Targets & therapy (Biologics)

Publications in this journal

• Article: Critical appraisal of axitinib in the treatment of advanced renal cell carcinoma.

  Jawaher Ansari, Syed A Hussain, Asif Ansari, John Glaholm
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  ABSTRACT: A growing understanding of the biology of renal cell carcinoma (RCC) has led to the development and US Food and Drug Administration approval of seven new molecular targeted agents over the past 7 years. Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors and the latest to join the armamentarium of drugs available for the treatment of metastatic RCC. Despite recent advances in the development of molecular targeted agents for metastatic RCC, the ideal sequencing of these agents remains unclear.
  Targets & therapy 01/2013; 7:39-46.
• Article: Hereditary angioedema: epidemiology, management, and role of icatibant.

  Aasia Ghazi, J Andrew Grant
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  ABSTRACT: Hereditary angioedema (HAE) is an autosomal dominant, potentially life-threatening condition, manifesting as recurrent and self-limiting episodes of facial, laryngeal, genital, or peripheral swelling with abdominal pain secondary to intra-abdominal edema. The estimated prevalence of HAE in the general population is one individual per 50,000, with reported ranges from 1:10,000 to 1:150,000, without major sex or ethnic differences. Various treatment options for acute attacks and prophylaxis of HAE are authorized and available in the market, including plasma-derived (Berinert®, Cinryze®, and Cetor®) and recombinant (Rhucin® and Ruconest™) C1 inhibitors, kallikrein inhibitor-ecallantide (Kalbitor®), and bradykinin B2 receptor antagonist-icatibant (Firazyr®). Some of these drugs are used only to treat HAE attacks, whereas others are only approved for prophylactic therapies and all of them have improved disease outcomes due to their different mechanisms of action. Bradykinin and its binding to B2 receptor have been demonstrated to be responsible for most of the symptoms of HAE. Thus icatibant (Firazyr®), a bradykinin B2 receptor antagonist, has proven to be an effective and more targeted treatment option and has been approved for the treatment of acute attacks of HAE. Rapid and stable relief from symptoms of cutaneous, abdominal, or laryngeal HAE attacks has been demonstrated by 30 mg of icatibant in Phase III clinical trials. Self-resolving mild to moderate local site reactions after subcutaneous injection of icatibant were observed. Icatibant is a new, safe, and effective treatment for acute attacks of HAE. HAE has been reported to result in enormous humanistic burden to patients, affecting both physical and mental health, with a negative impact on education, career, and work productivity, and with substantial economic burdens. The timely and proper use of disease-specific treatments could improve patients' quality of life, reduce the disease-specific morbidity and mortality, and, last but not least, reduce costs associated with hospitalizations and emergency room visits. Therefore, the paradigm of HAE treatment has the potential to evolve significantly, thereby exponentially improving a patient's quality of life.
  Targets & therapy 01/2013; 7:103-13.
• Article: Treatment of hemophilia B: focus on recombinant factor IX.

  Massimo Franchini, Francesco Frattini, Silvia Crestani, Cinzia Sissa, Carlo Bonfanti
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  ABSTRACT: Hemophilia B is a recessive X-linked bleeding disorder characterized by deficiency of the coagulation factor IX (FIX). In hemophilia B patients the severity of the bleeding phenotype is related to the degree of the FIX defect. Hemophilia B treatment has improved greatly in the last 20 years with the introduction first of plasma-derived and then of recombinant FIX concentrates. Replacement therapy may be administered through on-demand or prophylaxis regimens, but the latter treatment modality has been shown to be superior in prevention of hemophilic arthropathy and in improvement of patients' quality of life. The purpose of this narrative review is to summarize the current knowledge on treatment strategies for hemophilia B, focusing on recombinant FIX products either clinically used or in development. There is only one rFIX product that is licensed to treat hemophilia B patients; from the analysis of the literature data presented in this review, the authors conclude that this rFIX product has demonstrated an excellent safety profile and excellent clinical efficacy for halting and preventing bleeds in hemophilia B patients. While prophylaxis has emerged as the best therapeutic strategy for such patients because of its ability to prevent hemophilic arthropathy and to improve patients' quality of life, the pharmacokinetically tailored dosing of rFIX is another key point when planning hemophilia B treatment, as it allows optimization of the factor concentrate usage. Further clinical studies are needed to better assess the safety and efficacy (ie, the incidence of adverse reactions and inhibitor development) of newer rFIX products.
  Targets & therapy 01/2013; 7:33-8.
• Article: Profile of reslizumab in eosinophilic disease and its potential in the treatment of poorly controlled eosinophilic asthma.

  Garry M Walsh
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  ABSTRACT: Eosinophils are important proinflammatory cells that make a major contribution to the inflammation seen in allergic diseases including asthma. Interleukin-5 is central to eosinophil maturation, release from the bone marrow, and subsequent accumulation, activation, and persistence in the tissues. Reslizumab (Cinquil™) is a humanized monoclonal antibody with potent interleukin-5 neutralizing effects, which represents a potential treatment for poorly controlled eosinophilic asthma. This review will consider the current status of the clinical development of reslizumab for asthma and in other inflammatory diseases with a marked eosinophilic component.
  Targets & therapy 01/2013; 7:7-11.
• Article: Duration of remission after halving of the etanercept dose in patients with ankylosing spondylitis: a randomized, prospective, long-term, follow-up study.

  Fabrizio Cantini, Laura Niccoli, Emanuele Cassarà, Olga Kaloudi, Carlotta Nannini
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  ABSTRACT: The aim of this study was to evaluate the proportion of patients with ankylosing spondylitis maintaining clinical remission after reduction of their subcutaneous etanercept dose to 50 mg every other week compared with that in patients receiving etanercept 50 mg weekly. In the first phase of this randomized, prospective, follow-up study, all biologic-naïve patients identified between January 2005 and December 2009 as satisfying the modified New York clinical criteria for ankylosing spondylitis treated with etanercept 50 mg weekly were evaluated for disease remission in January 2010. In the second phase, patients meeting the criteria for remission were randomized to receive subcutaneous etanercept as either 50 mg weekly or 50 mg every other week. The randomization allocation was 1:1. Remission was defined as Bath Ankylosing Spondylitis Disease Activity Index < 4, no extra-axial manifestations of peripheral arthritis, dactylitis, tenosynovitis, or iridocyclitis, and normal acute-phase reactants. The patients were assessed at baseline, at weeks 4 and 12, and every 12 weeks thereafter. The last visit constituted the end of the follow-up. During the first phase, 78 patients with ankylosing spondylitis (57 males and 21 females, median age 38 years, median disease duration 12 years) were recruited. In January 2010, after a mean follow-up of 25 ± 11 months, 43 (55.1%) patients achieving clinical remission were randomized to one of the two treatment arms. Twenty-two patients received etanercept 50 mg every other week (group 1) and 21 received etanercept 50 mg weekly (group 2). At the end of follow-up, 19 of 22 (86.3%) subjects in group 1 and 19 of 21 (90.4%) in group 2 were still in remission, with no significant difference between the two groups. The mean follow-up duration in group 1 and group 2 was 22 ± 1 months and 21 ± 1.6 months, respectively. Remission of ankylosing spondylitis is possible in at least 50% of patients treated with etanercept 50 mg weekly. After halving of the etanercept dose, remission is maintained in a high percentage of patients during long-term follow-up, with important economic implications.
  Targets & therapy 01/2013; 7:1-6.
• Article: Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents.

  Katherine Ververis, Alison Hiong, Tom C Karagiannis, Paul V Licciardi
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  ABSTRACT: Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while discussing the safety and efficacy of these compounds in clinical studies to date.
  Targets & therapy 01/2013; 7:47-60.
• Article: Focus on the potential role of ficlatuzumab in the treatment of non-small cell lung cancer.

  Manolo D'Arcangelo, Federico Cappuzzo
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  ABSTRACT: Lung cancer treatment has rapidly changed in the last few years thanks to novel insights into cancer biology. Several biomarkers and signaling pathways have been recognized as conceivable targets for treatment, and among them is the mesenchymal-epithelial transition/hepatocyte growth factor (c-MET/HGF) axis. Alterations in the c-MET gene and aberrations of MET and HGF expression impact on lung cancer prognosis and are involved in resistance to epidermal growth factor receptor (EGFR) inhibitors in non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations. Several anti-MET and anti-HGF strategies are currently under investigation, including monoclonal antibodies. Ficlatuzumab is a monoclonal antibody directed against HGF that is currently under investigation in NSCLC. The aim of the present review is to critically review available data on HGF and ficlatuzumab in NSCLC.
  Targets & therapy 01/2013; 7:61-68.
• Article: Bosutinib in the management of chronic myelogenous leukemia.

  Gunhild Keller-von Amsberg, Philippe Schafhausen
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  ABSTRACT: Bosutinib (SKI-606) is an orally available, once-daily dual Src and Abl kinase inhibitor, approved by the US Food and Drug Administration for the treatment of adults with chronic, accelerated, or blast-phase Philadelphia chromosome-positive chronic myelogenous leukemia who are intolerant of or resistant to first- or second-generation tyrosine kinase inhibitors. Bosutinib effectively overcomes the majority of imatinib-resistance-conferring BCR-ABL mutations except V299L and T315I. In the Bosutinib Efficacy and Safety in chronic myeloid LeukemiA (BELA) trial, bosutinib attained a faster and deeper molecular response than imatinib in newly diagnosed chronic-phase chronic myelogenous leukemia patients. Treatment-emergent adverse events are usually very manageable. Low grade, mostly self-limiting diarrhea represents the most frequently observed toxicity of bosutinib. Anti-diarrheal drugs, antiemetic agents, and/or fluid replacement should be used to treat these patients. The improved hematological toxicity of bosutinib compared with other tyrosine kinase inhibitors has been ascribed to its minimal activity against platelet-derived growth factor receptor and KIT. In this review, we give an overview on the profile of bosutinib, the clinical potential and treatment-emergent adverse events.
  Targets & therapy 01/2013; 7:115-122.
• Article: Relapsed and refractory lymphoid neoplasms and multiple myeloma with a focus on carfilzomib.

  Ajay Nooka, Charise Gleason, Daniela Casbourne, Sagar Lonial
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  ABSTRACT: Proteasomal inhibition revolutionized myeloma therapies in this decade of novel agents. The only US Food and Drug Administration approved proteasome inhibitor so far, bortezomib effectively targets the constitutive proteasome subunit β5 of the 26S proteasome. Bortezomib induces high and quality response rates that are durable. However, myeloma cells acquire resistance to bortezomib through various mechanisms. Further, grade 3/4 peripheral neuropathy is seen in up to a quarter of patients treated with bortezomib. While the recent change in the mode of administration via the subcutaneous route is associated with a lower incidence of grade 3/4 peripheral neuropathy, it remains a major concern. The second generation proteasome inhibitors are promising, with increased preclinical efficacy and a better administration schedule. The current review spotlights the second generation proteasome inhibitors with special focus on the safety and efficacy of carfilzomib, an epoxyketone with lesser peripheral neuropathy, which exhibits irreversible proteasome inhibition. In this article, we review the pharmacology and preclinical and clinical efficacy and safety of carfilzomib alone and in combination with other chemotherapeutic agents in the various lymphoid neoplasms and multiple myeloma as well as ongoing clinical trials.
  Targets & therapy 01/2013; 7:13-32.
• Article: Factors correlated with improvement of endothelial dysfunction during rituximab therapy in patients with rheumatoid arthritis.

  Maurizio Benucci, Gianantonio Saviola, Mariangela Manfredi, Piercarlo Sarzi-Puttini, Fabiola Atzeni
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  ABSTRACT: Increased cardiovascular mortality has been associated with rheumatoid arthritis (RA). There are reports indicating that tumor necrosis factor (TNF) blockers may exert favorable but transient effects on the lipid profile, flow-mediated vasodilatation (FMD) of the brachial artery, and the common carotid intima-media thickness (ccIMT) in RA. We evaluated 38 RA patients (33 females and five males with a mean age of 66.7 ± 10.2 years) who were unresponsive to TNF blockers. The patients received one or more courses of two rituximab (RTX) 1000 mg infusions. Disease activity was evaluated at each visit. Investigations included erythrocyte sedimentation rate, C-reactive protein (CRP) levels, the 28-joint disease activity score (DAS28), DAS28CRP, the Health Assessment Questionnaire, the FMD percent change from baseline (FMD%), and the postnitroglycerine endothelium-independent vasodilatation. In comparison with the baseline, there was a significant improvement in clinical variables and acute-phase reactants 24 months after the start of RTX therapy. There was also a major improvement in FMD% (from baseline 5.24 ± 1.12 to 5.43 ± 1.16; P = -0.03) and a smaller change in the ccIMT (from baseline 0.69 ± 0.16 to 0.67 ± 0.12 mm P = 0.25). Univariate analysis showed that global health (P < 0.034) was associated with the improvement in FMD%. Multivariate models showed that GH (odds ratio [OR] 0.91; 95% CI: 0.99-0.83; P = 0.032), CD19+ cells (OR 1.024; 95% CI: 1.045-1.003; P = 0.025), IgM (OR 1.025; 95% CI: 1.045-1.004; P = 0.016), and interleukin (IL)-8 (OR 0.487; 95% CI: 0.899-0.264; P = 0.021) were statistically associated with the improvement of FMD%, and that IL-8 (OR 0.717; 95% CI: 0.926-0.555; P = 0.018) was also statistically associated with improvement of ccIMT. The findings of the study confirm that RTX reduces the progression of accelerated atherosclerosis in patients with RA. They also show that improvement in CD19+ cells, IgM and GH after treatment are statistically associated with the improvement of FMD%, and that improvement in IL-8 levels after treatment is statistically associated with improved FMD% and with decrease in the ccIMT.
  Targets & therapy 01/2013; 7:69-75.
• Article: Clinical use of crizotinib for the treatment of non-small cell lung cancer.

  Patrick J Roberts
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  ABSTRACT: Discoveries over the last decade have fundamentally transformed the way we define lung cancer. Gone are the days of the simple binary classification system of non-small cell lung cancer (NSCLC) and small cell lung cancer. Today, accurate identification of the histological and molecular subtype of NSCLC is required for selecting standard cytotoxic chemotherapy and targeted therapies. The identification of anaplastic lymphoma kinase (ALK) rearrangements in 5-7% of NSCLC patients and the rapid clinical development of crizotinib for these patients is the most recent clinical example necessitating the proper identification of the molecular characteristics of NSCLC for treatment decisions. The discovery of ALK rearrangements in NSCLC serendipitously coincided with the development of crizotinib for other ALK or MET driven malignancies. The clinical development of crizotinib for ALK-positive NSCLC patients has been an amazing success story of translational medicine that relied on the prior clinical experience of other targeted predecessors (i.e. erlotinib in EGFR mutant NSCLC) and a compound ready for clinical development to gain expedited FDA approval. This review discusses the clinical development and use of crizotinib in NSCLC.
  Targets & therapy 01/2013; 7:91-101.
• Article: Clofilium inhibits Slick and Slack potassium channels.

  Maria de Los Angeles Tejada, Kathleen Stolpe, Anne-Kristine Meinild, Dan A Klaerke
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  ABSTRACT: Slick and Slack high-conductance potassium channels have been recently discovered, and are found in the central nervous system and in the heart. Both channels are activated by Na(+) and Cl(-), and Slick channels are also inhibited by adenosine triphospate (ATP). An important role of setting the resting membrane potential and controlling the basal excitability of neurons has been suggested for these channels. In addition, no specific blockers for these channels are known up to the present. With the purpose of studying the pharmacological characteristics of Slick and Slack channels, the effects of exposure to the antiarrhythmic compound clofilium were evaluated. Clofilium was able to modulate the activity of Slick and Slack channels effectively, with a stronger effect on Slack than Slick channels. In order to evaluate the pharmacological behavior of Slick and Slack channels further, 38 commonly used potassium channel blockers were tested. Screening of these compounds did not reveal any modulators of Slick and Slack channels, except for clofilium. The present study provides a first approach towards elucidating the pharmacological characteristics of Slick and Slack channels and could be the basis for future studies aimed at developing potent and specific blockers and activators for these channels.
  Targets & therapy 01/2012; 6:465-70.
• Article: Anti-tumor necrosis factor (TNF) drugs for the treatment of psoriatic arthritis: an indirect comparison meta-analysis.

  Kristian Thorlund, Eric Druyts, J Antonio Aviña-Zubieta, Edward J Mills
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  ABSTRACT: To evaluate the comparative effectiveness of available tumor necrosis factor-α inhibitors (anti-TNFs) for the management of psoriatic arthritis (PsA) in patients with an inadequate response to disease-modifying antirheumatic drugs (DMARDs). We used an exhaustive search strategy covering randomized clinical trials, systematic reviews and health technology assessments (HTA) published on anti-TNFs for PsA. We performed indirect comparisons of the available anti-TNFs (adalimumab, etanercept, golimumab, and infliximab) measuring relative risks (RR) for the psoriatic arthritis response criteria (PsARC), mean differences (MDs) for improvements from baseline for the Health Assessment Questionnaire (HAQ) by PsARC responders and non-responders, and MD for the improvements from baseline for the psoriasis area and severity index (PASI). When the reporting of data on intervention group response rates and improvements were incomplete, we used straightforward conversions based on the available data. We retrieved data from 20 publications representing seven trials, as well as two HTAs. All anti-TNFs were significantly better than control, but the indirect comparison did not reveal any statistically significant difference between the anti-TNFs. For PsARC response, golimumab yielded the highest RR and etanercept the second highest; adalimumab and infliximab both yielded notably smaller RRs. For HAQ improvement, etanercept and infliximab yielded the largest MD among PsARC responders. For PsARC nonresponders, etanercept, infliximab, and golimumab yielded similar MDs, and adalimumab a notably lower MD. For PASI improvement, infliximab yielded the largest MD and golimumab the second largest, while etanercept yielded the smallest MD. In some instances, the estimated magnitudes of effect were notably different from the estimates of previous HTA indirect comparisons. There is insufficient statistical evidence to demonstrate differences in effectiveness between available anti-TNFs for PsA. Effect estimates seem sensitive to the analytic approach, and this uncertainty should be taken into account in future economic evaluations.
  Targets & therapy 01/2012; 6:417-27.
• Article: Limited cross-reactivity of mouse monoclonal antibodies against Dengue virus capsid protein among four serotypes.

  Megumi Noda, Promsin Masrinoul, Chaweewan Punkum, Chonlatip Pipattanaboon, Pongrama Ramasoota, Chayanee Setthapramote, Tadahiro Sasaki, Mikiko Sasayama, Akifumi Yamashita, Takeshi Kurosu, Kazuyoshi Ikuta, Tamaki Okabayashi
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  ABSTRACT: Dengue illness is one of the important mosquito-borne viral diseases in tropical and subtropical regions. Four serotypes of dengue virus (DENV-1, DENV-2, DENV-3, and DENV-4) are classified in the Flavivirus genus of the family Flaviviridae. We prepared monoclonal antibodies against DENV capsid protein from mice immunized with DENV-2 and determined the cross-reactivity with each serotype of DENV and Japanese encephalitis virus. To clarify the relationship between the cross-reactivity of monoclonal antibodies and the diversity of these viruses, we examined the situations of flaviviruses by analyses of phylogenetic trees. Among a total of 60 prepared monoclonal antibodies specific for DENV, five monoclonal antibodies stained the nuclei of infected cells and were found to be specific to the capsid protein. Three were specific to DENV-2, while the other two were cross-reactive with DENV-2 and DENV-4. No monoclonal antibodies were cross-reactive with all four serotypes. Phylogenetic analysis of DENV amino acid sequences of the capsid protein revealed that DENV-2 and DENV-4 were clustered in the same branch, while DENV-1 and DENV-3 were clustered in the other branch. However, these classifications of the capsid protein were different from those of the envelope and nonstructural 1 proteins. Phylogenetic distances between the four serotypes of DENV were as different as those of other flaviviruses, such as Japanese encephalitis virus and West Nile virus. Large variations in the DENV serotypes were comparable with the differences between species of flavivirus. Furthermore, the diversity of flavivirus capsid protein was much greater than that of envelope and nonstructural 1 proteins. In this study, we produced specific monoclonal antibodies that can be used to detect DENV-2 capsid protein, but not a cross-reactive one with all serotypes of DENV capsid protein. The high diversity of the DENV capsid protein sequence by phylogenetic analysis supported the low cross-reactivity of monoclonal antibodies against DENV capsid protein.
  Targets & therapy 01/2012; 6:409-16.
• Article: Systematic review and network meta-analysis of combination and monotherapy treatments in disease-modifying antirheumatic drug-experienced patients with rheumatoid arthritis: analysis of American College of Rheumatology criteria scores 20, 50, and 70.

  Michelle E Orme, Katherine S Macgilchrist, Stephen Mitchell, Dean Spurden, Alex Bird
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  ABSTRACT: Biologic disease-modifying antirheumatic drugs (bDMARDs) extend the treatment choices for rheumatoid arthritis patients with suboptimal response or intolerance to conventional DMARDs. The objective of this systematic review and meta-analysis was to compare the relative efficacy of EU-licensed bDMARD combination therapy or monotherapy for patients intolerant of or contraindicated to continued methotrexate. Comprehensive, structured literature searches were conducted in Medline, Embase, and the Cochrane Library, as well as hand-searching of conference proceedings and reference lists. Phase II or III randomized controlled trials reporting American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 between 12 and 30 weeks' follow-up and enrolling adult patients meeting ACR classification criteria for rheumatoid arthritis previously treated with and with an inadequate response to conventional DMARDs were eligible. To estimate the relative efficacy of treatments whilst preserving the randomized comparisons within each trial, a Bayesian network meta-analysis was conducted in WinBUGS using fixed and random-effects, logit-link models fitted to the binomial ACR 20/50/70 trial data. The systematic review identified 10,625 citations, and after a review of 2450 full-text papers, there were 29 and 14 eligible studies for the combination and monotherapy meta-analyses, respectively. In the combination analysis, all licensed bDMARD combinations had significantly higher odds of ACR 20/50/70 compared to DMARDs alone, except for the rituximab comparison, which did not reach significance for the ACR 70 outcome (based on the 95% credible interval). The etanercept combination was significantly better than the tumor necrosis factor-α inhibitors adalimumab and infliximab in improving ACR 20/50/70 outcomes, with no significant differences between the etanercept combination and certolizumab pegol or tocilizumab. Licensed-dose etanercept, adalimumab, and tocilizumab monotherapy were significantly better than placebo in improving ACR 20/50/70 outcomes. Sensitivity analysis indicated that including studies outside the target population could affect the results. Licensed bDMARDs are efficacious in patients with an inadequate response to conventional therapy, but tumor necrosis factor-α inhibitor combination therapies are not equally effective.
  Targets & therapy 01/2012; 6:429-64.
• Source

  Available from: PubMed Central

  Article: Ustekinumab in the therapy of chronic plaque psoriasis.

  Jenna L O'Neill, Robert E Kalb
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  ABSTRACT: Psoriasis is a chronic inflammatory disorder characterized by T cell dysregulation and a chronic inflammatory infiltrate within the epidermis. Several cytokines play an important role in the pathogenesis of psoriasis, including interleukin-12 (IL-12) and IL-23. These cytokines act via induction of pro-inflammatory cytokines which promote chronic inflammation and auto-reactivity. Ustekinumab is a fully human monoclonal antibody against the common p40 subunit of IL-12 and IL-23. Two randomized, double-blind, placebo-controlled trials of ustekinumab have demonstrated significant and prolonged efficacy in the treatment of plaque psoriasis. Adverse events were generally similar across treatment and control groups. Studies are ongoing to assess the long term safety and efficacy profiles of ustekinumab.
  Targets & therapy 02/2009; 3:159-68.
• Source

  Available from: PubMed Central

  Article: Infliximab in the treatment of rheumatoid arthritis.

  A Perdriger
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  ABSTRACT: Infliximab was the first monoclonal antibody to human necrosis factor alpha (TNFalpha) developed for treating rheumatoid arthritis (RA). This chimeric antibody binds with high affinity to both soluble and trans-membrane TNF and is able to reduce synovial inflammation, bone resorption and cartilage degradation. The efficacy of infliximab has been observed in active RA despite treatment with multiple disease modifying anti-rheumatic drugs (DMARDs), and in early disease with no prior treatment by methotrexate (MTX). Infliximab has been shown to reduce joint inflammation and to slow radiographic progression, in both clinical and non-clinical responders. Recent data suggest that using infliximab early in RA treatment increases the percentage of clinical remission and allows infliximab discontinuation. The recommended dosage of 3 mg/kg could be increased up to 10 mg/kg with partial efficacy of the dose escalation. Antibodies to infliximab have been observed in 7% to 61% of patients and are associated with a low trough level of infliximab and secondary response failure. Their occurrence could be prevented by co-medication with MTX. The combination of DMARDs other than MTX with infliximab was found to be safe and efficacious. Infections, principally tuberculosis, are increased in treated patients, and the risk is greater at higher dose. Even if the treatment is generally safe and well tolerated, patients treated with infliximab should be closely monitored.
  Targets & therapy 02/2009; 3:183-91.
• Source

  Available from: PubMed Central

  Article: HER2 breast cancer therapies: a review.

  Conleth G Murphy, Shanu Modi
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  ABSTRACT: Amplification of the HER2 gene and/or overexpression of its protein product have been found in up to 25% to 30% of human breast cancers and have been shown to be associated with poorer outcomes compared to 'HER2 normal' breast cancer. Research has focused on developing therapies directed to the HER2 receptor and its pathway. These include the monoclonal antibody trastuzumab, which has improved outcomes when used in patients with both advanced and early breast cancer. Lapatinib is a small-molecule tyrosine kinase inhibitor which has demonstrated activity in advanced breast cancer and is currently being evaluated in early stage disease. We discuss the therapeutic rationale and clinical trial experience with these agents. Other novel and emerging strategies targeting the HER2 receptor and its pathway are also discussed. These strategies include novel HER2 antibodies and small-molecule inhibitors, antibody-drug conjugates, agents targeting downstream components of the HER2 signaling pathway, and heat shock protein 90 (HSP90) inhibitors.
  Targets & therapy 02/2009; 3:289-301.
• Source

  Available from: PubMed Central

  Article: Management of chronic hepatitis C treatment failures: role of consensus interferon.

  Stevan A Gonzalez, Emmet B Keeffe
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  ABSTRACT: A significant proportion of patients with chronic hepatitis C virus (HCV) infection who undergo antiviral therapy have persistent or recurrent viremia and fail to achieve a sustained virologic response (SVR). Factors associated with treatment failure include HCV genotype 1 infection, high serum HCV RNA levels, and advanced fibrosis. Consensus interferon (CIFN) is a synthetic type I interferon derived from a consensus sequence of the most common amino acids found in naturally occurring alpha interferon subtypes. Several prospective clinical studies have demonstrated that CIFN may be a treatment option in patients who have failed prior interferon-based therapy, including those who have failed combination therapy with standard interferon or peginterferon plus ribavirin. Daily CIFN in combination with ribavirin may be an effective regimen in this setting; however, optimal dose and treatment duration of CIFN therapy have not been well established. Patients who achieve viral suppression during prior interferon-based therapy and those who do not have advanced fibrosis have a greater likelihood of achieving a SVR with CIFN retreatment. Individualized therapy targeting specific patient groups will be an important consideration in the successful management of prior treatment failures. Additional prospective studies are required in order to identify optimal treatment strategies for the use of CIFN in these patients.
  Targets & therapy 02/2009; 3:141-50.