Cost-utility model of brivaracetam in the adjunctive treatment of patients with epilepsy in Spain

[EN] Objective This study aims to assess the cost utility of Brivaracetam compared with the third-generation anti-epileptic drugs used as standard care. Methods A cost utility analysis of Brivaracetam was carried out with other third-generation comparators. The treatment pathway of a hypothetical cohort over a period of 2 years was simulated using the Markov model. Data for effectiveness and the QALYs of each health status for epilepsy, as well as for the disutilities of adverse events of treatments, were analyzed through a studies review. The cost of the anti-epileptics and the use of medical resources linked to the different health statuses were taken into consideration. A probabilistic sensitivity analysis was performed using a Monte Carlo simulation. Results Brivaracetam was shown to be the dominant alternative, with Incremental Cost Utility Ratio (ICUR) values from -11,318 for Lacosamide to -128,482 for Zonisamide. The probabilistic sensitivity analysis validates these results. The ICUR sensitivity is greater for increases in the price of Brivaracetam than for decreases, and for Eslicarbizapine over the other adjunctives considered in the analysis. Conclusions Treatment with Brivaracetam resulted in cost effective and incremental quality adjusted life years come at an acceptable cost.Barrachina Martínez, I.; Vivas-Consuelo, D.; Reyes-Santias, F. (2020). Cost-utility model of brivaracetam in the adjunctive treatment of patients with epilepsy in Spain. Expert review of pharmacoeconomics & outcomes research (Online). 1-10. https://doi.org/10.1080/14737167.2021.1838899S110WHO | Epilepsy: aISBN public health imperative. ISBN 978-92-4-151593-1. World Health Organization. 2019. Printed in Thailand.Ngugi, A. K., Kariuki, S. M., Bottomley, C., Kleinschmidt, I., Sander, J. W., & Newton, C. R. (2011). Incidence of epilepsy: A systematic review and meta-analysis. Neurology, 77(10), 1005-1012. doi:10.1212/wnl.0b013e31822cfc90Henning, O., Landmark, C. J., Henning, D., Nakken, K. O., & Lossius, M. I. (2019). Challenges in epilepsy—The perspective of Norwegian epilepsy patients. Acta Neurologica Scandinavica, 140(1), 40-47. doi:10.1111/ane.13098Brodie, M. J. (2005). Diagnosing and predicting refractory epilepsy. Acta Neurologica Scandinavica, 112(s181), 36-39. doi:10.1111/j.1600-0404.2005.00507.xGarcía-Ramos, R., Pastor, A. G., Masjuan, J., Sánchez, C., & Gil, A. (2011). FEEN: Informe sociosantario FEEN sobre la epilepsia en España. Neurología, 26(9), 548-555. doi:10.1016/j.nrl.2011.04.002Kwan, P., & Brodie, M. J. (2000). Early Identification of Refractory Epilepsy. New England Journal of Medicine, 342(5), 314-319. doi:10.1056/nejm200002033420503Brodie, M. J. (2008). Epilepsy: randomised trials and genetic tribulations. The Lancet Neurology, 7(1), 7-8. doi:10.1016/s1474-4422(07)70301-0French, J. A. (2006). Refractory Epilepsy: One Size Does Not Fit All. Epilepsy Currents, 6(6), 177-180. doi:10.1111/j.1535-7511.2006.00137.xLaxer, K. D., Trinka, E., Hirsch, L. J., Cendes, F., Langfitt, J., Delanty, N., … Benbadis, S. R. (2014). The consequences of refractory epilepsy and its treatment. Epilepsy & Behavior, 37, 59-70. doi:10.1016/j.yebeh.2014.05.031Giordano, C., Marchiò, M., Timofeeva, E., & Biagini, G. (2014). Neuroactive Peptides as Putative Mediators of Antiepileptic Ketogenic Diets. Frontiers in Neurology, 5. doi:10.3389/fneur.2014.00063European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Briviact brivaracetam. Assessment Report EMA/CHMP/822086/2015 Nov.Markham, A. (2016). Brivaracetam: First Global Approval. Drugs, 76(4), 517-522. doi:10.1007/s40265-016-0555-6Willems, L. M., Bauer, S., Rosenow, F., & Strzelczyk, A. (2019). Recent advances in the pharmacotherapy of epilepsy: brivaracetam and perampanel as broad-spectrum antiseizure drugs for the treatment of epilepsies and status epilepticus. Expert Opinion on Pharmacotherapy, 20(14), 1755-1765. doi:10.1080/14656566.2019.1637420Craig, D., Rice, S., Paton, F., Fox, D., & Woolacott, N. (2013). Retigabine for the Adjunctive Treatment of Adults with Partial-Onset Seizures in Epilepsy with and without Secondary Generalization. PharmacoEconomics, 31(2), 101-110. doi:10.1007/s40273-012-0018-1Charokopou, M., Harvey, R., Srivastava, K., Brandt, C., & Borghs, S. (2019). Relative performance of brivaracetam as adjunctive treatment of focal seizures in adults: a network meta-analysis. Current Medical Research and Opinion, 35(8), 1345-1354. doi:10.1080/03007995.2019.1584501Chhatwal J. Changing cycle lengths in state-transition models: doing it the right way; [cited 2018 Jan 23]. Available from: https://www.ispor.org/News/Connections_methodology_state-transition-models.PDFMulhern, B., Rowen, D., Snape, D., Jacoby, A., Marson, T., Hughes, D., … Brazier, J. (2014). Valuations of epilepsy-specific health states: a comparison of patients with epilepsy and the general population. Epilepsy & Behavior, 36, 12-17. doi:10.1016/j.yebeh.2014.04.011Kristian, B., Wachtmeister, K., Stefan, F., & Forsgren, L. (2013). Retigabine as add-on treatment of refractory epilepsy - a cost-utility study in a Swedish setting. Acta Neurologica Scandinavica, 127(6), 419-426. doi:10.1111/ane.12077Vera-Llonch, M., Brandenburg, N. A., & Oster, G. (2008). Cost-effectiveness of Add-on Therapy with Pregabalin in Patients with Refractory Partial Epilepsy. Epilepsia, 49(3), 431-437. doi:10.1111/j.1528-1167.2007.01279.xSimoens, S. (2010). Pharmacoeconomics of anti-epileptic drugs as adjunctive therapy for refractory epilepsy. Expert Review of Pharmacoeconomics & Outcomes Research, 10(3), 309-315. doi:10.1586/erp.10.18Wijnen, B. F. M., van Mastrigt, G. A. P. G., Evers, S. M. A. A., Gershuni, O., Lambrechts, D. A. J. E., Majoie, M. H. J. M., … de Kinderen, R. J. A. (2017). A systematic review of economic evaluations of treatments for patients with epilepsy. Epilepsia, 58(5), 706-726. doi:10.1111/epi.13655Boeck, J. D., Verpoorten, K., Luyten, K., & Coninx, K. (2007). A Comparison between Decision Trees and Markov Models to Support Proactive Interfaces. 18th International Conference on Database and Expert Systems Applications (DEXA 2007). doi:10.1109/dexa.2007.94Zhang, Y., Wu, H., Denton, B. T., Wilson, J. R., & Lobo, J. M. (2017). Probabilistic sensitivity analysis on Markov models with uncertain transition probabilities: an application in evaluating treatment decisions for type 2 diabetes. Health Care Management Science, 22(1), 34-52. doi:10.1007/s10729-017-9420-8Swallow, E., Fang, A., Signorovitch, J., Plumb, J., & Borghs, S. (2017). Can Matching-Adjusted Indirect Comparison Methods Mitigate Placebo Response Differences Among Patient Populations in Adjunctive Trials of Brivaracetam and Levetiracetam? CNS Drugs, 31(10), 899-910. doi:10.1007/s40263-017-0462-8Malyshkina NV, Mannering FL. Markov switching multinomial logit model: an application to accident injury severities; 2008 [cited 2019 Sep 25]. Available from: http://arxiv.org/abs/0811.3644Hawkins, N., Epstein, D., Drummond, M., Wilby, J., Kainth, A., Chadwick, D., & Sculpher, M. (2005). Assessing the Cost-Effectiveness of New Pharmaceuticals in Epilepsy in Adults: The Results of a Probabilistic Decision Model. Medical Decision Making, 25(5), 493-510. doi:10.1177/0272989x05280559Agencia Española del Medicamento. Utilización de medicamentos antiepilépticos en España durante el periodo 2008–2016 [Internet]; 2017 [cited 2019 Sep 25]. Available from: https://www.aemps.gob.es/medicamentosUsoHumano/observatorio/docs/antiepilepticos-periodo-2008-2016.pdfMegiddo, I., Colson, A., Chisholm, D., Dua, T., Nandi, A., & Laxminarayan, R. (2016). Health and economic benefits of public financing of epilepsy treatment in India: An agent‐based simulation model. Epilepsia, 57(3), 464-474. doi:10.1111/epi.13294De Andrés-Nogales, F., Oyagüez, I., Álvarez-Sala, L. A., García-Bragado, F., Navarro, A., González, P., … Soto, J. (2017). Análisis coste-efectividad y coste-utilidad de apixaban frente a dabigatrán y rivaroxaban en el tratamiento y prevención secundaria del tromboembolismo venoso. PharmacoEconomics Spanish Research Articles, 14(1), 7-18. doi:10.1007/s40277-016-0064-8Fricke-Galindo, I., Jung-Cook, H., LLerena, A., & López-López, M. (2018). Farmacogenética de reacciones adversas a fármacos antiepilépticos. Neurología, 33(3), 165-176. doi:10.1016/j.nrl.2015.03.005Steinhoff, B. J., Bacher, M., Bucurenciu, I., Hillenbrand, B., Intravooth, T., Kornmeier, R., … Staack, A. M. (2017). Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy—A monocenter survey. Seizure, 48, 11-14. doi:10.1016/j.seizure.2017.03.010De Kinderen, R. J. A., Wijnen, B. F. M., van Breukelen, G., Postulart, D., Majoie, M. H. J. M., Aldenkamp, A. P., & Evers, S. M. A. A. (2016). From clinically relevant outcome measures to quality of life in epilepsy: A time trade-off study. Epilepsy Research, 125, 24-31. doi:10.1016/j.eplepsyres.2016.05.005Cortés, J.-C., Navarro-Quiles, A., Romero, J.-V., & Roselló, M.-D. (2017). Randomizing the parameters of a Markov chain to model the stroke disease: A technical generalization of established computational methodologies towards improving real applications. Journal of Computational and Applied Mathematics, 324, 225-240. doi:10.1016/j.cam.2017.04.04

Gibberellin A1 Metabolism Contributes to the Control of Photoperiod-Mediated Tuberization in Potato

Some potato species require a short-day (SD) photoperiod for tuberization, a process that is negatively affected by gibberellins (GAs). Here we report the isolation of StGA3ox2, a gene encoding a GA 3-oxidase, whose expression is increased in the aerial parts and is repressed in the stolons after transfer of photoperiod-dependent potato plants to SD conditions. Over-expression of StGA3ox2 under control of constitutive or leaf-specific promoters results in taller plants which, in contrast to StGA20ox1 over-expressers previously reported, tuberize earlier under SD conditions than the controls. By contrast, StGA3ox2 tuber-specific over-expression results in non-elongated plants with slightly delayed tuber induction. Together, our experiments support that StGA3ox2 expression and gibberellin metabolism significantly contribute to the tuberization time in strictly photoperiod-dependent potato plants

Bioorthogonal Self-Immolative Linker Based on Grob Fragmentation.

A self-immolative bioorthogonal conditionally cleavable linker based on Grob fragmentation is described. It is derived from 1,3-aminocyclohexanols and allows the release of sulfonate-containing compounds in aqueous media. Modulation of the amine pKa promotes fragmentation even at slightly acidic pH, a common feature of several tumor environments. The Grob fragmentation can also occur under physiological conditions in living cells, highlighting the potential bioorthogonal applicability of this reaction

Sorsby syndrome: Report of a case representing the second reported family

Dismorfología y Genética ClínicaIn 1935, Sorsby [Br J Ophthalmol. 1935; 19:65-90] described a family with several affected individuals presenting with bilateral coloboma of macula, type B brachydactyly affecting hands and feet, and unilateral renal agenesis in one of its members. We describe a newborn girl presenting with the same pattern of congenital anomalies as the patients of the family originally described by Sorsby (OMIM 120400). However, the current case has as additional findings a single umbilical artery, and an anomaly of pulmonary vascularization consisting in: a ring in the lower right lobar artery and sequestration of the lower right lung lobe. Therefore, despite that our patient adds new clinical variability, it is not possible to disregard the diagnosis of Sorsby syndrome, because such clinical variability was also observed in the affected members of the original family described by Sorsby and some individuals of the next generations of the same family, according to the report by Thompson and Baraitser [J Med Genet. 1988; 25:313-321]. Based on the observed genealogy pattern of affected members in the only family published, it is considered that this syndrome is due to an autosomal dominant gene. The baby described here, is the first case in the family. She had a normal karyotype (~850 bands) and the subtelomeric Multi-FISH was also normal. Her father was 39 years old and, therefore, an age-related new mutation could be evaluated. The frequency of Sorsby syndrome is unknown, since only the original family has been published so far. However, as the case described here is part of the ECEMC Registry, we can estimate that its frequency is at least 1:2,750,000 newborn infants. We consider that, even in the “molecular era”, it remains important to clinically describe those extremely rare syndromes, in order to define their characteristics and clinical expressions. These aspects are essential to define the prognosis, clinical management and information to the family, and can help also to determine the gene(s) or pathogenetic pathways involved in their origin.N

Acquisition of uropygial gland microbiome by hoopoe nestlings

Mutualistic symbioses between animals and bacteria depend on acquisition of appropriate symbionts while avoiding exploitation by non-beneficial microbes. The mode of acquisition of symbionts would determine, not only the probability of encountering but also evolutionary outcomes of mutualistic counterparts. The microbiome inhabiting the uropygial gland of the European hoopoe (Upupa epops) includes a variety of bacterial strains, some of them providing antimicrobial benefits. Here, the mode of acquisition and stability of this microbiome is analyzed by means of Automated rRNA Intergenic Spacer Analysis and two different experiments. The first experiment impeded mothers’ access to their glands, thus avoiding direct transmission of microorganisms from female to offspring secretions. The second experiment explored the stability of the microbiomes by inoculating glands with secretions from alien nests. The first experiment provoked a reduction in similarity of microbiomes of mother and nestlings. Interestingly, some bacterial strains were more often detected when females had not access to their glands, suggesting antagonistic effects among bacteria from different sources. The second experiment caused an increase in richness of the microbiome of receivers in terms of prevalence of Operational Taxonomic Units (OTUs) that reduced differences in microbiomes of donors and receivers. That occurred because OTUs that were present in donors but not in receivers incorporated to the microbiome of the latter, which provoked that cross-inoculated nestlings got similar final microbiomes that included the most prevalent OTUs. The results are therefore consistent with a central role of vertical transmission in bacterial acquisition by nestling hoopoes and support the idea that the typical composition of the hoopoe gland microbiome is reached by the incorporation of some bacteria during the nestling period. This scenario suggests the existence of a coevolved core microbiome composed by a mix of specialized vertically transmitted strains and facultative symbionts able to coexist with them. The implications of this mixed mode of transmission for the evolution of the mutualism are discussedMinisterio de Ciencia e Innovación (España)Junta de Andalucí

Optimizing CIGB-300 intralesional delivery in locally advanced cervical cancer

Background:We conducted a phase 1 trial in patients with locally advanced cervical cancer by injecting 0.5 ml of the CK2-antagonist CIGB-300 in two different sites on tumours to assess tumour uptake, safety, pharmacodynamic activity and identify the recommended dose.Methods:Fourteen patients were treated with intralesional injections containing 35 or 70 mg of CIGB-300 in three alternate cycles of three consecutive days each before standard chemoradiotherapy. Tumour uptake was determined using 99 Tc-radiolabelled peptide. In situ B23/nucleophosmin was determined by immunohistochemistry.Results:Maximum tumour uptake for CIGB-300 70-mg dose was significantly higher than the one observed for 35 mg: 16.1±8.9 vs 31.3±12.9 mg (P=0.01). Both, AUC 24h and biological half-life were also significantly higher using 70 mg of CIGB-300 (P<0.001). Unincorporated CIGB-300 diffused rapidly to blood and was mainly distributed towards kidneys, and marginally in liver, lungs, heart and spleen. There was no DLT and moderate allergic-like reactions were the most common systemic side effect with strong correlation between unincorporated CIGB-300 and histamine levels in blood. CIGB-300, 70 mg, downregulated B23/nucleophosmin (P=0.03) in tumour specimens.Conclusion:Intralesional injections of 70 mg CIGB-300 in two sites (0.5 ml per injection) and this treatment plan are recommended to be evaluated in phase 2 studies.Fil: Sarduy, M. R.. Medical-surgical Research Center; CubaFil: García, I.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Coca, M. A.. Clinical Investigation Center; CubaFil: Perera, A.. Clinical Investigation Center; CubaFil: Torres, L. A.. Clinical Investigation Center; CubaFil: Valenzuela, C. M.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Baladrón, I.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Solares, M.. Hospital Materno Ramón González Coro; CubaFil: Reyes, V.. Center For Genetic Engineering And Biotechnology Havana; CubaFil: Hernández, I.. Isotope Center; CubaFil: Perera, Y.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Martínez, Y. M.. Medical-surgical Research Center; CubaFil: Molina, L.. Medical-surgical Research Center; CubaFil: González, Y. M.. Medical-surgical Research Center; CubaFil: Ancízar, J. A.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Prats, A.. Clinical Investigation Center; CubaFil: González, L.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Casacó, C. A.. Clinical Investigation Center; CubaFil: Acevedo, B. E.. Centro de Ingeniería Genética y Biotecnología; CubaFil: López Saura, P. A.. Centro de Ingeniería Genética y Biotecnología; CubaFil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes; ArgentinaFil: Gómez, R.. Elea Laboratories; ArgentinaFil: Perea Rodríguez, S. E.. Center For Genetic Engineering And Biotechnology Havana; Cuba. Centro de Ingeniería Genética y Biotecnología; Cub

The use of fluoroproline in MUC1 antigen enables efficient detection of antibodies in patients with prostate cancer

A structure-based design of a new gene22ration tumor-associated glycopeptides with improved affinity against two anti-MUC1 antibodies is described. These unique antigens feature a fluorinated proline residue, such as a (4S)-4-fluoro-L-proline or 4,4-difluoroproline, at the most immunogenic domain. Binding assays using bio-layer interferometry reveal 3-fold to 10-fold affinity improvement with respect to the natural (glyco)peptides. According to X-ray crystallography and MD simulations, the fluorinated residues stabilize the antigen-antibody complex by enhancing key CH/ interactions. Interestingly, a notable improvement in detection of cancer-associated anti-MUC1 antibodies from serum of patients with prostate cancer is achieved with the non-natural antigens, which proves that these derivatives can be considered better diagnostic tools than the natural antigen for this type of cancer.We thank the Ministerio de Economía y Competitividad (projects CTQ2015-67727-R, UNLR13-4E-1931, CTQ2013-44367-C2-2-P, CTQ2015-64597-C2-1P, and BFU2016-75633-P). I. A. B. thanks the Asociación Española Contra el Cancer en La Rioja for a grant. I. S. A. and G. J. L. B. thank FCT Portugal (PhD studentship and FCT Investigator, respectively) and the EPSRC for funding. G. J. L. B. holds a Royal Society URF and an ERC StG (TagIt). F.C. and G. J. L. B thank the EU (Marie-Sklodowska Curie ITN, Protein Conjugates). R.H-G. thanks Agencia Aragonesa para la Investigación y Desarrollo (ARAID) and the Diputación General de Aragón (DGA, B89) for financial support. The research leading to these results has also received funding from the FP7 (2007-2013) under BioStruct-X (grant agreement N°283570 and BIOSTRUCTX_5186). We thank synchrotron radiation source DIAMOND (Oxford) and beamline I04 (number of experiment mx10121-19). Hokkaido University group acknowledges to JSPS KAKENHI Grant Number 25220206 and JSPS Wakate B KAKENHI Grant Number 24710242. We also thank CESGA (Santiago de Compostela) for computer support

Antibiotics Threaten Wildlife: Circulating Quinolone Residues and Disease in Avian Scavengers

Antibiotic residues that may be present in carcasses of medicated livestock could pass to and greatly reduce scavenger wildlife populations. We surveyed residues of the quinolones enrofloxacin and its metabolite ciprofloxacin and other antibiotics (amoxicillin and oxytetracycline) in nestling griffon Gyps fulvus, cinereous Aegypius monachus and Egyptian Neophron percnopterus vultures in central Spain. We found high concentrations of antibiotics in the plasma of many nestling cinereous (57%) and Egyptian (40%) vultures. Enrofloxacin and ciprofloxacin were also found in liver samples of all dead cinereous vultures. This is the first report of antibiotic residues in wildlife. We also provide evidence of a direct association between antibiotic residues, primarily quinolones, and severe disease due to bacterial and fungal pathogens. Our results indicate that, by damaging the liver and kidney and through the acquisition and proliferation of pathogens associated with the depletion of lymphoid organs, continuous exposure to antibiotics could increase mortality rates, at least in cinereous vultures. If antibiotics ingested with livestock carrion are clearly implicated in the decline of the vultures in central Spain then it should be considered a primary concern for conservation of their populations

A multiproxy study distinguishes environmental change from diagenetic alteration in the recent sedimentary record of the inner Cadiz Bay (SW Spain)

In this study, we reconstruct the recent environmental evolution of the inner Cadiz Bay using sedimentary records reaching back as far as AD 1700. We report lithological descriptions of the sediments and extensive mineralogical and geochemical analyses. An extraction technique that identifies different Fe phases provides an assessment of diagenetic alteration, which allows an estimation of the original organic matter inputs to the inner Cadiz Bay. Downcore variations in Corg/N ratios, δ13Corg and δ15N are related to changes in organic matter sources and the trophic state of the water column. The downcore records of selected trace metals (e.g. Pb, Zn and Cu) are interpreted to reflect changes in heavy metal pollution in the bay, while records of other elements (e.g. Mn and P) are likely overprinted by diagenetic alteration. Major environmental shifts took place during the 20th century, when the population around Cadiz Bay increased exponentially. Increases in sediment accumulation rates, organic matter inputs and heavy metal contents, in parallel with increases in δ13Corg and δ15N over this period, are interpreted as direct effects of the increasing anthropogenic influence in the area. The results of this study suggest that multiproxy approaches and detailed consideration of diagenetic overprinting are required to reconstruct past environmental conditions from coastal sediments

High genetic diversity at the extreme range edge: nucleotide variation at nuclear loci in Scots pine (Pinus sylvestris L.) in Scotland

Nucleotide polymorphism at 12 nuclear loci was studied in Scots pine populations across an environmental gradient in Scotland, to evaluate the impacts of demographic history and selection on genetic diversity. At eight loci, diversity patterns were compared between Scottish and continental European populations. At these loci, a similar level of diversity (θsil=~0.01) was found in Scottish vs mainland European populations, contrary to expectations for recent colonization, however, less rapid decay of linkage disequilibrium was observed in the former (ρ=0.0086±0.0009, ρ=0.0245±0.0022, respectively). Scottish populations also showed a deficit of rare nucleotide variants (multi-locus Tajima's D=0.316 vs D=−0.379) and differed significantly from mainland populations in allelic frequency and/or haplotype structure at several loci. Within Scotland, western populations showed slightly reduced nucleotide diversity (πtot=0.0068) compared with those from the south and east (0.0079 and 0.0083, respectively) and about three times higher recombination to diversity ratio (ρ/θ=0.71 vs 0.15 and 0.18, respectively). By comparison with results from coalescent simulations, the observed allelic frequency spectrum in the western populations was compatible with a relatively recent bottleneck (0.00175 × 4Ne generations) that reduced the population to about 2% of the present size. However, heterogeneity in the allelic frequency distribution among geographical regions in Scotland suggests that subsequent admixture of populations with different demographic histories may also have played a role