Agency Committee Research Articles

Nintedanib: first global approval.

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.

Determination of dabigatran, rivaroxaban and apixaban by ultra‐performance liquid chromatography – tandem mass spectrometry (UPLC‐MS/MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants

BackgroundThree novel direct oral anticoagulants (DOACs) have recently been registered by the Food and Drug Administration and European Medicines Agency Commission: dabigatran, rivaroxaban, and apixaban. To quantify DOACs in plasma, various dedicated coagulation assays have been developed. ObjectiveTo develop and validate a reference ultra‐performance liquid chromatography – tandem mass spectrometry (UPLC‐MS/MS) method and to evaluate the analytical performance of several coagulation assays for quantification of dabigatran, rivaroxaban, and apixaban. MethodsThe developed UPLC‐MS/MS method was validated by determination of precision, accuracy, specificity, matrix effects, lower limits of detection, carry‐over, recovery, stability, and robustness. The following coagulation assays were evaluated for accuracy and precision: laboratory‐developed (LD) diluted thrombin time (dTT), Hemoclot dTT, Pefakit PiCT, ECA, Liquid anti‐Xa, Biophen Heparin (LRT), and Biophen DiXal anti‐Xa. Agreement between the various coagulation assays and UPLC‐MS/MS was determined with random samples from patients using dabigatran or rivaroxaban. ResultsThe UPLC‐MS/MS method was shown to be accurate, precise, sensitive, stable, and robust. The dabigatran coagulation assay showing the best precision, accuracy and agreement with the UPLC‐MS/MS method was the LD dTT test. For rivaroxaban, the anti‐factor Xa assays were superior to the PiCT‐Xa assay with regard to precision, accuracy, and agreement with the reference method. For apixaban, the Liquid anti‐Xa assay was superior to the PiCT‐Xa assay. ConclusionsStatistically significant differences were observed between the various coagulation assays as compared with the UPLC‐MS/MS reference method. It is currently unknown whether these differences are clinically relevant. When DOACs are quantified with coagulation assays, comparison with a reference method as part of proficiency testing is therefore pivotal.

Idelalisib: first global approval.

Idelalisib (Zydelig(®)) is a highly specific small-molecule phosphatidylinositol-3-kinase (PI3Kδ) inhibitor that has been developed as an oral treatment for B cell haematological cancers.It has received its first approval in the US in July 2014 for the treatment of relapsed chronic lymphocytic leukaemia(CLL), relapsed follicular B-cell non-Hodgkin lymphoma(NHL) and relapsed small lymphocytic lymphoma (SLL) [corrected]. Idelalisib is under regulatory review in the EU-where it has received a positive opinion from the European Medicines Agency Committee for Medicinal Products for Human Use-and in clinical development for CLL in Australia and Canada. This article summarizes the milestones in the development of Idelalisib leading to this first approval for relapsed CLL, NHL and SLL.

À propos des ivacaftor, bédaquiline, florbétapir F18 et propranolol

Among the new molecular entities approved by the EMEA and the FDA in 2012, four have caught our attention for their significant contribution to the health of patient. First of all, among the notable 2012 approvals, is ivacaftor or Kalydeco®. This is the first treatment that targets one of the gene defects that is underlying cause of cystic fibrosis. This is also an example of the promise of personalized medicine. The benefits with bedaquiline or Sirturo® are its ability to likely provide clinically relevant activity as part of multi-drug regimens against tuberculosis (TB) based on clinical data in multi-drug resistant tuberculosis (MDR TB) patients, who were defined as being at least resistant against the two major tuberculostatic medicines (isaoniazide and rifampicine). On December 2012 and then, on December 2013, the FDA and European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended granting a conditional marketing authorization for Sirturo® (bedaquiline), respectively, for use as part of a combination therapy for pulmonary multidrug resistant tuberculosis in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. Amyvid®, which is a solution for injection that contains the active substance florbetapir (18F), is a radiopharmaceutical that emits low amounts of radiation and works by targeting and attaching to β-amyloid plaques in the brain. This enables doctors to know whether or not significant amount of plaques are present in order to know if the patient is unlikely or not, to have Alzheimer's disease. Finally, the last topics addresses the propranolol, which is a beta-blocker, used alone or together with other medicines to treat high blood pressure. Propranolol is gaining a new lease of life for treating infantile hemangioma.

BG-12 (dimethyl fumarate) in the treatment of multiple sclerosis

BG-12 was recently approved in the USA, Canada and Australia as an oral treatment for relapsing–remitting multiple sclerosis after positive results from two large pivotal Phase III studies. Approval is also imminent in the EU, where BG-12 has received a positive opinion from the European Medicines Agency Committee for Medicinal Products for Human Use in March 2013. The active ingredient, dimethyl fumarate, is thought to act mainly by inducing NF-E2 p45-related factor, thereby reducing oxidative stress, which is considered to be one of the pathogenic mechanisms in multiple sclerosis. The agent is not only highly effective at reducing relapse rate but also appears to slow disability progression across a wide variety of patient groups. With the oral route of administration and a good safety profile, BG-12 will likely become a valuable treatment option for multiple sclerosis patients and neurologists.

Relationship between the Transactions and Trading Volume through the Commission Agency(Gongpanjang) of Farmers' Cooperatives in the Public Wholesale Markets

Relationship between the Transactions and Trading Volume through the Commission Agency(Gongpanjang) of Farmers' Cooperatives in the Public Wholesale Markets

Elosulfase alfa: First Global Approval

Elosulfase alfa (Vimizim™) is a recombinant form of N-acetylgalactosamine-6-sulfatase (GALNS) that was developed by BioMarin Pharmaceutical Inc. as an enzyme replacement therapy for patients with mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio A syndrome. Patients with MPS IVA have a GALNS deficiency, which results in serious musculoskeletal, cardiorespiratory and other system disturbances. Elosulfase alfa was approved by the US FDA on 14 February 2014 for the treatment of MPS IVA. The European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) has recently recommended that elosulfase alfa be approved for use in the EU in the same indication. Within the last year, the manufacturer has also filed applications for approval for the use of elosulfase alfa in MPS IVA in Brazil, Australia, Canada and Mexico. This article summarizes the milestones in the development of elosulfase alfa leading to its first global approval in MPS IVA.

Агентские соглашения и договоры комиссии во внешнеторговом обороте

The author analyzes the issues of conflict of law regulation of agency and commission agency agreements in Russia and foreign countries, examines the notion and characteristics of such contracts, gives the examples of consideration of the disputes arising from agency and commission agency agreements from Russian and foreign case law and arbitration practice. 

Sofosbuvir: First Global Approval

Sofosbuvir (Solvadi™), a nucleotide analogue hepatitis C virus NS5B polymerase inhibitor, is under development with Gilead Sciences for the once-daily, oral treatment of chronic hepatitis C. Oral sofosbuvir has been approved in the US for the treatment of chronic hepatitis C as a component of a combination antiviral regimen. In addition, the European Medicines Agency's Committee for Medicinal Products for Human Use has recommended the approval of sofosbuvir for the treatment of chronic hepatitis C. This article summarizes the milestones in the development of sofosbuvir leading to this first approval for chronic hepatitis C.

Reflections on Decisions Made on the Well-Established Use of Medicinal Products by EU Regulators and the ECJ.

Background: In the European Union (EU), a medicinal product needs a marketing authorization (MA) to be placed on the market. The EU’s medicinal products’ legislative framework allows for a reduced application for medicines outside their data exclusivity. One such type of application is the well-established use (WEU) medicinal product application (i.e. bibliographic applications). Recently, these MA applications have been subject to arbitration procedures at the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) because of disagreements between member states during the authorisation process. This paper reflects on these cases and highlights their potential impact on future WEU applications.Methods: Decisions adopted by the European Commission on WEU applications between 2009 and 2012 were identified from the EU Community Register on medicinal products for human use. Subsequently, decisions were reviewed to understand the potential serious risk to public health (PSRPH) that EU regulators raised during MA application procedures.Results: Four decisions were adopted by the EU commission between 2009 and 2012. Three followed disagreements between member states on PSRPH grounds. One decision was the outcome of a centralised marketing authorisation application. Six key messages were identified from the four cases reviewed and presented.Conclusion: A guideline on WEU to implement the technical specifications to fulfil Annex I of Directive 2001/83/EC for MA applications is not available. Thus, reflections on recent decisions on WEU applications provide scientific direction to the industry as well as the medicinal product regulators on the documentation required to successfully file and obtain a WEU MA.

Industry Update: the Latest Developments in Therapeutic Delivery

This article provides a snapshot of the news stories from the world of therapeutic delivery in the period 1-31 August 2013. During this month, the Boards of Amgen and Onyx Pharmaceuticals gave their approval to the purchase by Amgen of Onyx's outstanding shares in a deal worth US$10.4 billion, or $9.7 billion net of estimated Onyx cash. The deal, said to be the fifth largest involving a biotechnology company, is expected to close in Q4 2013 subject to customary closing conditions and regulatory approval. August also saw the publication of a reflection paper on the coating of nanomedicines by the European Medicines Agency's Committee for Medicinal Products for Human Use. This paper highlights the key considerations for the development of nanomedicine and nanosimilars (nanomedicines that are claimed to be similar to a reference nanomedicine) and makes recommendations with regard to the quality control and assurance of such products. As ever, the Industry Update is based mainly on information from press releases and company websites.

Review of intravenous iron medicines challenges renal practice in the UK

A review of the risks and benefits of intravenous iron medicines undertaken by the European Medicines Agency Committee for Medicinal Products for Human Use will have a significant impact on home haemodialysis and non-dialysis patients across the UK. Karen Jenkins outlines the main recommendations and implications for renal practice

Review article: biosimilars are the next generation of drugs for liver and gastrointestinal diseases

A biosimilar is a copy version of an approved original biological medicine whose data protection has expired. To provide an overview of the development of biosimilars worldwide. Literature review of manufacturing processes of biosimilars, differences and similarities between biosimilars and the reference product, approval pathways for biosimilars, challenges in clinical trial study design and available data from clinical trials. Biosimilars have the same amino acid sequence and highly similar glycosylation patterns that overlap with the originator product. Both efficacy and toxicity are difficult to predict due to subtle molecular changes that might have profound effects on clinical efficacy, safety and immunogenicity. Their main advantage is related to cost savings. Direct evidence of safety and benefit from clinical trials, post-marketing pharmacoviligance and unequivocal identification of the product as a biosimilar are requirements before approval. Non-inferiority or equivalence trials are required by regulatory agencies. Over the past years, several biosimilars have been approved such as erythropoietin or growth factors. Recently, two monoclonal antibodies, Remsima and Inflectra, have been shown to be equivalent to infliximab (INX) in safety and efficacy in rheumatologic conditions. Interchangeability, automatic substitution and switching are key issues when treating patients with biosimilars in clinical practice. Biosimilars represent a new generation of drugs in liver and gastrointestinal diseases. On June 27, 2013, Hospira's Inflectra (INX) was the first biosimilar monoclonal antibody to receive positive opinion from European Medicines Agency's Committee for Medicinal Products for Human Use for rheumatoid arthritis, inflammatory bowel disease and plaque psoriasis.

Afatinib: First Global Approval

Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases, is under development with Boehringer Ingelheim for the once-daily, oral treatment of cancer. Afatinib downregulates ErbB signalling by covalently binding to epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, irreversibly inhibiting tyrosine kinase autophosphorylation. It also inhibits transphosphorylation of HER3. Oral afatinib (Gilotrif™) has been approved in the US for the first-line treatment of patients with metastatic non-small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test. Afatinib has also been approved in Taiwan for the first-line treatment of patients with EGFR mutation-positive NSCLC. In addition, the European Medicines Agency's Committee for Medicinal Products for Human Use has recommended the approval of afatinib (Giotrif®) for the treatment of patients with locally advanced or metastatic NSCLC with activating EGFR mutations who are EGFR tyrosine kinase inhibitor naïve. Afatinib is also under regulatory review in Canada, Japan and other Asian countries. This article summarizes the milestones in the development of afatinib, leading to this first approval in patients with metastatic NSCLC.

An Investigation Survey on MPSIAC Model to Predict Sediment Yield in Iran

Lack of information to prepare erosion maps for quantitative and qualitative sediment evaluation is a major need in watershed management. MPSIAC (Modified Pacific South West International Agency Committee) Model is apparently known as an appropriate method to measure sediment yield of watersheds in Iran. In this study the results obtained from the research on Ivanaki's watershed and sixteen different research projects, which conducted by others, were selected and analyzed. The purposes of this study were to compare works done in the country and show the limitation of the model, usage of it in different conditions and possibility of calculating errors if the input data were not gathered carefully. A sensitivity analysis was conducted to find the sensitive parameters in different watersheds. A database for the model was prepared from six watersheds using Geographic Information System (GIS). By evaluation of nine main factors it was cleared that Land Use, Upland Erosion and Ground Cover were the most sensitive factors respectively and the Climate and Runoff factors were the least, while observation of Runoff and sediment yield did not show this matter. According to the results, each factor which had more input quantity had the highest sensitivity. Finally, the research indicated that the usage of MPSIAC model for watersheds with sediments more than 2.2 ton/ha/yr must not be used, since the model is so sensitive in this status and possible errors may get over 50%.

Sustained activation of sphingomyelin synthase by 2-hydroxyoleic acid induces sphingolipidosis in tumor cells

The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor drug, involves the rapid and specific activation of sphingomyelin synthase (SMS), leading to a 4-fold increase in SM mass in tumor cells. In the present study, we investigated the source of the ceramides required to sustain this dramatic increase in SM. Through radioactive and fluorescent labeling, we demonstrated that sphingolipid metabolism was altered by a 24 h exposure to 2OHOA, and we observed a consistent increase in the number of lysosomes and the presence of unidentified storage materials in treated cells. Mass spectroscopy revealed that different sphingolipid classes accumulated in human glioma U118 cells after exposure to 2OHOA, demonstrating a specific effect on C16-, C20-, and C22-containing sphingolipids. Based on these findings, we propose that the demand for ceramides required to sustain the SMS activation (ca. 200-fold higher than the basal level) profoundly modifies both sphingolipid and phospholipid metabolism. As the treatment is prolonged, tumor cells fail to adequately metabolize sphingolipids, leading to a situation resembling sphingolipidosis, whereby cell viability is compromised.

Animal models for metabolic, neuromuscular and ophthalmological rare diseases

Animal models are important tools in the discovery and development of treatments for rare diseases, particularly given the small populations of patients in which to evaluate therapeutic candidates. Here, we provide a compilation of mammalian animal models for metabolic, neuromuscular and ophthalmological orphan-designated conditions based on information gathered by the European Medicines Agency's Committee for Orphan Medicinal Products (COMP) since its establishment in 2000, as well as from a review of the literature. We discuss the predictive value of the models and their advantages and limitations with the aim of highlighting those that are appropriate for the preclinical evaluation of novel therapies, thereby facilitating further drug development for rare diseases.

Quantifying modern erosion rates and river-sediment contamination in the Bolivian Andes

We use petrographic, mineralogical and geochemical data on modern river sediments of the Tupiza basin in the Bolivian Andes to investigate the relationships among human activity, heavy-metal contamination of sediments and modern erosion rates in mountain fluvial systems. Forward mixing model was used to quantify the relative contributions from each main tributary to total sediment load of the Tupiza River. The absolute sediment load was estimated by using the Pacific Southwest Inter Agency Committee model (PSIAC, 1968) after two years of geological field surveys (2009; 2010), together with data obtained from the Instituto Nacional del Agua public authority (INA, 2007), and suspended-load data from Aalto et al. (2006).Our results indicate that the sediment yield in the drainage basin is 910 ± 752 ton/km2year and the mean erosion rate is 0.40 ± 0.33 mm/year. These values compare well with erosion rates measured by Insel et al. (2010) using 10Be cosmogenic radionuclide concentrations in Bolivian river sediments. More than 40% of the Tupiza river load is produced in the upper part of the catchment, where highly tectonized and weathered rocks are exposed and coupled with sporadic land cover and intense human activity (mines). In the Rio Chilco basin strong erosion of upland valleys produce an increase of erosion (∼10 mm/year) and the influx of large amounts of sediment by mass wasting processes. The main floodplain of the Tupiza catchment represents a significant storage site for the heavy metals (∼657 ton/year). Fluvial sediments contain zinc, lead, vanadium, chromium, arsenic and nickel. Since the residence time of these contaminants in the alluvial plain may be more than 100 years, they may represent a potential source of pollution for human health.

Journal of Diabetes NEWS

<i>Journal of Diabetes</i> NEWS

Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation.

Linaclotide is the first member of a novel class of drugs to be extensively evaluated for the treatment of chronic constipation (CC) and irritable bowel syndrome with constipation (IBS-C). To provide a comprehensive overview of the current state of knowledge on linaclotide, its pharmacological properties, mode of action and efficacy in clinical trials to date. We conducted a systematic review of the literature. The survey revealed that linaclotide is a minimally absorbed, 14-amino acid peptide which acts in the intestinal lumen on guanylate cyclase-C (GC-C). This results in generation of cyclic guanosine monophosphate (cGMP), which stimulates chloride secretion, resulting in increased luminal fluid secretion and an acceleration of intestinal transit. In animal models, linaclotide also decreased visceral hypersensitivity. Linaclotide softened stool and increased transit in CC and in IBS-C. Phase II and phase III clinical studies established efficacy of linaclotide in CC (linaclotide 145 µg daily approved in the United States for CC) and in IBS-C (linaclotide 290 µg daily US Food and Drug Administration-approved for IBS-C, with favourable recommendation for the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP). Linaclotide showed a favourable safety profile, and the main treatment-emerging adverse event was diarrhea, leading to discontinuation rates of up to 5%. Linaclotide is an important addition to the therapeutic possibilities for treating IBS-C and CC.