The role of tocilizumab in the management of rheumatoid arthritis

Introduction: The introduction of biological treatments has improved the outlook for patients diagnosed with rheumatoid arthritis. There are now a range of different agents, targeting various pathways involved in the inflammatory process. Tocilizumab, a fully humanised anti-interleukin-6 receptor monoclonal antibody is licensed for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis.

Areas covered: This article reviews and appraises the available evidence regarding the efficacy and safety of tocilizumab in rheumatoid arthritis, as identified in PubMed and Embase searches.

Expert opinion: Clinical trial data suggest that tocilizumab has similar efficacy both clinically and in reducing structural progression to that seen with the TNF inhibitors. Patients who might be particularly suitable for tocilizumab are those who have failed multiple TNF inhibitors, those with a high inflammatory response as part of their disease and those unable to tolerate methotrexate, given the good responses seen with monotherapy.     

Adalimumab in the treatment of plaque-type psoriasis and psoriatic arthritis

Introduction: Psoriasis and psoriatic arthritis (PsA) are chronic immune-mediated diseases, and TNF-α (tumor necrosis factor) is a pro-inflammatory cytokine that plays a critical role in the pathogenesis of these conditions. Adalimumab is an anti-TNF-α drug widely used for the treatment of both psoriasis and PsA. Controlled clinical trials demonstrated that adalimumab is characterized by a high degree of clinical response. The aim of this review is to report the safety, efficacy, and recent findings in the treatment of psoriasis and PsA with adalimumab.

Areas covered: This article reviews the results of Phase II, III, controlled, and observational clinical studies on adalimumab in the treatment of psoriasis and PsA. A systematic search was conducted using the Pubmed Medline database for primary articles.

Expert opinion: Treatment of psoriasis and PsA represents a therapeutic challenge for dermatologists and rheumatologists. The efficacy, tolerability, and safety profiles suggest adalimumab as a suitable anti-psoriatic drug in the long-term treatment of psoriasis and PsA. Management of long-term treatment, loss of efficacy, and comorbidities has been described.     

Is there still a role for abatacept in the treatment of lupus?

Introduction: The quest for safer and more effective treatments for systemic lupus erythematosus (SLE) has led to the development of many new biologic therapies. Abatacept is the first drug targeting co-stimulation between T cells and antigen presenting cells, with abundant pre-clinical evidence to support its use in SLE.

Areas covered: This review will present the relevant aspects of lupus pathophysiology pertaining to the mechanism of action of abatacept, a summary of murine studies and the latest human clinical trials.

Expert opinion: Abatacept has demonstrated efficacy in both rheumatoid arthritis and psoriatic arthritis, and earlier studies have suggested tantalising evidence of efficacy in SLE. However, the latest randomised double-blinded study showed disappointingly negative results, much like the case of rituximab in SLE. Currently, abatacept remains a possible therapeutic option as an off-label therapy, and it is a part of our therapeutic armamentarium in difficult cases. The need to find appropriate definitions of response and optimal study design continues to be paramount in the field of lupus therapies.     

Mavrilimumab,a human monoclonal GM-CSF receptor-α antibody for the management of rheumatoid arthritis: a novel approach to therapy

Introduction: Mavrilimumab, formerly known as CAM-3001, a GM-CSF receptor-α antibody, is the first human monoclonal antibody to be used in Phase II studies (2011) to modulate the innate immunity pathway targeting GM-CSF signaling in moderate rheumatoid arthritis (RA).

Areas covered: Analysis of available clinical trial data on GM-CSF receptor-α antibody and medical literature search using MEDLINE for molecular mechanisms of pathogenesis of RA and its treatment forms the basis of this expert opinion review. The mavrilimumab Phase II double blind, randomized, placebo-controlled ascending dose trial demonstrated statistically significant achievement of primary and secondary end points in patients with moderate RA. The trial demonstrated significant clinical benefit in the 100 mg mavrilimumab cohort compared to the placebo group.

Expert opinion: The novel molecular targeting mechanism of mavrilimumab together with its demonstrated clinical efficacy, tolerability and safety profile in Phase II clinical trials in moderate RA, suggests significant potential utility for this drug to induce clinical remission, reduce flares and improve morbidity and mortality in patients with RA.     

Belimumab – an anti-BLyS human monoclonal antibody for rheumatoid arthritis

Introduction: B lymphocyte stimulator (BLyS) is a major regulatory factor that controls the development and survival of B cells. Elevated serum levels of BLyS have been associated with rheumatoid arthritis (RA). Belimumab is a fully human monoclonal antibody that inhibits BLyS and it is being developed for the treatment of RA. This review aims to summarize up-to-date pharmacological and clinical data of belimumab in the treatment of RA.

Areas covered: A literature search was performed on PubMed using keywords, including belimumab, LymphoStat-B, benlysta, BLyS inhibitor, rheumatoid arthritis and autoimmune disease. References of relevant studies were searched by hand. Abstracts of international conferences up to October 2012 were also included. Belimumab was well tolerated in the treatment of RA over 24 weeks. It significantly increased American College of Rheumatology (ACR)20 responses at week 24, especially in patients with high disease activity, positive rheumatoid factor, no anti-TNF treatment experience and those who had failed methotrexate therapy. However, belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA.

Expert opinion: These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials. Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA.     

Subcutaneous abatacept in rheumatoid arthritis: current update

Introduction: A number of biologic agents have been approved for the treatment of rheumatoid arthritis (RA). They have changed the landscape of therapy and demonstrate substantial efficacy with a good safety record. One of these agents is intravenous (i.v.) abatacept (ABA), which has a novel mechanism of action by selectively inhibiting the interaction between T- and antigen-presenting cells. Recently, ABA administered by subcutaneous (s.c.) injection has also been approved for use in RA. In this review, will focus in recent data published in this agent.

Areas covered: This paper reviews Phase III clinical trials (ACQUIRE, ACCOMPANY, ALLOW, ATTUNE, AMPLE and AVERT) in terms of clinical efficacy including long-term efficacy, radiographic progression, safety and immunogenicity.

Expert opinion: Given the current trend in biologic therapy to s.c. administration, the availability of both i.v. and s.c. ABA provides considerable advantage both to patients and physicians in this competitive environment. The clinical trials have shown comparable efficacy and safety of s.c. ABA to i.v. ABA and others biologics.     

The use of desmoteplase (bat saliva) in the treatment of ischaemia

Introduction: In an era of ageing global populations and accumulation of cardiovascular risk factors, the importance of reperfusion/recanalisation therapies in treating vascular occlusive disease is growing. There are multiple thrombolytic agents available, including bat saliva-derived plasminogen activator.

Areas covered: A peer reviewed literature search was conducted and focus was on the data on the use of desmoteplase in the treatment of ischaemic stroke.

Expert opinion: Currently, there is not enough evidence for clinical use in ischaemic stroke and further Phase III studies are underway. At this stage, desmoteplase remains an investigational compound.     

Contemporary use of bevacizumab in ovarian cancer

Introduction: Ovarian cancer remains the most lethal gynecologic malignancy. Although standard platinum-based chemotherapy results in high response rates, more than 70% of patients with advanced disease will experience recurrence within 5 years. Therefore, novel treatment strategies to increase primary efficacy, decrease recurrence after primary treatment and improve the response rate for recurrent disease are needed.

Areas covered: This review covers antiangiogenesis therapy and the efficacy of bevacizumab as primary treatment and in platinum-sensitive and resistant recurrent disease.

Expert opinion: The evidence provided from Phase III trials has supported the efficacy of bevacizumab in primary and recurrent ovarian cancer management. Future investigation is needed to improve clinical performance (via biomarkers of efficacy, early discontinuation, additional agents, etc.), as well as, more sensitive tools to assess direct patient impact.     

Intradetrusor onabotulinumtoxinA for overactive bladder

Introduction: Overactive bladder is a life-compromising disease that affects approximately 11.8% of all men and women, with increasing rates in the elderly. The mainstay of pharmacotherapy for this disease, anticholinergics, has up to a 71% discontinuation rate at 6 months. The emerging data of intradetrusor onabotulinumtoxinA (onabotA) use for treatment of idiopathic overactive bladder is showing to be an efficacious and well-tolerated alternative to the mainstay of therapy.

Areas covered: This study covers the use of onabotA and its use for idiopathic overactive bladder, stemming from its use in neurogenic detrusor overactivity, by evaluating the conclusions of current studies. A literature search and review was carried out for onabotA in treatment of overactive bladder using PubMed.

Expert opinion: Multiple randomized clinical trials have shown that intradetrusor injection with onabotA is effective in treating non-neurogenic bladder with promising efficacy in patients who have failed traditional pharmacotherapy. This treatment may be superior in certain patients due to its higher rate of compliance and higher rates of complete symptom resolution. Long-term studies are needed.     

Belagenpumatucel-L for the treatment of non-small cell lung cancer

Introduction: Immunotherapy has become a promising approach for the treatment of NSCLC. In order to stimulate the host immune system against tumour antigens, several cancer vaccines have been generated and evaluated. Belagenpumatucel-L is a whole tumour cell vaccine expressing the antisense strand of the TGF-β2 gene.

Areas covered: The purpose of this article is to review the most relevant findings of clinical trials testing belagenpumatucel-L in advanced NSCLC patients.

Expert opinion: Although the Phase III trial investigating belagenpumatucel-L in stage III/IV patients did not meet its primary end point, a survival benefit was observed in several subgroups of patients. Further studies are needed in order to select patients who may benefit from this vaccine.     

Remestemcel-L for acute graft-versus-host disease therapy

Introduction: Remestemcel-L (Prochymal®, Osiris) is an off-the-shelf adult mesenchymal stromal cell product that has been applied to acute graft-versus-host disease (aGvHD) for its immunomodulatory properties.

Areas covered: This article discusses preclinical and clinical studies supporting the use of remestemcel-L in aGvHD as well as the current regulatory status. This information was based upon a PubMed and Internet search.

Expert opinion: Phase II studies suggest remestemcel-L may have clinical activity in aGvHD and confirm tolerability. However, these results must be interpreted cautiously with any use of remestemcel-L optimally occurring in the context of a clinical trial. Further clarity will be obtained when the results of a completed Phase III study are published. There is a small market for remestemcel-L in aGvHD. A possible future scenario is that a more prevalent indication is found and remestemcel-L is approved for that indication, but use continues for aGvHD.     

Mepolizumab for eosinophilic severe asthma: recent studies

Introduction: In September 2014 two large clinical studies of the anti-IL-5 monoclonal antibody mepolizumab in severe asthma were published in the New England Journal of Medicine (MENSA and SIRIUS).

Areas covered: Eosinophilic inflammation has long been recognised as a feature of asthma. Identification of IL-5 as a key cytokine specific for eosinophil development and survival lead to development of monoclonal antibody therapy targeting this pathway. These two important new studies suggested that this treatment could reduce exacerbation rates by 50% in asthmatic patients with persistent peripheral blood eosinophilia and persistent symptoms despite high-dose-inhaled corticosteroids and additional controller therapy, and frequent exacerbations. In the second study, mepolizumab was shown to reduce oral steroid requirement by a median of 50% in similar patients who additionally required oral prednisone to control disease.

Expert opinion: This represents an important new treatment option in an area of unmet need, and together with a large dose ranging study (DREAM) published in 2012 form the basis for filing for registration in the USA and Europe.     

Use of the 13-valent pneumococcal conjugate vaccine in children and adolescents aged 6 – 17 years

Introduction: The introduction of pneumococcal conjugate vaccines into infant immunization schedules has successfully reduced the incidence of pneumococcal disease caused by vaccine serotypes. Disease incidence is low in healthy 6 – 17-year-old children and young people; however, there are a number of clinical conditions that put individuals in this age group at increased risk. Expansion of the license of a 13-valent pneumococcal conjugate vaccine, PCV-13, to include the 6 – 17 age group has recently been approved by European and American regulatory bodies.

Areas covered: Studies assessing the safety, immunogenicity, and efficacy of pneumococcal conjugate vaccines in both healthy and high-risk 6 – 17-year-old children and adolescents are covered and the potential impact of PCV-13 in these populations is discussed. The use of the 23-valent pneumococcal polysaccharide vaccine, PPV-23, in high-risk children and adolescents is also considered.

Expert opinion: Expanding the use of PCV-13 to include high-risk children and adolescents aged 6 – 17 has the potential to prevent additional cases of disease; however, vaccination of this population may no longer be necessary when herd immunity to PCV-13 serotypes becomes fully established. Despite the broader serotype coverage of PPV-23, the benefits of this vaccine in high-risk populations are uncertain.     

The capsular group B meningococcal vaccine, 4CMenB: clinical experience and potential efficacy

Introduction: Capsular group B meningococcal disease is a leading cause of childhood meningitis and septicaemia. Up to 10% of sufferers die, and sequelae remain in > 30% of survivors. A vaccine, four component meningococcal group B (4CMenB), designed with the aim to induce broad coverage against this highly variable bacterium, has been licensed in countries including in the European Union, Canada and Australia.

Areas covered: Immunogenicity and safety data, published in peer-reviewed literature between 2004 and 2014, are presented in the context of the recent recommendation for the use of the vaccine in infants in the UK.

Expert opinion: 4CMenB induces significant reactogenicity when administered with routine infant vaccines, in particular with respect to fever rates. Fevers can be somewhat reduced using paracetamol. The efficacy of the vaccine is unknown but has been extrapolated from effectiveness data obtained from use of one of its components in New Zealand, immunogenicity data from clinical trials and estimation of coverage from in vitro studies. These data suggest that the vaccine will prevent a proportion of invasive meningococcal disease cases in infants and young children. Implementation and well-planned post-marketing surveillance will address uncertainties over field effectiveness.     

Omalizumab for treatment of allergic rhinitis

Introduction: Immunoglobulin E (IgE) is a key pathogenic factor of allergic rhinitis, a prevalent disease adversely affecting quality of life and productivity.

Areas covered: Binding of inhaled allergens to IgE on the surface of basophils and mast cells, with subsequent cross-linkage of IgE and aggregation of high-affinity receptors for IgE (Fc?RI), triggers the release of inflammatory mediators, followed by the onset of allergic rhinitis symptoms. Current therapeutic strategies include corticosteroids, mast cell stabilizers, leukotriene receptor antagonists, anticholinergics, antihistamines and allergen immunotherapy. Removal of circulating free IgE by the recombinant humanized monoclonal anti-IgE antibody, omalizumab (Xolair), represents a novel therapeutic approach. Omalizumab selectively binds to the C?3 domain of IgE at the site of Fc?R1 binding, thus blocking binding of IgE to effector cells. We review omalizumab's clinical efficacy, administration, use with immunotherapy and safety in allergic rhinitis.

Expert opinion: Omalizumab may provide a new treatment strategy for allergic rhinitis. The high cost of omalizumab precludes its chronic use for allergic rhinitis and it is not FDA approved for this indication; however, its periodic use may be justified in treatment resistant patients, especially those with seasonal disease.     

Pidilizumab in the treatment of diffuse large B-cell lymphoma

Introduction: The programmed death-1 (PD-1) immune checkpoint pathway is an emerging target in the treatment of hematologic malignancies. Pidilizumab is an mAb that binds to PD-1 and is a safe and well-tolerated therapy. Recent data have shown clinical activity utilizing this strategy in diffuse large B-cell lymphoma (DLBCL).

Areas covered: The role of PD-1 expression in hematologic malignancies is explored. Recent clinical trials including the results of a Phase I trial in hematologic malignancies and a Phase II trial of pidilizumab following autologous hematopoietic stem-cell transplant (AHSCT) are reviewed.

Expert opinion: We review data that suggest that PD-1 is a promising target in the treatment and management of DLBCL. Changes in immune subsets following administration of pidilizumab are felt to represent on-target responses. The improvement in progression-free survival (PFS) following AHSCT supports a response to therapy. Importantly, the improvement in PFS for patients with positive FDG-PET/CT following AHSCT indicating residual disease further supports direct activity of pidilizumab in DLBCL.     

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.     

Carfilzomib in multiple myeloma

Introduction: Advances in drug therapy for multiple myeloma (MM) during the previous decade have improved survival outcomes; however, the disease remains incurable as patients eventually relapse or become refractory to all available therapies. Therefore, there is a clear need for more effective and well-tolerated treatments.

Areas covered: We review preclinical and clinical data regarding the use of carfilzomib, a proteasome inhibitor that is structurally and mechanistically distinct from bortezomib, for the treatment of MM patients. Carfilzomib pharmacokinetics, pharmacodynamics, efficacy, safety and tolerability are summarized, based on Phase I/II trial data.

Expert opinion: Carfilzomib represents a significant advance in the management of relapsed and/or refractory MM patients, including those intolerant or resistant to bortezomib. High response rates have been demonstrated with carfilzomib as a single agent or in combination with alkylating agents, immunomodulators and corticosteroids, even among patients who have failed multiple prior therapies. Carfilzomib also has significant potential in the frontline setting, with encouraging response and survival rates observed for combination regimens. Further evaluation of carfilzomib-containing regimens is ongoing in Phase III trials and investigator-sponsored studies, which include combinations with novel investigational agents. These findings will shape the future role of carfilzomib for MM patients across multiple settings.     

Pegylated-IFNα2a for HIV/hepatitis C virus coinfected patients: out with the old,in with the new

Introduction: Liver disease is a major burden in patients co-infected with HIV and hepatitis C virus (HCV). From the time of its approval, pegylated-IFNα-2a (pegIFN-α2a) has played a major role in treatment of HCV in HIV/HCV co-infection.

Areas covered: This article briefly summarizes the epidemiology of HCV/HIV co-infection, the pharmacokinetic, and pharmacodynamic properties of pegIFN-α2a. Results from clinical trials investigating therapies containing pegIFN-α2a for HIV/HCV co-infected patients will be discussed with a focus on efficacy and safety.

Expert opinion: PegIFN-α2a has improved rates of sustained virologic response for co-infected patients. In combination with direct-acting antivirals (DAA), the disparity between mono- and co-infected patients is beginning to disappear. For the first time, IFN-free regimens are available in clinical practice. It is unlikely that pegIFN-α2a will continue to be a critical component in treatments for HCV in the general co-infected population.     

Ipilimumab in prostate cancer

Introduction: Immune checkpoint inhibitors, such as ipilimumab, are a new class of immunotherapeutic agents that have shown significant efficacy in melanoma. A number of ongoing clinical trials are investigating the role of ipilimumab in prostate cancer, either alone or in combination with immunomodulating agents such as radiation and chemotherapy, and in combination with cancer vaccines.

Areas covered: This article reviews the molecular basis, preclinical and clinical evidence on the safety and efficacy of ipilimumab in prostate cancer. Medical literature search using MEDLINE and online abstracts database of national meetings form the basis of this article.

Expert opinion: A number of preliminary clinical studies suggest the potential therapeutic utility of immune checkpoint inhibitors such as ipilimumab in prostate cancer. Pending the results of large-scale studies, the rationale of combining ipilimumab with standard anticancer therapeutics such as radiation, cytotoxic chemotherapy and other immunotherapeutic agents can be of great value in reducing mortality and morbidity in prostate cancer.