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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

The coming of ramucirumab in the landscape of anti-angiogenic drugs: potential clinical and translational perspectives

Introduction: Angiogenesis plays a pivotal role in the development and progression of tumors and it represents a crucial target for therapeutic strategies. Until now, regulatory agencies approved antiangiogenic agents targeting the VEGF and multi-target agents carrying antiangiogenic and anti-proliferative effects. They often provide only a modest survival benefit and their role in clinical practice is debated. The limited efficacy may be partially explained by the complexity of the molecular background of angiogenic processes, composed of several pathways interacting with both tumor cells and the microenvironment.

Areas covered: Ramucirumab is a fully human monoclonal antibody selectively binding and inhibiting the VEGF receptor 2 (VEGFR-2), a crucial molecule involved in angiogenesis. A series of Phase I–II trials conducted in a wide spectrum of malignancies reported promising antitumor activity. In 2014, data from large Phase III clinical trials in gastrointestinal, lung and breast malignancies were released.

Expert opinion: Considering the evidences of efficacy emerging from the available Phase III trials, the antiangiogenic approach emerged as a promising strategy particularly for the treatment of gastric cancer. Nevertheless, the identification and validation of potentially predictive biomarkers are necessary to improve the selection of patients and the globally awaited clinical benefit.     

Clinical experience with ramucirumab: outcomes in breast cancer

Introduction: Monoclonal antibodies and small molecules targeting the VEGF pathway are part of the arsenal to treat malignant tumors. Antiangiogenesis therapies has been studied in breast cancer with partial success, reflected by the approval of bevacizumab in Europe but not in United States, for metastatic breast cancer (mBC). Ramucirumab is a mAb against VEGFR-2 interfering with the normal activation of this receptor by its natural ligand VEGF.

Areas covered: This article will review the preclinical data available to date for ramucirumab, as well as survey the main clinical trials of antiangiogenic agents reported in breast cancer, focusing on Phase III clinical trials. It will also review the clinical trial data for ramucirumab in mBC, including the design of the Phase II trials, and report on the preliminary results of the TRIO-012 trial. This trial did not meet its primary end point in progression-free survival and has to be considered as a negative trial.

Expert opinion: Despite preliminary positive data with ramucirumab in other metastatic solid tumors reported to date, the results of TRIO-012 discourage pursuing more efforts with ramucirumab in mBC unless predictive and reproducible biomarkers can be established to select those patients who are most likely to benefit from it.     

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.     

Talimogene laherparepvec in the treatment of melanoma

Introduction: Metastatic melanoma continues to present a significant therapeutic challenge, with an incidence rate rising faster than that of any other cancer. The last 5 years have seen a revolution in the development of new treatments for advanced melanoma, with oncogene targeted agents and checkpoint inhibitor immunotherapies providing the first convincing evidence of a positive shift in overall survival. The role of oncolytic virotherapy in this rapidly evolving field has long been the subject of debate. However, it is with the development of Talimogene Laheparepvec (T-Vec), an intratumourally administered, genetically modified clinical herpes simplex virus-1 strain that has shown positive results in Phase III testing, that the potential for the use of OV may be realised.

Areas covered: This review will outline some of the recent advances in the treatment of advanced melanoma, with a detailed overview of evidence surrounding the development of T-Vec. A literature search was conducted using the databases ‘Medline’ and ‘Pubmed’, including a subsequent manual search of references to identify papers of further relevance.

Expert opinion: As the pivotal OPTiM trial concludes, we outline some of the potential new directions for T-Vec and OV therapy and evaluate the ever-increasing role these novel agents are likely to play in the future landscape of cancer immunotherapy.     

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.     

Mepolizumab treatment for asthma

Introduction: Five percent of asthmatics have severe symptoms despite high doses of inhaled (ICS) or additional oral corticosteroids (OCS): these patients have high morbidity, risk for asthma death, and account for half of asthma healthcare spending. A subgroup (20 – 40%) of these has persistent airway eosinophilia and frequent exacerbations. Mepolizumab is a humanized monoclonal antibody that blocks binding of the key cytokine implicated specifically in eosinophil maturation and survival, interleukin-5, to its receptor.

Areas covered: Pharmacology, Phase I/IIa and Phase II/III studies of mepolizumab for asthma. Mepolizumab depleted blood and sputum eosinophils and partially reduced airway and bone marrow eosinophils. It also reduced airway remodeling. In unselected patients with moderate/severe asthma there was no clinically significant effect on lung function, but a trend to reduced exacerbation rates. When patients were selected for persistent sputum eosinophilia despite high-dose ICS/OCS, and frequent exacerbations, mepolizumab reduced exacerbations by 50%.

Expert opinion: Mepolizumab can reduce exacerbation rates in the severe asthma cohort who have eosinophilic airway inflammation despite corticosteroid treatment. This may be 30% of severe asthmatics and represents a new and important treatment option. Further studies need to confirm efficacy and indications for asthma (and other eosinophilic airway disease), and to examine clinical consequences of reducing remodeling.     

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.     

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.     

The use of an antibody drug conjugate,glembatumumab vedotin (CDX-011), for the treatment of breast cancer

Introduction: Breast cancer (BC) is the most common malignancy in women in the USA. Despite the multi-modality treatments that are currently available, advanced BC has a persistent and unacceptable mortality rate. The need for new therapeutic strategies is extremely high. Experimental approaches with targeted therapies such as antibody drug conjugates provide hope for future treatment possibilities.

Areas covered: The development status and the possible role of antibody-mediated cytotoxic therapy are discussed in the setting of advanced BC. An overview of, mechanism of action, preclinical and Phase I/II results of glembatumumab vedotin (CDX-011) are discussed.

Expert opinion: The evidence that the glycoprotein NBM (GPNMB) target is a relevant target in BC, along with data showing that CDX-011 is safe and active in patients with advanced BC, provide a strong rationale to continue to explore this drug in patients with GPNMB-expressing breast tumors.     

Brentuximab vedotin for treatment of systemic T-cell lymphoma

Introduction: Brentuximab vedotin (BV) is an antibody-drug conjugate that consists of the anti-CD30 monoclonal antibody conjugated with monomethyl auristatin E. BV has been approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of relapsed or refractory Hodgkin lymphoma and anaplastic large cell lymphoma. These two diseases certainly show high levels of CD30 expression. Of interest, however, BV has shown activities in other lymphomas that express low or even undetectable levels of CD30.

Areas covered: We update and summarize a recent report of BV in T-cell lymphomas.

Expert opinion: Single-agent BV showed overall response rates of 54% in angioimmunoblastic T-cell lymphoma and 33% in peripheral T-cell lymphoma not otherwise specified in the recent trial. The efficacy of BV in T-cell lymphomas with low or undetectable CD30 expression was promising. The use of BV in combination with chemotherapy as frontline treatment is currently being investigated. Future studies should include correlative biomarker analysis and optimization of combination therapies.     

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.