Drugs

Roth, Michael

doi: 10.1007/s40265-014-0319-0pmid: 25414120

Lung tissue remodelling in chronic inflammatory lung diseases has long been regarded as a follow-up event to inflammation. Recent studies have indicated that, although airway and lung tissue remodelling is often independent of inflammation, it precedes or causes inflammation. None of the available therapies has a significant effect on airway and lung tissue remodelling in asthma, bronchiectasis, fibrosis and chronic obstructive pulmonary disease (COPD). The goal of stopping or reversing lung tissue remodelling is difficult, as the term summarizes the net effect of independent events, including (1) cell proliferation, (2) cell volume increase, (3) cell migration, (4) modified deposition and metabolism of specific extracellular matrix components, and (5) local action of infiltrated inflammatory cells. The extracellular matrix of the lung has a very high turnover, and thus small changes may accumulate to significant structural pathologies, which seem to be irreversible. The most important question is ‘why are pathological changes of the lung structure irreversible and resistant to drugs?’ Many drugs have the potential to reduce remodelling mechanisms in vitro but fail in clinical trials. New evidence suggests that muscarinic receptor inhibitors have the potential to improve lung function through modifying tissue remodelling. However, the role of muscarinic receptors in lung remodelling, especially their supportive role for other remodelling driving factors, needs to be further investigated. The focus of this review is the role of muscarinic receptors in lung tissue remodelling as it has been reported in the human lung.

Brownley, Kimberly; Peat, Christine; La Via, Maria; Bulik, Cynthia

doi: 10.1007/s40265-014-0327-0pmid: 25428709

In the USA, binge eating disorder (BED) is the most common eating disorder, with a lifetime prevalence of ~3.5 % in adult women, 2.0 % in adult men, and 1.6 % in adolescents. BED is characterized by frequent episodes of binge eating that are accompanied by a sense of loss of control over eating and result in marked psychological distress. BED is highly co-morbid with obesity and with depression and other psychiatric conditions, and it is associated with substantial role impairment. Currently, there are no US FDA-approved pharmacological treatments for BED. Animal and human studies implicate underlying dysregulation in dopamine, opioid, acetylcholine, and serotonin neurocircuitry within brain reward regions in the pathogenesis and maintenance of BED. To date, the efficacy of various agents that target these and other neurotransmitter systems involved in motivated feeding behavior, mood regulation, and impulse control have been investigated in the treatment of BED. Several antidepressant and anticonvulsant agents have demonstrated efficacy in reducing binge eating frequency, but only in limited cases have these effects resulted in patients achieving abstinence, which is the primary goal of treatment; they also range from less (fluvoxamine) to more (topiramate) effective in achieving weight loss that is both clinically meaningful and significantly greater than placebo. Collectively, the literature on pharmacological treatment approaches to BED is limited in that very few agents have been studied in multiple, confirmatory trials with adequate follow up, and almost none have been evaluated in large patient samples that are diverse with respect to age, sex, and ethnicity. In addition, prior trials have not adequately addressed, through study design, the high placebo response commonly observed in this patient population. Several novel agents are in various phases of testing, and recent animal studies focusing on glutamate-signaling circuits linking the amygdala to the lateral hypothalamus offer new avenues for exploration and potential therapeutic development. Studies of newly FDA-approved medications for long-term obesity treatment and further explorations of dietary supplements and neutraceuticals with appetite- and mood-altering properties may also be worthwhile.

Scheen, André

doi: 10.1007/s40265-014-0337-ypmid: 25488697

Inhibitors of sodium–glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug–drug interactions and a low renal elimination as parent drug. SGLT2 co-transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate. Results of numerous placebo-controlled randomised clinical trials of 12–104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets, and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors appears to be better; however, this remains to be more extensively investigated. The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin. Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure. Both effects were very consistent across the trials and they represent some advantages for SGLT2 inhibitors when compared with other oral glucose-lowering agents. The pharmacodynamic response to SGLT2 inhibitors declines with increasing severity of renal impairment, and prescribing information for each SGLT2 inhibitor should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction. Caution is also recommended in the elderly population because of a higher risk of renal impairment, orthostatic hypotension and dehydration, even if the absence of hypoglycaemia represents an obvious advantage in this population. The overall effect of SGLT2 inhibitors on the risk of cardiovascular disease is unknown and will be evaluated in several ongoing prospective placebo-controlled trials with cardiovascular outcomes. The impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy also deserve more attention. SGLT2 inhibitors are generally well-tolerated. The most frequently reported adverse events are female genital mycotic infections, while urinary tract infections are less commonly observed and generally benign. In conclusion, with their unique mechanism of action that is independent of insulin secretion and action, SGLT2 inhibitors are a useful addition to the therapeutic options available for the management of T2DM at any stage in the natural history of the disease. Although SGLT2 inhibitors have already been extensively investigated, further studies should even better delineate the best place of these new glucose-lowering agents in the already rich armamentarium for the management of T2DM.

Blair, Hannah; Deeks, Emma

doi: 10.1007/s40265-014-0326-1pmid: 25398674

Umeclidinium/vilanterol (Anoro® Ellipta™; Laventair™) is an inhaled fixed-dose combination of a long-acting muscarinic receptor antagonist and a long-acting β2-adrenoceptor agonist. It is available in several countries, including Japan, the USA, Canada and those of the EU, where it is indicated for oral inhalation in adults with chronic obstructive pulmonary disease (COPD). Umeclidinium/vilanterol is administered once daily using the Ellipta™ multi-dose dry powder inhaler, which is regarded as easy to use. Umeclidinium/vilanterol (62.5/25 µg once daily, equivalent to a delivered dose of 55/22 µg once daily) was effective and well tolerated in adult patients with COPD participating in large, multicentre trials of up to 24 weeks’ duration. Umeclidinium/vilanterol improved pulmonary function to a significantly greater extent than placebo and each of the individual components. Moreover, umeclidinium/vilanterol was significantly more effective than once-daily tiotropium bromide monotherapy and a twice-daily fixed combination of salmeterol/fluticasone propionate at improving pulmonary function. Umeclidinium/vilanterol also had beneficial effects on dyspnoea, use of rescue medication, exacerbations, health-related quality of life and, in one study, exercise endurance. Umeclidinium/vilanterol is generally well tolerated in patients with COPD, with the most common adverse events in clinical trials being headache and nasopharyngitis. Umeclidinium/vilanterol was not associated with a clinically relevant increased risk of cardiovascular adverse events in patients with COPD, when data from several clinical trials were pooled. Thus, inhaled umeclidinium/vilanterol extends the treatment options currently available for the maintenance treatment of adults with COPD and has the convenience of once-daily administration.

McKeage, Kate

doi: 10.1007/s40265-014-0329-ypmid: 25428710

Alectinib (Alecensa®) is a second-generation, orally active, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK). Alectinib is approved for the treatment of ALK fusion-gene positive, unresectable, advanced or recurrent non-small cell lung cancer (NSCLC) in Japan, where it has been given orphan drug designation. Approval was based on a phase 1–2 study in ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC who received twice-daily alectinib 300 mg. In the phase 2 portion, 93.5 % of patients achieved an objective response. Treatment response was rapid, with a partial response achieved in two-thirds of patients within 3 weeks (cycle 1). Patient follow-up is ongoing, and after approximately 2 years, 19.6 % of patients had achieved a complete response, and the 2-year progression-free survival rate is 76 %. During treatment with alectinib (median follow-up approximately 8 months), there was no progression of CNS lesions among patients with known CNS metastases at baseline (although prior radiation therapy may have confounded results). In preclinical models, alectinib was active against most ALK fusion-gene mutations related to crizotinib resistance, and preliminary results from clinical trials indicate efficacy in crizotinib-refractory NSCLC. Alectinib was generally well tolerated in clinical trials, and there were no treatment-related grade 4 adverse events or deaths. The most common grade 3 treatment-related adverse events were decreased neutrophil counts and increased creatinine phosphokinase. While more data are needed to confirm the efficacy of alectinib and to evaluate its activity in crizotinib-resistant disease, the drug provides a very promising option for the treatment of ALK-rearranged advanced NSCLC.

Yang, Lily; Deeks, Emma

doi: 10.1007/s40265-014-0328-zpmid: 25420446

Fixed-dose dextromethorphan/quinidine capsules (Nuedexta®) utilize quinidine to inhibit the metabolism of dextromethorphan, enabling high plasma dextromethorphan concentrations to be reached without using a larger dose of the drug. The drug combination is the first treatment to be approved for pseudobulbar affect (PBA), a condition of contextually inappropriate/exaggerated emotional expression that often occurs in adults with neurological damage conditions, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, traumatic brain injury, Alzheimer’s disease or Parkinson’s disease. Dextromethorphan/quinidine at the recommended dosages of 20/10 or 30/10 mg twice daily reduced the rate of PBA episodes and improved PBA severity in a 12-week, double-blind, placebo-controlled trial in adults with ALS or MS (STAR), with further improvements in the severity of the condition observed in a 12-week open-label extension phase. Dextromethorphan/quinidine 20/10 mg twice daily also improved PBA secondary to dementia in a cohort of a 12-week noncomparative trial (PRISM II). The drug combination was generally well tolerated in these studies, with no particular safety or tolerability concerns. Although longer-term efficacy and tolerability data for dextromethorphan/quinidine 20/10 or 30/10 mg twice daily would be beneficial, current evidence indicates that it is a useful option in the treatment of adults with PBA.

Blair, Hannah; Scott, Lesley

doi: 10.1007/s40265-014-0331-4pmid: 25404020

Delamanid (Deltyba®), a nitroimidazo-oxazole derivative, is a new anti-tuberculosis (TB) drug which exhibits potent in vitro and in vivo antitubercular activity against drug-susceptible and -resistant strains of Mycobacterium tuberculosis. It is approved in several countries, including Japan and those of the EU, for use as part of an appropriate combination regimen in adults with multidrug-resistant tuberculosis (MDR-TB) when an effective treatment regimen cannot otherwise be composed due to resistance or tolerability. In a robust phase II trial in adult patients with MDR-TB, oral delamanid 100 mg twice daily for 2 months plus an optimized background regimen improved sputum culture conversion rates to a significantly greater extent than placebo. In a 6-month extension study, long-term (≤8 months) treatment with delamanid was associated with a higher incidence of favourable outcomes (i.e. cured or completed all treatment) than short-term (≤2 months) treatment, with an accompanying reduction inunfavourable outcomes as defined by the WHO (i.e. pre-specified proportion of TB-positive sputum cultures, death or treatment discontinuation for ≥2 months without medical approval). Delamanid was not associated with clinically relevant drug-drug interactions, including with antiretroviral drugs and those commonly used in treating TB. Delamanid was generally well tolerated in patients with MDR-TB, with gastrointestinal adverse events and insomnia reported most commonly. Although the incidence of QT interval prolongation was higher with delamanid-based therapy, it was not associated with clinical symptoms such as syncope and arrhythmia. In conclusion, delamanid is a useful addition to the treatment options currently available for patients with MDR-TB.

Keating, Gillian

doi: 10.1007/s40265-014-0332-3pmid: 25428711

Ferric carboxymaltose (Ferinject®, Injectafer®) is an intravenous iron preparation approved in numerous countries for the treatment of iron deficiency. A single high dose of ferric carboxymaltose (up to 750 mg of iron in the US and 1,000 mg of iron in the EU) can be infused in a short time frame (15 min). Consequently, fewer doses of ferric carboxymaltose may be needed to replenish iron stores compared with some other intravenous iron preparations (e.g. iron sucrose). Ferric carboxymaltose improved self-reported patient global assessment, New York Heart Association functional class and exercise capacity in patients with chronic heart failure and iron deficiency in two randomized, placebo-controlled trials (FAIR-HF and CONFIRM-HF). In other randomized controlled trials, ferric carboxymaltose replenished iron stores and corrected anaemia in various populations with iron-deficiency anaemia, including patients with chronic kidney disease, inflammatory bowel disease or heavy uterine bleeding, postpartum iron-deficiency anaemia and perioperative anaemia. Intravenous ferric carboxymaltose was generally well tolerated, with a low risk of hypersensitivity reactions. It was generally better tolerated than oral ferrous sulfate, mainly reflecting a lower incidence of gastrointestinal adverse effects. The most common laboratory abnormality seen in ferric carboxymaltose recipients was transient, asymptomatic hypophosphataemia. The higher acquisition cost of ferric carboxymaltose appeared to be offset by lower costs for other items, with the potential for cost savings. In conclusion, ferric carboxymaltose is an important option for the treatment of iron deficiency.

McCormack, Paul

doi: 10.1007/s40265-014-0335-0pmid: 25430078

Nintedanib (Ofev®) is an orally available, small, multiple receptor tyrosine kinase inhibitor developed by Boehringer Ingelheim for the treatment of idiopathic pulmonary fibrosis (IPF) and cancer. Nintedanib received its first global approval in the US in October 2014 for the treatment of IPF. Nintedanib has received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use for the treatment of IPF, and for the second-line treatment in combination with docetaxel of locally advanced, metastatic or locally recurrent non-small cell lung cancer of adenocarcinoma tumour histology. Phase 3 development programmes are also underway for colorectal cancer and ovarian cancer. Phase 2 investigation is being conducted for a variety of other solid tumours, including hepatocellular carcinoma, mesothelioma, prostate cancer, glioblastoma, renal cell carcinoma and endometrial cancer. This article summarizes the milestones in the development of nintedanib leading to this first approval for IPF.

Scott, Lesley

doi: 10.1007/s40265-014-0336-zpmid: 25428712