Clinical efficacy and safety of ranibizumab in the treatment of wet age-related macular degeneration

Introduction: Although several approaches have been studied for treating wet age-related macular degeneration (w-AMD), currently, the most effective strategy in the management of this visual disorder is represented by anti-VEGF drugs. Among them, ranibizumab (RBZ) is widely adopted in clinical practice for treating w-AMD.

Areas covered: VEGF (vascular endothelial growth factor) is a hypoxia-induced growth factor promoting neoangiogenesis, which has been correlated to the pathogenesis of w-AMD.

RBZ is a humanized, recombinant, monoclonal antibody fragment (Fab), which binds all the isoform of VEGF-A and, therefore, exerts an inhibitory activity on the growth of new pathological vessels leading to the reabsorption of VEGF-related macular edema. The pivotal trials ANCHOR and MARINA revealed its clinical efficacy and good safety profile for treating w-AMD, leading ultimately to its FDA approval. Further trials have analyzed the best dosage and regimen modality, reporting RBZ at 0.5 mg with a ‘pro re nata’ regimen (PRN) to be non-inferior to the 0.5 mg formulation administered monthly. The treat-to-extend (TAE) regimen has also been investigated, demonstrating encouraging results in terms of clinical efficacy and nonetheless, it was proven to be a well-tolerated option with the possibility of reducing the treatment burden for the patients.

Conclusions: RBZ has been proven to be an effective anti-VEGF agent for treating w-AMD; however, more optimal therapeutic regimens and drug delivery systems are being investigated in order to improve patients’ compliance and treatment burden.     

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.     

Ranibizumab and aflibercept for the treatment of wet age-related macular degeneration

Introduction: Wet age-related macular degeneration (AMD) is a potentially blinding eye disease that causes vision loss among individuals > 50 years old. The main goal in the treatment of wet AMD is to inhibit the choroidal neovascularization (CNV). Currently, ranibizumab and aflibercept are two available anti-VEGF drug for the treatment of wet AMD. Here, we reviewed the clinical outcome of treatment with ranibizumab or aflibercept in patients with wet AMD from recent studies with a special focus on eyes with unusual presentations or treatment resistant and compared these agents with other available wet AMD therapies.

Areas covered: For this review, a literature search from 2011 to present was performed using the following terms (or combination of terms): anti-vascular endothelial growth factors, anti-VEGF, age-related macular degeneration, AMD, aflibercept, and ranibizumab. The studies were limited to studies used ranibizumab, and especially those switched from ranibizumab to aflibercept. Also the clinical trial website (www.clinicaltrials.gov) was searched for recently completed trials of aflibercept or ranibizumab for wet AMD treatment.

Expert opinion: Ranibizumab and aflibercept are effective for the treatment of wet AMD including those with retinal angiomatous proliferation (RAP) and CNV unresponsive to other anti-VEGF agents. Although high-dose ranibizumab has the potential to treat unresponsive CNV, switching to another anti-VEGF agent may be a preferable option in these eyes.     

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.     

Efficacy and safety of ustekinumab and etanercept for the treatment of psoriasis

Importance of the field: TNF-α inhibitors such as etanercept have been used for psoriasis for years. A fairly well defined efficacy and safety profile has developed. A new biologic agent, ustekinumab, an IL-12 and IL-23 inhibitor, has recently been released in the US for the treatment of moderate-to-severe psoriasis. The purpose of this article is to compare the efficacy and safety profiles of ustekinumab and etanercept.

Areas covered in this review: We examined safety and efficacy data regarding ustekinumab and etanercept from clinical reports, a head-to-head trial, review articles, and databases and registries from the last 20 years.

What the reader will gain: Evidence is reviewed about the efficacy for the treatment of psoriasis as well as the safety profiles for both agents, ustekinumab and etanercept.

Take home message: Both drugs have data to confirm efficacy and safety in patients with moderate-to-severe psoriasis in the short-term. The limited long-term data on the safety profile of ustekinumab requires careful judgment on the clinician's part, weighing well-defined benefits and potential unknown risks.     

Biologic agents in nail psoriasis: efficacy data and considerations

Introduction: Nail psoriasis plays a major role in the overall assessment of psoriatic disease. Four biologic agents are officially labeled for the treatment of moderate to severe, stable plaque psoriasis (adalimumab, etanercept, infliximab, ustekinumab) and have enriched subsequently the therapeutic armamentarium against psoriatic nails. However, evidence for the efficacy of these agents for nail psoriasis is under investigation.

Areas covered: In this review an effort has been made to summarize evidence regarding the efficacy of biologics in nail psoriasis. A systemic search for reports of biologic agents in psoriatic patients with nail involvement was carried out (MEDLINE and CENTRAL in the Cochrane Library). Relevant data are thoroughly presented.

Expert opinion: All four biologic agents have shown efficacy on psoriatic nail disease. However, published data are heterogeneous, based on studies assessing the therapeutic efficacy with different scoring indexes and at different time points, depending on the time table of each drug administration. Therefore, the need for consensus on core outcome to be used is mandatory. Additionally, optimization of the scoring systems and the conduction of further trials of high quality and validity could lead to more accurate conclusions on the efficacy of biologic agents in the treatment of nail psoriasis.     

Anti-VEGF therapy for the treatment of glaucoma: a focus on ranibizumab and bevacizumab

Introduction: Anti-VEGF therapy has been widely used in the treatment of ocular neovascular diseases. Because of their anti-angiogenic and anti-fibrotic properties, anti-VEGF antibodies such as bevacizumab and ranibizumab have emerged as an adjunctive treatment modality in glaucoma to improve success of conventional treatments.

Areas covered: Ranibizumab is an anti-VEGF-A antigen binding fragment currently indicated in neovascular age-related macular degeneration as well as macular edema following retinal vein occlusion. Several off-label uses include the treatment of neovascular glaucoma to regress/suppress iris and iridocorneal angle neovascularization and the modulation of wound healing after glaucoma filtration surgery. Bevacizumab is a full-length anti-VEGF antibody, which is also being used in aforementioned eye conditions off-label. An overview of these anti-VEGF antibodies and the results of preclinical and clinical studies regarding their use in the treatment of glaucoma are presented.

Expert opinion: Early studies on the utility of both bevacizumab and ranibizumab in neovascular glaucoma and filtration surgery reported promising results. However, a large-scale randomized clinical trial as well as comparative studies between the two anti-VEGF antibodies are currently lacking. A single dose of ranibizumab costs approximately 40 times as much as a single dose of bevacizumab. Clinicians should take this into account, in addition to their differences in the efficacy and safety, when treating patients.     

Certolizumab pegol for treating axial spondyloarthritis

ABSTRACT

Introduction: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease of the spine and sacroiliac (SI) joints. The spectrum of axSpA includes ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA). Evidence has supported the use of TNF alpha inhibitors (TNFi) in treating these diseases, with good efficacy and tolerable safety profiles. Certolizumab pegol (CZP) is an anti-TNF alpha (TNFa) agent with data to support its use in both AS and nr-axSpA.

Areas covered: The pharmacologic properties of CZP were reviewed. Data regarding the use and efficacy of CZP in axSpA were reviewed. Quality of life outcomes and safety profiles of CZP in axSpA patients were discussed as well.

Expert opinion: While there are several biologics with evidence for improved outcomes in AS, there is less evidence for biologic medications that have good efficacy in nr-axSpA. CZP has good evidence of improved outcomes in terms of clinical efficacy, patient reported outcomes and imaging outcomes in both conditions, with a tolerable safety profile.     

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.     

Immunogenicity of anti-TNFα therapy in psoriasis: a clinical issue?

Introduction: Immunogenicity of antitumor necrosis factor-alpha (TNFα) agents has been proven to play a significant role in the variability of clinical responses among patients with chronic inflammatory diseases. However, its clinical impact on the outcome of patients with psoriasis and psoriatic arthritis receiving anti-TNFα treatment is not yet fully clear. Despite the high rates of efficacy of anti-TNFα agents in psoriasis, a substantial proportion of patients remain who experience a primary or secondary failure or significant side effects, which are potentially ascribable to immunogenicity.

Areas covered: Topics include immunologic response elicited by anti-TNFα agents, the impact of immunogenicity on treatment response to anti-TNFα and the role played by immunogenicity in the lack of efficacy of anti-TNFα agents (infliximab, adalimumab and etanercept) in psoriasis.

Expert opinion: Based on data available in the literature and the clinical experience of the authors, this article suggests the optimal approach to drug monitoring and antidrug antibody assay and the most effective use of biologic immunotherapies in this setting. Immunogenicity should be taken into account in the adoption of therapeutic choices in psoriatic patients, such as anti-TNFα agent intensification, or switching to another anti-TNFα agent or a drug with a different mechanism of action.     

Biological therapies for psoriasis

Introduction: Biological therapies have revolutionized moderate-to-severe psoriasis treatment. Increased understanding of disease pathogenesis has yielded multiple therapeutic targets involving the IL-23/Th17 pathway, while current therapies continue to be monitored for long-term efficacy and safety.

Areas covered: This review details current understanding of psoriasis immunopathogenesis specifically related to therapeutic targets. Approved and emerging biological psoriasis therapies targeting TNF-α, IL-12/23p40, IL-17 and IL-23p19 are covered. Biological agent uses in special circumstances are reviewed together with the emerging debate on biosimilar therapies and their potential future role in psoriasis and other inflammatory diseases.

Expert opinion: Psoriasis treatment has expanded and has become more effective due to increased understanding of disease pathogenesis. However, lack of efficacy in select psoriasis patients, safety concerns and limited treatment efficacy in psoriasis variants (e.g., pustular) are areas which still need improvement. As such, pharmacogenomics will be of vital importance in future for individualized psoriasis care. Further, a better understanding of the multiple psoriasis comorbidities, especially cardiovascular disease, continues to be of significant interest in the psoriasis community. Last, the emergence of biosimilar agents has the potential to change psoriasis treatment, especially as it relates to better access for the psoriasis community worldwide.     

Pembrolizumab for the treatment of diffuse large B-cell lymphoma

ABSTRACT

Introduction: Pembrolizumab is a novel monoclonal antibody that targets the interaction between programmed cell death protein 1 (PD-1) and its ligand (PD-L1). Pembrolizumab has shown significant clinical efficacy in Hodgkin Lymphoma (HL), but results in non Hodgkin Lymphoma (NHL) are mixed. Some NHL subtypes, which share certain genetic features with HL, such as alterations in chromosome 9p24.1 and expression of PD-L1, have shown promising responses in early phase trials.

Areas covered: In this review, we provide an overview of pembrolizumab as a compound, and present the available clinical efficacy and safety data in the treatment of diffuse large B cell lymphomas.

Expert opinion: Current early phase data suggest that single agent pembrolizumab in NHL demonstrates both efficacy and a favorable safety profile. However, it is anticipated that future treatment strategies will be biomarker-driven and incorporate pembrolizumab into combination therapies with chemotherapy and/or immunotherapy agents.     

Betrixaban for first-line venous thromboembolism prevention in acute medically ill patients with risk factors for venous thromboembolism

ABSTRACT

Introduction: Compared to other direct oral anticoagulants, betrixaban has a longer half-life, smaller peak-trough variance, minimal renal clearance, and minimal hepatic Cytochrome P (CYP) metabolism. The Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial evaluated the efficacy and safety of extended duration betrixaban compared to standard duration enoxaparin in acutely ill hospitalized patients.

Areas covered: This article describes the role of betrixaban in the prevention of venous thromboembolism (VTE) in acutely ill medical patients. This article provides a consolidated summary of the primary APEX study findings as well as prespecified and exploratory substudies. This article also provides a review of the results of studies in which other direct factor Xa inhibitors have been evaluated in an extended duration regimen in this patient population.

Expert commentary: While previous agents have demonstrated that extended duration VTE prophylaxis can be efficacious, betrixaban is the first agent to demonstrate efficacy without an increase in major bleeding. The totality of the data from the APEX trial supports extended duration betrixaban for VTE prophylaxis in the acute medically ill patient population. As such, betrixaban has been approved in the USA for extended VTE prophylaxis in at-risk acute medically ill patients.     

Velimogene aliplasmid

Importance of the field: Immunotherapy for cancer has been investigated for several decades, achieving limited success. The development of effective new immunotherapeutic agents has reignited interest in the filed. Intralesional injection of plasmids in order to transfect genes capable of stimulating or augmenting immune recognition and destruction of tumors is a relatively new approach.

Areas covered in this review: Our objective is to discuss the role velimogene aliplasmid (Allovectin-7^®, Vical Incorporated), a plasmid–lipid complex containing the DNA sequences encoding HLA-B7 and β2 microglobulin, as an immunotherapeutic agent.

What the reader will gain: Intralesional velimogene aliplasmid induces anti-tumor responses in a proportion of melanoma patients with locoregional and limited distant metastases. Preclinical data and the results of Phase I, II and III clinical trials with this drug are reviewed. The limited data in other malignancies is also reviewed. Velimogene aliplasmid in humans appears safe, with minimal drug-related adverse events.

Take home message: Velimogene aliplasmid has activity in melanoma with local and limited distant disease associated with an excellent safety profile. The activity of this approach is also being investigated in other malignancies.     

Gemtuzumab ozogamicin for the treatment of acute promyelocytic leukemia: mechanisms of action and resistance,safety and efficacy

Introduction: Acute promyelocytic leukemia (APL) is characterized by peculiar biological features and high sensitivity to therapeutic agents such as anthracyclines, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Because cure rates of up to 80 – 90% have been reported using various combinations of the above agents, future strategies will probably aim at reducing therapy-related toxicity while maintaining therapeutic efficacy. Gemtuzumab ozogamicin (GO) is a calicheamicin-conjugated mAb directed against CD33, a surface antigen highly expressed on APL blasts. GO has been shown to be effective in this disease and better tolerated than conventional chemotherapy.

Areas covered: This review looks at the mechanism of action, pathways associated with resistance and toxicity profile of GO. Reported experience on the use of GO for relapsed or newly diagnosed APL is also discussed along with evidence on its efficacy and relative tolerability in APL management. In addition to its activity in advanced disease, data suggest that GO in various combinations may replace chemotherapy in APL front-line therapy. This should apply in particular to some subsets such as elderly patients or those unfit to receive conventional chemotherapy.

Expert opinion: GO has proven effective and relatively safe as a single agent in advanced APL. In combinations with ATRA and/or ATO, GO may substitute for conventional chemotherapy of APL, particularly in unfit patients.     

Treating anemia in heart failure patients: a review of erythropoiesis-stimulating agents

Importance of the field: Prevalence of chronic heart failure (CHF) is increasing, and despite improvements in the past decade the prognosis in terms of mortality and health-related quality of life remains poor. Anemia is often found concomitantly in CHF patients.

Areas covered in this review: Erythropoiesis-stimulating agents (ESAs) are a new treatment option for these anemic CHF patients, promising to decrease mortality and hospitalizations, and increase health-related quality of life.

What the reader will gain: CHF epidemiology is briefly dicussed. Currently available clinical efficacy and safety data are critically appraised. Health care utilization by CHF patients, particularly hospitalizations, are reviewed in order predict cost-effectiveness of ESAs.

Take home messages: The efficacy for the most pertinent endpoints has not been proven by a pivotal trial or a meta-analysis free of bias, and there might be increased cardiovascular events and cancer incidence rates above a currently unknown target value or with multiple doses. However, subgroups should be identified in which ESAs might prove to be more efficacious and as safe as usual care and either cost-saving or cost-effective. Nevertheless, depending on the subgroup, the budget effect for payors might be dramatic due to the large number of CHF patients.     

Biosimilar epoetin zeta: extrapolation of indications and real world utilization experience

ABSTRACT

Introduction: There is an essential need for clinicians to understand the development and approval process of biosimilars. Extrapolation of efficacy and safety data from one indication to another may be considered by a comprehensive comparability program including safety, efficacy and immunogenicity, which detect potentially clinically relevant differences.

Areas covered: This article specifically discusses the approval of epoetin zeta (Retacrit?, Hospira, a Pfizer company) and the EMA reasoning for extrapolation of indications. Additionally, the results of the ongoing utilization surveillance program that was approved in 2007 and has analyzed over 120 million patient days of epoetin zeta treatment are presented.

Expert opinion: At the time of approval, uncertainty of safety and efficacy is much less for biosimilars than for new innovative products. Approval of indications based on extrapolation of data is based on sound and objective scientific criteria and a logical consequence of the biosimilar concept that has been successfully implemented in the European Union.

Biosimilar epoetin has been used extensively in patients in Europe for nine years. Following a review of the known risks and ADR information received in almost 120 million patient-days’ worth of experience, the risks associated with treatment with epoetin zeta remain similar to those of the reference product.     

The comparative immunogenicity of biologic therapy and its clinical relevance in psoriatic arthritis: a systematic review of the literature

Introduction: Biologic agents have demonstrated efficacy in treating patients with psoriatic arthritis (PsA). Biologic agents also have an intrinsic capacity to induce an immune response in patients that could result in unwanted adverse events and/or treatment failure.

Areas covered: In this systematic literature review, the authors document the incidence of immune responses, primarily anti-drug antibodies (ADA), to the biologic therapeutic agents currently in clinical practice for the treatment of PsA. The authors discuss the importance of these responses with respect to clinical practice.

Expert opinion: Our evaluation of the published literature shows that the immune responses to the various biologic therapeutic agents currently being used to treat PsA are similar to those observed for these agents in other rheumatic diseases. Moreover, similar to observations in other rheumatic diseases, the incidence of ADA formation to biologic agents in patients with PsA is often decreased when patients are given concomitant treatment with disease-modifying anti-rheumatic drugs. These data strongly suggest that the immune response is a characteristic of the biologic agent. Using therapeutic drug monitoring may be an approach to assess the immune response to the agent and to mitigate the potential impact on efficacy and safety, and consequently optimize treatment.     

Bevacizumab for choroidal neovascularization secondary to age-related macular degeneration and pathological myopia

Introduction: Many retinal specialists have utilized intravitreal bevacizumab as an anti-VEGF to treat choroidal neovascularization (CNV), secondary to age-related macular degeneration (AMD) and pathological myopia, with favorable results. Bevacizumab is currently approved only for the systemic treatment of colon carcinoma, whereas it is widely used off-label for treating ocular neovascular diseases.

Areas covered: In this review, after thorough search, 33 relevant studies conducted in the last 4 years were found. These articles comprised 14 studies about use of bevacizumab alone or in combination with other therapeutic agents to treat exudative AMD, and 19 studies on the use of myopic CNV.

Expert opinion: Although bevacizumab is widely used as an anti-VEGF agent for the treatment of exudative AMD, data on its systemic side effects are limited because of studies’ short follow-up periods, absence of appropriate controls, limitation in reporting outcomes, and lack of controlled clinical trials in Phase III. Some safety studies demonstrated no difference between bevacizumab and ranibizumab in occurrence of heart attacks or stroke. Conducting proper randomized clinical trials with long-term follow-up is crucial to make sure about efficacy and safety of bevacizumab.