The role of biologic agents in the management of non-infectious uveitis

Introduction: Uveitis is an intriguing group of disorders characterized by inflammation of the uveal tract. Due to the potential grave consequences of the disease process, it is important to assess the various therapeutic options available for treating uveitis, and their outcomes.

Areas covered: This review discusses the use of conventional agents in the management of uveitis, including discussion of the molecular and clinical properties of corticosteroids, antimetabolites, calcineurin inhibitors and alkylating agents and their side effects. In addition, it also discusses the molecular and clinical properties of novel biologic agents and their side effects. Moreover, recommendations as to when biologic agents should be employed are also discussed.

Expert opinion: We recommend that in general (except in selected cases of Adamantiades-Behçet's disease) biologics should not be used as a first-line therapy for uveitis due to inconvenience, high cost, and potential immunosuppressive effects. However, many biologics are potent in inducing drug-free remission of uveitis and may be employed to manage recurrent diseases or diseases not responsive to conventional agents.     

A comprehensive review and update on the biologic treatment of adult noninfectious uveitis: part II

Introduction: Treatment of adult, noninfectious uveitis remains a major challenge for ophthalmologists around the world, especially in regard to recalcitrant cases. It is reported to comprise approximately 10% of preventable blindness in the USA. The cause of uveitis can be idiopathic or associated with infectious and systemic disorders. The era of biologic medical therapies provides new options for patients with otherwise treatment-resistant inflammatory eye disease.

Areas covered: This two-part review gives a comprehensive overview of the existing medical treatment options for patients with adult, noninfectious uveitis, as well as important advances for the treatment ocular inflammation. Part I covers classic immunomodulation and latest information on corticosteroid therapy. In part II, emerging therapies are discussed, including biologic response modifiers, experimental treatments and ongoing clinical studies for uveitis.

Expert opinion: The hazard of chronic corticosteroid use in the treatment of adult, noninfectious uveitis is well documented. Corticosteroid-sparing therapies, which offer a very favorable risk–benefit profile when administered properly, should be substituted. Although nothing is currently approved for on-label use in this indication, many therapies, through either translation or novel basic science research, have the potential to fill the currently exposed gaps.     

Melanoma-associated antigen-A3 vaccination in the treatment of non-small-cell lung cancer

ABSTRACT

Introduction: The pathophysiology of diabetic macular edema (DME) is complex, involving vascular endothelial growth factor (VEGF) and other inflammatory mediators. DME is currently treated first-line with intravitreal anti-VEGF treatments, though some cases are refractory to multiple anti-VEGF treatments.

Areas covered: This article examines the evolution of treatment practices for DME, with discussion of the recent studies that guide treatment for refractory cases of DME. A literature search was performed using the following terms: anti-VEGF, DME, aflibercept, bevacizumab, ranibizumab, refractory macular edema, and VEGF.

Expert opinion: Focal extrafoveal DME may be treated first-line with laser. In patients with center-involving DME and only mild vision loss, consider starting treatment with bevacizumab, especially when cost is an issue, whereas aflibercept may be considered more strongly in patients with moderate visual loss or worse. There are no standard protocols that define ‘treatment failure,’ but several studies have reported that switching from bevacizumab to either ranibizumab or aflibercept will result in further reduction of CSFT and improvement in BCVA. Further study with prospective randomized trials is warranted to validate these findings. Switching to intravitreal corticosteroids may be of particular benefit to pseudophakic patients. Anti-VEGF combination with sustained-release corticosteroids also appears promising for refractory DME.     

Intravitreal steroid and anti-vascular endothelial growth agents for the management of retinal vein occlusion: evidence from randomized trials

Introduction: Retinal vein occlusion (RVO) is a common retinal vascular disorder, affecting visual acuity and quality of life. Macular edema (ME) and retinal ischemia are the main causes for visual impairment in RVO. Although several modalities have been evaluated for the treatment of ME secondary to RVO in clinical trials, various questions need to be clarified when translating clinical trials into real-world practice.

Areas covered: Intravitreal steroids and anti-VEGF agents are now widely used for the treatment of ME due to RVO. Herein, evidence from randomized controlled trials regarding the use of steroids and anti-VEGF agents in ME related to RVO are presented. In addition, an approach regarding the optimal treatment regimen, the most suitable time for initiating treatment and monitoring patients, as well as the potential role of ischemia in the response to treatment and the impact of treatment on the natural course of the disease was made.

Expert opinion: A comprehensive presentation of randomized clinical trials evaluating intravitreal steroids and anti-VEGF treatment for RVO indicates that both are effective and safe. However, the comparative effectiveness of the various anti-VEGF agents, the most suitable dosing regimen and the effect of these agents on retinal ischemia remains unclear.     

Monoclonal antibodies currently in Phase II and III trials for multiple myeloma

Introduction: Despite the introduction of novel agents, such as thalidomide, lenalidomide and bortezomib, multiple myeloma (MM) remains an incurable disease and new therapies are needed. mAbs are a new promising anticancer treatment option.

Areas covered: This review will focus on mAbs that are currently under evaluation in Phase II and III clinical trials, as single agent and in combination with established treatment options.

Expert opinion: mAbs are a new strategy against MM, and they have demonstrated encouraging results in preclinical models. mAbs have a relatively benign side-effect profile and work synergistically with traditional chemotherapies and with immunomodulatory drugs and proteasome inhibitors.     

Proprotein convertase subtilisin kexin 9 inhibitors: next generation in lipid-lowering therapy

Introduction: Statins reduce low-density lipoprotein cholesterol (LDL-C) and are currently the mainstay in the treatment of hyperlipidaemia and subsequently the prevention of atherosclerotic cardiovascular disease (CVD). Nevertheless, there is a need to further lower LDL-C, especially in subjects with severe forms of hypercholesterolaemia despite maximum doses of conventional drugs and/or in those intolerant to existing therapies.

Areas covered: Emerging therapeutic approaches to lowering LDL-C involve blocking LDL-receptor degradation by serum proprotein convertase subtilisin kexin 9 (PCSK9). Human monoclonal antibodies that target PCSK9 and its interaction with the LDL-receptor (AMG145, REGN727 and RN316) have been tested in Phase I – III clinical trials for the treatment of hyperlipidaemia in patients at high CVD risk.

Expert opinion: These new agents are administered subcutaneously and have been shown to have major LDL-C and apoB lowering effects either alone or in combination with statins. These novel agents are generally well tolerated and once long-term safety data are available they appear promising therapeutic platforms for the treatment of patients with hypercholesterolaemia at risk for or with CVD not controlled by conventional therapies.     

Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration

Introduction: The consistent association between choroid neovascularization (CNV) and increased VEGF-A expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of neovascular age-related macular degeneration (AMD). The authors report the systemic side effects secondary to intravitreal administration of these compounds, that is, the main cardiovascular effects, as well as the less frequent cerebrovascular accidents, myocardial infarction, transient ischemic attacks, deep vein thrombosis, pulmonary embolism and thromboflebitis.

Areas covered: The authors reviewed major Clinical Trials and publications concerning systemic adverse events of anti-VEGF drugs in order to identify the main thromboembolic events related to the use of these agents and their occurrence. Anti-VEGF efficacy, safety and tolerability are also discussed.

Expert opinion: Three compounds (pegaptanib, ranibizumab and aflibercept) have been approved for the treatment of AMD; a fourth agent, bevacizumab, is used off-label. Anti-VEGF therapy has not shown the ability to fully eradicate the CNV, so that recurrences are common when the intravitreal injections are suspended. Although no evident rise in anti-VEGF-induced thromboembolic side effects was reported, more data are required to evaluate hemodynamic and pharmacokinetics of these compounds. Since only few studies have focused on these aspects, further researches are mandatory to determine distribution, effects and duration of these substances.     

Contribution of glycosylated recombinant human granulocyte colony-stimulating factor (lenograstim) use in current cancer treatment: review of clinical data

Importance of the field: Granulocyte colony-stimulating factors (G-CSFs) such as lenograstim have improved the management of cancer patient treatments for 15 years. Their use in preventing chemotherapy-induced febrile neutropenia and for progenitor-cell transplantation has been evaluated. Although the main indications are nowadays defined in academic guidelines, some changes in traditional G-CSF use are being induced by the emergence of new chemotherapy schedules and new drugs.

Areas covered in this review: Analyzing publications on G-CSFs and lenograstim identified in the PubMed database from 1985 to date, we summarise pharmacological data and clinical trials on lenograstim and discuss its effects and limits in current treatment regimens.

What the reader will gain: Lenograstim is a glycosylated form of recombinant human G-CSF, more similar to the endogenous cytokine. Clinical trials have proven its efficacy for preventing chemotherapy-induced neutropenia and for progenitor-cell transplantation, almost similar to filgrastim. Its benefit is compelling in some well-defined settings (highly myelosuppressive chemotherapy, advanced cancer, high-risk patients).

Take home message: If usual indications are well defined nowadays, further investigations are still needed to better define optimal use (optimal time to start, treatment duration) and effects on quality of life. In addition, since new strategies for cancer management are emerging, such as oral chemotherapy or targeted therapies, there is a need for clinical data to define lenograstim use in these recent settings.     

Management of infections caused by extended-spectrum β–lactamase-producing Enterobacteriaceae: current evidence and future prospects

Introduction: The spread of extended-spectrum β–lactamase (ESBL)-producing Enterobacteriaceae has become a major public health threat worldwide.

Area covered: A thorough systematic literature review describing the current evidence and future prospects of therapeutic options for infections caused by ESBL-producing Enterobacteriaceae.

Expert commentary: The methods of detecting ESBLs have been evolving. The Clinical and Laboratory Standards Institute and the European Committee on Antimicrobial Susceptibility Testing lowered the MIC breakpoints of cephalosporins against ESBL-producing Enterobacteriaceae in 2010. Phenotypic testing for ESBLs is no longer recommended. Instead, the selection of appropriate antimicrobial agents largely depends on the report of minimum inhibitory concentrations (MICs). To date, therapeutic options for these multidrug-resistant organisms remain limited. The clinical efficacy of piperacillin/tazobactam and cefepime on in vitro-susceptible ESBL-producing Enterobacteriaceae remains a concern. Many studies found an in vitro-in vivo discordance based on current breakpoints. Carbapenems are the most reliable antibiotics for severe infections caused by ESBL-producing Enterobacteriaceae. However, their overuse has led to a serious problem of increasing drug resistance. Recently, ceftolozane/tazobactam and ceftazidime/avibactam have been approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections. The introduction of these new β-lactam/β-lactamase inhibitor combinations offers new carbapenem-sparing options for the treatment of ESBL infections.     

Management of severe complications in Behçet’s disease with TNF inhibitors

Introduction: The efficacy of anti-TNFα agents has been recently evaluated in many studies in Behçet’s disease (BD), particularly in ocular and life-threatening manifestations such as neurological and vascular disease.

Areas covered: The following article aims to summarize the currently available efficacy and safety data of anti-TNFα agents in BD.

Expert opinion: Most studies have shown dramatic and rapid efficacy with anti-TNFα agents on the main BD-associated issues including posterior uveitis, gastro-intestinal and neurological complications as well as major vessel disease. Experts in the field do recommend the use of anti-TNF agents (either infliximab or adalimumab) as a first-line therapy in severe posterior uveitis in BD and now use anti-TNFα treatment in BD-associated life threatening manifestations. However, data is mainly based on retrospective cohorts or open-label prospective studies. Controlled studies (versus conventional immunosuppressants such as azathioprine and cyclophosphamide) are warranted to properly evaluate their efficacy as first line therapeutic in life-threatening manifestations of BD.     

Current clinical evidence for the use of mesenchymal stem cells in articular cartilage repair

ABSTRACT

Introduction: Articular cartilage is renowned for its poor intrinsic capacity for repair. Current treatments for osteoarthritis are limited in their ability to reliably restore the native articular cartilage structure and function. Mesenchymal stem cells (MSCs) present an attractive treatment option for articular cartilage repair, with a recent expansion of clinical trials investigating their use in patients.

Areas covered: This paper provides a current overview of the clinical evidence on the use of MSCs in articular cartilage repair.

Expert opinion: The article demonstrates robust clinical evidence that MSCs have significant potential for the regeneration of hyaline articular cartilage in patients. The majority of clinical trials to date have yielded significantly positive results with minimal adverse effects. However the clinical research is still in its infancy. The optimum MSC source, cell concentrations, implantation technique, scaffold, growth factors and rehabilitation protocol for clinical use are yet to be identified. A larger number of randomised control trials are required to objectively compare the clinical efficacy and long-term safety of the various techniques. As the clinical research continues to evolve and address these challenges, it is likely that MSCs may become integrated into routine clinical practice in the near future.     

Immune checkpoint blockade as a potential therapeutic target in non-small cell lung cancer

ABSTRACT

Introduction: The recent emergence of immune checkpoint blockade therapy and the progression of immunobiology in cancer have spurred an increasing interest in the immunotherapy for advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs), designed to directly target immune inhibitory molecules, have demonstrated efficacy in the treatment of patients with advanced NSCLC.

Areas covered: In the present article, the authors summarize the mechanism, efficacy and safety of major ICIs for the treatment of advanced or metastatic NSCLC. Combinations of different ICIs or conventional therapy and/or targeted agents for NSCLC treatment in clinical trials are also updated. In addition, immune-related adverse events and the roles of inhibitory immune checkpoint molecules as potential biomarkers in the immune checkpoint blockade therapy for NSCLC are emphatically elucidated.

Expert opinion: Immunotherapies targeting the immune checkpoint pathways have shown potential to generate durable responses and improve survival for NSCLC patients. Although the toxicity profile of this immunotherapy is manageable, immune-related adverse events and drug resistance may cause therapeutic failure. Therefore, a better understanding of the mechanisms underpinning its function and the potential side effects of ICIs, as well as the identification of predictive biomarkers for patient selection are essential.     

Interleukin-2 receptor blockade with humanized monoclonal antibody for solid organ transplantation

Importance of the field: Induction therapy has reduced the incidence of acute rejection compared with historical standards. The potency of currently available induction immunosuppression is not without risk and should be carefully considered. Induction with daclizumab, an IL-2 receptor antagonist, has been used safely and effectively for over 10 years across different transplant types. As a result of daclizumab use, transplant centers are able to implement steroid-sparing or calcineurin minimization protocols. Unfortunately, the manufacturing costs have resulted in withdrawal of this agent from the market reducing the options for patients undergoing transplantation.

Areas covered in this review: This review will update the reader on recently published daclizumab studies in adult solid organ transplant recipients, focusing on comparative studies with other induction agents.

What the reader will gain: This paper will provide a summary of comparative studies between daclizumab and other induction therapies focusing on their efficacy and safety.

Take home message: Novel applications, such as long-term use in combination with calcineurin-inhibitor dose reduction and its value in the treatment of acute or chronic rejection have yet to be explored. Since daclizumab has been withdrawn from the market, future IL-2 receptor blockade will have to be achieved with basiliximab, which is a chimeric, monoclonal antibody directed against the same epitope.     

Albiglutide: a new GLP-1 analog for the treatment of type 2 diabetes

Importance of the field: Despite the wide array of treatments available, a significant number of patients with type 2 diabetes continue to remain uncontrolled. The discovery of the incretin hormones and their role in glucose homeostasis has brought about a new class of medications called the glucagon-like peptide-1 (GLP-1) analogs. This new class of medications provides the benefits of weight loss as well as a lack of hypoglycemia. However, the currently available agents require once or twice daily injections.

Areas covered in this review: Relevant literature will be discussed on albiglutide, a new GLP-1 analog in Phase III clinical trials. Several clinical trials examining the use of albiglutide as combination therapy are currently ongoing.

What the reader will gain: To date, results of clinical trials suggest that albiglutide may provide a more attractive dosing profile compared with the currently available GLP-1 analogs.

Take home message: The results of ongoing trials will help define the role of albiglutide in treating patients with type 2 diabetes.     

Erythropoietin in stroke: quo vadis

Importance of the field: Recombinant erythropoietin (rEPO) failed in a recent clinical study to protect from damages induced by ischemic stroke. The lack of acute treatments in ischemic stroke and the promising outcome in numerous preclinical studies in vivo demands a more critical evaluation of the future use of EPO as an acute treatment.

Areas covered in this review: The current use and administration of rhEPO and its analogs in animal models and the future use of this cytokine in the treatment of ischemic stroke.

What the reader will gain: In this review the potential reasons for the failure of EPO in the clinical trial are analysed and whether the preclinical trials sufficiently evaluated the true potential of recombinant EPO and its analogs is assessed. Alternative methods for administration of EPO to enhance its potential as a neuroprotective drug in ischemic stroke are discussed.

Take home message: Failure in clinical trial does not necessarily indicate the lack of therapeutic potential of EPO. This review encourages further investigation of the true potential of EPO as a candidate drug for the treatment of ischemic stroke by improved preclinical experimental design and utilization of alternative administration methods.     

Developments in liposomal gene delivery systems

ABSTRACT

Introduction: Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology. Currently approved therapies include prednisone, TNF antagonists and anti-metabolites which often are ineffective and have frequent adverse effects. Consequently, UC patients are always at risk for developing serious complications that affect their quality of life. Therefore, new treatment options are required.

Areas covered: This article discusses etrolizumab, its mechanism and the potential role it can have in the future of treating UC. Etrolizumab is a humanized monoclonal antibody that selectively blocks lymphocyte trafficking and retention in the gut. The safety and efficacy data was reviewed from all randomized placebo-controlled trials which evaluated etrolizumab for the treatment of UC.

Expert opinion: Etrolizumab is an effective and well-tolerated drug for the treatment of UC. It appears to be a promising molecule that can benefit UC patients.     

Angiogenesis in esophageal and gastric cancer: a paradigm shift in treatment

Introduction: Esophageal and stomach cancers are leading cause of cancer death worldwide, killing more than 1 million people each year. In unscreened population, patients’ symptoms will trigger diagnostic workup. Most patients are diagnosed with advanced stage and their disease is not amenable to surgical resection. The disease is aggressive in nature and mostly even those patients who have early stage disease will eventually succumb to recurrence after definitive therapy. Patients with advanced esophageal and stomach cancers have very limited options for target agents and conventional chemotherapy has remained the standard of care.

Areas covered: Since its discovery, antiangiogenesis continues to be the repeating theme of cancer therapy of the modern era. However, although successful in other tumor types, the data from highly anticipated antiangiogenic agents from both the small molecule tyrosine kinase inhibitors and monoclonal antibodies for esophageal and gastric cancers had been disappointing. Many attribute the lack of survival benefit noted in clinical trials to the failure in identifying target in this patient population.

Expert opinion: The most recent clinical studies support that specifically attacking vascular endothelial growth factor receptors remain effective in esophageal and gastric cancers. These pivotal trials may prove to shift the paradigm of current therapy and will likely gain approval for the drug of interest. At the same time, the results generate more questions to understand the disease biology as well as to identify those patients who will benefit the most from such therapy.     

Conatumumab: a novel monoclonal antibody against death receptor 5 for the treatment of advanced malignancies in adults

Introduction: Advanced malignancies that are refractory to standard chemotherapy have few treatment options. Conatumumab is an investigational, fully human monoclonal agonist antibody directed at human death receptor DR5, which is expressed in multiple advanced cancers.

Areas covered: The rationale for the use of conatumumab based on in vitro, in vivo, Phase I, and Phase II data will be discussed.

Expert opinion: Conatumumab, at a dose of 20 mg/kg every 2 weeks, has demonstrated acceptable safety and tolerability in patients with advanced tumors based on available and published data. Further clinical trials are underway evaluating the use of conatumumab in combination with chemotherapeutic and targeted agents.     

Recombinant hormones in osteoporosis

Introduction: For the last 10 years, bone anabolic therapy with the recombinant human parathyroid hormone (rhPTH) analogue, teriparatide (rhPTH[1 – 34]), or full-length rhPTH(1 – 84) has been an option in the treatment of osteoporosis. Both drugs are given as a daily subcutaneous injection. In the USA, only teriparatide is marketed.

Areas covered: Mechanisms of action by which rhPTH induces bone anabolic effects includes changes in bone remodeling, geometry and mineral density. Data from randomized controlled trials on anti-fracture efficacy are reviewed as well as results from a number of recent studies on administration less than once-a-day or intermittent-/cyclic-therapy. Treatment effects are compared with those of anti-resorptive agents.

Expert opinion: In terms of anti-fracture efficacy, treatment with rhPTH is not superior to treatment with potent anti-resorptive agents. However, while the process by which osteoporosis emerges is arrested in response to anti-resorptives, rhPTH acts as a bone anabolic with reversal of the process. Although this mechanism of action seems favorable, the use of rhPTH is limited by a much higher cost than that of anti-resorptive agents. As long as a superior anti-fracture efficacy has not been proven, rhPTH should be confined to patients with severe spinal osteoporosis, including patients in whom treatment with an anti-resorptive has failed.