We estimated the long-term risks and benefits of disease modifying therapies. Benefits were favored by natalizumab with minimal increased risks in the negative anti-JC virus population.
Published Online: April 19, 2013
Jonathan D. Campbell, PhD; R. Brett McQueen, PhD; Augusto Miravalle, MD; John R. Corboy, MD; Timothy L. Vollmer, MD; and Kavita Nair, PhD
Objectives: To estimate the long-term comparative effectiveness of first-line treatment in patients negative for anti-JC virus (JCV) antibodies with glatiramer acetate (GA), fingolimod, or natalizumab for relapsing-remitting multiple sclerosis (RRMS).
Study Design: We developed a simulation model to estimate the average 20-year clinical risks and benefits of GA, fingolimod, and natalizumab for RRMS patients initially negative for anti-JCV antibodies.
Methods: Model inputs included published natural history progressions of the Expanded Disability Status Scale (EDSS), treatment effects from randomized controlled trials on slowing disease progression and reducing relapse rates, risk of progressive multifocal leukoencephalopathy (PML), and utility preference scores. Outputs were long-term risks (PML risk and other non-PML risks), benefits (average relapse rate and time to disability [EDSS >7]), and quality-adjusted lifeyears (QALYs).
Results: Compared with GA, natalizumab resulted in 4.6 fewer relapses, 0.6 more years of disabilityfree time, 0.0165 more cases of PML per treated patient, and an incremental 1.2 QALYs gained. Compared with fingolimod, natalizumab resulted in 1.7 fewer relapses, 0.1 more years of disabilityfree time, 0.0165 more cases of PML per treated patient, and an incremental 0.4 QALYs gained. The probability that incremental QALYs favored natalizumab over GA was 0.963 and natalizumab over fingolimod was 0.720.
Conclusions: Average QALYs, a measure that aggregates across risks and benefits, favored natalizumab, suggesting more aggressive early intervention with natalizumab in the negative anti-JCV population. For certain decision makers, more evidence may be needed to further reduce the uncertainty in these comparative projections prior to making population-based adoption decisions.
Am J Manag Care. 2013;19(4):278-285
Long-term clinical benefits were favored by natalizumab with minimal increased risks in the negative anti-JC virus population.
Average quality-adjusted life-years, a measure that aggregates across risks and benefits, favored natalizumab, suggesting more aggressive early intervention with natalizumab in the negative anti-JC virus population.
In the absence of long-term trials, we used traditional and standardized methodology from the cost-effectiveness field to quantify comparative effectiveness research goals.
Comparative effectiveness models like this may be used to provide projections about long-term risks and benefits in many different patient subpopulations, estimate the uncertainty in the comparative findings, and guide the design of future evidence generation.
Multiple sclerosis (MS) is a chronic and morbid condition of the central nervous system. Recent US approval of disease- modifying therapies (DMTs) including fingolimod and natalizumab for relapsing-remitting MS (RRMS) provide new options for the management of the disease. The ultimate treatment goal of any DMT is to delay or prevent the long-term disability of MS while minimizing DMT-related risks. This long-term treatment goal often remains untested in randomized controlled trials.1,2
Randomized controlled trials of DMTs in RRMS lack evidence of long-term clinical benefits and risks, as follow-up periods are typically limited to 1 to 2 years. Markov models are commonly used to project the long-term cost-effectiveness of DMTs for RRMS.3-10 Thompson and colleagues used a Markov model to examine the long-term risk-benefit or comparative-effectiveness of natalizumab as compared with interferon beta-1-alpha prior to available evidence on the risk stratification of patients treated with natalizumab.11
Natalizumab treatment based on post-marketing surveillance is associated with a risk of progressive multifocal leukoencephalopathy (PML) of 2.13 per 1000 patients treated per year.12 PML is often a fatal viral disease characterized by progressive inflammation and damage to the white matter.13 PML is caused by a pathogenic form of the JC virus (JCV).12 The increased risk of PML has limited natalizumab’s use as a first-line DMT in RRMS. A 2-step assay was developed for detecting and confirming the presence of anti-JCV antibodies in human serum and plasma.14 As described in the January 2012 revised natalizumab US Food and Drug Administration (FDA) label,15 this assay can stratify the risk of PML for prospective natalizumab patients where the majority of PML risk falls on approximately 55% of RRMS patients who test positive for anti-JCV antibodies.13 The ability to stratify prospective natalizumab patients by JCV status gives rise to the following question: should natalizumab be considered first-line therapy for JCV-negative patients?
There is a need to fill critical gaps in the comparative effectiveness of DMTs for RRMS to facilitate clinical decision making. Available evidence suggests the ability to minimize PML risk for natalizumab by targeting negative anti-JCV antibody patients. Further, the long-term risks and benefits associated with natalizumab treatment should be compared with other DMTs, including fingolimod, the first oral DMT approved by the FDA in 2010. Our objective was to estimate the long-term comparative effectiveness of first-line treatment in RRMS patients initially negative for anti-JCV antibodies with glatiramer acetate (GA), fingolimod, or natalizumab.
We created a Markov simulation model spreadsheet that followed good practices for decision analytic modeling in health technology evaluations.16 We used this model to project the long-term clinical benefits, risks, and quality-adjusted life-years (QALYs) of a cohort of RRMS patients negative for anti-JCV antibodies who were DMT treatment–naïve and had begun treatment with GA, fingolimod, or natalizumab (Figure 1). We selected GA as a representative of standard first-line agents because it is a market leader in the United States and 3 head-to-head trials comparing GA with interferons suggest no significant difference in clinical efficacy.17-19
We simulated a cohort of patients who progressed through health states defined by the Expanded Disability Status Scale (EDSS).20 Each year, patients could remain in their current EDSS state, progress to the next EDSS state, experience PML (for natalizumab-treated patients), or experience death due to all other causes. EDSS states were in 0.5 increments between 0 and 10 (no EDSS state of 0.5 existed and an EDSS of 10 was death due to MS). In all EDSS states, patients could experience an MS relapse or not experience a relapse during each yearly cycle.
This research was considered exempt by the Colorado Multiple Institutional Review Board.
We made the following model assumptions:
• During a 1-year cycle, patients could not improve in terms of their EDSS state (patients could not transition to a lower EDSS state).
• Patients were measured over a 20-year time period (consistent with a prior risk-benefit model).11
• The average starting age was 30 years (consistent with DMT clinical trials and prior models).1,8,11
• There was a 0% discount rate for future years of life (cost-effectiveness models typically discount future costs and clinical consequences at 3% per year in order to estimate the net present value of costs and consequences). Since our objective was to project the findings in clinical terms (comparative effectiveness, not cost-effectiveness) over the 20-year time horizon, a 0% discount rate was warranted. The 0% discount rate is synonymous with projecting 20-year survival (with quality adjustment) and therefore holds more face validity than discounting survival for this clinical objective.
• The average clinical efficacy for patients negative or positive for anti-JCV antibodies would be the same as observed from clinical trials.
• There was a 2% annual seroconversion risk of JCVnegative to JCV-positive status over the 20 years,14 and constant annual risk of PML from years 2 to 20 (PML incidence is shown to be constant from 2 to 6 years of natalizumab exposure time).12
• There was no prior immunosuppressant use in those that seroconverted to JCV-positive status (immunosuppressant therapy in combination with JCV-positive status is associated with higher risk of PML, but 90.4% to 97.3% of patients followed in large MS cohort studies do not have prior immunosuppressant use).12
• There was no additional risk of cardiac or other death risk related to fingolimod.
• Equal effect on relapse rate and EDSS changes regardless of relapse rate or EDSS level at outset, ie, clinical effectiveness is the same for individuals with less or more severe disease.
• Continuous treatment with each agent, and no switching to an alternative agent over time, regardless of clinical change.
RRMS Natural History Projections
The London, Ontario, Canada, MS cohort study tracked the 25-year progression of RRMS patients prior to DMTs (best supportive care only).21 Best supportive care in the London, Ontario, cohort was defined as symptom control, physiotherapy, psychiatric and social support, and disability aids. A patientlevel analysis of the London, Ontario, MS cohort was done by Tappenden and colleagues for the purposes of estimating EDSS initial state distribution, as well as the EDSS transitions for best supportive care.7 Tappenden and colleagues combined the information from the London, Ontario, cohort on best supportive care with other literature sources to estimate the cost-effectiveness of beta interferons and GA compared with best supportive care.7 We used Tappenden’s EDSS initial state distribution for all comparators, as well as the EDSS transitions for best supportive care as a foundation for EDSS transitions of DMTs added on to best supportive care, eAppendices A7 and B,7 available at www.ajmc.com).
The initial EDSS state distribution was consistent with DMT RCTs for GA, fingolimod, and natalizumab. Approximately 88% of patients in the model started in EDSS states 0 through 2.5 (minimal to mild disability) for all DMT scenarios. The average EDSS scores in previous RCTs of DMTs are in the 2 to 3 range.1,22 We used the National Center for Health Statistics estimates for the annual gender- and agespecific all-other cause mortality.23
We used relapse rates specific to EDSS state for best supportive care that were consistent with Tappenden and colleagues from the Patzold data9,24 (eAppendix C9). Patzold and colleagues reported relapse rates for best supportive care over a 19-year time period and showed that relapses decreased with increased disease exposure. We tested the validity of the modeled relapse rates by comparing the 1- and 2-year projected average annual relapse rates of best supportive care with that of the placebo arms of a natalizumab RCT.1
DMT Projections—Modeling Treatment-Specific Risks and Benefits
We compared 3 DMT strategies: GA 20-mg subcutaneous administration daily, fingolimod 0.5-mg oral (pill) administration daily, and natalizumab 300-mg intravenous administration every 4 weeks. We used the relative changes in relapse rates and EDSS progression from the pivotal RCTs for GA versus placebo,25 fingolimod versus placebo,22 and natalizumab versus placebo26 (Table 19,12,22,25-27). Due to a concern that the underlying risk of relapses may have decreased over calendar time, we modeled relative changes in risks because relative changes are thought to be more robust across ranges of underlying risk.28
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