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Effectiveness and safety of switching to teriflunomide in older patients with relapsing multiple sclerosis: A real-world retrospective multicenter analysis
Real-world data offer insight into teriflunomide use in older patients with RMS.
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Switching to teriflunomide from other DMTs significantly improved ARR over 2 years.
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EDSS scores were stable and most had stable or improved MRI outcomes to year 2.
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Teriflunomide had an acceptable safety profile in older patients with RMS.
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Percentage of patients with lymphopenia declined at years 1 and 2 post-index.
Abstract
Background
The prevalence of multiple sclerosis (MS) in older people is increasing due to population aging and availability of effective disease-modifying therapies (DMTs). Treating older people with MS is complicated by age-related and MS-related comorbidities, immunologic effects of prior DMTs, and immunosenescence. Teriflunomide is a once-daily oral immunomodulator that has demonstrated efficacy and acceptable safety in clinical trials of adults with relapsing forms of MS (RMS). However, there are limited clinical trial and real-world data regarding teriflunomide use in people with MS aged >55 years. We analyzed real-world data to assess the effectiveness and safety of teriflunomide in older people with RMS who had switched to this agent from other DMTs.
Methods
People with RMS (relapsing remitting and active secondary progressive MS) aged ≥55 years who had switched from other DMTs to teriflunomide (7 mg or 14 mg) for ≥1 year were identified retrospectively by chart review at four sites in the United States. Data were extracted from medical records from 1 year pre-index to 2 years post-index (index defined as the teriflunomide start date). Assessments of effectiveness included annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging (MRI) outcomes. Assessments of safety included lymphocyte counts, infections, and malignancies. We examined the effectiveness outcomes and lymphocyte counts within sub-groups defined by age (55–64, ≥65 years), sex, MS type, and prior route of DMT administration (oral, injectable, infusible).
Results
In total, 182 patients with RMS aged ≥55 years who switched from other DMTs to teriflunomide were identified (mean [SD] age: 62.5 [5.4] years). Mean ARR decreased from the start of teriflunomide treatment (mean [SD]: 0.43 [0.61]) to year 1 post-index (0.13 [0.65]) and year 2 post-index (0.05 [0.28]). Mean EDSS score remained unchanged from index (mean [SD]: 4.5 [1.8]) to 1 year post-treatment (4.5 [1.8]) and increased slightly at 2 years post-treatment (4.7 [1.7]). MRI scans from index and years 1 and 2 post-index compared with scans from the previous year indicated that most patients had stable or improved MRI outcomes at index (87.7%) and remained stable or improved at years 1 (96.0%) and 2 (93.6%). Lymphopenia decreased at years 1 (21.4%) and 2 post-index (14.8%, compared to index (23.5%). By 1 year post-index, fewer patients had grade 3 or 4 lymphopenia, and at 2 years post-index, there were no patients with grade 3 or 4 lymphopenia. Infection incidence was low (n = 40, 22.0%) and none were related to teriflunomide. The decreases in lymphopenia were driven by decreases among people who switched from a prior oral DMT; there were no notable differences in lymphopenia across the other sub-groups examined. ARR, EDSS score, and MRI outcomes across all sub-groups were similar to the results of the overall population.
Conclusion
Our multicenter, longitudinal, retrospective study demonstrated that patients with RMS aged 55 or older switching to teriflunomide from other DMTs had significantly improved ARR, stable disability, and stable or improved MRI over up to 2 years’ follow up. Safety results were acceptable with fewer patients exhibiting lymphopenia at years 1 and 2 post-index.
Multiple sclerosis is a lifelong immune-mediated neuroinflammatory and neurodegenerative disease. Lifespans of people with multiple sclerosis (MS) have increased (
). Age-related factors represent challenges to treating older patients. These factors include disability accumulation and higher rates of brain atrophy (
). Due to the age-related risks of disability progression in older patients with MS, it is critical to include older patients in studies, though currently, clinical trial and real world data from patients with MS treated with DMTs over the age of 55 are limited (
). Due to the higher rates of brain atrophy in older people with MS, there is particular interest in evaluating treatments with a pronounced effect on brain atrophy, such as teriflunomide (
Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial.
). In clinical trials, the most common adverse events (AEs) associated with teriflunomide treatment were mild and resolved spontaneously when patients remained on treatment, rarely leading to discontinuation (
G. Teriflunomide Multiple Sclerosis Trial and M. S. M. R. I. R. G. University of British Columbia A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses.
Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial.
). Notably, in phase 4 studies, teriflunomide-treated patients who switched from another DMT had improved treatment satisfaction, stable EDSS scores, and safety profiles consistent with those reported in the phase 2 and 3 clinical trials with no new safety signals (
To date, a few studies have described the efficacy and safety of teriflunomide in the older population. In the real-world Teri-PRO study, a post-hoc analysis of pooled phase 2 and 3 data, teriflunomide-treated patients >55 years of age had fewer relapses and similar safety profiles when compared with younger age groups (
). In the TAURUS-MS I prospective longitudinal study, ARRs were low across teriflunomide-treated patients in all age groups including patients >55 years of age and decreased after 12 months compared with ARRs in the year prior to teriflunomide initiation. EDSS scores were stable over 24 months in all age groups including older patients (>55 years) (
) and safety profiles were similar across all age groups. Though limited in scope, these studies support the effective and safe use of teriflunomide in older patients, but do not address critical safety issues related to the potential impact on immune response.
In this real-world analysis, we assessed the effectiveness and safety of teriflunomide in older adults ≥55 years with RMS who switched to teriflunomide from other DMTs. Assessments of effectiveness included ARR, EDSS score, and MRI data. Assessments of safety included malignancies, infections, and white blood cell counts. Due to the immunosenescence that can occur in older people, and the potential impact that DMTs have on immune function, we sought to address related clinical considerations in older people with MS.
2. Methods
2.1 Study design
We performed a retrospective, observational, multicenter chart review (
) conducted at four sites in the United States. Data were collected from medical records from 1 year pre-index to 2 years post-index (index is the teriflunomide start date). Inclusion criteria were patients who had relapsing multiple sclerosis (RMS) (RRMS and active secondary progressive MS, hereafter referred to as RMS) with age at index of 55 years or older, who had switched from other DMTs to teriflunomide (7 mg or 14 mg) for at least one year.
2.2 Assessments
Demographic, clinical, and MRI data were collected from chart review. Patient demographic data included site location, age, sex, race, time since diagnosis, follow-up duration, MS subtype, most recent prior DMT, and reasons for switching from other DMTs to teriflunomide. Assessments of effectiveness, including relapses, EDSS score, and MRI data, when available, were recorded at approximately one year pre-index, index, 1 year post-index, and 2 years post-index. Relapses were identified from patient charts. If EDSS scores were not available, EDSS was estimated from chart notes. EDSS score was estimated by clinician based on documented history and physical exams and knowledge of patient disability using the standard EDSS functional systems to calculate an estimated EDSS score. For MRI scans, we compared 1 year post-index and 2 years post-index scans to the previous year to measure worsening, stable, or improved MRI status. Safety assessments were recorded at 1 year pre-index, index, 1 year post-index, and 2 years post-index, and included white blood cell (WBC) counts, absolute lymphocyte counts, infections, and malignancies. All malignancies were recorded, including those that occurred during the pre-index period or during teriflunomide treatment, and were determined by the investigator's judgement to be either “related” or “not-related” to teriflunomide treatment.
2.3 Statistical analysis
Median values, ranges, and interquartile ranges were calculated for measures of effectiveness and safety, including ARR, EDSS score, WBC, and lymphocyte counts.
ARR and change in ARR from 1 year and 2 years post-index compared to index were estimated using negative binomial regression; standardized follow-up duration was used as an offset variable. Individual patient ARR was calculated as the number of relapses for a patient divided by the follow-up duration in patient years. For MRI scans, we calculated the proportions of patients with an outcome of worsening, stable, or improved MRI status. Stable MRI was defined as no new or enlarging T2 lesions or new gadolinium-enhancing lesions.
The percentages of patients with lymphopenia were determined at pre-index, index, 1 year post-index, and 2 years post-index. Lymphopenia was defined as a total lymphocyte count of <1 × 109 cells per liter of blood. Grades of lymphopenia were defined as: grade 0/normal: ≥ 1.0 × 109 cells/L; grade 1: 0.8 - 0.999 × 109 cells/L; grade 2: 0.5 - 0.799 × 109 cells/L; grade 3: 0.2 - 0.499 × 109 cells/L; and grade 4: < 2.0 × 109 cells/L.
We conducted sub-group analyses for age (55–64 and ≥65 years), sex, MS type (relapsing-remitting MS versus secondary progressive MS) and prior route of DMT administration. The prior routes of DMT administration were classified as injectable (glatiramer acetate [GA], interferon-β [IFNB]), oral (dimethyl fumarate [DMF], fingolimod), and infusion (alemtuzumab, natalizumab, ocrelizumab).
To examine the robustness of several results, sensitivity analyses were performed for change in ARR, MRI status over time (improved, stable, or worsening), and lymphopenia at each time-point. For each sensitivity analysis, the data were restricted to patients who had these measures available at all 3 timepoints, index, 1 year post-index, and 2 years post-index.
All statistical analyses were conducted using SAS v9.4 software. We reported 95% confidence intervals (CI), and all statistical tests were two-sided.
3. Results
We performed chart reviews of 182 patients with RMS aged 55 years or older from four MS centers who switched from other DMTs to teriflunomide. The mean (SD) age at index date (teriflunomide initiation) was 62.5 (5.4) years, 76.4% were female, and 85.2% were White. The study included patients taking teriflunomide 7 mg (n = 2) and teriflunomide 14 mg (n = 180). The mean (SD) years since diagnosis was 14.1 (9.5), and 135 (74.2%) patients had relapsing-remitting MS and 47 (25.8%) had secondary progressive MS. Characteristics of the patients at the index date are presented in Table 1.
Table 1Patient characteristics at teriflunomide index date.
Parameters
Teriflunomide N=182
Site locations, n(%)
Baltimore, MD West Hollywood, CA Sarasota, FL Northbrook, IL
41 (22.5) 49 (26.9) 45 (24.7) 47 (25.8)
Age, mean (SD)
62.5 (5.4)
Sex, n(%)
Female Male
139 (76.4) 43 (23.6)
Race, n(%)
Black White East Asian Hispanic or Latinx Multi-racial Pacific Islander Other
*Percentages calculated for “most recent prior DMTs” were based on known values (N = 167), with missing data from 15 patients. †Percentages calculated for “reasons for switching from other DMTs” were based on known values (N = 160), with missing data from 22 patients.
The patients with MS in our study switched to teriflunomide from other DMTs, including injectables, GA and IFNB (70.0%); other oral DMTs, DMF and fingolimod (19.2%); and infusibles, alemtuzumab, natalizumab and ocrelizumab (7.8%). The primary reasons for switching from other DMTs were relapse (22.5%), needle fatigue (20%), and tolerability (18.1%). The reasons for switching involving safety included infection (5.0%), lymphopenia (8.1%), polyoma JC virus risk consideration (4.4%), and other safety concerns (5.0%).
We observed a decrease in mean ARR from the start of teriflunomide treatment (index) (mean [SD]: 0.43 [0.61]) to year 1 post-index (0.13 [0.65]) and year 2 post-index (0.05 [0.28]) (Fig. 1A). Compared to index, ARR was significantly lower at post-index years 1 (means difference [95% CI]) (-0.30; [−0.41, −0.20]) and 2 (-0.39; [−0.49, −0.30]) (Fig. 1B). Sensitivity analysis restricted to patients who had complete follow-up data for ARR at each time point yielded similar results (Supplemental Table 1). Sixteen people had relapses from index to post-index year 1. No treatment was reported for 4 of these patients. Among the remaining 12 patients, 6 of the relapses occurred within 4 months of starting teriflunomide. The mean EDSS score stayed the same from index (mean [SD]: 4.5 [1.8]) to 1 year post-treatment (4.5 [1.8]) and increased slightly at 2 years post-treatment (4.7 [1.7]). Sub-group analyses of age group, sex, MS type, and route of administration of prior DMT did not show notable differences in ARR (Supplemental Table 2) or EDSS score (Supplemental Table 3).
Fig. 1Annualized Relapse Rate (ARR) (A) and Change in ARR from Index to Year 2 (B). Population includes patients taking teriflunomide 7 mg and teriflunomide 14 mg. ARR was estimated through negative binomial regression and log transformed; standardized follow-up duration was used as an offset variable. Individual patient ARR was calculated as the number of relapses for a patient divided by the follow-up duration in patient years Change in ARR was estimated using the Wilcoxon signed rank test. *P<0.0001 for comparison with index ARR.
MRI scans from index and years 1 and 2 post-index compared to scans from the previous year indicated that the majority of participants had stable or improved MRI outcomes at index (90.4%) and remained stable or improved at years 1 (96.0%) and 2 (93.6%) (Fig. 2). Sensitivity analysis restricted to patients who had MRI scans at each time point yielded similar results (Supplemental Table 4). Sub-group analyses of MRI data by age group, sex, MS type, and route of administration of prior DMT did not show marked differences (Supplemental Table 5).
Fig. 2MRI outcome at pre-index, index, and 1 and 2 years post-index. Population includes patients taking teriflunomide 7 mg and teriflunomide 14 mg. MRI scans from index and years 1 and 2 post-index were compared to scans from the previous year.
We observed that the frequency of lymphopenia decreased over time (index: 35/149 [23.5%]; post-index 1 year: 33/154 [21.4%]; and 2 years: 19/128 [14.8%]) (Fig. 3A, Supplemental Table 6). Notably, by 1 year post-index, fewer patients had grade 3 or 4 lymphopenia, and at 2 years post-index, there were no patients with grade 3 or 4 lymphopenia (Supplemental Table 7, Supplemental figure 1). Distribution of lymphocyte counts through 2 years post-index from patients taking teriflunomide are shown (Fig. 3B). Sensitivity analysis restricted to patients who had lymphocyte counts at each time point yielded similar percent of patients with lymphopenia (Supplemental Table 6). Most patients were within the normal range of 4.0–11.0 × 109 cells/L for WBC count (post-index year 1: 89.2%; post-index year 2: 91.2%) (Supplemental Table 8).
Fig. 3Lymphopenia (A) lymphocyte counts (B), and (C) lymphopenia grade in patients switching from oral, infusion, or injectable DMTs at pre-index, index, post-index 1 year, and post-index 2 years. Population includes patients taking teriflunomide 7 mg and teriflunomide 14 mg. Lymphopenia was defined as ≤ 1.0 × 109 lymphocytes/L. Normal adult lymphocyte count is 1.0 to 4.8 × 109 cells/L, indicated by dashed lines (Fig. 3B). The lower, middle, and upper box lines represent the 25th, 50th (median), and 75th percentiles, respectively, with outliers denoted by circles. The error bars are 1.5*(75th – 25th percentiles) and values above or below the error bars are indicated.
Lymphocyte count in patients switching from other oral DMTs to teriflunomide showed an increase in normal ALC from index (9/28 [32.1%]) to 1 year post-index (17/31 [54.8%]) and to 2 years post-index (19/26 [73.1%]) (Fig. 3C). In patients that switched from injectables or infusion, lymphocyte counts remained stable from index to post-index (Fig. 3C).
Of 182 patients, 40 (22.0%) reported infections, the most common of which were urinary tract infections (12.6%), and no infections were assessed by clinicians as being related to teriflunomide (Table 2). Throughout the 2 years of teriflunomide treatment, no patient reported more than 1 infection.
No infections were assessed by clinicians as being related to teriflunomide. No patient had more than 1 infection. Population includes patients taking teriflunomide 7 mg (n = 2) and teriflunomide 14 mg (n = 180).
Two malignancies occurred during the post-index period and 14 others were reported that occurred in the historical pre-index period before starting teriflunomide (Supplemental Table 9). Both malignancies were determined by the investigators to be unrelated to teriflunomide (Supplemental Table 10).
4. Discussion
Data on teriflunomide from clinical trials in the older population is limited, leading to a lack of guidance on prescribing to elderly patients (
). Additionally, age-related changes in the immune system may impact susceptibility to consequences of some DMTs, including decline in immune responses and risk of infection (
). Our real-world, multi-center study demonstrates safety of teriflunomide treatment in our data set and provides information for treatment and management strategies for the older patient population.
We found that older adults with MS who switched to teriflunomide from other DMTs exhibited significantly reduced ARR after 2 years. This result aligns with findings from a prospective analysis of TAURUS-MS I data that showed ARR significantly decreased after 12 months of treatment with teriflunomide compared to 12 months before the treatment start date in patients >55 years old (
). This study had a similar number of patients > 55 years old (N = 107) and included patients that switched from other DMTs and those with no previous treatment. Post-hoc analyses of the real-world Teri-PRO study, and the prospective TAURUS-MS I, data from patients >55 years showed decreases in ARR in patients taking teriflunomide at 2 years (
). In our study, patients had stable EDSS through year 2 after starting teriflunomide treatment. Stable EDSS for older patients (>55 years) taking teriflunomide has been described in other studies (
). Accordingly, the use of DMTs which act as immunosuppressive or immunomodulating agents may increase the risk of developing lymphopenia and infections in susceptible patients (
). Analyses of immune function in older patients on teriflunomide are limited, therefore, we had a special interest in investigating immune cell counts and infection in patients ≥55 years of age.
Safety results from our study demonstrated overall stability of WBC and lymphocyte counts in patients ≥55 years of age, up to two years from the start of teriflunomide treatment. This is consistent with the post-hoc analysis of the Teri-PRO data, which showed that mean lymphocyte counts stayed above the lower limit of normal at 1 year post-treatment compared to baseline in patients >55 years of age, though there was a small decrease (
In our study, fewer patients exhibited lymphopenia after 1 and 2 years of teriflunomide treatment compared to index and pre-index. The results from the Teri-PRO study showed that lymphopenia occurred in fewer than 10% of patients >55 years of age through year 1 of teriflunomide treatment, and the proportion of patients with lymphopenia was similar across age groups (
When we performed subgroup analyses of lymphocyte counts and lymphopenia of patient categories, including age, gender, MS subtype, and the route of administration of the most recent prior DMT, we observed that lymphopenia most notably decreased for patients who switched to teriflunomide from other oral DMTs. Indeed, grade 3 and 4 lymphopenia did not occur in patients at 1 and 2 years post index who switched from other oral DMTs. Lymphopenia is a known adverse event seen with S1P modulators such as fingolimod and with dimethyl fumarate, so the improvement of lymphopenia once patients switched from these therapies is not unexpected (
Predictors of hematological abnormalities in multiple sclerosis patients treated with fingolimod and dimethyl fumarate and impact of treatment switch on lymphocyte and leukocyte count.
Results from this study showed low numbers of infections in patients ≥55 years of age after switching to teriflunomide for 2 years. Older patients ≥65 years of age had similar numbers of infection (21.9%) compared to patients ≥55–65 years of age (22.0%). Similarly, results from the Teri-PRO and the TAURUS-MS I studies indicated low numbers of infections and demonstrated that there was not an increased risk of infection in older patients (
). Data from the TAURUS-MS I study analyzed upper respiratory infections and influenza only. Age did not appear to be a risk factor for those infections (
Limitations of the study should be considered when interpreting the results. Our study used a retrospective observational design, which may lead to selection bias. Our results were based on chart reviews from multiple centers, so data available from the medical records may have varied. Some EDSS scores were reconstructed based on the review of medical records, and thus are not standardized. Our data were from four sites which may limit the generalizability of the findings. A larger study could further substantiate the conclusions.
Conclusions
Our study assessed the effectiveness and safety of teriflunomide in patients ≥55 years with RMS who switched to teriflunomide from other DMTs. We found that patients exhibited significantly improved ARR from index to year 2 post-index, stable or improved MRI from index to years 1 and 2 post-index, and stable disability from index to year 2 post-index. Safety results showed overall stability with fewer patients exhibiting lymphopenia at years 1 and 2 post-index compared to pre-index and index. Our findings suggested a benefit from teriflunomide for older patients ≥55 years of age.
Regina Berkovich: Writing – original draft, Writing – review & editing. Donald Negroski: Writing – review & editing. Daniel Wynn: Writing – review & editing. Daniel Sellers: Writing – review & editing. Kristen G. Bzdek: Methodology, Writing – review & editing. Alex L. Lublin: Conceptualization, Methodology, Writing – review & editing. Andreea M. Rawlings: Writing – review & editing, Formal analysis. Cuc Quach: Methodology, Writing – review & editing. Danelle P. Wells: Writing – review & editing. Melanie Dumlao: Writing – review & editing. Adriana Bora: Writing – review & editing. Anthony E. Ranno: Writing – review & editing. Kevin Lin Luo: Writing – review & editing. Jeffrey Chavin: Conceptualization, Methodology, Writing – review & editing. Le H. Hua: Writing – review & editing. Daniel Becker: Writing – review & editing.
Funding
This work was funded by Sanofi.
Disclosures
Regina Berkovich received support from Alexion, Biogen, BMS, EMD Serono, Mallinckrodt, Novartis, J&J, Sanofi. Donald Negroski received personal compensation for serving on Speakers Bureaus for Biogen, EMD, Genentech, Sanofi, Novartis, Alexion, Janssen, BMS, and Banner Life Science; he has received research support from Biogen Sanofi, Adamas, Alkermes, EMD, and Novartis. Daniel Wynn received personal compensation for serving on a Scientific Advisory or Data Safety Monitoring board for Mylan, on Speakers Bureaus for AbbVie, EMD Serono, Sanofi, TEVA, and Banner Life, and for serving as an Expert Witness for Biogen; he has received research support from Novartis, Sanofi, Adamas Pharmaceutics, EMD Serono, Roche; he has a non-compensated relationship as a Director, Consultants in Neurology Comprehensive Care Center with National MS Society that is relevant to AAN interests or activities. Daniel Sellers has received honoraria for speaking, consulting activities, and/or research support from Biogen, EMD Serono, Sanofi, Bristol Myers Squibb, and became a Sanofi employee after the research within this manuscript was complete. Le H. Hua received honoraria for speaking, consulting, and/or advisory board activities from Sanofi, Novartis, Genentech, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, Horizon Therapeutics, and Alexion, and receives research support paid to her institution from Biogen. Kristen G. Bzdek, Alex L. Lublin, Andreea M. Rawlings, Cuc Quach, Danelle P. Wells, Melanie Dumlao, Adriana Bora, Anthony E. Ranno, Kevin Lin Luo, and Jeffrey Chavin are employees of Sanofi and may be shareholders. Daniel Becker received honoraria for speaking, consulting activities, and/or research support from Biogen, Sanofi, Novartis, Genentech, Bristol Myers Squibb, EMD Serono, AbbVie, Horizon, and Janssen.
Data sharing statement
Anonymized data will be shared by reasonable request from any qualified investigator.
Acknowledgments
Writing assistance (assistance in drafting and editing of the manuscript text, figures, and tables, as directed by the authors, data checking and incorporation of comments from reviewers, and assisting with the submission process) was provided by Tiha M. Long, PhD of Elevate Scientific Solutions, and funded by Sanofi.
Predictors of hematological abnormalities in multiple sclerosis patients treated with fingolimod and dimethyl fumarate and impact of treatment switch on lymphocyte and leukocyte count.
Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial.
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