Early treatment responses to peginterferon beta-1a are associated with longer-term clinical outcomes in patients with relapsing-remitting multiple sclerosis: Subgroup analyses of ADVANCE and ATTAIN
Journal: 2022/February - Multiple Sclerosis and Related Disorders
Abstract:
Background: Early intervention with well-tolerated disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) is recommended in order to delay disease progression, reduce neurologic damage, preserve brain volume, and optimize long-term patient outcomes. Lack of conversion of new/newly enlarging T2 (NET2) or gadolinium-enhancing (Gd+) lesions to chronic hypointensities (black hole conversion) and achievement of no evidence of disease activity (NEDA) early in the course of treatment are considered potential indicators of treatment effect and predictors of longer-term clinical outcomes.
Methods: Patients with RRMS who were treated with peginterferon beta-1a in the 2-year ADVANCE phase 3 clinical trial (NCT0090639) and its 2-year open-label extension study, ATTAIN (NCT01332019), were grouped as newly diagnosed (diagnosed ≤1 year prior to enrollment and DMT naive) or non-newly diagnosed. For analyses of the impact of early treatment and disease activity control, the newly diagnosed and non-newly diagnosed subgroups were further divided based on whether they initiated peginterferon beta-1a every 2 weeks (Q2W) starting in study year 1 (continuously treated) or peginterferon beta-1a Q2W or every 4 weeks in study year 2 (delayed treatment). Patient subgroups were evaluated for conversion of NET2 or Gd+ lesions to persistent black holes (PBHs), brain atrophy (percentage change in whole brain volume [WBV]), achievement of NEDA composite outcomes, and the association of these disease activity measures with longer-term clinical outcomes (annualized relapse rate [ARR] and confirmed disability worsening [CDW]).
Results: At 2 years, significantly fewer PBHs developed from NET2 lesions or Gd+ lesions in newly diagnosed and non-newly diagnosed patients continuously treated with peginterferon beta-1a than in the corresponding delayed-treatment groups (all p<0.0001). Percentage decrease in WBV from 6 months (rebaselined) to 2 years was significantly lower for newly diagnosed and non-newly diagnosed patients who received continuous peginterferon beta-1a treatment than for patients who received delayed treatment (both p ≤ 0.0442). In study year 1, a higher proportion of newly diagnosed and non-newly diagnosed patients treated with peginterferon beta-1a than those treated with placebo achieved NEDA (newly diagnosed: 28.3% vs 13.5% [p = 0.0010]; non-newly diagnosed: 40.8% vs 15.8% [p<0.0001]). NEDA rates remained stable over study years 2-4 for the newly diagnosed (range: 50.0%-53.9%) and non-newly diagnosed (range: 54.4%-57.0%) subgroups. Patients without PBH conversion had significantly lower ARR at 2 years (newly diagnosed: p = 0.0109; non-newly diagnosed: p = 0.0044) and a lower proportion of patients with 12-week CDW at 2 years (newly diagnosed: p = 0.2787; non-newly diagnosed: p = 0.0045) than the corresponding patient subgroups with PBH conversion. Patients who achieved NEDA in ADVANCE (study years 1-2) had a significantly lower ARR in ATTAIN (study years 3-4) than patients who did not achieve NEDA (newly diagnosed, p = 0.0003; non-newly diagnosed, p = 0.0001). Over 4 years, safety outcomes did not differ for the newly diagnosed and non-newly diagnosed patient subgroups.
Conclusions: These results indicate that newly diagnosed and non-newly diagnosed patients treated continuously with peginterferon beta-1a Q2W experienced better disease control over time than those who received delayed treatment. Patients with NEDA or evidence of less radiological disease activity in the first 2 years of treatment had better longer-term clinical outcomes than those with evidence of greater disease activity.
Keywords: Brain atrophy; Early treatment; No evidence of disease activity; Peginterferon beta-1a; Persistent T1 hypointensities.
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