Drugs

Samson, Susan

doi: 10.1007/s40265-016-0615-ypmid: 27473537

Pasireotide (Signifor®) long-acting release (LAR) is a next-generation somatostatin receptor ligand (SRL) approved for treatment of patients with acromegaly who have had an inadequate response to surgery or for whom surgery is not an option. Pasireotide LAR has been shown to be more effective than other SRLs in providing biochemical control in patients with acromegaly. However, hyperglycemia-related adverse events were more frequent in patients treated with pasireotide LAR than in those treated with other SRLs. Given the effectiveness of pasireotide LAR, it is important to understand whether these hyperglycemia-related events are manageable and, if so, the appropriate steps to take to manage them. In patients treated with pasireotide LAR, levels of fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) increased in the first 1–3 months and stabilized for as long as 26 months thereafter. In phase III trials of patients with acromegaly, only 3.4–3.8 % discontinued pasireotide LAR because of hyperglycemia-related adverse events. In cases in which pasireotide LAR was discontinued, FPG and HbA1c levels returned to baseline. Frequent monitoring of glucose levels is recommended, especially immediately after initiating and discontinuing pasireotide LAR. The treatment strategies suggested herein are made on the basis of available clinical data from healthy volunteers and post hoc analyses of phase III trials. Data from several clinical trials indicate a predictable and possibly reversible hyperglycemic effect that is manageable with proactive monitoring and available antidiabetic medications.

Jamieson, Gene; Fox, Judith; Poi, Ming; Strickland, Stephen

doi: 10.1007/s40265-016-0614-zpmid: 27484675

Vosaroxin is a first-in-class anticancer quinolone derivative that targets topoisomerase II and induces site-selective double-strand breaks in DNA, leading to tumor cell apoptosis. Vosaroxin has chemical and pharmacologic characteristics distinct from other topoisomerase II inhibitors due to its quinolone scaffold. The efficacy and safety of vosaroxin in combination with cytarabine were evaluated in patients with relapsed/refractory acute myeloid leukemia (AML) in a phase III, randomized, multicenter, double-blind, placebo-controlled study (VALOR). In this study, the addition of vosaroxin produced a 1.4-month improvement in median overall survival (OS; 7.5 months with vosaroxin/cytarabine vs. 6.1 months with placebo/cytarabine; hazard ratio [HR] 0.87, 95 % confidence interval [CI] 0.73−1.02; unstratified log-rank p $$=$$ = 0.061; stratified log-rank p $$=$$ = 0.024), with the greatest OS benefit observed in patients ≥60 years of age (7.1 vs. 5.0 months; HR 0.75, 95 % CI 0.62−0.92; p $$=$$ = 0.003) and patients with early relapse (6.7 vs. 5.2 months; HR 0.77, 95 % CI 0.59−1.00; p $$=$$ = 0.039), two AML patient groups that typically have poor prognosis. Here we review the chemical and pharmacologic properties of vosaroxin, how these properties are distinct from those of currently available topoisomerase II inhibitors, how they may contribute to the efficacy and safety profile observed in the VALOR trial, and the status of clinical development of vosaroxin for treatment of AML.

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

doi: 10.1007/s40265-016-0625-9pmid: 27506851

Chronic obstructive pulmonary disease (COPD) is a disorder characterized by a complex chronic inflammatory response that is largely poorly responsive to treatment with corticosteroids. Consequently, there is a huge need to find effective anti-inflammatory agents for the treatment of patients with this disease. Inhibition of cytokines and chemokines or their receptors using monoclonal antibodies (mAbs) could be a potential strategy to treat the inflammatory component of COPD. In this article, we review the therapeutic potential of some of these mAbs; however, to date there has been little or no therapeutic effect of any mAb directed against cytokines or chemokines in patients with COPD. This may reflect the complexity of COPD in which there is no dominant role for any single cytokine or chemokine. It is also likely that since the umbrella term COPD covers many endotypes having different underlying mechanisms, mAbs directed towards specific cytokines or chemokines should be tested in restricted and focused populations.

Blair, Hannah; Scott, Lesley

doi: 10.1007/s40265-016-0621-0pmid: 27438290

Chronic hand eczema is a common but frequently disabling skin condition which poses a significant social and economic burden. Although skin protection measures and topical therapies are fundamental in its management, some patients are refractory to first-line therapy with topical corticosteroids and require systemic treatment. Alitretinoin (9-cis-retinoic acid; Toctino®) is an endogenous vitamin A derivative with high binding affinity for both retinoic acid receptors and retinoid X receptors. Alitretinoin is the first systemic treatment to be approved in the EU for use in patients with severe chronic hand eczema unresponsive to potent topical corticosteroids. This article updates an earlier review of alitretinoin in this indication, focusing on recently published data. In clinical trials, treatment with alitretinoin 10 or 30 mg once daily for up to 24 weeks improved the severity and extent of severe chronic hand eczema in adults, with significantly more alitretinoin than placebo recipients achieving ratings of ‘clear’ or ‘almost clear’ hands on the Physician Global Impression of Change scale. For the most part, data obtained in real-world studies were consistent with those observed in clinical trials. Alitretinoin was generally well tolerated, with most adverse events being reversible, dose-dependent and of mild or moderate severity. Thus, oral alitretinoin is a useful treatment option for patients with severe chronic hand eczema unresponsive to potent topical corticosteroids.

Frampton, James

doi: 10.1007/s40265-016-0622-zpmid: 27487799

Efmoroctocog alfa (Elocta®, Eloctate®, Eloctate™), a first-in-class recombinant factor VIII-Fc fusion protein (rFVIIIFc), has an extended half-life compared with conventional factor VIII (FVIII) preparations, including recombinant FVIII (rFVIII) products. It is approved for the treatment and prophylaxis of bleeding in patients with haemophilia A in multiple countries worldwide. Data accumulated from pivotal phase III studies (A-LONG in adults and adolescents aged ≥12 years; Kids A-LONG in children aged <12 years) and their ongoing extension study (ASPIRE) have demonstrated the long-term effectiveness of efmoroctocog alfa for the treatment of acute bleeding episodes, perioperative management and routine prophylaxis in previously treated males with severe haemophilia A. Among patients on individualized efmoroctocog alfa prophylaxis who had previously received FVIII prophylaxis, all but one of those aged ≥12 years and three-quarters of those aged <12 years reduced their injection frequency compared with their pre-study regimen. FVIII replacement therapy with efmoroctocog alfa was generally well tolerated in previously treated patients, with no evidence of increased immunogenicity. The safety and efficacy of FVIII replacement therapy with efmoroctocog alfa in previously untreated males aged <6 years with severe haemophilia A are currently being evaluated. Although there are no direct, head-to-head studies, the available clinical trial evidence indicates that efmoroctocog alfa provides an effective alternative to conventional FVIII preparations (including rFVIIIs) for the management of haemophilia A. Moreover, by reducing the frequency of injections required, it has the potential to reduce treatment burden, and hence improve adherence to prophylaxis.

Scott, Lesley

doi: 10.1007/s40265-016-0623-ypmid: 27498199

Oral opicapone (Ongentys®), a potent, third-generation, long-acting, peripheral catechol-O-methyltransferase (COMT) inhibitor, is approved as adjunctive treatment to levodopa (L-Dopa)/dopa-decarboxylase inhibitor (DDCI) therapy in adults with Parkinson’s disease (PD) and end-of-dose motor fluctuations who cannot be stabilized on those combinations. In 14- to 15-week, double-blind, multinational trials and in 1-year, open-label extension studies in this patient population, opicapone was an effective and generally well tolerated adjunctive therapy to L-Dopa plus a DDCI and other PD therapy. During the double-blind phase, adjunctive opicapone 50 mg once daily provided significantly greater improvements in motor fluctuations than placebo, with these improvements noninferior to those with entacapone. These beneficial improvements in motor fluctuations with opicapone were maintained in patients who continued adjunctive opicapone during the extension studies, with patients who switched from placebo or entacapone to opicapone experiencing significant improvements in motor fluctuations during this year. No new unexpected safety concerns were identified after ≈1.4 years’ treatment with opicapone, with no serious cases of hepatotoxicity reported in clinical trials. With its convenient once-daily regimen, oral opicapone is an emerging COMT inhibitor option for use as adjunctive therapy to L-Dopa/DDCI therapy in adults with PD and end-of dose motor fluctuations who cannot be stabilized on those combinations.

Scott, Lesley

doi: 10.1007/s40265-016-0626-8pmid: 27506852

Tetravalent, live-attenuated, dengue vaccine (Dengvaxia®; CYD-TDV) is the first vaccine approved for the prevention of dengue disease caused by dengue virus (DENV) serotypes 1–4 in individuals aged 9–45 or 9–60 years living in high dengue endemic areas. This narrative review discusses the immunogenicity, protective efficacy, reactogenicity and safety of CYD-TDV in the prevention of dengue disease. In Latin American and Asian phase 3 trials in children and adolescents (n > 30,000), the recommended three-dose CYD-TDV regimen was efficacious in preventing virologically-confirmed dengue (VCD) during the period from 28 days after the last dose (month 13) to month 25, meeting the primary endpoint criteria. Protective efficacy against VCD in the respective individual trials was 60.8 and 56.5 % (primary analysis). During the 25-month active surveillance phase, CYD-TDV also provided protective efficacy against VCD, severe dengue, any grade of dengue haemorrhagic fever and VCD-related hospitalization in children aged 9 years and older. CYD-TDV was generally well tolerated, with no safety concerns identified after up to 4 years’ follow-up (i.e. from post dose 1) in ongoing long-term studies. Based on evidence from the dengue clinical trial program, the WHO SAGE recommended that countries with high dengue endemicity consider introducing CYD-TDV as part of an integrated disease prevention strategy to lower disease burden. Pharmacoeconomic considerations will be pivotal to implementing dengue vaccination prevention strategies in these countries. The availability of a dengue vaccine is considered essential if the 2012 WHO global strategy targets for reducing the burden of dengue disease by 2020 are to be attained. Hence, CYD-TDV represents a major advance for the prevention of dengue disease in high dengue endemic regions.

Syed, Yahiya

doi: 10.1007/s40265-016-0620-1pmid: 27438291

Pitolisant (Wakix™) is an inverse agonist of the histamine H3 receptor that is being developed by Bioproject. Oral pitolisant is approved in the EU for the treatment of narcolepsy with or without cataplexy in adults. Pitolisant has received a Temporary Authorization of Use in France for this indication in case of treatment failure, intolerance or contraindication to currently available treatment. Pitolisant has orphan drug designation in the EU and the USA. In the pivotal HARMONY I trial, pitolisant significantly decreased excessive daytime sleepiness versus placebo in adults with narcolepsy with or without cataplexy (primary endpoint). Pitolisant also significantly decreased cataplexy rate versus placebo in these patients. This article summarizes the milestones in the development of pitolisant leading to this first approval for narcolepsy.

Chang, Anna; Fox, Susan

doi: 10.1007/s40265-016-0624-xpmid: 27503375