Niklas Bergvall

Relapse rates in patients with multiple sclerosis switching from interferon to fingolimod or glatiramer acetate: a US claims database study.

Background Approximately one-third of patients with multiple sclerosis (MS) are unresponsive to, or intolerant of, interferon (IFN) therapy, prompting a switch to other disease-modifying therapies. Clinical outcomes of switching therapy are unknown. This retrospective study assessed differences in relapse rates among patients with MS switching from IFN to fingolimod or glatiramer acetate (GA) in a real-world setting. Methods US administrative claims data from the PharMetrics Plus™ database were used to identify patients with MS who switched from IFN to fingolimod or GA between October 1, 2010 and March 31, 2012. Patients were matched 1∶1 using propensity scores within strata (number of pre-index relapses) on demographic (e.g. age and gender) and disease (e.g. timing of pre-index relapse, comorbidities and symptoms) characteristics. A claims-based algorithm was used to identify relapses while patients were persistent with therapy over 360 days post-switch. Differences in both the probability of experiencing a relapse and the annualized relapse rate (ARR) while persistent with therapy were assessed. Results The matched sample population contained 264 patients (n = 132 in each cohort). Before switching, 33.3% of patients in both cohorts had experienced at least one relapse. During the post-index persistence period, the proportion of patients with at least one relapse was lower in the fingolimod cohort (12.9%) than in the GA cohort (25.0%), and ARRs were lower with fingolimod (0.19) than with GA (0.51). Patients treated with fingolimod had a 59% lower probability of relapse (odds ratio, 0.41; 95% confidence interval [CI], 0.21–0.80; p = 0.0091) and 62% fewer relapses per year (rate ratio, 0.38; 95% CI, 0.21–0.68; p = 0.0013) compared with those treated with GA. Conclusions In a real-world setting, patients with MS who switched from IFNs to fingolimod were significantly less likely to experience relapses than those who switched to GA.

Persistence with and adherence to fingolimod compared with other disease-modifying therapies for the treatment of multiple sclerosis: a retrospective US claims database analysis

Abstract Objective: Achieving therapeutic goals in multiple sclerosis (MS) requires strict adherence to treatment schedules. This retrospective study analyzed persistence with, and adherence to, fingolimod compared with injectable/infusible disease-modifying therapies (DMTs) in patients with MS. Methods: Patients in the PharMetrics Plus™ US administrative claims database with at least one prescription for, or administration of, fingolimod, glatiramer acetate (GA), interferon (IFN), or natalizumab (index DMT) between October 1, 2010 and September 30, 2011 were included. Patients were naïve to index DMT (no claim in the previous 360 days) and had an MS diagnosis code within 360 days of the first index DMT prescription. Outcomes were persistence, risk of discontinuing index DMT (evaluated by a Cox proportional hazards model), adherence (measured using the medication possession ratio [MPR] and proportion of days covered [PDC] in patients with at least two index DMT prescriptions), and the risk of being non-adherent (MPR <80% and PDC <80%, assessed using a logistic regression model). Results: The study included 3750 patients (fingolimod, n = 889; GA, n = 1233; any IFN, n = 1341; natalizumab, n = 287). Discontinuation rates (fingolimod, 27.9%; GA, 39.5%; IFN, 43.7%; natalizumab, 39.5%; all p < 0.001) and risk of discontinuation were significantly higher (hazard ratios vs fingolimod [95% confidence interval]: GA, 1.75 [1.49–2.07]; IFN, 2.01 [1.71–2.37]; natalizumab, 1.53 [1.22–1.91]) for patients receiving other DMTs compared with fingolimod. The risk of being non-adherent was also lower for patients in the fingolimod cohort than the other treatment cohorts, irrespective of whether non-adherence was defined as MPR <80% (p < 0.05 for all) or PDC <80% (p < 0.05 for GA and IFN). Limitations: As with all studies assessing real-world treatment patterns it is unclear if medications were used as prescribed. Conclusions: In a real-world setting, persistence with, and adherence to, oral fingolimod was higher than for injectable and infusible DMTs.

Comparative effectiveness of fingolimod versus interferons or glatiramer acetate for relapse rates in multiple sclerosis: a retrospective US claims database analysis

Abstract Objective: Disease-modifying therapies, such as fingolimod, interferon (IFN) and glatiramer acetate (GA), have differing effects on relapse rates in patients with multiple sclerosis (MS), but little is known about the real-world differences in relapse rates with these treatments. This retrospective study assessed relapse rates in patients with active MS initiating fingolimod, IFN or GA therapy in a real-world setting. Methods: Using administrative claims data from the US PharMetrics Plus database, we identified previously treated and untreated patients with MS who initiated fingolimod, IFN or GA treatment between 1 October 2010 and 31 March 2011 and had experienced a relapse in the previous year. A claims-based algorithm was used to identify relapses over the persistence period in patients with 540 days of post-index continuous enrolment. A logistic regression model assessed the probability of having at least one relapse and a generalized linear model estimated differences in annualized relapse rates (ARRs). Results: The study enrolled 525 patients (fingolimod, n = 128; combined IFN/GA cohort, n = 397) of the 31,041 initially identified. Similar findings for fingolimod and IFN/GA were observed for the unadjusted proportion of patients experiencing relapses (31.3% vs. 34.0%, respectively; p = 0.5653) and ARRs (0.50 vs. 0.55, respectively) while persistent to treatment. After adjusting for baseline differences, fingolimod was associated with a 52% reduction in the probability of having a relapse (odds ratio, 0.48; 95% confidence interval [CI], 0.28–0.84; p = 0.0097) and a 50% reduction in ARR (rate ratio, 0.50; 95% CI, 0.34–0.75; p = 0.0006) compared with IFN/GA. Limitations: Identification of relapses is based on the claims in the database rather than on a clinical assessment. Conclusions: In a real-world setting, fingolimod was shown to be associated with significantly lower relapse rates than IFN/GA in patients with MS who had a history of relapses.

Healthcare resource use and relapses with fingolimod versus natalizumab for treating multiple sclerosis: a retrospective US claims database analysis

Abstract Objective: Healthcare resource utilization in patients with multiple sclerosis (MS) is linked to relapses and disease progression. This retrospective cohort database analysis compared healthcare resource use and proxy measures of relapse outcomes in patients with active disease who switched to fingolimod or natalizumab. Methods: Using administrative claims data from the US PharMetrics Plus database, we identified patients with an MS diagnosis and a claim for fingolimod or natalizumab between 1 October 2010 and 30 June 2012 (index period) who had experienced a relapse (identified using a claims-based algorithm) and used other disease-modifying therapies (DMTs) in the previous year. Patients in the fingolimod and natalizumab cohorts were propensity score matched (1:1). MS-related inpatient stays, corticosteroid use and the proportion of patients experiencing claims-based relapses were assessed in the pre-index and post-index persistence periods. Time to first claims-based relapse in the post-index persistence period was assessed using a Kaplan–Meier curve. Results: The study included 623 unmatched patients (299 and 324 patients in the fingolimod and natalizumab cohorts, respectively) and 370 matched patients (185 in each cohort). In the matched analysis, MS-related inpatient stays and corticosteroid use were similar in the fingolimod and natalizumab cohorts during the post-index persistence period, and were significantly reduced versus the pre-index period (p < 0.01). A similar proportion of patients in the fingolimod and natalizumab cohorts were free from claims-based relapses in the persistence period (68.1% and 68.6%, respectively). There was no significant difference in the likelihood of experiencing a claims-based relapse (p = 0.8696). Limitation: Identification of relapses is based on database claims rather than on clinical assessment. Conclusions: In analyses of patients with MS with a history of relapse and DMT use, fingolimod and natalizumab reduce healthcare resource utilization and have similar effectiveness in a real-world setting.

Efficacy of fingolimod in patients with highly active relapsing–remitting multiple sclerosis

Abstract Objective: There is a need to identify effective switch therapies for patients with relapsing–remitting multiple sclerosis (RRMS) who experience high disease activity despite receiving disease-modifying therapy (DMT). The objective of this study was to assess the efficacy of fingolimod versus placebo in patients with RRMS who had experienced high disease activity despite previously receiving DMT, using post hoc analyses of two phase 3 trials: FREEDOMS (NCT00289978) and FREEDOMS II (NCT00355134). Research design and methods: Clinical and magnetic resonance imaging outcomes over 24 months were analyzed in patients from FREEDOMS and FREEDOMS II who had received treatment in the previous year and had: (1) ≥1 relapse in the previous year and either ≥1 gadolinium (Gd) enhancing T1 lesion or ≥9 T2 lesions at baseline and/or (2) as many or more relapses in the year before baseline as in the previous year (as per fingolimod’s EU label). Main outcome measures: The inclusion criteria were fulfilled by 249 and 257 patients in the fingolimod and placebo groups, respectively. Annualized relapse rates were reduced by 48% for fingolimod versus placebo (p < 0.001). Fingolimod reduced the risk of 3 month and 6 month confirmed disability progression by 34% (p = 0.031) and 45% (p = 0.016), respectively, versus placebo. Brain volume loss was reduced by 46% for fingolimod versus placebo (p < 0.001). The reduction in Gd-enhancing T1 lesion counts for fingolimod versus placebo was 65% (p < 0.001). Furthermore, fingolimod reduced the number of new or newly enlarged T2 lesions by 69% relative to placebo (p < 0.001). Limitation: The analyses are post hoc, but the population is specified by the European Medicines Agency in the label for fingolimod. Conclusions: Fingolimod demonstrated efficacy across all four key RRMS disease measures analyzed in patients with high disease activity despite previous DMT.

Cost-utility of fingolimod compared with dimethyl fumarate in highly active relapsing-remitting multiple sclerosis (RRMS) in England

Abstract Objective: The cost-effectiveness of new oral disease-modifying therapies (DMTs) has not been modeled in highly active (HA) relapsing-remitting multiple sclerosis (RRMS) requiring escalation therapy. This study sought to model the cost-effectiveness of fingolimod compared to dimethyl fumarate (DMF), for which relevant HA RRMS sub-group data were available, from the perspective of the National Health Service (NHS) in England. Methods: A cohort Markov model based on Expanded Disability Status Scale scores, similar to previous model designs, was constructed. Published post hoc clinical data in the HA RRMS sub-groups were taken from the pivotal trials for fingolimod and DMF vs placebo. Utility data for each health state and for relapses were used in line with previous similar models. Published costs were inflated to NHS cost year 2013–2014 and UK list prices used for both drugs. Possible Patient Access Scheme (PAS) discount scenarios were investigated. Results: In the base case, using list prices for each DMT, the average probabilistic incremental cost-effectiveness ratio (ICER) for fingolimod vs DMF was found to be £14,076, with a 73% chance of fingolimod being cost-effective at a willingness-to-pay threshold of £30,000. Scenario and sensitivity analyses showed that uncertainty in disability progression efficacy was a key model driver. The model was robust to other changes and the majority of PAS permutations do not contradict the base case finding of cost-effectiveness of fingolimod. Conclusions: In conclusion, fingolimod remains cost-effective in HA RRMS following the introduction of DMF to the UK market, and this paper supports the evidence that has led fingolimod to be the only oral DMT reimbursed for HA RRMS in England. This model supports the restriction imposed by National Institute for Health and Care Excellence (NICE) on DMF in HA RRMS and highlights the importance of considering different sub-groups of multiple sclerosis when performing health economic analyses.

Cost-minimization analysis of fingolimod compared with natalizumab for the treatment of relapsing–remitting multiple sclerosis in Sweden

Abstract Background: Fingolimod and natalizumab have the same European Union licence for the treatment of relapsing multiple sclerosis, and are considered by the Committee for Medicinal Products for Human Use (CHMP) to have broadly similar efficacy. Objective: A cost-minimization analysis was performed to compare differences in treatment costs between fingolimod and natalizumab from a societal perspective in Sweden. Methods: This analysis included costs associated with initiating and following treatment (physician visits and monitoring), continuing therapy (drugs and administration), and lost patient productivity and leisure time. Unit costs (in Swedish krona [SEK]) were based on regional data (median prices for physician visits and monitoring sessions). Natalizumab infusion costs were obtained from the national cost-per-patient database. Drug costs for both therapies were 15,651 SEK/28 days. Results: After 3 years, fingolimod use was associated with savings of 124,823 SEK/patient compared with natalizumab (total cost/patient: 566,718 SEK vs 691,542 SEK). Cost savings with fingolimod were 40,402 SEK/patient after 1 year and 301,730 SEK/patient after 10 years. Treatment with natalizumab was 18% more expensive than fingolimod therapy after 1 year and 23% more expensive after 10 years. Limitations: Based on the CHMP assessment, it was assumed that fingolimod and natalizumab have similar efficacy. The analysis was conducted for Sweden, and caution is needed in extrapolating the results to other countries. Conclusion: Fingolimod is cost-saving compared with natalizumab for the treatment of relapsing–remitting multiple sclerosis in Sweden.

Confirmed Disability Improvement In Patients With Active Multiple Sclerosis Treated With Fingolimod Versus Brace: A Matched Comparison of Treatments From The Pangaea And Pearl Registry Studies

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Re: Hutchinson M, Fox RJ, Havrdova E, et al. Efficacy and safety of BG-12 (dimethyl fumarate) and other disease modifying therapies for the treatment of relapsing-remitting multiple sclerosis: a systematic review and mixed treatment comparison. Curr Med Res Opin 2014;30:613-27.

In this recent article published in CMRO, Hutchinson et al. conducted network meta-analyses between BG-12 (dimethyl fumarate) and other disease-modifying treatments (DMTs) and concluded: ‘‘Based on the cumulative evidence on efficacy and safety, the BG-12 benefit to risk ratio in RRMS can be considered more favorable than that of IFNs, GA, and teriflunomide, and superior to that of fingolimod’’. This statement is, at best, misleading as such a statement is normally the conclusion of a formal benefit–risk assessment that was not performed as part of this manuscript. ‘‘A holistic review of the analyzed safety outcomes suggests that BG-12 has the potential to reduce treatment burden by reducing some highly prevalent events associated with existing therapies such as injection-site reactions with injectable therapies and cardiac events for fingolimod, although BG-12 is associated with gastrointestinal and skin flushing events’’. This conclusion cannot be connected to the results of the manuscript as ‘cardiac events’ was not part of the analyses and results. We therefore find that the methodologies used do not address the study objectives. Furthermore, and most importantly, the conclusions are not substantiated by the performed analyses, are actually a misrepresentation of the results, and therefore misleading to the scientific community and patients. A summary of concerns are summarized below and address concerns on both the safety and efficacy analyses performed.