Pitfalls associated with the therapeutic reference pricing practice of asthma medication

ABSTRACT: BACKGROUND: Therapeutic reference pricing (TRP) based on the WHO daily defined dose (DDD) is frequently employed method for the cost-containment of pharmaceuticals. Our objective was to compare average drug use in real world to DDD and to evaluate whether TRP based on DDD could result in cost savings in the maintenance medication and the total direct health expenditures for asthma patients treated with Symbicort Turbuhaler (SYT) and Seretide Diskus (SED) in Hungary. METHODS: Real-world data was derived from the NHIF database. Average doses and costs were compared between the high-dose and medium dose SYT and SED groups. Multiple linear regressions were employed to adjust the data for differences in the gender and age distribution of patients. RESULTS: 27,779 patients with asthma were included into the analysis. Average drug use was lower than DDD in all groups, 1.38-1.95 inhalations in both SED groups, 1.28-1.97 and 1.74-2.49 inhalations in the medium and high-dose SYT groups, respectively. Although the cost of SED based on the DDD would be much lower than the cost of SYT in the medium-dose groups, no difference was found in the actual cost of the maintenance therapy. No significant differences were found between the groups in terms of total medical costs. CONCLUSIONS: Cost-containment initiatives by payers may influence clinical decisions. TRP for inhalation asthma drugs raises special concern, because of differences in the therapeutic profile of pharmaceuticals and the lack of proven financial benefits. Our findings indicate that the presented TRP approach of asthma medications based on the daily therapeutic costs according to the WHO DDD do not result in reduced public health care spending in Hungary. Further analysis is required to answer whether TRP generates even additional expenditures by inducing switching costs and reducing patient compliance. Potential confounding factors may limit the generalizability of our conclusions.     

Local anaesthetic lidocaine modulates epiphyllous bud differentiation in Kalanchoe pinnata

A single treatment with lidocaine(2-Diethylamino-N-[2,6-dimethylphenyl]-acetamide) – a potent localanaesthetic(LA), caused significant and extensive inhibition of epiphyllous buddifferentiation in Kalanchoe pinnata, in a long –term irreversible manner. These effects were both concentration and treatmentduration dependent, with either variant generating similar and additiveeffects.The growth responses studied had differential sensitivity towards the applieddosage of the anaesthetic. Lidocaine also appears to influence expression oftheorganogenic potential of buds since for all inhibitory doses a significantpercentage produced shoots but not roots.     

A novel IgE-neutralizing antibody for the treatment of severe uncontrolled asthma

The critical role played by IgE in allergic asthma is well-documented and clinically precedented, but some patients in whom IgE neutralization may still offer clinical benefit are excluded from treatment with the existing anti-IgE therapy, omalizumab, due to high total IgE levels or body mass. In this study, we sought to generate a novel high affinity anti-IgE antibody (MEDI4212) with potential to treat a broad severe asthma patient population. Analysis of body mass, total and allergen-specific IgE levels in a cohort of severe asthmatics was used to support the rationale for development of a high affinity IgE-targeted antibody therapeutic. Phage display technology was used to generate a human IgG1 lead antibody, MEDI4212, which was characterized in vitro using binding, signaling and functional assay systems. Protein crystallography was used to determine the details of the interaction between MEDI4212 and IgE. MEDI4212 bound human IgE with an affinity of 1.95 pM and was shown to target critical residues in the IgE Cε3 domain critical for interaction with FcεRI. MEDI4212 potently inhibited responses through FcεRI and also prevented the binding of IgE to CD23. When used ex vivo at identical concentration, MEDI4212 depleted free-IgE from human sera to levels ~1 log lower than omalizumab. Our results thus indicate that MEDI4212 is a novel, high affinity antibody that binds specifically to IgE and prevents IgE binding to its receptors. MEDI4212 effectively depleted free-IgE from human sera ex vivo to a level (1 IU/mL) anticipated to provide optimal IgE suppression in severe asthma patients.     

New approaches in the treatment of asthma

Asthma is a common and complex inflammatory disease of the airways that remains incurable. Current forms of therapy are long term and may exhibit associated side-effect problems. Major participants in the development of an asthma phenotype include the triggering stimuli such as the allergens themselves, cells such as T cells, epithelial cells and mast cells that produce a variety of cytokines including IL-5, GM-CSF, IL-3, IL-4 and IL-13 and chemokines such as eotaxin. Significantly, the eosinophil, a specialized blood cell type, is invariably associated with this disease. The eosinophil has long been incriminated in the pathology of asthma due to its ability to release preformed and unique toxic substances as well as newly formed pro-inflammatory mediators. The regulation of eosinophil production and function is carried out by soluble peptides or factors. Of these IL-5, GM-CSF and IL-3 are of paramount importance as they control eosinophil functional activity and are the only known eosinophilopoietic factors. In addition they regulate the eosinophil life span by inhibiting apoptosis. While one therapeutic approach in asthma is directed at inhibiting single eosinophil products such as leukotrienes or single eosinophil regulators such as IL-5, we believe that the simultaneous inhibition of more than one component is preferable. This may be particularly important with eosinophil regulators in that not only IL-5, but also GM-CSF has been repeatedly implicated in clinical studies of asthma. The fact that GM-CSF is produced by many cells in the body and in copious amounts by lung epithelial cells highlights this need further. Our approach takes advantage of the fact that the IL-5 and GM-CSF receptors (as well as IL-3 receptors) utilize a shared subunit to bind, with high affinity, to these cytokines and the same common subunit mediates signal transduction culminating in all the biological activities mentioned. By generating the monoclonal antibody BION-1 to the cytokine binding region of the common subunit (betac) we have shown that the approach of inhibiting IL-5, GM-CSF and IL-3 binding and the resulting stimulation of eosinophil production and function with a single agent is feasible. Furthermore we have used BION-1 as a tool to crystallize and define the structure of the cytokine binding domain of betac. This knowledge and this approach may lead to the generation of novel therapeutics for the treatment of asthma.     

Occasional Reviews: An anachronistic treatment for asthma

Dry cupping is an ancient practice that died out in England over a hundred years ago. In certain cultures it survives and if not recognised can lead to a little diagnostic confusion.     

Cytokine and anti-cytokine therapy for the treatment of asthma and allergic disease

Until recently, the only controller treatment for chronic asthma has been corticosteroids. However, identification of specific effector molecules in asthma has led to targeting of specific pathways by using cytokines and cytokine inhibitors. Administration of a monoclonal blocking antibody against IgE has been shown to be highly efficacious in severe allergic asthma, but blockade of eosinophils using anti-IL-5 monoclonal antibodies has no clinical benefit. In more severe asthma, blockade of TNF-alpha using the decoy etanercept has revealed efficacy in a small open study suggesting that Th-1 in addition to Th-2 pathways are important as the disease adopts a more severe phenotype. It is likely that asthma is not a single disease but a group of disorders which differ in the relative contribution of specific pathophysiological pathways.     

Inhaled Janus Kinase (JAK) inhibitors for the treatment of asthma

Multiple asthma-relevant cytokines including IL-4, IL-5, IL-13, and TSLP depend upon JAKs for signaling. JAK inhibition may, therefore, offer a novel intervention strategy for patients with disease refractory to current standards of care. Multiple systemically delivered JAK inhibitors have been approved for human use or are under clinical evaluation in autoimmune diseases such as rheumatoid arthritis. However, the on-target side effect profiles of these agents are likely not tolerable for many asthmatic patients. Limiting JAK inhibition to the lung is expected to improve therapeutic index relative to systemic inhibition. Thus, inhaled JAK inhibitors with lung-restricted exposure are of high interest as potential treatments for asthma.