Combined In Silico, Ex Vivo, and In Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Neuro- and Cardioprotective and Antidepressant Effects.

Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepressants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17), a recently designed thiadiazine derivative with putative neuro- and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c-Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT3 and 5-HT1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT3 and 5-HT1A receptors, respectively. L-17 robustly increased c-Fos immunoreactivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT3 and 5-HT1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro- and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs.

Cost-per-responder analysis for eltrombopag and rituximab in the treatment of primary immune thrombocytopenia in Spain.

OBJECTIVE: Splenectomy, thrombopoietin receptor agonists and rituximab are  the second-line treatments for steroid-resistant adult primary immune  thrombocytopenia. The last two are becoming the most widely used treatments  to avoid splenectomy adverse effects and inconveniences. However, the choice  between rituximab and thrombopoietin receptor agonists is unclear. Therefore,  the treatment cost may be of particular interest to prioritize the therapy option.  Our aim is to determine the cost per responding-patient after 6 months of use of rituximab compared to thrombopoietin receptor agonists eltrombopag in the  treatment of chronic primary immune thrombocytopenia in the Spanish National  Health Service. METHOD: A 26-week decision tree model was developed to assess the cost of  treatment response of adult patients with chronic-refractory primary immune  thrombocytopenia to eltrombopag and rituximab from the perspective of the  Spanish National Health System. Effectiveness was obtained from the literature,  and cost was obtained from the official rates. Costs were expressed in € (2018).  Due to the short period of assessment, no discount rate was applied. RESULTS: The average cost per patient after 6 months of treatment was slightly  higher for eltrombopag (€13,089.40) than for rituximab (€11,852.60). However, the greater response rate of eltrombopag decreases the bleeding costs, resulting in a 29% higher cost per responding-patient with rituximab (€18,964.15) than  for eltrombopag (€14,732.65). This result is consistent with the results of the 15 sensitivity analyses carried out where eltrombopag always represents a lower  cost per responding patient, except in the sensitivity analysis in which treatment with eltrombopag is performed at its maximum dose (75mg). Only in this case,  the cost per responder of eltrombopag is €48 more expensive than that of  rituximab. Likewise, the greatest difference in favor of eltrombopag occurs in the scenario that uses the minimum dose of this drug -25mg- (eltrombopag  €7,622.14 compared to €18,964.15 for rituximab). Thus, the cost per  responding patient is lower in eltrombopag even if a second cycle of retreatment with rituximab is not performed (€14,732.65 versus €15,298.61). CONCLUSIONS: The treatment cost of rituximab, including monitoring and bleeding costs, is higher than eltrombopag, favoring the latter over  rituximab treatment.

Objetivo: La esplenectomía, los agonistas del receptor de trombopoyetina y el  rituximab son los tratamientos de segunda línea para la trombocitopenia inmune primaria. Los dos últimos se están convirtiendo en los más utilizados para evitar  los efectos adversos de la esplenectomía. Sin embargo, la elección entre ambos  no está clara. El coste puede ser de interés para priorizar el tratamiento.  Nuestro objetivo es determinar el coste por paciente respondedor después de 6  meses de tratamiento de la trombocitopenia inmune primaria crónica con  rituximab frente al agonista del receptor de trombopoyetina eltrombopag en el  Sistema Nacional de Salud español.Método: Se desarrolló un modelo de árbol de decisión de 26 semanas para  evaluar el coste de la respuesta al tratamiento con eltrombopag y rituximab en  pacientes adultos con trombocitopenia inmune primaria crónica refractaria a  esteroides. Debido al corto periodo de evaluación, no se aplicó tasa de  descuento.Resultados: El coste medio por paciente tras 6 meses de tratamiento fue  ligeramente superior para eltrombopag (13.089,40 €) que para rituximab  (11.852,60 €). Sin embargo, la mayor tasa de respuesta de eltrombopag disminuye los costes de hemorragia, lo que se traduce en un coste por paciente  respondedor un 29% mayor con rituximab (18.964,15 €) que con eltrombopag  (14.732,65 €). Este resultado concuerda con los de los 15 análisis de  sensibilidad realizados, donde eltrombopag siempre representa un menor coste  por paciente respondedor, excepto cuando el tratamiento con eltrombopag se  realiza en su dosis máxima (75 mg). Sólo en este caso, el coste por respondedor a eltrombopag es 48 € más caro que el del rituximab. En coherencia con lo  anterior, la mayor diferencia a favor de eltrombopag se da en el escenario que  utiliza la dosis mínima de éste ­25 mg­ (eltrombopag 7.622,14 € frente a  18.964,15 € de rituximab). Así, el coste por paciente respondedor es menor en  eltrombopag aunque no se realice un segundo ciclo de retratamiento con  rituximab (14.732,65 € frente a 15.298,61 €).Conclusiones: El coste del tratamiento con rituximab, incluidos los costes de  monitorización y sangrado, es más alto que el de eltrombopag, lo cual favorece  a este último por encima de rituximab.

The Cost-effectiveness of Eltrombopag for the Treatment of Immune Thrombocytopenia in the United States.

PURPOSE: Eltrombopag was evaluated as a second-line treatment for adult chronic immune thrombocytopenia (ITP) in the 2006 Phase III RAISE (Eltrombopag for Management of Chronic Immune Thrombocytopenia) randomized, placebo-controlled trial. More than 80% of patients reached satisfactory platelet counts within 2 weeks. However, the economic value of eltrombopag as a second-line treatment for ITP remains to be formally assessed. This study aimed to estimate the cost-effectiveness of treating ITP with a comparable thrombopoietin receptor agonist (eltrombopag vs romiplostim). METHODS: A Markov model was implemented over a lifetime time horizon to estimate the benefits and costs of each treatment. The model featured 3 health states based on current guidelines: (1) on treatment; (2) treatment failure/discontinuation; and (3) mortality. In line with therapeutic goals in ITP, model patients could experience 3 events: no bleeding, mild/moderate bleeding, or severe bleeding. Data on eltrombopag use were obtained from an open-label extension of previous Phase II/III trials, including RAISE. Romiplostim data were obtained from Phase III trials and an extension study. Lifetime overall survival was extrapolated by using treatment-specific mortality rates derived from severe bleeding and natural mortality rates. The costs of drugs, routine care, bleeding episodes, adverse events, and mortality were represented in the model. FINDINGS: Eltrombopag-treated patients gained 17.58 life years and 14.68 quality-adjusted life years, whereas romiplostim-treated patients gained 17.52 life years and 14.67 quality-adjusted life years. The total lifetime cost of eltrombopag treatment was estimated at $1.58 million versus $2.13 million for romiplostim. Sensitivity analyses supported base case findings. Deterministic sensitivity analysis predicted the greatest sensitivity to the rates of severe bleeding, discontinuation, and natural mortality. Probabilistic sensitivity analysis showed that eltrombopag would be an efficient use of resources at a $50,000 threshold in 52.8% of cases. In all probabilistic iterations, the total cost of eltrombopag treatment was lower than with romiplostim, primarily because of lower drug costs. IMPLICATIONS: Clinical data were applied in an economic analysis, and eltrombopag exhibited economic dominance compared with romiplostim, driven largely by the reduced costs of primary therapy. This model was limited by a lack of specific patient-level data and robust data on the duration of secondary therapy, as well as by the fact that utilization values are likely conservative estimates for routine care use.

Burden of illness among patients with severe aplastic anemia who have had insufficient response to immunosuppressive therapy: a multicenter retrospective chart review study.

This study assessed treatment patterns and healthcare resource utilization (HRU) of patients with severe aplastic anemia (SAA) with insufficient response to immunosuppressive therapy (IST). A retrospective chart review was conducted at Dana-Farber Cancer Institute (DFCI), United States, and Hôpital Saint-Louis (HSL), France. Eligible patients were ≥ 18 years old, diagnosed with acquired SAA between January 1, 2006, and July 31, 2016, had insufficient response to IST, and had ≥ 12 months of follow-up post-diagnosis. Overall survival (OS) was estimated using the Kaplan-Meier method. Among the 40 patients, mean age at diagnosis was 44 years and 53% were women. Median follow-up time after SAA diagnosis was 48.3 months. Ninety-five percent of patients received antithymocyte globulin (ATG) as primary therapy prior to hematopoietic stem cell transplant (HSCT). Most common secondary SAA therapies prior to HSCT were eltrombopag (28%) and androgens (15%). Seventy-five percent of patients received HSCT. Prior to HSCT, patients received an average of 2.7 red blood cell (RBC) and 3.3 platelet transfusions per month; patients had 0.9 hospitalizations, 0.4 emergency room visits, and 12.8 office visits per year. Five-year OS was 75%, with infection as the primary cause of death. Additionally, this study provides information on the subgroup of patients receiving eltrombopag which was the most common secondary therapy. This study quantified transfusion and HRU burden associated with SAA and demonstrated high 5-year survival in a recently treated cohort.

Healthcare resource use and direct costs in severe aplastic anemia (SAA) patients before and after treatment with eltrombopag.

Purpose: This study evaluated healthcare resource utilization (HCRU), and direct costs among severe aplastic anemia (SAA) patients treated with eltrombopag (EPAG) using US claims data.Methods: This retrospective, real-world claims database study identified SAA patients aged ≥2 years treated with EPAG who initiated any SAA treatment between 1 July 2014 and 31 December 2017 (identification period) using the Truven MarketScan databases. A subset of 82 patients treated with EPAG during the identification period were evaluated for all-cause and SAA-related HCRU and direct costs as well as blood transfusion 1 month before EPAG initiation (baseline) and at Month 6 after EPAG initiation (follow-up period).Results: The average patient age was 50.8 (SD = 20.6) years old, predominantly female (n = 43, 52.4%), and had a mean CCI at baseline of 1.1 (SD = 1.7). Hospitalizations, and ER, office, and outpatient visits were significantly lower at Month 6 after EPAG initiation compared with 1 month before EPAG initiation (p < .05 for all four all-cause HCRU and SAA-related hospitalizations). An almost two-fold decrease in reliance on biweekly blood transfusions was observed: 1.0 at weeks 1-2 to 0.5 at Month 6 after EPAG initiation. Although prescription costs (mean [SD]) were significantly higher at Month 6 after EPAG initiation compared with 1 month before EPAG initiation (difference of $11,045 USD [SD = $18,801]), these increases were offset by savings in direct costs. Overall, a mean reduction in total all-cause costs of $29,391 USD [SD = $137,770] was reported at Month 6 after EPAG initiation due to substantial reductions in hospitalization ($40,060 USD [SD = $123,198]) and outpatient visits ($2,043 USD [SD = $25,264]).Conclusion: All-cause and SAA-related HCRU were reduced following EPAG treatment. Prescription costs were higher following treatment; however, these costs were generally offset by reductions in direct costs. These results provide real-world evidence around the role of EPAG in SAA treatment.

Mapping health-related quality of life scores from FACT-G, FAACT, and FACIT-F onto preference-based EQ-5D-5L utilities in non-small cell lung cancer cachexia.

BACKGROUND: Health-related quality of life (HRQoL) measurements from disease-specific tools cannot be directly used in economic evaluations. This study aimed to develop and validate mapping algorithms that predicted EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) utilities from Functional Assessment of Anorexia-Cachexia Therapy (FAACT) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and their common component (Functional Assessment of Cancer Therapy-General-FACT-G) in patients with non-small cell lung cancer cachexia. METHODS: Data were collected on five occasions over a 12-week period in two multicenter placebo-controlled trials. EQ-5D-5L utilities were calculated using both English and Dutch value sets. The study sample was divided into development and validation datasets according to patients' geographical residence. Generalized estimating equations were applied to five different sets of independent variables including overall, Trial Outcome Index (TOI), and individual subscales results. The best performing models were selected based on mean absolute error (MAE) and root-mean square error (RMSE). RESULTS: EQ-5D-5L and FAACT/FACIT-F results were available for 96 patients. The developed algorithms showed a good predictive performance, with acceptable MAE/RMSE and small differences between mean observed and predicted EQ-5D-5L utilities. In FACT-G models, Physical Well-Being had the highest explanatory value, while Emotional Well-Being did not significantly affect the EQ-5D-5L score; Anorexia-Cachexia and Fatigue subscales were highly statistically significant in FAACT and FACIT-F models, respectively, as well as the TOI scores. The Eastern Cooperative Oncology Group status was included as covariate in all models. CONCLUSION: The developed algorithms enable the estimation of EQ-5D-5L utilities from three cancer-specific instruments when preference-based HRQoL data are missing.

Cost per response analysis of strategies for chronic immune thrombocytopenia.

OBJECTIVES: This analysis estimated the cost per response and the incremental cost per additional responder of romplostim, eltrombopag, and the "watch-and-rescue" (monitoring until rescue therapies are required) strategy in adults with chronic immune thrombocytopenia (ITP). STUDY DESIGN: The decision tree is designed to estimate the total cost per response for romiplostim, eltrombopag, and watch and rescue over a 24-week time horizon; cost-effectiveness was evaluated in terms of incremental cost per additional responder. METHODS: Model inputs including response rates, bleeding-related episode (BRE) rates, and costs were estimated from registrational trial data, an independent Bayesian indirect comparison, database analyses, and peer-reviewed publications. Costs were applied to the proportions of patients with treatment response and nonresponse (based on platelet count). The total cost per response and the incremental cost per additional responder for each treatment were calculated. Sensitivity analyses and alternative analyses were performed. RESULTS: With higher total costs and greater treatment efficacy, romiplostim and eltrombopag had a lower 24-week cost per response and a lower average number of BREs than watch and rescue. Eltrombopag was weakly dominated by romiplostim. The incremental cost-effectiveness ratio of romiplostim versus watch and rescue was $46,000 per additional responder. The model results are most sensitive to response rates of romiplostim and watch and rescue and the BRE rate for splenectomized nonresponders. Alternative analyses results were similar to the base case. CONCLUSIONS: In adults with chronic ITP, romiplostim represents an efficient way to achieve response, with lower costs per response than eltrombopag; both romiplostim and eltrombopag had lower costs per response than watch and rescue.

A decision framework for treating chronic immune thrombocytopenia with thrombopoietin receptor agonists.

Aim: Eltrombopag and romiplostim are comparable second-line therapies in chronic immune thrombocytopenia. Treatment decisions are made in different contexts. A framework was created to outline decision pathways for physicians and payers. Materials & methods: The costs of drugs, administration, routine care, bleeding, other adverse events and mortality were included in the year-long calculation of total costs from a US private payer perspective. Treatment parameters and outcome data were obtained from relevant clinical trials. Results: The total cost per year, per patient of eltrombopag was US$51,000 versus US$76,000 for romiplostim. Drug costs and costs associated with bleeding-related events were the main drivers of cost difference. Conclusion: This framework facilitates decision-making in the management of chronic immune thrombocytopenia with eltrombopag and romiplostim.

[Novelties in the treatment of pediatric immune thrombocytopenia - 2017]. / Újdonságok a gyermekkori immunthrombocytopenia kezelésében ­ 2017.

Immune thrombocitopenia in children is a very variable disease. International recommendations give therapeutic possibilities without strong protocols. In 2011, a therapeutic algorithm was published based on Hungarian practice. Recently, new innovative drugs have been available even in Hungary, so there is a need for modification of the therapeutic protocols. In this summary we give an overview about the current up-to-date management. In infancy and in childhood, high-dose immunglobulin treatment is recommended henceforward. In older children an alternative can be steroid therapy (pulses or long-term low-dose treatment). In resistant cases, a new thrombopoetin receptor stimulant, eltrombopag can be administered. This drug is registered in Hungary, and can very effectively influence the prognosis. Splenectomy is very rare nowadays in children. Immune thrombocytopenia is an unpredictable disease. Cure rate is about 70-80% of the cases, but management of the patients needs special care and specialist. Orv Hetil. 2017; 158(48): 1891-1896.

In vitro generation of platelets: Where do we stand?

Millions of platelets, specialized cells that participate in haemostatic and inflammatory functions, are transfused each year worldwide, but their supply is limited. Platelets are produced by megakaryocytes by extending proplatelets, directly into the bloodstream. Bone marrow structure and extracellular matrix composition together with soluble factors (e.g. Thrombopoietin) are key regulators of megakaryopoiesis by supporting cell differentiation and platelet release. Despite this knowledge, the scarcity of clinical cures for life threatening platelet diseases is in a large part due to limited insight into the mechanisms that control the developmental process of megakaryocytes and the mechanisms that govern the production of platelets within the bone marrow. To overcome these limitations, functional human tissue models have been developed and studied to extrapolate ex vivo outcomes for new insight on bone marrow functions in vivo. There are many challenges that these models must overcome, from faithfully mimicking the physiological composition and functions of bone marrow, to the collection of the platelets generated and validation of their viability and function for human use. The overall goal is to identify innovative instruments to study mechanisms of platelet release, diseases related to platelet production and new therapeutic targets starting from human progenitor cells.

Cost-Effectiveness of Eltrombopag versus Romiplostim for the Treatment of Chronic Immune Thrombocytopenia in England and Wales.

OBJECTIVES: To evaluate the cost-effectiveness of eltrombopag compared with romiplostim to be used in the treatment of chronic immune thrombocytopenia in patients in England and Wales who are splenectomized or ineligible for splenectomy and are refractory to other treatments. METHODS: A Markov cohort model in which patients were administered a sequence of treatments was used to predict long-term outcomes associated with each treatment. The model was informed by data from the eltrombopag clinical trial program and the available literature. The analysis was conducted from the perspective of the UK National Health Service, and a lifetime time horizon was used. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Eltrombopag dominated romiplostim (i.e., eltrombopag was as effective as but less costly than romiplostim) in both splenectomized and nonsplenectomized patients, assuming a class effect for the two treatments. Eltrombopag also dominated romiplostim in most deterministic sensitivity analyses with the exception of when indirect efficacy estimates were incorporated into the model. In this analysis, eltrombopag no longer dominated romiplostim but remained cost-effective versus romiplostim at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. Probabilistic sensitivity analysis demonstrated that there was a 99% and 92% chance of eltrombopag being cost-effective at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year in splenectomized and nonsplenectomized patients, respectively. CONCLUSIONS: Results of this study demonstrate that eltrombopag is cost-effective when compared with romiplostim to be used in the treatment of chronic immune thrombocytopenia, representing good value for the UK National Health Service.

Economic assessment of eltrombopag in the treatment of thrombocytopenia.

OBJECTIVE: This study assesses the cost-effectiveness of eltrombopag in the treatment of hepatitis C virus (HCV)-related thrombocytopenia. METHODS: A Markov model was constructed on the basis of the clinical trials ENABLE 1 and ENABLE 2. Three alternatives were considered: scenario 1; treatment with eltrombopag in both the enabling phase and during antiviral therapy, as in the ENABLE trial design; scenario 2; no eltrombopag treatment and no antiviral therapy; scenario 3; no eltrombopag treatment and subsequent administration of a reduced dose of peg-IFN. RESULTS: Base case results demonstrate that scenario 1 is associated with a cost per QALY of €30,020.94 in comparison with scenario 2. The incremental cost-effectiveness ratio reaches a value of €32,752.44 per QALY when scenario 1 is compared with scenario 3. CONCLUSION: The use of eltrombopag in HCV patients with thrombocytopenia is cost-effective as it leads to a reduction in disease progression and thus a drop in the number of patients with advanced liver disease.

Brief versions of the FACIT-fatigue and FAACT subscales for patients with non-small cell lung cancer cachexia.

PURPOSE: Cancer anorexia-cachexia syndrome (CACS) is common in advanced cancer patients and associated with weight loss, fatigue, impaired quality of life (QoL), and poor prognosis. The goal of this project was to identify the most responsive items from two QoL measures in the ROMANA 2 (NCT01387282) phase III global study evaluating anamorelin HCl in the treatment of non-small cell lung cancer (NSCLC) cachexia: the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and the Functional Assessment of Anorexia/Cachexia Therapy (FAACT). METHODS: In the ROMANA 2 trial, 477 patients with unresectable stage III or IV NSCLC and cachexia were to be enrolled and randomized (2:1) to receive anamorelin HCl or placebo once daily for 12 weeks. All 203 patients who reached the week 12 visit at the time of data analysis were included. Co-primary endpoints were change from baseline in lean body mass and handgrip strength. QoL was a secondary outcome with FACIT-F and FAACT questionnaires administered at baseline and at weeks 3, 6, 9, and 12. RESULTS: Two 4-item scales (fatigue/activity and appetite/eating) from the FACIT-F and FAACT questionnaires, respectively, demonstrated good internal consistency reliability, validity, and responsiveness (also referred to as the Simplified Evaluation of Fatigue (SEF) and Simplified Evaluation of Appetite (SEA), respectively). The estimated important difference for each scale was 1-2 points. CONCLUSIONS: These brief scales provide the psychometric properties necessary to promote future research in NSCLC patients with CACS. Additional work should examine the clinical utility of these scales and their impact on treatment decision-making.

Cost effectiveness of romiplostim for the treatment of chronic immune thrombocytopenia in Ireland.

BACKGROUND: Romiplostim, a thrombopoietin receptor agonist (TPOra), is a second-line medical treatment option for adults with chronic immune thrombocytopenia (ITP). Clinical trials have shown that romiplostim increases platelet counts, while reducing the risk of bleeding and, in turn, the need for costly rescue medications. AIMS: The objective of this study was to assess the cost effectiveness of romiplostim in the treatment of adult ITP in Ireland, in comparison with eltrombopag and the medical standard of care (SoC). METHODS: A lifetime treatment-sequence cost-utility Markov model with embedded decision tree was developed from an Irish healthcare perspective to compare romiplostim with eltrombopag and SoC. The model was driven by platelet response (platelet count ≥50 × 10(9)/L), which determined effectiveness and progression along the treatment pathway, need for rescue therapy (e.g. intravenous immunoglobulin [IVIg] and steroids) and risk of bleeding. Probability of response, mean treatment duration, average time to initial response and utilities were derived from clinical trials and other published evidence. Treatment sequences and healthcare utilization practice were validated by Irish clinical experts. Costs were assessed in for 2011 and included drug acquisition costs and costs associated with monitoring patients and management of bleeding, as available from published Irish reimbursement lists and other relevant sources. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Romiplostim treatment resulted in an average of 20.2 fewer administrations of rescue medication (IVIg or intravenous steroids) over a patient lifetime than eltrombopag, and 29.3 fewer rescue medication administrations than SoC. Romiplostim was dominant, with cost savings of 13,258 and 22,673 and gains of 0.76 and 1.17 quality-adjusted life-years (QALYs), compared with eltrombopag and SoC, respectively. Romiplostim remained cost effective throughout a variety of potential scenarios, including short-term TPOra treatment duration (1 year). One-way sensitivity analysis showed that the model was most sensitive to variation in the cost of IVIg and use of romiplostim and IVIg. Probabilistic sensitivity analysis showed that romiplostim was likely to be cost effective in over 90 % of cases compared with eltrombopag, and 96 % compared with SoC at a willingness-to-pay threshold of 30,000 per QALY. CONCLUSIONS: Use of romiplostim in the ITP treatment pathway, compared with eltrombopag or SoC, is likely to be cost effective in Ireland. Romiplostim improves clinical outcomes by increasing platelet counts, reducing bleeding events and the use of IVIg and steroids, resulting in both cost savings and additional QALYs when compared with current treatment practices.

[Economic evaluation of Thrombopoietin Receptor Agonists in the treatment of chronic primary immune thrombocytopenia]. / Evaluación económica del tratamiento de la trombocitopenia inmune primaria crónica refractaria con agonistas del receptor de la trombopoyetina.

PURPOSE: To develop a tool to assist the decision-making for selection of Thrombopoyetin Receptor Agonists of adult patients with chronic immune primary thrombocytopenia (PTI). METHODS: Stochastic cost-effectiveness analysis with a 6-Health- States Markov model: stable, bleeding type 2, 3 or 4, post-type 4 bleeding and death. Each simulation analyzes a randomly generated scenario that describes patients characteristics, results measured in quality adjusted life years (QALYs) and costs (in ?2011). Distributions were obtained from the Spanish data of the European health survey of 2009, the INE estimate of population for 2011 and the 6-months clinical studies for Eltrombopag and Romiplostim. Utility values were obtained from the literature and the costs from Spanish official rates lists. A set of 10.000 random scenarios were generated and the patients evolution of each scenario was simulated during a time horizon of five years (in 2-weeks cycles). National Health System Perspective was used and the annual discount rate was set at 3%. RESULTS: Eltrombopag showed more effectiveness in 9.983 scenarios and there was no difference in 17. In 7.048 scenarios the alternative Eltombopag was dominant. It was cost-effective in another 19 (threshold 30,000 ??/AVAC). CONCLUSIONS: Eltrombopag was the most cost-effective alternative in 70,67% of the simulated scenarios and its use could produce lower costs to the NHS.

Objetivo: Desarrollar una herramienta de apoyo a la decisión en la selección de agonistas del receptor de trombopoyetina en el tratamiento de pacientes adultos con trombocitopenia inmune primaria crónica (PTI) refractaria. Métodos: Análisis coste-efectividad estocástico con un modelo de Markov de seis estados: estable, sangrado tipo 2, 3 ó 4, post-sangrado 4 y muerte. Cada simulación analiza un escenario aleatoriamente generado que describe las características del paciente, los resultados medidos en años de vida ajustados a calidad (AVACs) y los costes (en ?2011). Se obtuvieron distribuciones a partir de los datos para España de la Encuesta Europea de Salud de 2009, de la estimación de población para 2011 del INE, de los estudios a 6 meses de Eltrombopag y Romiplostim, de las utilidades obtenidas de la bibliografía y de las tarifas oficiales en España para procesos y actividad. Se generaron 10.000 escenarios aleatorios y se simuló la evolución de los pacientes de cada escenario durante un horizonte temporal de cinco años (ciclos de dos semanas). Perspectiva del Sistema Nacional de Salud (SNS). Tasa de descuento anual del 3% para costes y efectos. Resultados: En 9.983 escenarios Eltrombopag mostró mayor efectividad y en 17 no hubo diferencias. Eltombopag fue la alternativa dominante en 7.048 escenarios y la más coste efectiva en otros 19 (umbral 30.000 ?/AVAC). Conclusiones: Eltrombopag es la alternativa más coste-efectiva en el 70,67% de los escenarios simulados, por lo que su uso podría producir menores costes al SNS.

Eltrombopag for the treatment of chronic immune or idiopathic thrombocytopenic purpura: a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of eltrombopag (GlaxoSmithKline) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with chronic immune or idiopathic thrombocytopenic purpura (ITP), as part of the their Single Technology Appraisal (STA) process. The Aberdeen Technology Assessment Review (TAR) Group, commissioned to act as the evidence review group (ERG), critically reviewed and supplemented the submitted evidence. This paper describes the company submission, the ERG review and NICE's subsequent decisions. The ERG critically appraised the clinical and cost-effectiveness evidence submitted by the manufacturer, independently searched for relevant literature, conducted a critical appraisal of the submitted economic models and explored the impact of altering some of the key model assumptions as well as combining relevant sensitivity analyses. Three trials were used to inform the safety and efficacy aspects of this submission; however, one high-quality randomized controlled trial (RAISE study) was the principal source of evidence and was used to inform the economic model. Eltrombopag had greater odds of achieving the primary outcome of a platelet count between 50 × 10^9/L and 400 × 10^9/L during the 6-month treatment period than placebo (odds ratio [OR] 8.2, 99% CI 3.6, 18.7). In the eltrombopag group, 50/83 (60%) of non-splenectomized patients and 18/49 (37%) of splenectomized patients achieved this outcome. The median duration of response was 10.9 weeks for eltrombopag (splenectomized 6 and non-splenectomized 13.4) compared with 0 for placebo. Eltrombopag patients required less rescue medication and had lower odds of bleeding events for both the splenectomized and the non-splenectomized patients. For a watch-and-rescue strategy of care, the comparator was placebo and the ERG found that substantial reductions in the cost of eltrombopag are needed before the incremental cost per QALY is less than £30,000. There was significant uncertainty, with the incremental cost-effectiveness ratio (ICER) reported varying from £33,561 to £103,500 per QALY (splenectomized) and £39,657 to £150,245 per QALY (non-splenectomized). All costs are presented in £, year 2008 values, as this was the costing year for the manufacturer's model. Other than bleeding, no adverse events were modelled. In relation to the long-term treatment model, the ERG questioned the robustness of the use of non-randomized non-comparative data. The base-case results restricting the time horizon to 2 years and prescribing eltrombopag as second-line treatment post-rituximab were found to be favourable towards eltrombopag. As rituximab is not a licensed treatment for ITP, the ERG were concerned that its inclusion may not be reflective of clinical practice. None of the treatment sequences resulted in an ICER approaching the recommended threshold of £30,000 per QALY gained. Eltrombopag appears to be a safe treatment for ITP (although long-term follow-up studies are awaited) and has short-term efficacy. However, NICE found based on the evidence submitted and reviewed that there was no robust evidence on the long-term efficacy or cost effectiveness of eltrombopag and a lack of direct evidence for eltrombopag tested against other relevant comparators.

The European Medicines Agency review of eltrombopag (Revolade) for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura: summary of the scientific assessment of the Committee for Medicinal Products for Human Use.

On 11(th) March 2010, the European Commission issued a marketing authorization valid throughout the European Union for Revolade for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura. Revolade is an orphan medicinal product indicated for splenectomized patients with immune (idiopathic) thrombocytopenic purpura who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) and as second-line treatment for non-splenectomized patients where surgery is contraindicated. The active substance of Revolade is eltrombopag (ATC code B02BX05). Eltrombopag increases platelet production through activation of the thrombopoietin receptor. The recommended oral dose is 50 mg once daily to achieve and maintain a platelet count of the 50×10(9)/L or more necessary to reduce or prevent the risk of bleeding. The benefit of Revolade is a durable response in maintaining platelet levels. The most common side effects include headache, nausea, hepatobiliary toxicity, diarrhea, fatigue, paresthesia, constipation, rash, pruritus, cataract, arthralgia and myalgia. The decision to grant the marketing authorization was based on the favorable recommendation of the Committee for Medicinal Products for Human Use of the European Medicines Agency. The objective of this paper is to describe the data submitted to the European Medicines Agency and to summarize the scientific review of the application. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (www.ema.europa.eu).

Eltrombopag for the treatment of chronic idiopathic (immune) thrombocytopenic purpura (ITP).

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of eltrombopag for the treatment of adults with chronic idiopathic (immune) thrombocytopenic purpura (ITP), based on a review of the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. ITP is an autoimmune disorder by which antibodies are formed against platelets with annual incidence rates in the UK/USA ranging from 1.13 to 6.62 cases per 100,000 adults. Eltrombopag increases the production of platelets at a rate that outpaces their destruction by the immune system, and has a UK marketing authorisation both for the treatment of adult ITP in splenectomised patients who are refractory to other treatments and as a second-line treatment for adult non-splenectomised patients for whom surgery is contraindicated. Both splenectomised and non-splenectomised patient groups were considered in the analysis. Two economic models were presented, one for a watch-and-rescue treatment scenario and the second for the long-term treatment of patients with more severe ITP. The submission's evidence was sourced from the relatively high-quality RAISE [RAndomized placebo-controlled Idiopathic thrombocytopenic purpura (ITP) Study with Eltrombopag] randomised controlled trial. The study indicated a statistically significant difference in favour of eltrombopag compared with placebo in the odds of achieving the primary outcome of a platelet count of between 50 and 400 × 109/l during the 6-month treatment period (odds ratio 8.2, 99% confidence interval 3.6 to 18.7). In the eltrombopag group, 50/83 (60%) non-splenectomised patients and 18/49 (37%) splenectomised patients achieved this outcome. Median duration of response for all patients was 10.9 weeks (splenectomised patients 6 weeks and non-splenectomised patients 13.4 weeks). Patients treated with eltrombopag required less rescue medication and had lower odds of bleeding events than placebo-treated subjects in both patient groups. In the watch-and-rescue economic model, the ERG found that substantial reductions in the cost of eltrombopag are needed for the incremental cost-effectiveness ratio (ICER) to fall below £ 30,000. Further analyses found that the ICER varied from £33,561 to £ 103,500 per quality-adjusted life-year (QALY) (splenectomised) and from £ 39,657 to £ 150,245 per QALY (non-splenectomised). Other than bleeding, no adverse events were modelled. In relation to the long-term treatment model, the ERG found that using non-randomised non-comparative data may result in biased estimates of unknown magnitude and direction. None of the treatment sequences resulted in an ICER approaching the recommended threshold of £ 30,000. The base-case results, using a 2-year time horizon and prescribing eltrombopag as second-line treatment post rituximab, were found to be favourable towards eltrombopag. In conclusion, based on the MS and additional ERG work, eltrombopag appears to be a safe treatment for ITP (although long-term follow-up studies are awaited) and has short-term efficacy. However, there is no robust evidence on long-term efficacy or cost-effectiveness of eltrombopag, and there is a lack of robust direct evidence on the effectiveness and cost-effectiveness of eltrombopag compared with other relevant comparators. NICE did not recommend eltrombopag for the treatment of chronic ITP within its marketing authorisation for splenectomised or non-splenectomised patients.