Effect of peginterferon beta-1a on MRI measures and achieving no evidence of disease activity: results from a randomized controlled trial in relapsing-remitting multiple sclerosis

Subcutaneous (SC) peginterferon beta-1a, a pegylated form of interferon (IFN) beta-1a, is a new treatment for relapsing multiple sclerosis (MS) [1]-[3]. Pegylation (modification via attachment of polyethylene glycol [PEG] molecules), has been used to increase half-life and reduce the immunogenicity of certain drugs with either increased or sustained efficacy [4]-[9]. Results from the first year (placebo-controlled period prior to cross-over onto active drug) of the 2-year pivotal Phase 3, multicenter, randomized ADVANCE study in patients with relapsing-remitting MS (RRMS) showed that peginterferon beta-1a (125 μg SC) administered every 2 or 4 weeks significantly improved clinical endpoints, with a reduction in annualized relapse rate (primary endpoint), and risk of relapse and 12-week confirmed disability progression (both secondary endpoints), and several MRI-related endpoints versus placebo, with a safety profile reflecting established IFN beta-1a therapies [10]. Furthermore, every 2 week dosing provided numerically greater reductions relative to placebo versus every 4 week dosing across relapse and all MRI endpoints [10].

Magnetic resonance imaging (MRI) of lesions in the brain is an important tool for monitoring MS disease activity and progression [11],[12], providing a sensitive measure of the effects of treatment on focal inflammatory activity in the central nervous system [13], which initiates the demyelination and axonal damage associated with MS disease progression [14],[15]. Lesions detected on MRI scans have been shown to correlate with MS prognosis [16]-[18]; thus early reduction in MRI lesions is an important treatment goal [12].

With the development of effective biological therapies, no evidence of disease activity (NEDA; absence of clinical [defined as no relapses and no onset of 12-week confirmed disability progression] and MRI [no gadolinium-enhancing lesions and no new or newly-enlarging T2 hyperintense lesions] disease activity) is now achievable in many patients with RRMS [19]. As treatments have improved, annualized relapse rates recorded in clinical studies have decreased to the point where there is a need to consider alternative endpoints to evaluate new treatments for RRMS [20]. NEDA has been proposed for use as an endpoint in MS studies [20]. It has been evaluated in several MS studies to date [13],[19],[21],[22], with some variation in its definition to allow for minimal MRI activity [23]. Although complete NEDA would be the ideal treatment aspiration, for many physicians, local guidelines and/or switch recommendations apply (e.g. two or more new or newly-enlarging T2-lesions or even a clinical relapse with incomplete remission before escalation is recommended) [24].

The objectives of the present analyses were to explore the effect of peginterferon beta-1a every 2 and 4 weeks on MS disease activity as measured by brain MRI lesions during Year 1 of the ADVANCE study versus placebo (at Week 48 ([Year 1], as previously reported [10], and at the earlier time point of Week 24), with presentation of new post-hoc statistical analyses for every 2 week versus every 4 week dose regimen comparisons at these time points, and to determine the effect of peginterferon beta-1a on the combined endpoint of NEDA via post-hoc investigations of Year 1 data (looking at a range of time-scales to evaluate timing of NEDA impact: baseline to Week 48, baseline to Week 24, and Week 24 to Week 48). Sensitivity analyses of disease activity were also carried out to include an allowance for patients who did not undergo all MRI measures during the study, but had no evidence of disease activity on any recorded assessment (last observation carried forward [LOCF] approach), and using alternative definitions that mimic thresholds used in clinical practice to guide decision-making on treatment continuation due to efficacy, or treatment switch due to inadequate efficacy (no clinical activity with minimal MRI activity).

The MRI outcomes of peginterferon beta-1a observed here are consistent with the robust benefits on clinical outcomes after one year of treatment (reductions in risk of 12-week confirmed disability progression [every 2 and 4 weeks 38%], risk of relapse [every 2 weeks 39%; every 4 weeks 26%], and annualized relapse rate [every 2 weeks 36%; every 4 weeks 28%]), as reported previously for the Phase 3 ADVANCE study [10]. Peginterferon beta-1a every 2 weeks provided superior outcomes for MRI lesion-based endpoints (including numbers of new or newly-enlarging T2 lesions, new T1 lesions, Gd+ lesions, and new active lesions, and volumes of new or newly-enlarging T2 lesions, and new T1 lesions) versus placebo and versus peginterferon beta-1a every 4 weeks, with statistical significance observed at the first brain MRI scheduled at Week 24 of treatment, and greater reductions through to Week 48 of the ADVANCE study. Peginterferon beta-1a every 4 weeks also provided superior results versus placebo at Weeks 24 and 48 for numbers of new or newly-enlarging T2 lesions and new active lesions, and the volume of T2 lesions, but not for numbers of Gd+ or T1 lesions, nor volume of T1 lesions.

An early decrease in brain inflammation, as shown by reductions in MRI disease activity, is particularly desirable in MS, as it may impact on associated injury to myelin and axons, with consequences for the accumulation of disability [12]. Indeed, MRI lesion measures have been shown to be strong predictors of clinical prognosis for MS patients [15]-[18],[27],[28].

This study also carried out post-hoc analyses of ADVANCE Year 1 data using composites of clinical and radiological indicators of disease activity, which are commonly used as endpoints in MS clinical trials [29]-[33]. Efficacy data show that proportions of patients with NEDA and MRI-NEDA only) were significantly higher with peginterferon beta-1a every 2 weeks from baseline to Week 48, from baseline to Week 24 and from Weeks 24 to 48, versus placebo and peginterferon beta-1a every 4 weeks. Furthermore, the sensitivity analyses of disease activity conducted support the robustness of the results of the primary NEDA analyses, indicating that the effects of peginterferon beta-1a are sustained when including an allowance for patients who did not undergo all MRI measures during the study, but had no evidence of disease activity on any recorded assessment, and when applying definitions with allowances for minimal MRI activity. These observations are important because brain MRIs within 12 months of starting a disease-modifying therapy are a sensitive tool in predicting response to treatment, along with the early identification of patients who will develop long-term disability progression [15],[27],[28],[34]. MRI allowance is pertinent to current practice, as scans obtained 6–12 months after starting a new therapy may include MRI activity occurring before efficacy of a new therapy is apparent. Of note, fewer lesions were seen in the present study from Weeks 24–48, versus baseline to Week 24, and comparative ORs for NEDA and MRI-NEDA were higher from Week 24 to 48, compared with baseline to Week 24 and baseline to Week 48. Therefore, an MRI baseline established 6 months after treatment initiation may more effectively demonstrate differences between treatment arms. Further, activity on MRI may also indicate a need to switch to a treatment with an alternative mode of action, with the aim of avoiding irreversible clinical neurological disability [34],[35]; however this need may be more appropriately assessed by establishing a baseline for new disease activity (e.g. at 24 weeks) thus avoiding switch to potentially less safe treatments.

NEDA analyses in the ADVANCE study reflect efficacy levels previously reported in other Phase 3 trials of agents approved for the treatment of relapsing forms of MS, however, it is important to consider that direct comparisons across studies may not be advisable due to differences between study design, patient populations, MRI techniques and MRI reading techniques used across different studies. In the FREEDOMS II study in RRMS, at Month 24 significantly more patients had freedom from indicators of new inflammatory activity (i.e. no gadolinium-enhanced T1 lesions and no new or newly-enlarged T2 lesions) on fingolimod (0.5 mg 50%; 1.25 mg 63%) compared with those on placebo (26%); no composites of clinical-NEDA or complete NEDA were reported in the FREEDOMS II study [36]; although no OR were reported, the relative differences between placebo and actives arms are similar to the findings in the present study.

It is important to compare methods of analysis (e.g. LOCF or non-LOCF), sensitivity of MRI analyses (e.g. computerized or visual read of scans) and numbers of scans when trying to estimate efficacy by endpoints like NEDA, or FMDA (Freedom from Measured Disease Activity), as termed by others, among different treatment options; it would therefore be optimal to make comparisons versus placebo-treated patients and to also compare OR results, rather than just absolute numbers.

Further analyses will be necessary to determine whether these early patients who had NEDA in the ADVANCE study remain NEDA over the longer term (i.e., after 96 weeks). A multicenter, dose-frequency blinded minimum 2-year extension of the ADVANCE study is also underway (ATTAIN; NCT01332019), which may allow for the provision of 4-year data.

Analyses of MRI outcomes and NEDA, along with efficacy for single clinical endpoints reported previously [10], support SC peginterferon beta-1a every 2 weeks as an effective treatment option for patients with RRMS, with the benefit of less frequent administration.