and-conditions/arthritis/map-kinase-inhibitors http://healthandpills.com/disorders-and-conditions/arthritis/map-kinase-inhibitors#comments Wed, 11 May 2011 10:22:35 +0000 admin http://healthandpills.com/?p=896
                          Contents

                              Overview

                              Biotechnology companies such as Scios (a subsidiary of John-son&Johnson), Vertex, Celgene, and Cephalon dominate the field of mitogen-activated protein (MAP) kinase-based therapeutics. These companies are developing oral small-molecule inhibitors of MAP kinase for the treatment of inflammatory disorders such as rheumatoid arthritis and Crohn’s disease as well as oncology indications. This section discusses those agents that have advanced to Phase II trials, the most advanced stage of development for members of this class.

                              Mechanism Of Action

                              The enzyme p38 MAP kinase is part of an intracellu-lar signal transduction cascade involved in regulating the expression of several proinflammatory cytokines, including IL-1β and tumor necrosis factor-alpha. Patients with active rheumatoid arthritis exhibit increased activation of p38 MAP kinase. Researchers believe that p38 MAP kinase plays an important role in the induction of inflammation, and that agents targeting this pathway may provide a more effective and complete blockade of inflammatory cytokines than biological cytokine inhibitors. The potential therapeutic benefit of targeting the MAP kinase pathway in rheumatoid arthritis is also suggested by preclinical studies with selective inhibitors of p38 MAP kinase. In one study, SmithKline Beecham’s (now GlaxoSmithKline’s) research compounds SB-203580 and SB-202190 arrested disease progression in a rat adjuvant-induced arthritis model. In a later study, these same agents blocked the expression of the matrix metalloproteinases MMP-1 and MMP-13. MMP-1 and MMP-13 play a role in cartilage destruction and inflammation in rheumatoid arthritis.

                              SCIO-469

                              Scios is developing SCIO-469, an oral p38 MAP kinase inhibitor, for the treatment of rheumatoid arthritis and Crohn’s disease. The agent is in Phase II development in the United States and Europe. No development in Japan has been reported.

                              SCIO-469 blocks the activity of MAP kinase, which in turn inhibits the production of pro inflammatory factors such as tumor necrosis factor-alpha, IL-1β, and COX-2 mRNA. Thus, the agent can be thought of as an indirect tumor necrosis factor-alpha inhibitor with additional anti-inflammatory effects.

                              By July 2004, Japanohnson&Johnson reported that two Phase Ha studies of SCIO-469 for rheumatoid arthritis had been successfully completed and a Phase lib efficacy and tolerability trial was under way. The main objective of the first of these studies was to evaluate six escalating doses of SCIO-469 compared with placebo in 120 patients with active rheumatoid arthritis receiving concomitant methotrexate. The second study was a 24-week, placebo-controlled trial to determine the efficacy of SCIO-469 in rheumatoid arthritis patients not receiving Disease-modifying antirheumatic drugs other than hydroxychloroquine. Results from the studies have not yet been reported.

                              In April 2001, Scios reported data from a randomized, double-blind, placebo-controlled Phase lb trial conducted in the United Kingdom that evaluated safety, tolerability, and pharmacokinetics in 30 healthy volunteers over a wide range of doses. According to the company, the drug demonstrated excellent bioavailability and pharmacokinetics and was well tolerated.

                              In October 2002, at the 66th annual ACR meeting, the company presented preclinical data on SCIO-469. In a 28-day study involving rats with preexisting rheumatoid arthritis, administration of SCIO-469 (10 mg/kg or 40 mg/kg) once daily resulted in a significant dose-related reduction in the severity of arthritis (joint swelling and erythema). By day 28, the clinical severity score (a measure of disease severity with higher scores indicating greater disease severity) was 5.10 in the control group compared with 4.25 for SCIO-469 10 mg/kg group and 2.16 for SCIO-469 40 mg/kg group. In addition, the mean radiographic score for the control group was 3.30 compared with 2.62 for SCIO-469 10 mg/kg group and 0.16 for SCIO-469 40 mg/kg group.

                              Doramapimod

                              Boehringer Ingelheim’s doramapimod (BIRB-796) is in Phase II trials in the United States and Europe for rheumatoid arthritis, psoriasis, and Crohn’s disease. No development has been reported in Japan.

                              Doramapimod, a pyrazole phenyl urea derivative, is a reversible, competitive inhibitor of p38 MAP kinase that acts by interfering with adenosine triphosphate (ATP) binding of p38. Like SCIO-469, this agent blocks tumor necrosis factor-alpha and IL-1β synthesis.

                              Multiple Phase I trials have demonstrated the agent’s tolerability and lack of significant adverse events. The first human study conducted with this drug was a randomized, double-blind, placebo-controlled, 64-patient trial presented at the 2002 annual meeting of the American Academy of Asthma, Allergy, and Immunology. In this study, doramapimod administered as an oral solution with PEG400 exhibited safety in doses ranging from 1 mg to 600 mg.

                              A maximal serum concentration of 2.2 mg/mL was observed with the 600 mg dose, and the half-life ranged from 6.7 to 9.6 hours. Only transient elevations in serum levels of liver enzymes were observed.

                              ]]> http://healthandpills.com/disorders-and-conditions/arthritis/map-kinase-inhibitors/feed 0 Rheumatoid Arthritis: Nonpharmacological Therapies http://healthandpills.com/disorders-and-conditions/arthritis/rheumatoid-arthritis-nonpharmacological-therapies http://healthandpills.com/disorders-and-conditions/arthritis/rheumatoid-arthritis-nonpharmacological-therapies#comments Wed, 11 May 2011 10:11:16 +0000 admin http://healthandpills.com/?p=893
                              Contents

                                  Prosorbd Column

                                  Developed by Cypress Bioscience as a novel blood-filtering device, the Prosorba column was licensed for comarketing in the United States, Europe, and Japan to Fresenius Hemotechnology. The column received FDA approval in 1999 for patients unresponsive to or intolerant of Disease-modifying antirheumatic drug therapy, and it was launched in the United States and Europe in 2000. This device uses approximately 200 mg of protein A (a component of the Staphylococcus bacterium that selectively binds IgG and IgG-bound antigens) covalently bound to an inert silica matrix. In a process similar to kidney dialysis, a patient’s blood is removed from a vein in one arm and passed through a machine that separates the blood cells from the plasma. The plasma is then passed through the Prosorba column, where circulating immune complexes are removed, recombined with the blood cells, and returned to the patient through the other arm. The standard course of therapy involves 12 weekly, two-hour outpatient sessions. A 99-patient, double-blind trial resulted in a 41.7% ACR 20 improvement in Prosorba-treated patients versus 15.6% with placebo.

                                  Surgery

                                  Surgical treatment for rheumatoid arthritis takes three main forms: carpal tunnel relief and metatarsal head resections, synovectomies (partial removal of the diseased joint lining), and arthroplasty (total joint replacement). Carpal tunnel and metatarsal head procedures are rarely performed, but they are useful when corticosteroid injections have failed or the maximum dose provides no further improvement. Synovectomies are perhaps even rarer because the long-term benefits are outweighed by the procedure’s cost. Arthroplasty of the knee and hip are the most common type of surgery for rheumatoid arthritis. Approximately 15-25% of all rheumatoid arthritis patients eventually undergo this procedure for one or more joints. Most of these patients have end-stage disease, and many have secondary OA.

                                  ]]> http://healthandpills.com/disorders-and-conditions/arthritis/rheumatoid-arthritis-nonpharmacological-therapies/feed 0 Corticosteroids http://healthandpills.com/disorders-and-conditions/arthritis/corticosteroids http://healthandpills.com/disorders-and-conditions/arthritis/corticosteroids#comments Wed, 11 May 2011 10:10:17 +0000 admin http://healthandpills.com/?p=891
                                  Contents

                                      Overview

                                      Corticosteroids have long been employed in the treatment of rheumatoid arthritis and remain a key component of symptom management. They produce potent, rapid suppression of inflammation with consequent improvements in joint pain and swelling. Studies showing that corticosteroids can reduce the rate of joint damage in rheumatoid arthritis patients led to their initial classification as disease-modifying agents. However, rheumatologists caution that the disease-modifying properties of corticosteroids are limited, and they should not be administered as a monotherapy to rheumatoid arthritis patients with active disease. Instead, true Disease-modifying antirheumatic drugs, either conventional or biological, should be initiated, and corticosteroids used as supplemental therapy to control symptoms as needed.

                                      Corticosteroids are associated with many side effects. Insomnia, night sweats, mood changes, and altered glucose metabolism may occur shortly after beginning corticosteroids. Prolonged corticosteroid therapy can lead to adrenal atrophy, and abrupt cessation can cause adrenal insufficiency, hypotension, and even death. Long-term use of systemic corticosteroids is associated with osteoporosis, hypertension, cataracts, acne, abnormal fat deposition, and excessive hair growth. These side effects generally occur less often with corticosteroid injections, but injection site infections, post-injection flares, and crystal-induced synovitis can occur with parenteral delivery.

                                      A wide variety of generic corticosteroids, salts, and formulations are available in the markets under study. This section assesses two of the most commonly prescribed agents, orally administered prednisone (Pfizer’ s Deltasone, generics) and intra-articular (IA) methylprednisolone acetate (Pfizer’s Depo-Medrol, generics).

                                      Mechanism Of Action

                                      Corticosteroids act as anti-inflammatory and immunosuppressive agents through multiple effects: inhibiting synthesis of proinflammatory mediators (prostaglandins, leukotrienes, and cytokines); disrupting cellular activation, migration, and proliferation; and blocking edema formation. Corticosteroids can also inhibit the expression of COX-2 and the activity of collagenase and other cartilage-damaging enzymes.

                                      Formulation

                                      Rheumatologists employ a wide variety of corticosteroid formulations and doses to relieve rheumatoid arthritis symptoms. Oral corticosteroids are often used as bridge therapy, meaning they are initiated by primary care physicians or rheumatologists upon diagnosis, but then discontinued when the slower-acting, conventional Disease-modifying antirheumatic drug therapy takes effect. Intravenous corticosteroids are occasionally used as bridge therapy, as well. In addition, oral and intravenous corticosteroids are used during periodic flare-ups to control symptoms during times of high disease activity.

                                      For alleviating severe rheumatoid arthritis symptoms, high doses of intravenous corticosteroids can be used on a short-term basis (up to 1 g per day for three days). The intravenous treatment can be repeated after four to six weeks if necessary. Alternatively, oral corticosteroids can be initiated at a high dose (e.g., 30-40 mg prednisone daily) and then gradually tapered down in 5 mg steps to a continuous dosage of 5-10 mg per day. For milder symptoms, a low dose of oral corticosteroids can be used as short-term or long-term therapy. Because of the serious side effects associated with corticosteroids, rheumatologists prefer to discontinue these drugs as soon as possible. However, abrupt cessation of corticosteroids can cause adrenal insufficiency, hypotension, and even death, so doses must be carefully tapered to a level where these drugs may be safely discontinued.

                                      To minimize side effects and to prevent problems with abrupt discontinuation of systemic therapy, intramuscular or IA injections are used for relief of localized, aggressive joint flare-ups. A single intramuscular dose of a depot corticosteroid, such as methylprednisolone acetate or triamcinilone acetonide (both 40 mg/mL), is preferred by rheumatologists when rapid control is required. Furthermore, physicians and researchers have expressed concern that repeated corticosteroid injections into joints can actually exacerbate progressive cartilage damage. As a result, many rheumatologists consider this strategy a last resort and will not use it in more than one joint at a time. The ACR also recommends that intra-articular injections not be administered in the same joint more than once within three months.

                                      Prednisone

                                      Methylprednisolone Acetate

                                      ]]> http://healthandpills.com/disorders-and-conditions/arthritis/corticosteroids/feed 0 Prednisone http://healthandpills.com/disorders-and-conditions/arthritis/prednisone http://healthandpills.com/disorders-and-conditions/arthritis/prednisone#comments Wed, 11 May 2011 10:08:52 +0000 admin http://healthandpills.com/?p=889 Oral prednisone (Pfizer’s Deltasone, generics) is commonly prescribed in low doses (less than 10 mg daily) to treat the signs and symptoms of rheumatoid arthritis. Oral corticosteroids — including prednisone — can be used as a short-term therapy during periods of high disease activity or as a bridge therapy and can be administered for long-term use in combination with Disease-modifying antirheumatic drugs.

                                      Corticosteroids act as anti-inflammatory and immunosuppressive agents through multiple effects: inhibiting synthesis of proinflammatory mediators (prostaglandins, leukotrienes, and cytokines); disrupting cellular activation, migration, and proliferation; and blocking edema formation. Corticosteroids can also inhibit the expression of COX-2 and block the activity of collagenase and other cartilage-damaging enzymes.

                                      Low-dose oral prednisone (7.5 mg) has been shown to provide a rapid and significant decrease in rheumatoid arthritis symptoms between two and eight weeks after treatment initiation, an effect that was maintained for three months and that was not associatedwith rebound in symptoms after treatment cessation.

                                      In a prior study, the efficacy, disease-modifying properties, and safety of low-dose oral prednisone were compared with those of placebo. This two-year, randomized, double-blind study involved 81 patients with early active rheumatoid arthritis who had not been treated previously with Disease-modifying antirheumatic drugs. Trial participants received either 10 mg daily oral prednisone or placebo, and both treatment groups were given 500 mg daily of elementary calcium. Patients were allowed to take acetaminophen or NSAIDs for pain, if necessary, and sulfasalazine (2 g daily) could be added as a rescue medication after six months if the activity of rheumatoid arthritis warranted the addition of a Disease-modifying antirheumatic drug.

                                      At the conclusion of the two-year trial, treatment with prednisone was associated with a greater mean improvement over baseline scores for most efficacy measures, including early-morning stiffness, morning pain, general well-being, and 28-joint score for swelling. There were significant differences between the improvements for the two groups on two efficacy measures: grip strength (measured by a vigorimeter) and the 28-joint score for tenderness. A clinically relevant improvement (defined as 20% or greater improvement in the 28-joint scores for swelling and tenderness, and 20% or greater improvement in two of the following four variables: pain, general well-being, HAQ, and CRP level) was demonstrated by 33% and 30% of patients receiving prednisone at 12 and 24 months and by 24% and 22% of placebo recipients at these two time periods, respectively. Treatment with prednisone was associated with significant increases in mean body weight and mean serum glucose level compared with placebo. Additionally, the incidence of new vertebral fractures was higher in the prednisone group compared with the group treated with placebo.

                                      Perhaps the most interesting finding from the study is the ability of prednisone to reduce progression of radiologically detected joint damage over the course of two years. At the start of the trial, radiologic evidence demonstrated that 40% of patients randomized to prednisone and 37% of patients randomized to placebo had erosive disease. After 24 months, the percentage of patients with erosive disease was 70% for the prednisone group and 78% for the placebo group. Total radiologic scores (sum of erosion and joint-space narrowing scores using the van der Heijde modification of the Sharp method for scoring radiographs) were significantly lower for the prednisone group compared with placebo at 12, 18, and 24 months. The prednisone group demonstrated a mean 8-point and 16-point increase from baseline in total radiologic score at 12 and 24 months, respectively, compared with mean 15-point and 29-point increases from baseline for the placebo group at these two time periods, respectively. However, corticosteroids are not considered true Disease-modifying antirheumatic drugs because their disease-modifying properties are far inferior to those of conventional and biological Disease-modifying antirheumatic drugs. For example, the combination of etanercept with methotrexate has achieved a 69% ACR 50 response in reducing the signs and symptoms of rheumatoid arthritis and a negative Sharp score, indicating no progression of joint damage at 52 weeks.

                                      ]]>                                       http://healthandpills.com/disorders-and-conditions/arthritis/prednisone/feed 0