Lupin-Derived Bioactive Peptides: Intestinal Transport, Bioavailability and Health Benefits.

There is a renewed interest on the reliance of food-based bioactive compounds as sources of nutritive factors and health-beneficial chemical compounds. Among these food components, several proteins from foods have been shown to promote health and wellness as seen in proteins such as α/γ-conglutins from the seeds of Lupinus species (Lupin), a genus of leguminous plant that are widely used in traditional medicine for treating chronic diseases. Lupin-derived peptides (LDPs) are increasingly being explored and they have been shown to possess multifunctional health improving properties. This paper discusses the intestinal transport, bioavailability and biological activities of LDPs, focusing on molecular mechanisms of action as reported in in vitro, cell culture, animal and human studies. The potentials of several LDPs to demonstrate multitarget mechanism of regulation of glucose and lipid metabolism, chemo- and osteoprotective properties, and antioxidant and anti-inflammatory activities position LDPs as good candidates for nutraceutical development for the prevention and management of medical conditions whose etiology are multifactorial.

Neuroprotective Cationic Arginine-Rich Peptides (CARPs): An Assessment of Their Clinical Safety.

Cationic arginine-rich peptides represent a novel class of peptides being developed as neuroprotective agents for stroke and other acute and chronic neurological disorders. As a group, cationic arginine-rich peptides have a diverse range of other biological properties including the ability to traverse cell membranes, modulate immune responses, antagonise ion channel receptor function, as well as possessing cardioprotective, anti-nociceptive, anti-microbial and anti-cancer properties. A sound understanding of their safety profile is essential for the design of future clinical trials and for ensuring translational success with these compounds. At present, while many neuroprotective cationic arginine-rich peptides have been examined in preclinical animal neuroprotection studies, few have been assessed in human safety studies. Despite this, the safety of the prototypical cationic arginine-rich peptide, protamine, which has been in clinical use for over 70 years to reverse the anticoagulant effects of heparin and as an excipient in certain insulin preparations, is well established. In addition, the poly-arginine peptide R9 (ALX40-4C) was developed as an anti-human inmmunodeficiency virus therapeutic in the mid-1990s, and more recently, the neuroprotective cationic arginine-rich peptides TAT-NR2B9c (NA-1), CN-105 and RD2 are being evaluated for the treatment of ischaemic stroke, haemorrhagic stroke and Alzheimer's disease, respectively. Based on the available clinical data, cationic arginine-rich peptides as a group appear to be safe when administered at therapeutic doses by a slow intravenous infusion. While protamine, owing to its isolation from salmon milt and homology with human sperm protamine, can trigger anaphylactic and anaphylactoid reactions in a small proportion of patients previously exposed to the peptide (e.g. diabetic patients), who are allergic to fish or have undergone a vasectomy, such reactions are unlikely to be triggered in individuals exposed to non-protamine cationic arginine-rich peptides.

Comparison of lixisenatide in combination with basal insulin vs other insulin regimens for the treatment of patients with type 2 diabetes inadequately controlled by basal insulin: Systematic review, network meta-analysis and cost-effectiveness analysis.

AIMS: To evaluate the comparative efficacy and safety of lixisenatide combined with basal insulin (BI) vs intensive premix insulin (premix), BI plus prandial insulin with the main meal (basal-plus) or progressively covering all meals (basal-bolus) in patients with type 2 diabetes mellitus (T2DM) inadequately controlled by BI, and the long-term cost-effectiveness of lixisenatide from a Chinese healthcare system perspective. MATERIALS AND METHODS: Randomized controlled trials (RCTs) published between 1998 and 2018 were systematically searched. The clinical efficacy and safety of each treatment were compared by network meta-analysis (NMA). The IQVIA CORE Diabetes Model was used to estimate the lifetime quality-adjusted life-years (QALYs) and direct medical costs of patients treated with different strategies. RESULTS: Eight RCTs were finally included. Lixisenatide plus BI showed a similar reduction in HbA1c from baseline compared with premix, basal-plus and basal-bolus. There were significant differences in the change of body weight in favour of lixisenatide plus BI compared with the three insulin regimens. The risk of symptomatic hypoglycaemia of lixisenatide plus BI was significantly lower compared with premix and basal-bolus. Lixisenatide plus BI was cost-effective compared with premix, basal-plus and basal-bolus with incremental cost-effectiveness ratios of Chinese yuan (CNY) 87 219, 48 173 and 48 670 per QALY gained, respectively, under the threshold of three times the gross domestic product (GDP) per capita in China. CONCLUSIONS: Lixisenatide plus BI shows a similar HbA1c reduction compared with insulin regimens, accompanied by lower risk of hypoglycaemia and greater body weight reduction. It is a cost-effective treatment alternative for patients with T2DM inadequately controlled by BI in China.

Lixisenatide versus insulin glulisine on top of insulin glargine in patients with type 2 diabetes mellitus: a cost-per-responder analysis in China.

Objective: To compare the cost per responder of lixisenatide versus insulin glulisine once daily (basal-plus) and three times daily (basal-bolus) on top of basal insulin for the treatment of patients with type 2 diabetes mellitus (T2DM) inadequately controlled by basal insulin in China.Methods: The cost per responder was estimated based on clinical data obtained from the GetGoal Duo-2 clinical trial and direct medical costs from the perspective of the Chinese healthcare system over a 52-week time horizon. The response was assessed at week 26 in the clinical trial, which was extrapolated to 52 weeks to estimate the annual cost per responder. Responders were primarily defined using a composite endpoint that based on an HbA1c ≤ 7.0% threshold AND no weight gain With or Without no documented symptomatic hypoglycemia. Composite endpoints with varied HbA1c thresholds were defined in secondary analyses.Results: For the composite endpoint of HbA1c threshold ≤7.0% AND no weight gain, the annual cost per responder results were 96,722 CNY, 122,552 CNY and 135,926 CNY (14,616, 18,520 and 20,541 US dollars) for lixisenatide combined with basal insulin, basal-plus, and basal-bolus, respectively. For the composite endpoint of HbA1c threshold ≤7.0% AND no weight gain AND no documented symptomatic hypoglycemia, the annual cost per responder results were 136,290 CNY, 231,487 CNY and 222,424 CNY (20,596, 34,982 and 33,612 US dollars) for lixisenatide combined with basal insulin, basal-plus, and basal-bolus, respectively. The secondary analyses proved similar results.Conclusion: Lixisenatide combined with basal insulin is associated with a lower cost per responder compared with basal-plus and basal-bolus for T2DM patients inadequately controlled by basal insulin in China.

Modeling Cost-Effectiveness of On-Demand Treatment for Hereditary Angioedema Attacks.

BACKGROUND: Hereditary angioedema (HAE) is a rare C1-inhibitor (C1-INH) deficiency disease. Low levels of functional C1-INH can lead to recurrent attacks of severe swelling occurring in areas such as the limbs, face, gastrointestinal tract, and throat. These attacks are both painful and disabling and, if not treated promptly and effectively, can result in hospitalization or death. Agents targeting the specific physiologic pathway of HAE attacks can offer improved outcomes with limited side effects compared with nonspecific therapies. However, these treatments display varying efficacy in HAE patients, including the need to redose or seek additional care if the treatment does not resolve symptoms effectively. OBJECTIVE: To analyze the expected cost and utility per HAE attack when treated on-demand with HAE therapies indicated for the treatment of acute attacks. METHODS: A decision-tree model was developed using TreeAge Pro software. Four on-demand HAE treatments were included: ecallantide, icatibant, plasma-derived (pd)C1-INH, and recombinant human (rh)C1-INH. The model uses probabilities for redosing, self-administration versus health care provider administration, and risk of hospitalization. Costs within the model consisted of the HAE treatments and associated health care system expenses. Nonattack baseline utility and attack utility were implemented for effectiveness calculations; time to attack resolution was considered as well. Effectiveness and overall costs per attack were calculated and used to estimate cost per quality-adjusted life-year (QALY). Variability and ranges in cost-effectiveness were determined using probabilistic sensitivity analyses. Finally, a budget impact model for a health plan with 1 million covered lives was also developed. RESULTS: The base case model outputs show costs and calculated effectiveness per attack at $12,905 and 0.806 for rhC1-INH, $14,806 and 0.765 for icatibant, $14,668 and 0.769 for pdC1-INH, and $21,068 and 0.792 for ecallantide, respectively. Cost per QALY was calculated using 26.9 attacks per person-year, leading to results of $420,941 for rhC1-INH, $488,349 for icatibant, $483,892 for pdC1-INH, and $689,773 for ecallantide. Sensitivity analyses demonstrate that redose rates (from 3% for rhC1-INH to 44% for icatibant) are a primary driver of variability in cost-effectiveness. Annual health plan costs from the budget impact model are calculated as $6.94 million for rhC1-INH, $7.97 million for icatibant, $7.90 million for pdC1-INH, and $11.33 million for ecallantide. CONCLUSIONS: Accounting for patient well-being and additional cost components of HAE attacks generates a better estimation of cost-effectiveness than drug cost alone. Results from this model indicate that rhC1-INH is the dominant treatment option with lower expected costs and higher calculated effectiveness than comparators. Further analyses reinforce the idea that low redose rates contribute to improved cost-effectiveness. DISCLOSURES: Funding support was contributed by Pharming Healthcare. Relan and Adams are employed by Pharming Healthcare. Tyson and Magar are employed by AHRM, which received fees to perform the analysis and develop the manuscript. Bernstein reports grants, personal fees, and nonfinancial support from Shire, CSL Behring, and Pharming Healthcare; grants and personal fees from Biocryst; and nonfinancial support from HAEA, unrelated to this study.

The Impact of Stool Consistency on Bowel Movement Satisfaction in Patients With IBS-C or CIC Treated With Linaclotide or Other Medications: Real-World Evidence From the CONTOR Study.

GOALS: This study aimed to characterize the impact of stool consistency on patient-reported bowel movement (BM) satisfaction in patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation, with a focus on linaclotide. BACKGROUND: As new medications for constipation become available, understanding patients' perceptions of treatment effects may help clinicians manage patient expectations and inform clinical decision-making. MATERIALS AND METHODS: Data were derived from the Chronic Constipation and IBS-C Treatment and Outcomes Real-world Research Platform (CONTOR) study from 2 patient-reported 7-day daily BM diaries to create a dataset of 2922 diaries representing 26,524 BMs for 1806 participants. Binary variables were created for: medication(s) used in the past 24 hours and categorization of BMs as loose or watery stools (LoWS), hard or lumpy stools (HoLS), or intermediate (neither LoWS nor HoLS). The relationship between stool consistency, medication use, and BM satisfaction was analyzed using logistic regression with SEs corrected for repeated observations. RESULTS: BMs characterized as intermediate stools and LoWS were satisfactory more often (61.2% and 51.2%, respectively) than HoLS (19.4%). Participants who reported taking linaclotide rated a similar proportion of BMs as satisfactory when described as LoWS (65.6%) or intermediate (64.1%). Linaclotide use was associated with higher odds of BMs being reported as satisfactory compared with nonlinaclotide use (odds ratio: 1.23, P<0.05). CONCLUSIONS: Overall, CONTOR participants were more likely to report BMs classified as LoWS or intermediate as satisfactory, versus HoLS. Participants taking linaclotide were more likely to be satisfied, particularly those reporting LoWS, versus those not taking linaclotide.

Coadministration of Polypeptide-k and Curcumin Through Solid Self-Nanoemulsifying Drug Delivery System for Better Therapeutic Effect Against Diabetes Mellitus: Formulation, Optimization, Biopharmaceutical Characterization, and Pharmacodynamic Assessment.

An attempt has been made to prepare solid self-nanoemulsifying drug delivery system (SNEDDS) of polypeptide-k (PPK) and curcumin (CRM) using Labrafil M1944 CS as oil, Tween-80 as surfactant, Transcutol P as cosurfactant and Aerosil-200 (A-200) as porous hydrophobic carrier for improving their antidiabetic potential through oral delivery. Box-Behnken Design was used to optimize the liquid formulation based on the results of the mean droplet size, polydispersity index, percentage drug loading, and zeta potential. The formulation was adsorbed on Aerosil-200 through spray drying. The formulation showed desirable micromeritic, disintegration, and dissolution properties. About fivefold rise in the dissolution and permeation rate for drugs was observed from formulations vis a vis their unprocessed forms. The formulation was found to be stable with variation in pH, dilution, and temperature. The individual solid SNEDDS formulation of PPK and CRM and their combination were evaluated for antidiabetic potential and the results were compared with their naive forms on streptozotocin-induced diabetic rats. The results revealed better control of serum glucose level and other biochemical tests, such as liver parameters, lipid profiles, and antioxidant levels, as well as histological evaluation of pancreatic tissues in all the solid SNEDDS formulation as compared with their naive forms.

Cost-effectiveness of once-weekly semaglutide versus dulaglutide and lixisenatide in patients with type 2 diabetes with inadequate glycemic control in Sweden.

Aims: This analysis evaluated the cost-effectiveness of once-weekly semaglutide vs glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) uncontrolled on metformin or basal insulin in Sweden. Materials and methods: This cost-effectiveness analysis (CEA) was conducted using the Swedish Institute of Health Economics (IHE) Diabetes Cohort Model. Analyses were conducted from the Swedish societal perspective over a time horizon of 40 years. For patients uncontrolled on metformin, dulaglutide was the comparator, and data from the SUSTAIN 7 clinical trial was used. For patients uncontrolled on basal insulin, lixisenatide was chosen as the comparator and data was obtained from a network meta-analysis (NMA). Results: The results show that, in patients with inadequate control on metformin, semaglutide 1.0 mg dominated (i.e. provided greater clinical benefit, and was less costly) dulaglutide 1.5 mg. In patients with inadequate control on basal insulin, semaglutide 1.0 mg dominated lixisenatide. The reduction in costs is largely driven by the reduction in complications seen with once-weekly semaglutide. Limitations and conclusions: It is likely that this analysis is conservative in estimating the cardiovascular (CV) cost benefits associated with treatment with once-weekly semaglutide. In patients inadequately controlled on basal insulin, the analyses vs lixisenatide were based on results from an NMA, as no head-to-head clinical trial has been conducted for this comparison. These CEA results show that once-weekly semaglutide is a cost-effective GLP-1 RA therapy for the treatment of T2D in patients inadequately controlled on metformin or basal insulin, addressing many current clinician, patient, and payer unmet needs in Sweden.

Assessment of Drug-Drug Interactions between Taspoglutide, a Glucagon-Like Peptide-1 Agonist, and Drugs Commonly Used in Type 2 Diabetes Mellitus: Results of Five Phase I Trials.

BACKGROUND AND OBJECTIVE: Taspoglutide, a glucagon-like peptide-1 agonist, like native glucagon-like peptide-1, delays gastric emptying time and prolongs intestinal transit time, which may alter the pharmacokinetics of concomitantly administered oral drugs. The effect of taspoglutide on the pharmacokinetics of five oral drugs commonly used in patients with type 2 diabetes mellitus was assessed in healthy subjects. METHODS: Five clinical pharmacology studies evaluated the potential drug-drug interaction between multiple subcutaneous taspoglutide doses and a single dose of lisinopril, warfarin, and simvastatin and multiple doses of digoxin and an oral contraceptive containing ethinylestradiol and levonorgestrel. The extent of interaction was quantified using geometric mean ratios and 90% confidence intervals for the maximum plasma concentration and area under the plasma concentration-time curve. In addition to pharmacokinetics, pharmacodynamic effects were assessed for warfarin and the oral contraceptive. RESULTS: Among the tested drugs, the effect of taspoglutide on the pharmacokinetics of simvastatin was most pronounced, on the day of taspoglutide administration, the average exposure to simvastatin was decreased by - 26% and - 58% for the area under the plasma concentration-time curve and maximum plasma concentration, respectively, accompanied by an increase in average exposure to its active metabolite, simvastatin ß-hydroxy acid (+ 74% and + 23% for area under the plasma concentration-time curve and maximum plasma concentration, respectively). Although statistically significant changes in exposure were observed for other test drugs, the 90% confidence intervals for the geometric mean ratio for maximum plasma concentration and area under the plasma concentration-time curve were within the 0.7-1.3 interval. No clinically relevant changes on coagulation (for warfarin) and ovulation-suppressing activity (for the oral contraceptive) were apparent. CONCLUSION: Overall, multiple doses of taspoglutide did not result in changes in the pharmacokinetics of digoxin, an oral contraceptive containing ethinylestradiol and levonorgestrel, lisinopril, warfarin, and simvastatin that would be considered of clinical relevance. Therefore, no dose adjustments are warranted upon co-administration.

Romiplostim para púrpura trombocitopênica idiopática (PTI) crônica e refratária em alto risco de sangramento / Romiplostim for chronic idiopathic thrombocytopenic purpura (ITP) and refractory at high risk of bleeding

INTRODUÇÃO: A púrpura trombocitopênica idiopática crônica (PTI), atualmente denominada trombocitopenia imune primária (TIP) é uma doença autoimune adquirida, de causa desconhecida, caracterizada predominantemente pela presença isolada de trombocitopenia (baixas contagens de plaquetas). Fisiologicamente, observa-se a destruição aumentada das plaquetas causada por autoanticorpos contra os antígenos das plaquetas e por linfócitos T citotóxicos, associada a uma produção prejudicada de plaquetas pela medula óssea. Não existe exame laboratorial específico para o diagnóstico de PTI, sendo feito diagnóstico por exclusão: presença de trombocitopenia isolada, sem alterações nas outras séries do hemograma e no esfregaço de sangue periférico; e a exclusão de outras causas de trombocitopenia. O tratamento é recomendado apenas para pacientes com trombocitopenia grave (plaquetas < 20 x 109 /L) ou àqueles com sangramentos associados à trombocitopenia (plaquetas < 50 x 109 /L) e tem como objetivo controlar precocemente os sintomas, diminuir o risco de sangramento e causar menos impacto na qualidade de vida. Os agonistas do receptor de trombopoietina (TPO) aumentam a produção de plaquetas estimulando o receptor de TPO em pessoas com ITP crônica. Segundo o Protocolo Clínico e Diretrizes Terapêuticas - púrpura trombocitopênica idiopática (PCDT - PTI) do Ministério da Saúde, de 2013, as práticas de tratamento atuais para pacientes adultos com PTI crônica devem ter a seguinte abordagem: corticosteroides, imunoglobulina humana intravenosa, esplenectomia, azatioprina, ciclofosfamida, danazol e vincristina. TECNOLOGIA: Romiplostim (Nplate®). PERGUNTA: O romiplostim é seguro, eficaz e custo-efetivo em pacientes com PTI crônica, esplenectomizados, refratários e em alto risco de sangramento, quando comparado ao tratamento atual disponível no SUS? EVIDÊNCIAS CIENTÍFICAS: Baseada em dois ensaios clínicos randomizados e uma revisão sistemática da Cochrane (2011) com 6 ensaios clínicos randomizados (ECR) que avaliaram a eficácia e segurança dos agonistas do receptor de TPO em pacientes com PTI crônica. O ECR realizado por Bussel et. al. (2006) demostrou que o romiplostim causa um aumento significativo na contagem de plaquetas quando comparado ao placebo (RR= 3,00; IC95% 0,54 - 16,77), achado que foi corroborado pelo estudo de Kuter et. al. (2008) que encontrou taxas de duração da resposta plaquetária significativamente maiores (RR= 16,88; IC95% 1,06 - 268,42) e melhora significativa na taxa de resposta plaquetária global (RR= 34,28; IC95% 2,20 ­ 533,41), quando comparado o romiplostim com o placebo. A revisão sistemática confirmou esse achado, visto que, na análise combinada o uso de agonistas do receptor de TPO (romiplostim e eltrombopague) apresentou melhora significativa nas taxas de resposta plaquetária global comparado ao placebo (RR= 4,06; IC95% 2,93 - 5,63; valor de p< 0,00001) e ao tratamento padrão (RR= 1,81; IC95% 1,37 - 2,37; valor de p< 0,0001) , e maiores taxas de duração da resposta no número de plaquetas, com significância estatística, comparado ao placebo (RR= 14,16; IC95% 2,91 - 69,01; valor de p=0,001). Apesar desse aumento significativo na contagem de plaquetas, a RS demonstrou que não houve diferença significativa para incidência de eventos hemorrágicos importantes (classificados como graves, com risco de morte ou fatais) na PTI crônica quando comparado com placebo (RR= 0,48; IC95% 0,19 - 1,16; valor de p=0,10) ou tratamento padrão (RR= 0,49; IC95% 0,15 - 1,63; valor de p=0,24), resultado também encontrado no estudo de Kuter et. al. (2008) comparado com o placebo (RR= 0,50; IC95% 0,14 - 1,80). Nenhum dos estudos incluiu sobrevida global como desfecho, portanto, não foi possível avaliar se o romiplostim ajuda a prolongar a vida dos pacientes. Embora faltem estudos de longo prazo, a RS demonstrou que os agonistas do receptor de TPO são bem tolerados, apresentando o total de efeitos adversos semelhantes ao do grupo placebo (RR= 1,04; IC95% 0,95 - 1,15; valor de p=0,35). No que se refere ao total de eventos adversos graves, os 3 estudos não encontraram diferença significativa entre o romiplostim comparado ao placebo (RR= 0,12, IC 95% 0,01 - 1,00) (Bussel, 2006), (RR= 0,94, IC 95% 0,48 - 1,85) (Kuter, 2008) e (RR= 0,92; IC95% 0,61 - 1,38; valor de p= 0,68) (Zeng, 2011), entretanto a RS demonstrou uma redução significativa entre o romiplostim e o tratamento padrão (RR= 0,61; IC95% 0,40 - 0,92; valor de p=0,02). Não existe evidência suficiente para afirmar a eficácia do romiplostim na PTI crônica, sendo necessários mais estudos para explorar o papel desse medicamento no tratamento da PTI crônica de forma mais completa. AVALIAÇÃO ECONÔMICA: O demandante realizou avaliação de custo-utilidade, com modelo de Markov, com ciclo de 4 semanas, em um horizonte temporal de até o fim da vida, na perspectiva do SUS. Foram definidos os seguintes parâmetros: população de pacientes esplenectomizados, com PTI crônica, recebendo um tratamento a partir de segunda linha, com contagem de plaqueta (CP) < 20x109/L; possibilidade de 3 estados de saúde abrangentes (Plaquetas ≥ 50×109/L; Plaquetas < 50×109/L; Morto); comparação entre romiplostim e a terapia de regaste usada nos pacientes em observação e sem tratamento (imunoglobulina intravenosa - IVig); resposta ao tratamento (CP > 50x109/L); eficácia de cada tratamento (probabilidade de resposta inicial ao tratamento; tempo médio à resposta (CP > 50x109/L); tempo até a falha do tratamento (CP < 50x109/L durante 4 semanas consecutivas)); e desfechos primários (custos incrementais incorridos e os anos de vida ajustados por qualidade (QALYs) ganhos a partir da introdução do romiplostim). Os custos foram avaliados em Reais (R$) com base nos anos 2016 e 2017, extraídos do banco de dados SIGTAP do Ministério da Saúde (MS), lista de preço de medicamentos publicada pela Câmara de Regulação do Mercado de Medicamentos e parecer de especialistas locais. O custo do tratamento para cada intervenção incluiu: custos de compra dos medicamentos, administração de testes laboratoriais e monitoramento. Taxa de desconto de 5% para efetividade e custos. A razão de custo-efetividade incremental (RCEI) foi de R$ - 121.213,45 /QALY, mostrando que o tratamento da PTI com o romiplostim quando comparado com o grupo de pacientes em observação e sem tratamento é uma estratégia custo-efetiva (dominante). Foram realizadas análises de sensibilidade determinista e probabilística cujos resultados demonstraram que a RCEI foi robusta, visto que a estratégia de tratamento com o romiplostim continuou dominante, mesmo com a variação dos valores dos parâmetros utilizados no modelo. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: Foi estimada considerando duas possibilidades de prevalência de PTI, uma de "baixa prevalência" e outra de "alta prevalência", e dois panoramas de difusão da tecnologia, um conservador e outro otimista, totalizando a possibilidade de 4 diferentes cenários. Como resultado, o demandante encontrou que, durante 5 anos, em todos os quatro cenários, a incorporação do romiplostim resultaria em economias de R$ 49.386.749 a R$ 196.521.197 no cenário de "alta prevalência" e de R$ 49.725.986 a R$ 79.164.764 no cenário de "baixa prevalência". Na análise de sensibilidade unilateral, a incorporação do romiplostim permaneceu resultando em economias, mesmo com a variação dos valores dos dois parâmetros direcionadores do modelo. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Há tecnologias em fase de desenvolvimento clínico para tratamento de púrpura trombocitopênica idiopática. Porém, essas novas tecnologias ainda não tiveram seu registro aprovado pela Anvisa para a indicação clínica pesquisada. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes em sua 65ª reunião ordinária, no dia 04 de abril de 2018, indicaram que o tema seja submetido à Consulta Pública com recomendação preliminar a não incorporação no SUS do romiplostim para PTI crônica e refratária em alto risco de sangramento. Considerou-se que apesar do aumento significativo na contagem de plaquetas, a evidência atualmente disponível não foi suficiente para afirmar que o romiplostim reduz significativamente a incidência de eventos hemorrágicos importantes, comparado ao placebo e ao tratamento padrão e que os estudos econômicos apresentaram fragilidades, sobretudo, devido ao comparador utilizado. CONSULTA PÚBLICA: Foram recebidas 7 contribuições técnico-científicas e 14 contribuições de experiência ou opinião, sendo que todas discordaram totalmente da recomendação preliminar da CONITEC. De maneira geral, as contribuições apresentarem oito artigos e alguns comentários acerca: do PCDT vigente, do desfecho avaliado e da população alvo, entretanto não acrescentaram e nem mudaram os aspectos anteriormente discutidos e apresentados no relatório inicial da CONITEC. Assim, a CONITEC entendeu que não houve argumentação suficiente para alterar sua recomendação preliminar. RECOMENDAÇÃO FINAL: Os membros da CONITEC em 08/11/2018 deliberaram por unanimidade recomendar a não incorporação do romiplostim para tratamento de púrpura trombocitopênica idiopática, ao SUS. Foi assinado o Registro de Deliberação nº 393/2018. DECISÃO: Não incorporar o romiplostim para púrpura trombocitopênica idiopática (PTI) crônica e refratária em alto risco de sangramento, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 69, publicada no DOU nº 238, seção 1, página 71, em 11 de dezembro de 2018.

Valuing injection frequency and other attributes of type 2 diabetes treatments in Australia: a discrete choice experiment.

BACKGROUND: Multiple pharmacotherapy options are available to control blood glucose in Type 2 Diabetes Mellitus (T2DM). Patients and prescribers may have different preferences for T2DM treatment attributes, such as mode and frequency of administration, based on their experiences and beliefs which may impact adherence. As adherence is a pivotal issue in diabetes therapy, it is important to understand what patients value and how they trade-off the risks and benefits of new treatments. This study aims to investigate the key drivers of choice for T2DM treatments, with a focus on injection frequency, and explore patients' associated willingness-to-pay. METHODS: A discrete choice experiment (DCE) was used to present patients with a series of trade-offs between different treatment options, injectable and oral medicines that were made up of 10 differing levels of attributes (frequency and mode of administration, weight change, needle type, storage, nausea, injection site reactions, hypoglycaemic events, instructions with food and cost). A sample of 171 Australian consenting adult T2DM patients, of which 58 were receiving twice-daily injections of exenatide and 113 were on oral glucose-lowering treatments, completed the national online survey. An error components model was used to estimate the relative priority and key drivers of choice patients place on different attributes and to estimate their willingness to pay for new treatments. RESULTS: Injection frequency, weight change, and nausea were shown to be important attributes for patients receiving injections. Within this cohort, a once-weekly injection generated an additional benefit over a twice-daily injection, equivalent to a weighted total willingness to pay of AUD$22.35 per month. CONCLUSIONS: Based on the patient preferences, the importance of frequency of administration and other non-health benefits can be valued. Understanding patient preferences has an important role in health technology assessment, as the identification of the value as well as the importance weighting for each treatment attribute may assist with funding decisions beyond clinical trial outcomes.

Health Care Resource Use and Costs Pre- and Post-Treatment Initiation With Linaclotide: Retrospective Analyses of a U.S. Insured Population.

As expected, pharmacy costs increased with the introduction of this new treatment in a market dominated by over-the-counter and generic treatments. On the other hand, outpatient GI-related and irritable bowel disease health care resource use and costs substantially decreased among commercial and Medicare patients following linaclotide treatment initiation.

Cost-effectiveness of liraglutide versus lixisenatide as add-on therapies to basal insulin in type 2 diabetes.

BACKGROUND: We assessed the cost-effectiveness of the glucagon-like peptide 1 receptor agonists liraglutide 1.8 mg and lixisenatide 20 µg (both added to basal insulin) in patients with type 2 diabetes (T2D) in Sweden. METHODS: The Swedish Institute for Health Economics cohort model for T2D was used to compare liraglutide and lixisenatide (both added to basal insulin), with a societal perspective and with comparative treatment effects derived by indirect treatment comparison (ITC). Drug prices were 2016 values, and all other costs 2015 values. The cost-effectiveness of IDegLira (fixed-ratio combination of insulin degludec and liraglutide) versus lixisenatide plus basal insulin was also assessed, under different sets of assumptions. RESULTS: From the ITC, decreases in HbA1c were -1.32% and -0.43% with liraglutide and lixisenatide, respectively; decreases in BMI were -1.29 and -0.65 kg/m2, respectively. An estimated 2348 cases of retinopathy, 265 of neuropathy and 991 of nephropathy would be avoided with liraglutide compared with lixisenatide in a cohort of 10,000 patients aged over 40 years. In the base-case analysis, total direct costs were higher with liraglutide than lixisenatide, but costs associated with complications were lower. The cost/quality-adjusted life-year (QALY) for liraglutide added to basal insulin was SEK30,802. Base-case findings were robust in sensitivity analyses, except when glycated haemoglobin (HbA1c) differences for liraglutide added to basal insulin were abolished, suggesting these benefits were driving the cost/QALY. With liraglutide 1.2 mg instead of liraglutide 1.8 mg (adjusted for efficacy and cost), liraglutide added to basal insulin was dominant over lixisenatide 20µg.IDegLira was dominant versus lixisenatide plus basal insulin when a defined daily dose was used in the model. CONCLUSIONS: The costs/QALY for liraglutide, 1.8 or 1.2 mg, added to basal insulin, and for IDegLira (all compared with lixisenatide 20 µg added to basal insulin) were below the threshold considered low by Swedish authorities. In some scenarios, liraglutide and IDegLira were cost-saving.

Cost Effectiveness of Exenatide Once Weekly Versus Insulin Glargine and Liraglutide for the Treatment of Type 2 Diabetes Mellitus in Greece.

OBJECTIVE: The objective of this study was to evaluate the long-term cost effectiveness of exenatide once weekly (ExQW) versus insulin glargine (IG) or liraglutide 1.2 mg (Lira1.2mg) for the treatment of adult patients with type 2 diabetes mellitus (T2DM) not adequately controlled on oral antidiabetic drug (OAD) therapy in Greece. METHODS: The published and validated Cardiff Diabetes Model was used to project clinical and economic outcomes over a patient's lifetime. Clinical data were retrieved from a head-to-head clinical trial (DURATION 3) and a published network meta-analysis comparing ExQW with IG or Lira1.2mg, respectively. Following a Greek third-party payer perspective, direct medical costs related to drug acquisition, consumables, developed micro- and macrovascular complications, maintenance treatment, as well as treatment-related adverse events were considered. Cost and utility data were extracted from literature and publicly available official sources and assigned to model parameters to calculate total quality-adjusted life-years (QALYs) and total costs as well as incremental cost-effectiveness ratios (ICERs). Sensitivity analyses explored the impact of changes in input data. RESULTS: Over a patient's lifetime, ExQW was associated with 0.458 or 0.039 incremental QALYs compared with IG or Lira1.2mg, respectively, at additional costs of €2061 or €110, respectively. The ICER for ExQW was €4499/QALY compared with IG and €2827/QALY compared with Lira1.2mg. Results were robust across various one-way and scenario analyses. At the defined willingness-to-pay threshold of €36,000/QALY, probabilistic sensitivity analysis showed that ExQW had a 100 or 88.2% probability of being cost effective relative to IG or Lira1.2mg, respectively. CONCLUSIONS: ExQW was estimated to be cost effective relative to IG or Lira1.2mg for the treatment of T2DM in adults not adequately controlled on OAD therapy in Greece.

Evaluating the short-term cost-effectiveness of liraglutide versus lixisenatide in patients with type 2 diabetes in the United States.

AIMS: Bringing patients with type 2 diabetes to recommended glycated hemoglobin (HbA1c) treatment targets can reduce the risk of developing diabetes-related complications. The aim of the present analysis was to evaluate the short-term cost-effectiveness of once-daily liraglutide 1.8 mg vs once-daily lixisenatide 20 µg as an add-on to metformin for treatment of type 2 diabetes in the US by assessing the cost per patient achieving HbA1c-focused and composite treatment targets. MATERIALS AND METHODS: Percentages of patients achieving recommended targets were obtained from the LIRA-LIXI trial, which compared the efficacy and safety of once-daily liraglutide 1.8 mg and once-daily lixisenatide 20 µg as an add-on to metformin in patients with type 2 diabetes failing to achieve glycemic control with metformin. Annual costs were estimated from a healthcare payer perspective. An economic model was developed to evaluate the annual cost per patient achieving target (cost of control) with liraglutide 1.8 mg vs lixisenatide 20 µg for five end-points. RESULTS: Annual treatment costs were higher with liraglutide 1.8 mg than lixisenatide 20 µg, but this was offset by greater clinical efficacy, and the cost of control was lower with liraglutide 1.8 mg than lixisenatide 20 µg for all five end-points. The annual cost of control was USD 3,850, USD 11,404, USD 3,807, USD 4,299, and USD 6,901 lower for liraglutide 1.8 mg than lixisenatide 20 µg for targets of HbA1c < 7.0%, HbA1c ≤ 6.5%, HbA1c < 7.0% and no weight gain, HbA1c < 7.0% with no weight gain and no confirmed hypoglycemia, and HbA1c < 7.0% with no weight gain and systolic blood pressure <140 mmHg, respectively. CONCLUSIONS: Once-daily liraglutide 1.8 mg was associated with greater clinical efficacy than once-daily lixisenatide 20 µg, which resulted in a lower annual cost of control for HbA1c-focused and composite treatment targets.

Cost-effectiveness of exenatide twice daily vs insulin glargine as add-on therapy to oral antidiabetic agents in patients with type 2 diabetes in China.

AIMS: To estimate the long-term cost-effectiveness of exenatide twice daily vs insulin glargine once daily as add-on therapy to oral antidiabetic agents (OADs) for Chinese patients with type 2 diabetes (T2DM). METHODS: The Cardiff Diabetes Model was used to simulate disease progression and estimate the long-term effects of exenatide twice daily vs insulin glargine once daily. Patient profiles and treatment effects required for the model were obtained from literature reviews (English and Chinese databases) and from a meta-analysis of 8 randomized controlled trials comparing exenatide twice daily with insulin glargine once daily add-on to OADs for T2DM in China. Medical expenditure data were collected from 639 patients with T2DM (aged ≥18 years) with and without complications incurred between January 1, 2014 and December 31, 2015 from claims databases in Shandong, China. Costs (2014 Chinese Yuan [¥]) and benefits were estimated, from the payers' perspective, over 40 years at a discount rate of 3%. A series of sensitivity analyses were performed. RESULTS: Patients on exenatide twice daily + OAD had a lower predicted incidence of most cardiovascular and hypoglycaemic events and lower total costs compared with those on insulin glargine once daily + OAD. A greater number of quality-adjusted life years (QALYs; 1.94) at a cost saving of ¥117 706 gained was associated with exenatide twice daily vs insulin glargine once daily. (i.e. cost saving of ¥60 764/QALY) per patient. CONCLUSIONS: In Chinese patients with T2DM inadequately controlled by OADs, exenatide twice daily is a cost-effective add-on therapy alternative to insulin glargine once daily, and may address the problem of an excess of medical needs resulting from weight gain and hypoglycaemia in T2DM treatment.

Evaluating drug cost per responder and number needed to treat associated with lixisenatide on top of glargine when compared to rapid-acting insulin intensification regimens on top of glargine, in patients with type 2 diabetes in the UK, Italy, and Spain.

OBJECTIVES: This study investigated the cost per responder and number needed to treat (NNT) in type 2 diabetes mellitus (T2DM) patients for lixisenatide compared to insulin intensification regimens using composite endpoints in the UK, Italy, and Spain. METHODS: Efficacy and safety outcomes were obtained from GetGoal Duo-2, a 26-week phase 3 trial comparing lixisenatide vs insulin glulisine (IG) once daily (QD) and three times daily (TID). Response at week 26 was extrapolated to 52 weeks, assuming a maintained treatment effect, based on long-term evidence in other T2DM populations. Responders were defined using composite end-points, based on an HbA1c threshold and/or no weight gain and/or no hypoglycemia. The HbA1c threshold was varied in sensitivity analyses. Annual treatment costs were estimated in euros (1 GBP = 1.26 EUR), including drug acquisition and resource use costs. Cost per responder was computed by dividing annual treatment costs per patient by the proportion of responders. RESULTS: Lixisenatide was associated with the lowest cost per responder for all composite end-points that included a weight-related component. For the main composite end-point of HbA1c ≤7.5% AND no weight gain AND no symptomatic hypoglycemia, cost per responder results were: UK: 6,867€, 8,746€, and 12,410€; Italy: 7,057€, 9,160€, and 12,844€; Spain: 8,370€, 11,365€, and 17,038€, for lixisenatide, IG QD, and TID, respectively. The NNT analysis showed that, for every 6.85 and 5.86 patients treated with lixisenatide, there was approximately one additional responder compared to IG QD and TID, respectively. LIMITATIONS: A limitation of the clinical inputs is the lack of 52-week trial data from GetGoal Duo-2, which led to the assumption of a maintained treatment effect from week 26 to 52. CONCLUSIONS: This analysis suggests lixisenatide is an efficient economic resource allocation in the UK, Italy, and Spain.

Healthcare resource utilization and related financial costs associated with glucose lowering with either exenatide or basal insulin: A retrospective cohort study.

AIMS: Type 2 diabetes is a major health problem placing increasing demands on healthcare systems. Our objective was to estimate healthcare resource use and related financial costs following treatment with exenatide-based regimens prescribed as once-weekly (EQW) or twice-daily (EBID) formulations, compared with regimens based on basal insulin (BI). MATERIALS AND METHODS: This retrospective cohort study used data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES). Patients with type 2 diabetes who received exenatide or BI between 2009 and 2014 as their first recorded exposure to injectable therapy were selected. Costs were attributed to primary care contacts, diabetes-related prescriptions and inpatient admissions using standard UK healthcare costing methods (2014 prices). Frequency and costs were compared between cohorts before and after matching by propensity score using Poisson regression. RESULTS: Groups of 8723, 218 and 2180 patients receiving BI, EQW and EBID, respectively, were identified; 188 and 1486 patients receiving EQW and EBID, respectively, were matched 1:1 to patients receiving BI by propensity score. Among unmatched cohorts, total crude mean costs per patient-year were £2765 for EQW, £2549 for EBID and £4080 for BI. Compared with BI, the adjusted annual cost ratio (aACR) was 0.92 (95% CI, 0.91-0.92) for EQW and 0.82 (95% CI, 0.82-0.82) for EBID. Corresponding costs for the propensity-matched subgroups were £2646 vs £3283 (aACR, 0.80, 0.80-0.81) for EQW vs BI and £2532 vs £3070 (aACR, 0.84, 0.84-0.84) for EBID vs BI. CONCLUSION: Overall, exenatide once-weekly and twice-daily-based regimens were associated with reduced healthcare resource use and costs compared with basal-insulin-based regimens.

Treatment patterns in patients with type 2 diabetes mellitus treated with glucagon-like peptide-1 receptor agonists: Higher adherence and persistence with dulaglutide compared with once-weekly exenatide and liraglutide.

AIMS: To compare adherence (proportion of days covered [PDC]), persistence, and treatment patterns among patients with type 2 diabetes mellitus (T2DM) newly initiating glucagon-like peptide-1 receptor agonists (GLP-1RAs). More specifically, the main objectives were to compare dulaglutide vs exenatide once weekly and dulaglutide vs liraglutide. METHODS: Patients with T2DM newly initiating dulaglutide, albiglutide, exenatide once weekly, exenatide twice daily and liraglutide between November 2014 and April 2015 were hierarchically selected from Truven Health's MarketScan Research Databases. Propensity score matching was used to account for selection bias. Adherence to and persistence with the index GLP-1RA, and switching and augmentation patterns were assessed during the 6-month post-index period. RESULTS: Mean adherence for the matched cohorts was significantly higher for dulaglutide than for exenatide once weekly (0.72 vs 0.61; P < .0001) and liraglutide (0.71 vs 0.67; P < .0001). The percentage of patients achieving PDC ≥ 0.80 was significantly higher for dulaglutide compared with exenatide once weekly (54.2% vs 37.9%; P < .0001) and liraglutide (53.5% vs 44.3%; P < .0001). The mean (standard deviation) days on treatment for all matched patients was significantly higher for patients in the dulaglutide cohort compared with those in the exenatide once-weekly (148.4 [55.4] vs 123.6 [61.6]; P < .0001) and liraglutide cohorts (146.0 [56.9] vs 137.4 [60.1]; P < .0001). A significantly lower proportion of patients on dulaglutide discontinued treatment compared with those on exenatide once weekly (26.2% vs 48.4%; P < .0001) and those on liraglutide (28.0% vs 35.6%; P < .0001). CONCLUSIONS: Dulaglutide initiators had significantly higher adherence, were more persistent, and had lower discontinuation rates compared with initiators of exenatide once weekly or liraglutide during the 6-month follow-up period.

ANG1005 for breast cancer brain metastases: correlation between 18F-FLT-PET after first cycle and MRI in response assessment.

PURPOSE: Improved therapies and imaging modalities are needed for the treatment of breast cancer brain metastases (BCBM). ANG1005 is a drug conjugate consisting of paclitaxel covalently linked to Angiopep-2, designed to cross the blood-brain barrier. We conducted a biomarker substudy to evaluate 18F-FLT-PET for response assessment. METHODS: Ten patients with measurable BCBM received ANG1005 at a dose of 550 mg/m2 IV every 21 days. Before and after cycle 1, patients underwent PET imaging with 18F-FLT, a thymidine analog, retention of which reflects cellular proliferation, for comparison with gadolinium-contrast magnetic resonance imaging (Gd-MRI) in brain metastases detection and response assessment. A 20 % change in uptake after one cycle of ANG1005 was deemed significant. RESULTS: Thirty-two target and twenty non-target metastatic brain lesions were analyzed. The median tumor reduction by MRI after cycle 1 was -17.5 % (n = 10 patients, lower, upper quartiles: -25.5, -4.8 %) in target lesion size compared with baseline. Fifteen of twenty-nine target lesions (52 %) and 12/20 nontarget lesions (60 %) showed a ≥20 % decrease post-therapy in FLT-PET SUV change (odds ratio 0.71, 95 % CI: 0.19, 2.61). The median percentage change in SUVmax was -20.9 % (n = 29 lesions; lower, upper quartiles: -42.4, 2.0 %), and the median percentage change in SUV80 was also -20.9 % (n = 29; lower, upper quartiles: -49.0, 0.0 %). Two patients had confirmed partial responses by PET and MRI lasting 6 and 18 cycles, respectively. Seven patients had stable disease, receiving a median of six cycles. CONCLUSIONS: ANG1005 warrants further study in BCBM. Results demonstrated a moderately strong association between MRI and 18F-FLT-PET imaging.