Drugs

Matera, Maria; Rogliani, Paola; Calzetta, Luigino; Cazzola, Mario

doi: 10.1007/s40265-014-0303-8pmid: 25300411

Phosphodiesterase-4 (PDE4) inhibitors have broad anti-inflammatory activity, inhibiting the airway inflammation associated with chronic obstructive pulmonary disease (COPD), especially by reducing airway neutrophils that are key cells in COPD. A careful evaluation of the results of several meta-analyses allows us to consider the use of PDE4 inhibitors as very important in those patients with COPD who are particularly susceptible to exacerbations, the so-called ‘frequent exacerbators’. Consequently, PDE4 inhibitors should be used earlier and more frequently than is the case today, but they are prescribed sporadically because of side effects. Several strategies are conceivable to avoid side effects, but, unfortunately, many of these approaches are yet to be successfully translated into clinical effectiveness after several decades of research. A novel alternative approach is to administer multiple drugs simultaneously or drugs capable of two distinct primary pharmacological actions based on distinct pharmacophores (bifunctional drugs) in order to produce additive or synergistic effects and, consequently, to dispense these drugs at lower doses, inducing fewer side effects. The fact that we have realized that there is a need to target simultaneously more PDEs unquestionably represents an advance in the possible use of PDE inhibitors. Actually, the possibility that multivalent (multifunctional) ligands, which feature two or more pharmacophores, may deliver superior efficacy is an approach that is being explored. Recognizing the role of specific targeted therapy aimed at subcellular domains has changed our understanding of the use of PDE inhibitors, and offers an opportunity to improve both the therapeutic tolerability and efficacy of these drugs.

Shih, Kent; Arkenau, Hendrik-Tobias; Infante, Jeffrey

doi: 10.1007/s40265-014-0305-6pmid: 25344022

Immune responses are tightly regulated via signaling through numerous co-stimulatory and co-inhibitory molecules. Exploitation of these immune checkpoint pathways is one of the mechanisms by which tumors evade and/or escape the immune system. A growing understanding of the biology of immune checkpoints and tumor immunology has led to the development of monoclonal antibodies designed to target co-stimulatory and co-inhibitory molecules in order to re-engage the immune system and restore antitumor immune responses. Anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies were among the first to be tested in the clinic, and ipilimumab was the first immune checkpoint inhibitor approved for an anticancer indication. Agents targeting the programmed death 1 (PD-1) pathway, either PD-1 or one of its ligands, programmed death ligand 1, are in active clinical development for numerous cancers, including advanced melanoma and lung cancer. Understanding the different mechanisms of action, safety profiles, and response patterns associated with inhibition of the CTLA-4 and PD-1 pathways may improve patient management as these therapies are moved in to the clinical practice setting and may also provide a rationale for combination therapy with different inhibitors. Additional immune checkpoint molecules with therapeutic potential, including lymphocyte activation gene-3 and glucocorticoid-induced tumor necrosis factor receptor-related gene, also have inhibitors in early stages of clinical development. Clinical responses and safety data reported to date on immune checkpoint inhibitors suggest these agents may have the potential to markedly improve outcomes for patients with cancer.

Dobesh, Paul; Fanikos, John

doi: 10.1007/s40265-014-0301-xpmid: 25300410

Venous thromboembolism (VTE) is a major cause of morbidity, mortality, and healthcare expenditure. In the United States, approximately 0.1 % of the population experiences an initial VTE event each year. Anticoagulation therapy is the cornerstone of acute VTE treatment and for prevention of recurrent VTE events. Conventional anticoagulants, including heparin, low-molecular-weight heparins, fondaparinux, and vitamin K antagonists are widely used but have limitations. Newer oral anticoagulant agents, including direct thrombin inhibitors (e.g., dabigatran etexilate) and direct factor Xa inhibitors (e.g., rivaroxaban, apixaban, and edoxaban) have been developed to attempt to overcome some of the limitations of conventional anticoagulant therapy. These new oral agents have been evaluated for safety and efficacy in large, randomized clinical trials in the treatment and secondary prevention of VTE with results that are comparable to conventional therapy. Dabigatran, rivaroxaban, apixaban, and edoxaban are important new treatment options for patients with VTE. In this review, we compare these new agents and their associated clinical trials in VTE treatment.

Kjeldsen, Sverre; Feldman, Ross; Lisheng, Liu; Mourad, Jean-Jacques; Chiang, Chern-En; Zhang, Weizhong; Wu, Zhaosu; Li, Wei; Williams, Bryan

doi: 10.1007/s40265-014-0306-5pmid: 25315030

Despite the availability of effective pharmacological treatments to aid the control of blood pressure, the global rate of uncontrolled blood pressure remains high. As such, further measures are required to improve blood pressure control. Recently, several national and international guidelines for the management of hypertension have been published. These aim to provide easily accessible information for healthcare professionals and patients to aid the diagnosis and treatment of hypertension. In this review, we have compared new and current guidelines from the American and International Societies of Hypertension; the American Heart Association, American College of Cardiology and the US Center for Disease Control and Prevention; the panel appointed to the Eighth Joint National Committee; the European Societies of Hypertension and Cardiology; the French Society of Hypertension; the Canadian Hypertension Education Program; the National Institute for Health and Clinical Excellence (UK); the Taiwan Society of Cardiology and the Chinese Hypertension League. We have identified consensus opinion regarding best practises for the management of hypertension and have highlighted any discrepancies between the recommendations. In general there is good agreement between the guidelines, however, in some areas, such as target blood pressure ranges for the elderly, further trials are required to provide sufficient high-quality evidence to form the basis of recommendations.

McCormack, Paul L.

doi: 10.1007/s40265-014-0316-3pmid: 25352392

Extended-release tacrolimus (tacrolimus ER) [Advagraf®; Astagraf XL®; Graceptor®; Prograf XL®] is a once-daily formulation of the immunosuppressive calcineurin inhibitor, which is approved in many countries worldwide for the prophylaxis of transplant rejection in adult de novo kidney transplant recipients. It is absorbed more slowly than the conventional, twice-daily, immediate-release formulation, initially producing lower exposure when administered at the same daily dosage, but providing equivalent exposure upon repeat administration with therapeutic drug monitoring. In randomized, controlled, phase III/IV trials, with extended follow-up to 4 years, the efficacy of tacrolimus ER was similar to that of twice-daily tacrolimus with regard to the prevention of acute rejection or graft dysfunction in adult de novo kidney transplant recipients. Renal function was significantly better with tacrolimus ER, but not tacrolimus, than with ciclosporin. The tolerability profile of tacrolimus ER was descriptively similar to that of the original twice-daily formulation, with no notable differences. Therefore, tacrolimus ER retains the immunosuppressive activity of the original formulation in the prophylaxis of transplant rejection in adult de novo kidney transplant recipients and offers the benefits of once-daily administration.

Garnock-Jones, Karly

doi: 10.1007/s40265-014-0317-2pmid: 25352393

Riociguat (Adempas®), a soluble guanylate cyclase stimulator, is a new, first-in-class drug approved for the treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) [inoperable or persistent/recurrent following surgery] or pulmonary arterial hypertension (PAH). It has been designated an orphan medicine by the European Medicines Agency and the US FDA. This article reviews the available pharmacological properties of oral riociguat and its clinical efficacy and tolerability in adults with CTEPH or PAH. Riociguat is effective and well tolerated in patients with inoperable CTEPH or persistent/recurrent CTEPH following pulmonary endarterectomy, and in patients with PAH. It has a positive result on exercise capacity and pulmonary haemodynamics, and improves WHO functional class. Most adverse events can be attributed to the vasodilatory mechanism of riociguat; however, there is a potential for serious bleeding and fetal harm, and riociguat use is contraindicated in pregnant patients. Pulmonary endarterectomy remains the first treatment of choice for CTEPH, as it is potentially curative. Head-to-head trials comparing riociguat with the approved phosphodiesterase type 5 inhibitors in patients with PAH would be of value for the placement of riociguat in the management of this disease. Riociguat is a promising addition to the treatment options for patients with CTEPH or PAH.

Deeks, Emma D.

doi: 10.1007/s40265-014-0318-1pmid: 25352394

The nucleos(t)ide reverse transcriptase inhibitors, emtricitabine and tenofovir disoproxil fumarate (tenofovir DF), and the non-nucleoside reverse transcriptase inhibitor, rilpivirine, are now available as a fixed-dose single-tablet regimen (emtricitabine/rilpivirine/tenofovir DF; Complera®, Eviplera®) for the treatment of adults infected with HIV-1. In treatment-naïve adults, once-daily emtricitabine/rilpivirine/tenofovir DF was noninferior to once-daily emtricitabine/efavirenz/tenofovir DF with regard to establishing virological suppression over 96 weeks of therapy in a randomized, open-label, phase IIIb study (STaR). These data confirmed the findings of a pooled subset analysis of two earlier 96-week, double-blind, phase III trials (ECHO and THRIVE) in which treatment-naïve adults received either rilpivirine or efavirenz in combination with emtricitabine/tenofovir DF. However, the virological benefit of emtricitabine/rilpivirine/tenofovir DF in this setting appeared limited in patients with low CD4+ cell counts or high viral loads at baseline. In 48-week phase IIIb (SPIRIT) and IIb (Study 111) trials in treatment-experienced patients already virologically suppressed with a single- or multiple-tablet antiretroviral regimen and without prior virological failure, switching to once-daily emtricitabine/rilpivirine/tenofovir DF maintained virological suppression and was noninferior to remaining on a more complex multiple-tablet regimen in this regard. Emtricitabine/rilpivirine/tenofovir DF is generally well tolerated and appears to have a more favourable tolerability profile than emtricitabine/efavirenz/tenofovir DF. Thus, emtricitabine/rilpivirine/tenofovir DF is a welcome addition to the other single-tablet regimens currently available for the treatment of HIV-1 infection, providing a convenient and effective option for some adults who are treatment-naïve, as well as those who are already virologically suppressed on their current treatment regimen and wish to switch because of intolerance or to simplify their regimen.

Sanford, Mark

doi: 10.1007/s40265-014-0320-7pmid: 25367716

Dulaglutide (Trulicity™) is a long-acting, glucagon-like peptide-1 (GLP-1) receptor agonist that has been developed by Eli Lilly and Company for the treatment of type 2 diabetes mellitus. It consists of a dipeptidyl peptidase-IV-protected GLP-1 analogue covalently linked to a human IgG4-Fc heavy chain by a small peptide linker. The subcutaneous formulation is approved for use in type 2 diabetes in the US, has been recommended for approval in the EU in this indication, and is under regulatory review in other countries. This article summarizes the milestones in the development of subcutaneous dulaglutide leading to this first approval for type 2 diabetes.