Dimethyl Fumarate and Peginterferon Beta-1a: New Insights Into the Pivotal Trials

Dimethyl Fumarate and Peginterferon Beta-1a: New Insights Into the Pivotal Trials

Pavan Bhargava, MD

Johns Hopkins University School of Medicine, Baltimore, Maryland

Treatment options for multiple sclerosis (MS) continue to expand. Balancing efficacy with the adverse effects of a given treatment is paramount in choosing disease-modifying therapies. Beyond the cut-and-dry clinical and radiologic findings that generally become the primary and secondary outcomes of clinical trials, other less-tangible outcomes, such as quality of life and the tolerability of medications, also play a role in treatment decisions. Long-term follow-up of participants in clinical trials provides further data to help with these decisions. During the 2014 Annual Meeting of the American Academy of Neurology, post hoc analyses of the DEFINE and CONFIRM trials, which evaluated dimethyl fumarate in patients with relapsing-remitting MS, and data from the pivotal ADVANCE trial of peginterferon β-1a were presented. The outcomes of these clinical trials provide us with a better perspective of the usefulness of these agents in patients with MS.

Pavan Bhargava, MDThe armamentarium of medications approved by the US Food and Drug Administration (FDA) to treat multiple sclerosis (MS) continues to grow,1 presenting a plethora of additional considerations. Treatment decisions must balance the efficacy of a disease-modifying therapy (DMT) with its adverse effects.2 Other factors, such as its impact on patient quality of life (QOL), may play a role in determining the real-world effectiveness of a medication as compared with its efficacy in a trial setting. Long-term follow-up data are needed to establish the continued efficacy and safety of medications.

This article describes post hoc analyses of the Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (DEFINE) and the Efficacy and Safety Study of Oral BG00012 with Active Reference in RRMS (CONFIRM), interim data from the extension Dose-Blind, Multicenter, Extension Study to Determine the Long-Term Safety and Efficacy of Two Doses of BG00012 Monotherapy in Subjects with RRMS (ENDORSE), and findings from the Efficacy and Safety Study of BIIB017 (PEGylated Interferon β-1a) in Participants with RRMS (ADVANCE). In this fast-changing therapeutic landscape, these additional data may aid clinicians in choosing the right DMT for their patients.

DIMETHYL FUMARATE
Dimethyl fumarate is an oral, second-generation fumarate ester that was approved by the FDA in 2013 to treat RRMS.3 Dimethyl fumarate apparently exerts its effects primarily through activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, a protective cellular defense mechanism against oxidative stress and immune homeostasis.4 Other postulated mechanisms of action include induction of interleukin (IL)-4–producing CD4+ T cells, induction of type II dendritic cells that produce IL-10 rather than IL-12 and IL-23, suppression of other pro-inflammatory cytokines, and direct inhibition of proinflammatory pathways.5

The efficacy of dimethyl fumarate was demonstrated in two pivotal phase 3 clinical trials—DEFINE and CONFIRM.

In the DEFINE study, patients with RRMS were randomized to receive placebo or 240 mg of dimethyl fumarate given two or three times a day for 2 years.6 Analysis of the trial data showed a significant reduction in annualized relapse rate (ARR), magnetic resonance imaging (MRI) outcomes (number of new or enlarging T2 lesions and gadolinium-enhancing lesions), and confirmed 3-month disability progression in both groups of patients receiving dimethyl fumarate as compared with the group given placebo.

Table 1The CONFIRM trial was a four-arm study that included an active comparator group that received 20 mg/d of glatiramer acetate in addition to the two groups receiving dimethyl fumarate and the single placebo group studied in the DEFINE trial.7 The duration of CONFIRM, 2 years, was the same as DEFINE's. The major inclusion and exclusion criteria of DEFINE and CONFIRM are summarized in Table 1. All active treatment groups demonstrated significant reductions in ARR and MRI outcomes when compared with the placebo group. A significant benefit of dimethyl fumarate over glatiramer acetate was not demonstrated.

Efficacy in Patients with Highly Active Disease
Hutchinson et al8 described the clinical efficacy of dimethyl fumarate in RRMS patients with highly active disease who participated in DEFINE and CONFIRM. Highly active disease was defined by at least two relapses in the year prior to study entry and the presence of at least one gadolinium-enhancing MRI lesion at baseline. Of 2,301 patients treated with dimethyl fumarate given two or three times daily or placebo, 136 met the criteria for highly active disease.

Twice-daily dosing of dimethyl fumarate reduced the ARR by 60.3% (P = 0.0018) as compared with placebo (Figure 1).8 The proportion of relapsing patients in each group was estimated using the Kaplan-Meier product limit method; it revealed a significantly reduced risk of relapse for patients treated with dimethyl fumarate twice daily as compared with those given placebo (hazard ratio [HR] = 0.368; P = 0.003). Effects on clinical efficacy measures in the group given dimethyl fumarate three times daily were not significant. This post hoc analysis suggested that twice-daily dimethyl fumarate showed efficacy in patients with highly active disease. The authors recommended caution, however, in interpreting the results of this study due to the small number of patients involved who had highly active disease.

Figure 1

FIGURE 1 Annualized relapse rate (ARR) at 2 years in patients with highly active multiple sclerosis who participated in the DEFINE and CONFIRM studies. When compared with placebo, delayed-release dimethyl fumarate given twice daily (bid) significantly reduced the ARR. In patients given dimethyl fumarate three times a day (tid), the reduction in the ARR was not statistically significant. Adapted, with permission, from Hutchinson et al.8

Efficacy in Minority Populations
There is some evidence that MS severity may be greater among African-Americans than among other racial or ethnic groups.9 Hutchinson et al10 studied the efficacy of dimethyl fumarate in minority populations in DEFINE and CONFIRM.

Of 2,651 patients enrolled in the two phase 3 trials, those given either placebo or dimethyl fumarate two or three times daily were identified by race and ethnicity. In all, 29 were African-American, 54 were Hispanic, and 136 were Asian. Similar to the intent-to treat populations in the original trial, patients given twice-daily dimethyl fumarate from all three subgroups showed a reduction in ARR and in the proportion of patients who relapsed at 2 years, with the greatest effect noted among African-Americans and the smallest effect seen among Asian patients. Due to the small sample sizes in each group, the confidence intervals of all estimates were wide and did not reach statistical significance. A similar trend was also noted in 12-week confirmed disability progression at 2 years. These results, though preliminary, suggested the need for larger prospective studies to determine the effects of dimethyl fumarate in various minorities.

Health-Related Quality of Life (HRQOL)
MS has a significant impact on HRQOL, and assessing the effects of DMTs on measures of HRQOL may have an important impact on treatment decisions. Since MS leads to detriments in both the physical and mental domains, HRQOL test instruments must capture both. The HRQOL measures used in DEFINE and CONFIRM included the Short Form-36 Health Survey (SF-36) and the European Quality of Life–Five Dimensions Health Survey (EQ-5D).11,12 Table 2 provides an overview of these two measurement scales.

Table 2

Kita et al13 presented an integrated analysis of the effect of dimethyl fumarate treatment on HRQOL in US patients who participated in DEFINE and CONFIRM. A total of 464 patients were included in the analysis; 136 were given placebo, 128 were given dimethyl fumarate twice daily, 135 were given dimethyl fumarate three times daily, and 65 were given glatiramer acetate. Effects on HRQOL were assessed using the mean change in SF-36 and EQ-5D scores between baseline and the end of the study 2 years later, adjusting for study region and baseline values.

There was a significant increase in the SF-36 physical component summary (PCS) scores among patients given dimethyl fumarate twice daily (0.70; P = 0.003) or three times daily (0.96; P = 0.014), but no significant change was observed among patients receiving glatiramer acetate compared with those given placebo. There was a significant increase in the SF-36 mental component summary (MCS) score among those taking dimethyl fumarate twice daily (1.17; P = 0.017) group, but this was not noted among the other treatment groups. The increase in SF-36 scores in the group taking twice-daily dimethyl fumarate was seen across all subscales. A significantly greater number of patients receiving dimethyl fumarate showed a clinically significant increase of 5 points in the SF-36 PCS score (P < 0.001). Patients taking dimethyl fumarate two or three times daily also demonstrated increased EQ-5D scores at 24, 48, and 96 weeks when compared with those taking placebo, whereas a similar change was not observed in the glatiramer acetate group. However, fewer patients were using glatiramer acetate, and a lack of effect could have resulted from insufficient statistical power to demonstrate such an effect in those who took the drug.

Kappos et al14 performed a post hoc analysis of the effect of dimethyl fumarate on HRQOL in the DEFINE and CONFIRM trials based on previous therapy. They used the SF-36 and a global well-being visual analog scale (VAS) as their outcome measures. Patients were divided into those who were treatment naïve at trial entry, those who had received interferon β or glatiramer acetate (ABCRE) previously, and those who had been on any other treatment.

In the treatment-naïve subgroup, SF-36 PCS scores increased over the 96-week study period in patients taking dimethyl fumarate two or three times daily and in the glatiramer acetate group, whereas there was a decline in scores in the placebo group. In the ABCRE group, however, a significant difference in PCS scores was seen in the dimethyl fumarate groups but not in the glatiramer acetate group. A similar trend was observed in the other treatment group, but it did not reach statistical significance.

MCS scores remained stable in the treatment-naïve subgroup for all treatments, but only dimethyl fumarate given twice daily produced a significant increase in MCS scores in the ABCRE group. MCS scores increased significantly in the other treatment subgroup in patients taking dimethyl fumarate two or three times daily.

The authors also evaluated stability or improvement of HRQOL using a 5-point increase in the PCS or MCS as a minimal clinically significant difference. In the treatment-naïve subgroup, a significantly greater proportion of patients taking dimethyl fumarate two or three times daily showed improvements or no change in their PCS scores, but not in their MCS scores, as compared with the placebo group. In the ABCRE group, a significant proportion of patients using dimethyl fumarate two or three times daily showed an increase in both their PCS and MCS scores or had no change in their scores. In the glatiramer acetate subgroup, no significant differences in these scores were noted compared with patients given placebo.

These results continue to demonstrate the benefit of dimethyl fumarate on HRQOL, irrespective of previous therapy.

Freedom from Disease Activity
As treatment options for MS expand, more experts are advocating freedom from clinical and radiologic disease activity as the goal of DMTs.15 Havrdova et al16 performed a pooled analysis of data from DEFINE and CONFIRM to assess the effect of dimethyl fumarate treatment on freedom from clinical and neuroradiologic disease activity. Absence of measured clinical disease activity was defined as no evidence of relapse or 12-week sustained progression on the Expanded Disability Status Scale (EDSS). No measured neuroradiologic activity was defined as no evidence of new and/or enlarging T2 lesions or gadolinium-enhancing lesions. Patients with no measured overall disease activity had no evidence of clinical or neuroradiologic activity. A total of 2,301 patients were included in the analysis for clinical disease activity, and 1,046 patients were included in the MRI cohort to assess neuroradiologic disease activity.

A significantly larger proportion of patients taking dimethyl fumarate two (69%) or three (71%) times daily had no measurable clinical disease activity at 2 years, as compared with those who received placebo (53%; P = 0.0001). In the MRI cohort, a significantly larger proportion of patients taking dimethyl fumarate two (34%) or three (35%) times daily had no measured neuroradiologic disease activity at 2 years when compared with those who received placebo (20%; P = 0.0001). In the same cohort, a significantly larger proportion of patients taking dimethyl fumarate two (23%) or three (23%) times daily had no measured overall disease activity at 2 years, when compared with the placebo group (11%; P = 0.0001). These findings were similar to those reported in the individual trials and supported the use of dimethyl fumarate as an effective DMT for MS.

Long-Term Follow Up Data from the ENDORSE Extension Study
ENDORSE is a 5-year extension study of the DEFINE and CONFIRM trials that evaluated the long-term safety and efficacy of dimethyl fumarate. This study enrolled patients who completed either DEFINE or CONFIRM. Patients on dimethyl fumarate given two or three times daily were continued on the same medication, whereas those on placebo or glatiramer acetate were randomized 1:1 to treatment with dimethyl fumarate given two or three times daily. All patients continued to have MRI scans yearly at their original trial site.

Gold et al17 reported integrated clinical efficacy data from DEFINE, CONFIRM, and ENDORSE (interim 2-year data). Of the 2,651 patients originally enrolled in DEFINE and CONFIRM, 1,736 were enrolled in ENDORSE. In this study, 501 patients continued taking dimethyl fumarate twice daily, and 502 continued taking the drug three times a day. A total of 248 patients who had taken placebo started taking dimethyl fumarate three times daily, 118 patients who had taken glatiramer acetate started taking dimethyl fumarate twice daily, and an additional 118 patients who had taken glatiramer acetate started taking dimethyl fumarate three times daily.

Among the patients who continued taking dimethyl fumarate twice daily, the ARR was 0.142 (95% confidence interval [CI] = 0.108, 0.187) after 2 years. At 4 years, the ARR rose to 0.198 (95% CI = 0.155, 0.252), suggesting continued efficacy of dimethyl fumarate. Similar results were noted in the proportions of patients who relapsed while taking dimethyl fumarate: 15.4% of those taking the drug twice daily and 16.8% of those taking it three times a day showed disability progression.

Among patients switching from placebo or glatiramer acetate to dimethyl fumarate two or three times a day, the ARR was similar to that observed at the end of 2 years in DEFINE and CONFIRM (Figure 2),17 suggesting the sustained clinical efficacy of dimethyl fumarate at 4 years of treatment.

Figure 2

FIGURE 2 Annualized relapse rate (ARR) by yearly intervals in the DEFINE, CONFIRM, and integrated ENDORSE studies. This graph depicts the yearly ARR in different subgroups of the ENDORSE study. Transition of treatment from placebo (PBO) or glatiramer acetate (GA) to dimethyl fumarate (DMF) twice daily (bid) or three times daily (tid) led to reductions in ARR similar to those seen in these groups in the original DEFINE and CONFIRM studies. The adjusted ARR and 95% confidence interval were based on negative binomial regression adjusted for baseline Expanded Disability Status Scale score (≤ 2.0 vs > 2.0), baseline age (< 40 years vs ≥ 40 years), region, and number of relapses in the 1 year before entry into DEFINE or CONFIRM. Data after patients switched to alternative medications for multiple sclerosis during this period were excluded. Adapted, with permission, from Gold et al.17

Arnold et al18 reported on the integrated MRI outcomes from DEFINE, CONFIRM, and ENDORSE (interim 2-year data). The MRI endpoints included new and/or enlarging T2 lesions, new nonenhancing T1 hypointense lesions, gadolinium-enhancing lesions, and the adjusted mean number of T2 and T1 hypointense lesions. The MRI cohort in DEFINE and CONFIRM consisted of 1,221 patients; 718 went on to participate in the ENDORSE study. Among patients who continued dimethyl fumarate twice daily, 68% were free of new/enlarging T2 lesions, 76% were free of new T1 hypointense lesions, and 88% were free of gadolinium-enhancing lesions at 2 years in the ENDORSE trial. Similar results were seen among patients switching from placebo or glatiramer acetate to twice-daily dimethyl fumarate (Figure 3).17

Figure 3

FIGURE 3 Number of new and/or enlarging T2 lesions by yearly intervals in the DEFINE, CONFIRM, and integrated ENDORSE studies. The number of new and/or enlarging T2 lesions at yearly intervals in various subgroups of the ENDORSE study are depicted. There was a sustained reduction in new and/or enlarging T2 lesions in subjects who continued dimethyl fumarate (DMF) twice daily (bid) or three times daily (tid) and a reduction in new and/or enlarging T2 lesions in the placebo (PBO) and glatiramer acetate (GA) groups to a level comparable to those of the dimethyl fumarate groups. The adjusted mean and 95% confidence intervals (CI) were based on negative binomial regression, adjusted for region and baseline volume of T2 lesions at the start and end of the DEFINE and CONFIRM trials. Data after patients switched to alternative medications for multiple sclerosis were excluded. Adapted, with permission, from Gold et al.17

Thus, at year 2 of ENDORSE, the MRI activity in patients switched from placebo or glatiramer acetate to dimethyl fumarate seemed to be about the same as that noted in the parent studies. The two groups that remained on dimethyl fumarate seemed to continue showing a low frequency of new MRI lesions similar to that seen in DEFINE and CONFIRM, suggesting that dimethyl fumarate is effective at reducing disease activity over 4 years.

PEGINTERFERON Β-1A
Peginterferon β-1a is a modified form of interferon β-1a that has a polyethylene glycol (PEG) group attached to the α-amino group of the N-terminus of interferon β-1a. Alterations in pharmacokinetics and pharmacodynamics allow for a reduced dosing frequency of interferon β-1a.19

ADVANCE was a phase 3 randomized clinical trial that compared placebo with 125 μg of peginterferon β-1a given subcutaneously every 2 or 4 weeks for 1 year.20 The design of this trial is shown in Figure 4.20 Reductions in ARR, disability progression, and MRI measures were noted in both peginterferon β-1a groups as compared with the placebo group at 48 weeks. At 2 years, the group treated with peginterferon β-1a every 2 weeks had significantly greater reductions in ARR, the proportion of patients with relapses, and MRI outcomes than did patients who were treated with the drug every 4 weeks.

Figure 4

FIGURE 4 Design of the ADVANCE study of peginterferon β-1a (PEG-IFN). During year 1, patients were randomized 1:1:1 to receive treatment with PEG-IFN given every 2 weeks (q2w) or every 4 weeks (q4w) or placebo. During year 2, patients in the placebo arm were randomized to receive PEG-IFN given either q2w or q4w. Adapted, with permission, from Calabresi et al.20

Less than 1% of patients receiving peginterferon β-1a in the ADVANCE trial developed neutralizing antibodies to interferon over 2 years. Adverse events were similar to those noted for other interferon β preparations and included injection-site erythema, influenza-like reactions, pyrexia, and headache. Peginterferon β-1a is currently under review by the FDA for use in the treatment of relapsing forms of MS.

Pharmacokinetics and Pharmacodynamics of Peginterferon β-1a
Results of phase 1 studies suggested that peginterferon β-1a had greater biologic activity with less frequent dosing due to a prolonged terminal half-life, a higher area under the curve, and consistent elevation in pharmacodynamic markers of interferon receptor activation. Hu and colleagues21 reported on the pharmacokinetics and pharmacodynamics of peginterferon β-1a among patients enrolled in the ADVANCE study.

All patients in the trial had blood samples drawn for pharmacodynamic and/or pharmacokinetic assessment. A subset of patients gave consent for an intensive pharmacokinetic study, with blood draws at 6, 24, 28, 36, 72, 120, 168, and 240 hours post dose during weeks 4 and 24. The remaining patients had one sample taken after each dose at weeks 4, 12, 24, 56, and 84. Sufficient intensive samples were obtained from 25 patients.

The maximum serum concentration of peginterferon β-1a was reached at 1–1.5 days after injection, and the terminal half-life was 2–5 days for every-2-week and every-4-week regimens (Figure 5a).21 By doubling the frequency of dosing, the every-2-week regimen provided twice the area under the curve as did the every-4-week regimen. There were weak negative correlations between interferon exposure and body size and creatinine clearance.

Figure 5

FIGURE 5 Pharmacokinetics and pharmacodynamics of peginterferon β-1a given every 2 weeks. These figures depict pharmacokinetic (PK) and pharmacodynamic (PD) data obtained from subjects in the intensive PK/PD sampling arm of the ADVANCE study after a single injection of peginterferon β-1a. (a) Change in serum peginterferon β-1a concentration over time with complete clearance of the drug 10 days post injection. (b) Change in serum neopterin concentration (a marker of interferon receptor activation) over time. Adapted, with permission, from Hu et al.21

Interestingly, anti-PEG antibodies had no effect on the pharmacokinetics of peginterferon β-1a. The number of patients with interferon-neutralizing or interferon-binding antibodies was low; the effect of these antibodies on the pharmacokinetics or pharmacodynamics of peginterferon β-1a could not be determined.

In the intensive pharmacodynamic group, neopterin levels reached a peak elevation at 3 days post peginterferon β-1a injection and remained elevated for 10–14 days (Figure 5b).21 These findings help to explain the additional efficacy of the every-2-week regimen of peginterferon β-1a over the every-4-week regimen.

Effect on Relapse-Associated Costs
O'Day et al22 studied the impact of peginterferon β-1a given every 2 or 4 weeks on potential cost savings associated with reductions in relapse rate, MS-related hospitalizations, and intravenous (IV) corticosteroid usage. This is an important consideration, since the annual cost of MS management per patient in the United States is estimated to range from $44,000 to $88,000 in 2006 dollars.23 The costs are proportional to the level of disability. Expenses related to treating relapses are related to the severity of the relapses.24

The researchers created an economic model in which the mean cost of hospitalization, treatment with IV corticosteroids, and management of MS relapses in the placebo group were calculated by multiplying the estimated cost by the annualized rate of the occurrence of such an event over 1 year. For groups given peginterferon β-1a every 2 or 4 weeks, these estimates were multiplied by the HR to yield mean estimates. HRs were derived from the 1-year interim analysis of the ADVANCE trial. The costs of hospitalization and MS relapse were derived from the Bureau of Labor Statistics Medical Care Component of the Consumer Price Index.25 The cost of IV corticosteroid treatment was based on a 5-day course.

Treatment with peginterferon β-1a every 2 weeks reduced the cost of hospitalization by $1,297 (95% CI = $288, $2,173), the cost of IV corticosteroids by $62 (95% CI = $20, $99), and the cost of MS relapse by $1,941 (95% CI = $877, $2,931) when compared with placebo over 1 year. Administration of peginterferon β-1a every 2 weeks had a high probability of reducing costs when compared with therapy given every 4 weeks.

Limitations of this study include the inability to generalize results consistently from the clinical trial setting to routine clinical practice, lack of comparison with the costs of other active DMTs, and the fact that the costs associated with treating adverse effects of the drug and the costs of the medication itself were not considered. Future studies also may incorporate indirect costs in their analyses.

Reducing the Impact of Relapses on HRQOL
Kinter et al26 reported on the impact of peginterferon β-1a treatment on HRQOL in the first year of the ADVANCE trial. The patient-reported outcomes (PRO) included the MS Impact Scale-29 (MSIS-29), SF-12 Health Survey, and EQ-5D.27 All patients with such information were included in the analysis.

The authors used mixed-effects regression models with treatment, time, sustained disability progression, relapses, and adverse events as predictors of MSIS-29 physical and mental scores. Baseline characteristics were similar between the treatment groups. Over the course of the first year, the MSIS-29 physical score worsened in the placebo group, but it did not change significantly in the groups given peginterferon β-1a every 2 or 4 weeks. All treatment groups showed a significant improvement in the MSIS-29 psychological scale. There were no significant differences in PRO scores between the treatment groups over the course of the first year. In the multivariate regression model, relapses and disability progression, but not adverse events, were linked with worse HRQOL.

As compared with the placebo group (rise of 6.04), disability progression was associated with a lower rise in MSIS-29 physical scores among patients using peginterferon β-1a every 2 weeks (reduced by 4.16; P < 0.05). Similarly, the rise of MSIS-29 psychological scores associated with a relapse in the placebo group (rise of 9.95) was greatly attenuated in these patients (reduced by 6.41; P < 0.05). A similar effect was also noted on other PRO measures, such as the SF-12 and EQ-5D. These results suggested that peginterferon β-1a given every 2 weeks not only reduces relapse rates and disability progression but also reduces the impact of these events on patient's HRQOL.

CONCLUSION
The data presented in these studies help clarify the efficacy and safety of dimethyl fumarate, an important oral DMT for MS. Post hoc analyses of the DEFINE and CONFIRM trials and interim data from the ENDORSE extension study suggest continued evidence of clinical and radiologic efficacy in addition to HRQOL benefits. Further data from the ENDORSE study will help elucidate the long-term efficacy and safety of this medication.

Results from the pivotal ADVANCE study help establish the efficacy and safety of peginterferon β-1a given every 2 weeks. Pegylated interferon β-1a will be an important addition to the MS therapeutic armamentarium, since it preserves the efficacy of previous interferon β-1a formulations with markedly fewer injections. This could potentially translate into better patient adherence with peginterferon β-1a therapy. In addition, these findings demonstrated possible cost savings related to MS-related healthcare costs and a reduction in the impact of relapses and disability progression on HRQOL.

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Dr. Bhargava is a Neuroimmunology Fellow in the Department of Neurology at Johns Hopkins University School of Medicine, Baltimore, Maryland.

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