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ISSN (Print) 0012-6667 - ISSN (Online) 1179-1950
Published by Adis Homepage  [21 journals]
  • Leave it to Lefamulin: A Pleuromutilin Treatment Option in
           Community-Acquired Bacterial Pneumonia
    • Abstract: Lefamulin (BC-3781) is the first systemic pleuromutilin antibiotic found to be safe and effective in the treatment of community-acquired bacterial pneumonia (CABP) in humans. This novel antibiotic was developed to combat the increasing incidence of bacterial resistance to current therapies. As the first semisynthetic pleuromutilin for systemic use in humans, lefamulin has demonstrated efficacy against the most common bacteria responsible for CABP, including strains exhibiting resistance to macrolides, fluoroquinolones, tetracyclines, vancomycin, and beta-lactams. In vitro studies have demonstrated efficacy against Staphylococcus aureus, beta-hemolytic and viridans group streptococci, coagulase-negative staphylococci, Enterococcus faecium, Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophilia, and Moraxella catarrhalis at MIC values lower than those of currently available therapies. Two phase III trials (LEAP-1 and LEAP-2) have demonstrated similar findings, meeting non-inferiority criteria for CABP with a minimal side-effect profile. Pharmacokinetic and pharmacodynamic evaluations have shown sufficient drug levels in plasma, subcutaneous adipose tissue, skeletal muscle, and epithelial lining fluid, warranting further investigation for other clinical uses. Lefamulin was approved by the United States Food and Drug Administration (FDA) on 19 August 2019 for the treatment of CABP.
      PubDate: 2019-11-08
  • Correction to: Benefit:Risk Profile of Budesonide in Obstructive Airways
    • Abstract: Page 5, Fig. 2 Key milestones in the development of budesonide.
      PubDate: 2019-11-05
  • Targeting Granulocyte-Monocyte Colony-Stimulating Factor Signaling in
           Rheumatoid Arthritis: Future Prospects
    • Abstract: Rheumatoid arthritis (RA) is a systemic, autoimmune disease that affects joints and extra-articular structures. In the last decade, the management of this chronic disease has dramatically changed with the introduction of several targeted mechanisms of action, such as tumor necrosis factor-α inhibition, T-cell costimulation inhibition, B-cell depletion, interleukin-6 blockade, and Janus kinase inhibition. Beyond its well-known hematopoietic role on the proliferation and differentiation of myeloid cells, granulocyte-monocyte colony-stimulating factor (GM-CSF) is a proinflammatory mediator acting as a cytokine, with a proven pathogenetic role in autoimmune disorders such as RA. In vitro studies clearly demonstrated the effect of GM-CSF in the communication between resident tissue cells and activated macrophages at chronic inflammation sites, and confirmed the elevation of GM-CSF levels in inflamed synovial tissue of RA subjects compared with healthy controls. Moreover, a pivotal role of GM-CSF in the perception of pain has been clearly confirmed. Therefore, blockade of the GM-CSF pathway by monoclonal antibodies directed against the cytokine itself or its receptor has been investigated in refractory RA patients. Overall, the safety profile of GM-CSF inhibitors seems to be very favorable, with a particularly low incidence of infectious complications. The efficacy of this new mechanism of action is comparable with main competitors, even though the response rates reported in phase II randomized controlled trials (RCTs) appear to be numerically lower than the response rates observed with other biological disease-modifying antirheumatic drugs already licensed for RA. Mainly because of this reason, nowadays the development program of most GM-CSF blockers for RA has been discontinued, with the exception of otilimab, which is under evaluation in two phase III RCTs with a head-to head non-inferiority design against tofacitinib. These studies will likely be useful for better defining the potential role of GM-CSF inhibition in the therapeutic algorithm of RA. On the other hand, the potential role of GM-CSF blockade in the treatment of other rheumatic diseases is now under investigation. Phase II trials are ongoing with the aim of evaluating mavrilimumab for the treatment of giant cell arteritis, and namilumab for the treatment of spondyloarthritis. Moreover, GM-CSF inhibitors have been tested in osteoarthritis and diffuse subtype of systemic sclerosis. This review aims to describe in detail the available evidence on the GM-CSF blocking pathway in RA management, paving the way to a possible alternative treatment for RA patients. Novel insights regarding the potential use of GM-CSF blockers for alternative indications will be also addressed.
      PubDate: 2019-11-01
  • Benefit:Risk Profile of Budesonide in Obstructive Airways Disease
    • Abstract: Airway inflammation is a major contributing factor in both asthma and chronic obstructive pulmonary disease (COPD) and represents an important target for treatment. Inhaled corticosteroids (ICS) as monotherapy or in combination therapy with long-acting β2-agonists or long-acting muscarinic antagonists are used extensively in the treatment of asthma and COPD. The development of ICS for their anti-inflammatory properties progressed through efforts to increase topical potency and minimise systemic potency and through advances in inhaled delivery technology. Budesonide is a potent, non-halogenated ICS that was developed in the early 1970s and is now one of the most widely used lung medicines worldwide. Inhaled budesonide’s physiochemical and pharmacokinetic/pharmacodynamic properties allow it to reach a rapid and high airway efficacy due to its more balanced relationship between water solubility and lipophilicity. When absorbed from the airways and lung tissue, its moderate lipophilicity shortens systemic exposure, and its unique property of intracellular esterification acts like a sustained release mechanism within airway tissues, contributing to its airway selectivity and a low risk of adverse events. There is a large volume of clinical evidence supporting the efficacy and safety of budesonide, both alone and in combination with the fast- and long-acting β2-agonist formoterol, as maintenance therapy in patients with asthma and with COPD. The combination of budesonide/formoterol can also be used as an as-needed reliever with anti-inflammatory properties, with or without regular maintenance for asthma, a novel approach that is already approved by some country-specific regulatory authorities and currently recommended in the Global Initiative for Asthma (GINA) guidelines. Budesonide remains one of the most well-established and versatile of the inhaled anti-inflammatory drugs. This narrative review provides a clinical reappraisal of the benefit:risk profile of budesonide in the management of asthma and COPD.
      PubDate: 2019-11-01
  • Tenapanor: First Approval
    • Abstract: The selective sodium hydrogen exchanger 3 (NHE3) inhibitor tenapanor is being developed by Ardelyx Inc. for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) [under the tradename IBSRELA®] and for hyperphosphataemia in patients with chronic kidney disease (CKD) on dialysis or with end stage renal disease (ESRD). Based on positive results from the phase III T3MPO trial program, tenapanor was recently approved in the USA for the treatment of IBS-C in adults. This article summarises the milestones in the development of tenapanor leading to this first approval.
      PubDate: 2019-11-01
  • Lanadelumab: A Review in Hereditary Angioedema
    • Abstract: Lanadelumab (Takhzyro™), a first-in-class fully human monoclonal antibody against plasma kallikrein, has been approved in several countries, including Australia, Canada, those of the EU, Switzerland and the USA, for the prevention of hereditary angioedema (HAE) attacks in patients aged ≥ 12 years. Subcutaneous lanadelumab significantly reduced HAE attack rates relative to placebo in the pivotal HELP trial. The clinical benefits of lanadelumab were seen regardless of prior long-term prophylaxis use, baseline disease activity, sex or body mass index. Lanadelumab therapy was associated with clinically meaningful improvements in HAE-specific quality of life. Lanadelumab was generally well tolerated. The most common adverse events with lanadelumab were injection-site reactions, which were generally mild and transient. Lanadelumab has a low potential for immunogenicity. It offers the convenience of self-administered subcutaneous injections once every 2 weeks (starting dosage). Currently available data indicate that lanadelumab is an effective, well-tolerated, novel prophylactic option for patients with HAE aged ≥ 12 years.
      PubDate: 2019-11-01
  • Correction to: As-needed ICS-LABA in Mild Asthma: What Does the Evidence
    • Abstract: , fourth to last sentence, which currently reads:
      PubDate: 2019-10-29
  • Dapagliflozin: A Review in Type 1 Diabetes
    • Abstract: Oral dapagliflozin (Edistride®, Forxiga®) is approved in the EU at a dosage of 5 mg/day as an adjunct to insulin in adults with type 1 diabetes (T1D) and a body mass index (BMI) of ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy. As a highly selective SGLT2 inhibitor, dapagliflozin decreases plasma glucose levels independently of insulin action and enables glycaemic control improvement without increasing the risks associated with intensive insulin therapy. In the phase III DEPICT-1 and -2 trials, dapagliflozin 5 mg/day as an adjunct to insulin improved glycaemic control and reduced total daily insulin dose and bodyweight relative to placebo in adults with inadequately controlled T1D, including in patients with a BMI of ≥ 27 kg/m2, over 24 weeks of treatment. In extensions of these trials, these improvements were maintained up to 52 weeks. Dapagliflozin was generally well tolerated with a manageable safety profile and a hypoglycaemia profile generally similar to placebo. The incidence of diabetic ketoacidosis with dapagliflozin in patients with a BMI ≥ 27 kg/m2 was less than half that of the overall population who received dapagliflozin. Dapagliflozin is the first SGLT2 inhibitor to be approved for use in T1D and, while further clinical experience in T1D is required to more definitively establish its efficacy and safety profile, it provides a promising adjunctive treatment option for adults with T1D and a BMI of ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy.
      PubDate: 2019-10-29
  • Upadacitinib: First Approval
    • Abstract: Upadacitinib (Rinvoq™), an orally-administered Janus kinase 1 (JAK-1) inhibitor, is being developed by AbbVie for the treatment of rheumatoid arthritis. In August 2019, based on positive results from multinational phase III trials conducted in patients with rheumatoid arthritis, upadacitinib received marketing approval in the USA for the treatment of moderately to severely active rheumatoid arthritis and an inadequate response or intolerance to methotrexate. This article summarizes the milestones in the development of upadacitinib leading to this first approval for the treatment of rheumatoid arthritis.
      PubDate: 2019-10-22
  • Advances in Endocrine-Based Therapies for Estrogen Receptor-Positive
           Metastatic Breast Cancer
    • Abstract: Approximately 70% of breast cancers are estrogen-receptor positive. Tamoxifen and aromatase inhibitors have been the mainstay of endocrine therapy and have improved breast cancer survival. However, a large number of patients experience disease recurrence either during or following completion of endocrine therapy. Recent improvements in our understanding of the various mechanisms underlying the development of endocrine resistance have led to a dramatic change in the landscape of current endocrine treatment with the introduction of new drugs targeting molecular pathways involved in endocrine resistance. Over the past years we have witnessed the use of combination endocrine therapy with mammalian target of rapamycin antagonists, whilst most recently the introduction of cyclin-dependent kinase 4/6 inhibitors has significantly improved response to endocrine therapy. Whilst not a formal systematic review, this article will provide historical background and summarise key clinical trials and current strategies in both first-line and second-line endocrine therapy.
      PubDate: 2019-10-19
  • Correction to: Polatuzumab Vedotin: First Global Approval
    • Abstract: The article Polatuzumab Vedotin: First Global Approval, written by Emma D. Deeks, was originally published Online First without Open Access. After publication in volume 79, issue 13, pages 1467–1475 Roche/GCC requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by Roche/GCC. The article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial.
      PubDate: 2019-10-15
  • Stiripentol: A Review in Dravet Syndrome
    • Abstract: Stiripentol (Diacomit®) is an orally-active, structurally unique anti-epileptic drug (AED) with multiple potential mechanisms of action, including enhancement of central γ-aminobutyric acid transmission. In the EU, stiripentol is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with Dravet syndrome (DS; previously known as severe myoclonic epilepsy of infancy), whose seizures are not adequately controlled with clobazam and valproate. This approval (and similar DS indications in the USA, Canada and Japan), reflect the results of the STICLO studies, two small, randomized controlled trials in which stiripentol as adjunctive therapy was associated with a markedly superior response rate after 2 months compared with placebo in patients aged between 3 and ≈ 21 years with DS that was inadequately controlled with clobazam and valproate. These short-term results have subsequently been supported and extended by findings from longer-term, open-label, observational studies, including a retrospective longitudinal cohort study, which showed that the efficacy of combining stiripentol with clobazam and valproate when started at paediatric age was maintained in mid-adulthood with up to 24 years of exposure, and up to 40 years of age. Drowsiness, appetite loss, weight loss, ataxia and tremor are the most common adverse events associated with the addition of stiripentol to clobazam and valproate. Based on the available evidence, stiripentol, as an adjunct to clobazam and valproate, is a demonstrably beneficial and generally well-tolerated second-line treatment for patients with DS.
      PubDate: 2019-10-15
  • Darolutamide: First Approval
    • Abstract: Darolutamide (NUBEQA™) is a structurally distinct non-steroidal androgen receptor antagonist being developed by Orion and Bayer as a treatment for prostate cancer. Based on positive results in the phase III ARAMIS trial, darolutamide was recently approved in the USA for the treatment of men with non-metastatic castration-resistant prostate cancer. This article summarizes the milestones in the development of darolutamide leading to this first approval.
      PubDate: 2019-10-11
  • Fixed and Low-Dose Combinations of Blood Pressure-Lowering Agents: For the
           Many or the Few'
    • Abstract: Despite the widespread availability of several effective classes of drugs, systemic arterial hypertension remains poorly controlled in the majority of patients worldwide. In this article, we discuss the different modalities and effects of combination therapy and possible future research questions. Treatment with a single antihypertensive agent can effectively reduce blood pressure in only a limited number of patients, while most require therapy with two or more agents to achieve target levels. As initial therapy, American and European guidelines suggest a combination of two antihypertensive drugs and the use of a third antihypertensive drug when hypertension is still uncontrolled. Initial combination therapy is recommended in high-risk patients for an immediate blood pressure response, improved tolerability and possibly increased patient adherence. In addition to the potential benefits of combining different drug classes with synergistic pharmacological and physiological actions, this approach is useful for increasing the patient compliance with treatment, in particular if provided at fixed doses in a single pill. The minimisation of side effects is critical for the long-term treatment of a largely asymptomatic condition such as systemic hypertension. Low-dose combinations of different drugs from classes with complementary actions may provide the best ratio of lower side effects and improved tolerability with a significant blood pressure reduction, particularly in high-risk patients. This approach could be aided by a multidisciplinary lifestyle intervention on risk factors.
      PubDate: 2019-10-10
  • Pexidartinib: First Approval
    • Abstract: Pexidartinib (TURALIO™) is an orally administered small molecule tyrosine kinase inhibitor with selective activity against the colony-stimulating factor 1 (CSF1) receptor, KIT proto-oncogene receptor tyrosine kinase (KIT) and FMS-like tyrosine kinase 3 harboring an internal tandem duplication mutation (FLT3-ITD). In August 2019, the US FDA approved pexidartinib capsules for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. This approval was based on positive results from the phase III ENLIVEN trial. Pexidartinib is being investigated in various malignancies as monotherapy or combination therapy. This article summarizes the milestones in the development of pexidartinib leading to its first approval for TGCT.
      PubDate: 2019-10-10
  • Immunotherapy Against Gliomas: is the Breakthrough Near'
    • Abstract: Immunotherapeutic approaches have been, and continue to be, aggressively investigated in the treatment of infiltrating gliomas. While the results of late-phase clinical studies have been disappointing in this disease space thus far, the success of immunotherapies in other malignancies as well as the incremental gains in our understanding of immune-tumour interactions in gliomas has fuelled a strong continued interest of their evaluation in these tumours. We discuss a range of immunotherapeutic approaches including, but not limited to, vaccines, checkpoint inhibitors, oncolytic viruses, and gene therapies. Potential biomarkers under investigation to help elucidate which patients may respond or not respond to immunotherapeutic regimens are reviewed. Directions for future investigations are also noted.
      PubDate: 2019-10-09
  • As-needed ICS-LABA in Mild Asthma: What Does the Evidence Say'
    • Abstract: For the last three decades, the guidelines for asthma management have supported a stepwise therapeutic approach, based on the administration of controller medications (especially inhaled corticosteroids) complemented by on-demand use of rescue medication. Classically, the rescue medication recommended comprised short-acting β agonists (SABA). Some years ago, the use of Symbicort Maintenance and Reliever Therapy (SMART) demonstrated the benefits of a combination of budesonide-formoterol, an inhaled corticosteroid, and a long-acting β agonist (ICS-LABA) as rescue medication in moderate and severe asthma. The results were enthusiastically received, and this therapeutic option was adopted in the guidelines for moderate to severe asthma patients. Recently, four trials (two randomised placebo control trials under the auspices of the SYGMA project and two real-life studies, Novel START, and the PRACTICAL trial) have explored the potential benefits of substituting SABA with budesonide-formoterol as rescue medication in mild asthma patients. The SYGMA 1 and 2 studies showed that the combination with formoterol-budesonide as rescue medication provides better asthma control than short-acting β-agonists alone in GINA step 2 patients, although the superiority was slight. Compared to budesonide maintenance therapy, the fixed combination of ICS-LABA on demand provides poorer asthma control. Regarding exacerbations, the fixed dose ICS-LABA combination on demand showed the same benefits for the prevention of exacerbations as chronic ICS treatment in mild asthma patients. The Novel START study, which assessed a population with milder symptoms, concluded that the fixed dose ICS-LABA combination used as needed was superior to SABA (albuterol) as needed for the prevention of asthma exacerbations. These results in fact show that, in undertreated GINA step 2 with only SABA as needed, ICS-LABA is more effective than SABA. The authors of PRACTICAL concluded that the study provided modest evidence that the ICS-LABA combination used as-needed for symptom relief reduces the rate of severe exacerbations compared with maintenance low-dose budesonide plus terbutaline as needed, although the study was not limited to mild asthma since according to the treatment consumed, it was evident that they had recruited some moderate asthma patients. Despite this poor evidence, and ignoring the clinical histological benefits of chronic inhaled corticosteroids (especially when administered promptly), GINA 2019 recently recommended daily low dose ICS or ICS-ICS as needed as a first option for step 2 patients. For step 1, symptom-driven or as-needed treatment with ICS-LABA is recommended rather than SABA alone (the preferred option until the last GINA update). Finally, the SIENA study showed that 73% of patients with mild asthma do not have an eosinophilic phenotype and that these patients have a similar clinical response to ICS (mometasone) and antimuscarinic drugs (tiotropium), results that challenge the indication of a drug combination that incorporates ICS as a first option. Overall, we believe there is insufficient evidence for the systematic recommendation of as-needed ICS-LABA instead of SABA on request for GINA step 1 or as a replacement for chronic ICS in GINA step 2.
      PubDate: 2019-10-04
  • Pretomanid: First Approval
    • Abstract: Pretomanid, an oral nitroimidazooxazine antimycobacterial agent administered as part of the BPaL (bedaquiline, pretomanid and linezolid) and BPaMZ (bedaquiline, pretomanid, moxifloxacin and pyrazinamide) regimens, has been developed by the Global Alliance for TB Drug Development (TB Alliance) under license from Novartis, for the treatment for tuberculosis (TB). TB Alliance has licensed Mylan to manufacture and commercialize pretomanid for use as part of the BPaMZ and BPaL regimens. The license is non-exclusive in low- and middle-income countries and exclusive in high-income markets. Pretomanid, as part of the BPaL regimen, was recently approved in the USA under the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) pathway for the treatment of adults with pulmonary extensively drug-resistant (XDR) or treatment-intolerant or non-responsive multidrug-resistant (MDR) TB. Pretomanid is also under regulatory review in the EU. This article summarizes the milestones in the development of pretomanid leading to this first regulatory approval.
      PubDate: 2019-10-03
  • The Safety and Efficacy of Tranexamic Acid in Adult Spinal Deformity
           Surgery: A Systematic Review and Meta-Analysis
    • Abstract: Objectives Major spinal corrective surgeries can be associated with critical intra-operative blood loss. The objective of this systematic review and meta-analysis was to assess the safety and efficacy of tranexamic acid (TXA), a commonly used antifibrinolytic agent, in adult spinal deformity (ASD) surgery, defined as fusion of five or more levels. Methods Articles from PubMed, Embase, Cochrane, and were screened using PRISMA guidelines through December 2018. Thromboembolic events, blood loss, and transfusion levels were primary outcomes of interest. Randomized controlled trials (RCTs) and observational studies (OBSs) with adult patients (≥ 18 years) were included. Continuous variables were analyzed using mean difference (MD) and categorical variables were analyzed using Peto odds ratio (OR), via random effects models. Results Of the 604 articles screened, seven studies (two RCTs and five cohort studies) were included. Incidence of thromboembolic events was not statistically significantly different between TXA (1 event/19) and placebo (0 events/13) in the RCT (Peto OR = 1.41, 95% CI 0.05–37.2; 32 patients; 1 study) and in the OBSs (TXA [2 events/135] vs control [0 events/72]; Peto OR = 1.09, 95% CI 0.16–7.61; p-heterogeneity = 0.85; 207 patients; 3 studies). Data from OBSs showed that the pooled MD was statistically significantly lower in the TXA group compared with the control group for intraoperative blood loss (MD: − 620.2 mL, 95% CI − 1066.6 to − 173.7; p-heterogeneity = 0.14; 228 patients; 4 studies) and total transfusion volume (MD: − 958.2 mL, 95% CI − 1867.5 to − 49.0; p-heterogeneity = 0.23; 93 patients; 2 studies). Conclusion In this meta-analysis, TXA was not significantly associated with increased risk of thromboembolic events but was associated with lower intraoperative blood loss and lower total transfusion volumes in ASD surgery.
      PubDate: 2019-10-01
  • Correction to: Trifluridine/Tipiracil: A Review in Metastatic Gastric
    • Abstract: The article Trifluridine/Tipiracil: A Review in Metastatic Gastric Cancer, written by Connie Kang, Sohita Dhillon and Emma D. Deeks, was originally published Online First without open access
      PubDate: 2019-09-18
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