cronicità e la progressione della malattia con ricadute e disabilità crescente incidono sulla qualità di vita del paziente e sui costi per la società. L'esordio della malattia nella fase giovaneadulta coincide con il pieno della vita affetIntroduzIone L'organizzazione mondiale della sanità (OMS) ha definito la sclerosi multipla (SM) una delle malattie sociali maggiormente costose. L'esordio nella fase giovane-adulta, la AbstrActBACKGROUND: Peginterferon beta-1a is indicated in adult patients for the treatment of relapsing remitting multiple sclerosis (RRMS). The efficacy and safety of peginterferon beta-1a was demonstrated in the placebo-controlled ADVANCE trial. OBJECTIVE: The objective of this study was to assess the cost-effectiveness of peginterferon beta-1a as compared with injectable first-line treatments for RRMS in Italy. METHODS: The cost-effectiveness analysis was developed through a Markov model with lifetime simulation in the perspective of the Italian National Healthcare Service (NHS). It was added an alternative scenario to take into account the Italian societal perspective. Outcomes were measured in terms of life years (LYs), quality adjusted life years (QALYs), lifetime costs and incremental cost-effectiveness ratio (ICER). The natural progression of the disease was informed by the published literature and previously published modelling exercises. The efficacy of treatments was simulated as reduction of disability progression (EDSS) and relapse rate. Efficacy data were derived from a published network meta-analysis. Unit costs were based on current prices and tariffs, and the published literature. A 3.5% discount rate was applied to costs and outcomes. One-way and probabilistic sensitivity analyses were developed and cost-effectiveness acceptability curves generated. RESULTS: Peginterferon beta-1a was more effective than the comparators in terms of survival (19.94 vs.19.68-19.81 discounted LYs, respectively), and QALYs (9.07 vs. 8.06 and 8.55 discounted QALY, respectively). In the perspective of the Italian NHS, the ICER was € 11,111/QALY vs. interferon beta-1a 30 µg, € 12,604/QALY vs. interferon beta-1a 22 µg, € 10,580/QALY and € 16,702/QALY vs. interferon beta-1b 250 µg and € 22,023/QALY vs. glatiramer acetate 20 mg. Peginterferon beta-1a dominated interferon beta-1a 44 µg. In the societal perspective, peginterferon beta-1a was dominant due to being more effective and with a lower social cost compared to first-line injectable treatments (interferon beta -1a, interferon beta-1b, glatiramer acetate) for RRMS. The outcomes of the sensitivity analyses confirmed the trend of the base case results. CONCLUSIONS: Peginterferon beta-1a shows a favourable pharmaco-economic profile for the treatment of RRMS. Even if an official threshold for the cost-effectiveness does not exist in Italy, the ICER values obtained were far below the commonly accepted thresholds (30,000-50,000 €/per QALY gained). Keywords Cost-effectiveness; Peginterferon beta-1a; Multiple SclerosisAnalisi di costo-efficacia dell'utilizzo ...

to disability progression rate. ConClusions: The incremental cost effectiveness ratio of 17.433 € is considerably below the threshold usually accepted for financing medicines in Portugal (around 30.000 € /QALY). Dimethyl Fumarate should be seen as a cost-effective therapy for the Portuguese setting. PND57Cost-EffECtivENEss ANAlysis of PEgiNtErfEroN BEtA-1A iN itAliAN rElAPsiNg rEmittiNg multiPlE sClErosis mANAgEmENt

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with a very high economic impact. Peginterferon beta-1a is the first approved pegylated interferon beta-1a for the treatment of relapsing-remitting multiple sclerosis (RRMS). Its efficacy and safety were demonstrated in the placebo-controlled ADVANCE trial. A complete path to the assessment of a new health technology requires, in addition to a clinical evaluation, also an economic evaluation. In Italy, two economic evaluations were conducted and recently published. The objective of this article is focused on the two Italian economic analyses in order to describe the methods used, to summarize the main results, and to give a comprehensive picture of the pharmacoeconomic profile of peginterferon beta-1a in Italy in approved indication. The two analyses were conducted to evaluate such profile; the former was a cost-effectiveness analysis, the latter was a budget impact analysis:1) The cost-effectiveness analysis -developed through a lifetime Markov model -compared peginterferon beta-1a with injectable first-line treatments for RRMS in Italy from the perspective of the Italian National Healthcare Service (NHS) and from the societal perspective. Efficacy data were derived from a published Network Meta-analysis. Unit costs were based on current prices and tariffs, and the published literature. From the Italian NHS perspective, peginterferon beta-1a was dominant in one case, while in all others its incremental cost-effectiveness ratio (ICER) was between €10,580/QALY and €22,023/QALY. From the societal perspective, peginterferon beta-1a was dominant versus every comparator.2) The budget impact analysis estimated -using a simple decision analytic model from the perspective of the Italian NHS -the financial impact due to the introduction of peginterferon beta-1a on the Italian drug market. The cumulative budget impact over 3 years was a cost saving of approximately €3.1 million. Based on the results of both analyses, the adoption of peginterferon beta-1a for the treatment of RRMS is not only clinically effective, but also economically efficient and financially sustainable from the Italian NHS perspective.

cinetica e la farmacodinamica mediante l'aumento dell'idrosolubilità, la riduzione della clearance renale e la riduzione della tossicità. È anche in grado di conferire maggior stabilità rispetto alle variazioni di pH e di temperatura. Tali vantaggi risultano particolarmente rilevanti ai giorni nostri, dal momento che sono sempre di più i polipeptidi approvati e in studio per l'uso clinico e che spesso il loro principale difetto consiste nella suscettibilità alla distruzione da parte di enzimi proteolitici, nella bassa emivita e bassa durata di conservazione, nella bassa solubilità, nella rapida clearance renale e nella tendenza a causare la produzione di anticorpi neutralizzanti [2]. La pegiLazioneLa pegilazione è un processo chimico che si realizza legando covalentemente una molecola di polietilenglicole (PEG) a un farmaco (Figura 1). Il polietilenglicole è una molecola approvata per l'utilizzo come additivo in cibi, cosmetici e prodotti farmaceutici (vedi Tabella I per gli utilizzi di PEG approvati). Il suo metabolismo e la sua escrezione sono stati studiati approfonditamente e sono ben compresi negli animali e nell'uomo, nel quale non sono state riportate tossicità renali critiche [1]. Per le dosi generalmente utilizzate in campo farmaceutico l'indice terapeutico è piuttosto ampio, di circa 600 volte, pertanto non è considerata una molecola tossica né immunogenica per l'uomo [1]. Il suo uso è approvato anche da solo sotto forma di idrogel per la cicatrizzazione delle ferite [2]. Sin dagli anni Settanta gli studi di Frank Davis [3] hanno dimostrato che la pegilazione di proteine è in grado di migliorarne la farmaco- Figura 1. Una molecola di polietilenglicole (PEG) Corresponding author Diego Centonze centonze@uniroma2.it DisclosureIl presente supplemento è stato supportato da Biogen Italia. Gli autori hanno avuto il completo controllo editoriale del manoscritto e hanno approvato tutti i contenuti abstract Pegylation is a procedure used for drug development since the 1970s and consists of the conjugation of a polyethylene glycol molecule (PEG) to a drug. PEG has shown to be safe and effective in improving the pharmacokinetic and pharmacodynamic profile of drugs. Recently, a 20 kDa linear chain of PEG was conjugated to interferon beta-1a with the aim to offer a new treatment option to relapsing-remitting multiple sclerosis (RRMS) patients. Due to a prolonged bioavailability, this new drug can be administered less frequently (every two weeks) than the other interferons beta available, thus allowing to hypothesize a better adherence to the treatment, which, in turn, should result in better clinical and economic outcomes. A phase III clinical trial has proven its effectiveness compared to placebo in RRMS patients, as well as a safety profile comparable to that found in other interferon beta preparations. The immunogenicity of this new molecule is < 1%, thus minimizing the suppression or reduction of interferon beta biological activity that could come from the development of Neutralizing Antibodies (NAbs).

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BACKGROUND: Peginterferon beta-1a, injected every two weeks, is the first approved pegylated interferon beta-1a for the treatment of relapsing remitting multiple sclerosis (RRMS). The objective of this analysis was to estimate the economic impact due to the introduction of peginterferon beta-1a in Italy.METHODS: This analysis was conducted with a three-year time horizon with the support of a simple decision-analytic model adopting the perspective of the Italian National Healthcare Service (NHS). Healthcare costs sustained by the Italian NHS to manage the RRMS population (drug treatment, monitoring, relapse management, adverse events management) were calculated over 3 years and compared in two scenarios: the base scenario where interferons-beta and glatiramer acetate (GA) are used to treat RRMS patients, and an alternative scenario where peginterferon beta-1a can also be used to treat RRMS patients. The target population was approximately 35,500, 37,500 and 39,500 patients at year 1, 2 and 3 respectively, based on the published literature and market data. The efficacy of treatments was simulated as a reduction of relapse rates and was derived from a Network Meta-analysis. Unit costs were based on current prices and tariffs, and the published literature. A one-way sensitivity analysis was developed.RESULTS: According to current price and described assumptions, it was estimated that the introduction of peginterferon beta-1a would result in a decrease of total costs when compared with the base scenario. The cost in the base scenario was estimated to be  € 321.5, € 339.7 and € 357.8 million in years 1, 2, and 3, respectively. In the alternative scenario, the same costs resulted in about € 321.1, € 338.6 and € 356.2 million, respectively. The cumulative budget impact over three years period was approximately a cost saving of € 3.1 million (about 0.3% saving).CONCLUSION: The adoption of peginterferon beta-1a for the treatment of RRMS would be viewed as economically sustainable by the Italian NHS.[Article in Italian]

background Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system, is causing a progressive disability that impacts patients' quality of life and societal costs [1]. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing form) or building up over time (progressive form) [2]. Between attacks, symptoms may disappear completely; however, permanent neurological problems often remain, especially as the disease advances [2]. In 85% of patients with MS the onset form is relapsing-remitting MS (RRMS) [3]. While MS is currently considered incurable, treatment has advanced significantly over the past several decades. Disease modifying therapies (DMTs) can reduce the frequency of clinical relapses and delay disability progression [4]. As is the case in many different therapeutic areas, clinical progress in treating the disease has accompanied a rise in costs to purchase biologic products. In this light, economic evaluations are key elements for healthcare decision-making.In 2016 we published in this journal a cost-effectiveness analysis that compared subcutaneous peginterferon beta-1a 125 μg every 2 weeks (Plegridy ® ) to the other injectable DMTs used in first-line therapy of RRMS from both the perspective of the Italian National Healthcare Service (NHS) and of the Italian Society [5]. The comparators considered in the analysis were: interferon (IFN) beta-1a 30 μg (Avonex ® ), IFN beta-1a 22 μg (Rebif ® 22), IFN beta-1a 44 μg (Rebif ® 44), glatiramer acetate (GA, Copaxone ® ) 20 mg, IFN beta-1b 250 μg (Betaferon ® and Extavia ® ). The 2016 analysis showed that peginterferon beta-1a was an alternative dominant or cost-effective vs IFNs and GA for the treatment of RRMS in Italy from the NHS and societal perspectives. While the design of the model and the choice of clinical parameters remains well aligned with the most recent cost-effectiveness studies published in the literature [6], some economic inputs of that analysis appear now outdated. The objective of the current work is thus to provide an update of the original analysis [5].

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