Cost-effectiveness analysis of escalating to natalizumab or switching among immunomodulators in relapsing-remitting multiple sclerosis in Italy

Furneri et al. BMC Health Services Research https://doi.org/10.1186/s12913-019-4264-1 (2019) 19:436 RESEARCH ARTICLE Open Access Cost-effectiveness analysis of escalating to natalizumab or switching among immunomodulators in relapsing-remitting multiple sclerosis in Italy Gianluca Furneri1* , Laura Santoni2, Chiara Ricella2 and Luca Prosperini3 Abstract Background: Published literature suggests that early treatment with natalizumab (“escalation strategy”) is more effective than switch within the same class of immunomodulators (interferons/glatiramer acetate, “switching strategy”) in relapsing-remitting multiple sclerosis (RRMS) patients who failed first-line self-injectable diseasemodifying treatment (DMT). The present analysis aims to evaluate the cost-effectiveness profile of escalation strategy vs. switching strategy, adopting the Italian societal perspective. Methods: A lifetime horizon Markov model was developed to compare early escalation to natalizumab vs. switching among immunomodulators, followed by subsequent escalation to natalizumab. The two compared treatment algorithms were: a) early escalation until progression to Expanded Disability Status Scale (EDSS) = 7.0 vs. b) switching until EDSS = 4.0, followed by escalation until EDSS = 7.0. The model analyzed social costs, qualityadjusted survival and effects of therapies in prolonging time without disability progression and burden of relapses. Clinical data were mainly extracted from a published observational study. Results: Lifetime costs of early escalation to natalizumab and switching among immunomodulators amounted to €699,700 and €718,600 per patient, respectively. Early escalation was associated with prolonged quality-adjusted survival (11.19 vs. 9.67 QALYs, + 15.8%). A slight overall survival increase was also observed (20.10 vs. 19.67 life years). Both deterministic and probabilistic sensitivity analyses confirmed the robustness of findings. Conclusions: Adopting the Italian social perspective, early escalation to natalizumab is dominant vs. switching among immunomodulators, in RRMS patients who do not respond adequately to conventional immunomodulators. Keywords: Multiple sclerosis, Natalizumab, Glatiramer acetate, Interferon-beta, Cost-effectiveness, Markov Background Multiple Sclerosis (MS) is a chronic condition, affecting young adults in the active working phase, with a significant economic and social burden [1, 2]. In most cases, patients with relapsing-remitting MS (RRMS) suffer from episodes of neurological deterioration (relapses), between periods of complete or partial remission. Transition to secondary progressive multiple sclerosis (SPMS), with or without superimposed relapses, can occur after an initial relapsing-remitting (RR) phase, * Correspondence: 1 EBMA Consulting, Melegnano (Milan), Italy Full list of author information is available at the end of the article leading to accumulation of irreversible disability [3]. Optimal treatment strategy then aims to minimize the occurrence of relapses and prolong the time to disability progression. As first-line treatment, RRMS patients can receive self-injectable disease-modifying treatments (DMTs), namely interferon beta (IFN) or glatiramer acetate (GA). However, a significant proportion of patients experience disease activity despite first-line DMT treatment [4]. At this stage, neurologists can decide whether switching treatment to another immunomodulator (i.e. from GA to IFN, or vice versa, or from a lower to a higher dose and/or more frequently administered IFN, hereafter called “switching strategy”) or initiating © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Furneri et al. BMC Health Services Research (2019) 19:436 treatment with second-line therapy (i.e. from GA or IFN, to a high-efficacy DMT such as natalizumab, hereafter called “escalation strategy”) [5]. Several studies have shown that escalating to second-line therapy is more effective than switching [6, 7]. Although this evidence supports escalation from a clinical perspective, prescription of second-line treatment could lead to a relevant increase of therapeutic costs, being second-line options more expensive than first-line immunomodulators. Therefore, the economic investment for escalation should be measured against the incremental clinical benefit over switching. This analysis aims to evaluate cost-effectiveness of early escalation to natalizumab vs. switching among immunomodulators, followed by late escalation to natalizumab, in patients affected by RRMS who have failed first-line treatment with either IFNs or GA [6], adopting the Italian Societal perspective. Method Design and parameters The present analysis is an economic elaboration of a previously published clinical study, conducted by Prosperini et al. [6]. Patients enrolled in this study had > 2 relapses, or 1 relapse associated with sustained disability worsening while receiving first-line DMT for at least 1 year, according to the past Italian Medicine Agency rules for escalation to natalizumab [8, 9]. In the study, patients who failed first-line therapy with one of the available IFNs or GA were split into two groups: patients Fig. 1 Scheme of the Markov model [15] Page 2 of 9 switching among different IFN formulations, or from IFN to GA, or vice versa (switching strategy, SWI); patients receiving natalizumab (escalation strategy, ESC). Duration of follow-up was 24 months. At the end of the study, a larger proportion of patients were free from relapse (p < 0.0001), disability progression (p = 0.0045), magnetic resonance (MRI) activity (p = 0.0003), and combined activity (p < 0.0001), in the ESC group than in the SWI group. The findings of this study were used to develop a Markov model (Fig. 1) projecting the clinical and economic outcomes of ESC vs. SWI over a lifetime horizon (50 years) and comparing two treatment strategies: i) early escalation (ESC), in which patients were treated with natalizumab until Expanded Disability Status Scale (EDSS) = 7.0 was reached [10]; ii) switching (SWI), in which patients received IFN/GA until EDSS = 4.0, and then were switched to natalizumab (late escalation) and treated until EDSS = 7.0 was reached. No efficacy waning effects were modelled for natalizumab (over time), consistently with the findings of a large real-world, observational, prospective study of patients with RRMS, showing that the risk of disability pro (...truncated)