Effect of Peginterferon Beta-1a on MRI Measures in RRMS
Subcutaneous (SC) peginterferon beta-1a, a pegylated form of interferon (IFN) beta-1a, is a new treatment for relapsing multiple sclerosis (MS). 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. 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. Furthermore, every 2 week dosing provided numerically greater reductions relative to placebo versus every 4 week dosing across relapse and all MRI endpoints.
Magnetic resonance imaging (MRI) of lesions in the brain is an important tool for monitoring MS disease activity and progression, providing a sensitive measure of the effects of treatment on focal inflammatory activity in the central nervous system, which initiates the demyelination and axonal damage associated with MS disease progression. Lesions detected on MRI scans have been shown to correlate with MS prognosis; thus early reduction in MRI lesions is an important treatment goal.
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. 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. NEDA has been proposed for use as an endpoint in MS studies. It has been evaluated in several MS studies to date, with some variation in its definition to allow for minimal MRI activity. 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).
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, 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).
Background
Subcutaneous (SC) peginterferon beta-1a, a pegylated form of interferon (IFN) beta-1a, is a new treatment for relapsing multiple sclerosis (MS). 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. 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. Furthermore, every 2 week dosing provided numerically greater reductions relative to placebo versus every 4 week dosing across relapse and all MRI endpoints.
Magnetic resonance imaging (MRI) of lesions in the brain is an important tool for monitoring MS disease activity and progression, providing a sensitive measure of the effects of treatment on focal inflammatory activity in the central nervous system, which initiates the demyelination and axonal damage associated with MS disease progression. Lesions detected on MRI scans have been shown to correlate with MS prognosis; thus early reduction in MRI lesions is an important treatment goal.
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. 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. NEDA has been proposed for use as an endpoint in MS studies. It has been evaluated in several MS studies to date, with some variation in its definition to allow for minimal MRI activity. 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).
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, 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).
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