PLEGRIDY efficacy

ATTAIN was a 2-year open-label extension study of ADVANCE. The ATTAIN study was a dose-frequency blinded extension study of ADVANCE. Implementation of a protocol amendment changed ATTAIN to an open-label study, in which all ongoing patients on peginterferon beta-1a every-4-weeks dosing were switched to every-2-weeks dosing; the original dosing schedules remained blinded.

The study was considered complete when the last patient completed 96 weeks in the ATTAIN study. At this time point, some patients with relapsing multiple sclerosis (MS) had received up to nearly 6 years of treatment. Primary endpoints for the ATTAIN study were the incidence of AEs, SAEs, discontinuations of study treatment due to an AE, and laboratory abnormalities.

• Open-label extension studies are prone to patient self-selection bias
• Patients who withdrew from the original study are not available for the follow-up
• Patients who experienced favorable outcomes during the main study are more likely to agree to participate than those who had less-than-favorable experiences
• The every-2-weeks continuously dosed analysis group included only those patients who received peginterferon beta-1a every 2 weeks from the start of ADVANCE; it did not include patients who switched to every-2-weeks dosing at the time of the protocol amendment

ATTAIN, Long-Term Safety and Efficacy Study of Peginterferon Beta-1a.

Data reflect patients who received PLEGRIDY continuously. Adjusted ARRs are based on negative binomial regression for each treatment group, with adjustment for baseline EDSS score (<4.0 vs ≥4.0), baseline relapse rate, and age (<40 vs ≥40 years). Placebo group results are from the ADVANCE ITT population and are presented for year 1 only. Year 6 data are not shown due to small n values (41 patients).

24-week confirmed disability worsening over ADVANCE and ATTAIN. Confirmed disability worsening is defined as a ≥1.0-point increase on the EDSS from a baseline EDSS score ≥1.0 or a 1.5-point increase on the EDSS from a baseline EDSS score of 0.0 that is sustained for at least 24 weeks. Patients were censored if they withdrew from the study or switched to an alternative MS medication without progression. Percentage with disability worsening and probability of worsening are obtained using the Kaplan–Meier estimator. The Kaplan–Meier estimate was not calculated if the number of patients at risk was less than 30.

A matching-adjusted comparison of individual-level data of patients with relapsing MS who took PLEGRIDY SC 125 mcg every 2 weeks (PLEGRIDY Q2WK) in ADVANCE and its open-label 2-year extension, ATTAIN, with pooled aggregated data of patients who took oral teriflunomide 14 mg once daily (teriflunomide QD) in pivotal phase 3 studies TEMSO and TOWER. Patients were matched based on age, sex, EDSS score, years since symptom onset, and number of relapses in the prior year. The matching-adjusted analysis excluded patients randomized to placebo in the clinical trials.

• Due to the matching nature of this analysis, it is not known if all potential biases were matched
• The matching process decreased the sample size for both cohorts

TEMSO, Teriflunomide Multiple Sclerosis Oral; TOWER, Oral teriflunomide for patients with relapsing multiple sclerosis.

^b Adjusted for baseline EDSS strata (≤ 3.5 or > 3.5) in TEMSO and TOWER.

Effectiveness of PLEGRIDY SC 125 mcg every 2 weeks (PLEGRIDY Q2WK) vs glatiramer acetate SC injections of 40 mg/mL 3 times a week (GA TIW) or 20 mg/mL daily (GA QD) is assessed using matched data from across the respective clinical trials of these drugs and formulations thereof. Patients were matched based on age, sex, EDSS score, years since symptom onset, number of Gd+ lesions at baseline (PLEGRIDY/GA TIW), and number of relapses in the prior year (PLEGRIDY/GA QD).

• All indirect comparisons have a potential for bias due to the presence of unobserved, thus nonbalanced, confounders in the treatment populations 
• Differences in study protocols, including inclusion and exclusion criteria, might also have affected the results 
• In addition, for matching-adjusted methods that rely on aggregate data, the reduction in sample size after matching reduces the statistical power of the analysis, and the generalizability of the findings is limited to patients with baseline characteristics similar to those in the matching analysis 
• Matching-adjusted comparison analysis used here is limited by the lack of a common comparator arm between the ADVANCE and GALA studies beyond 1 year 
• Prognostic significance of NEDA has yet to be firmly established, and while some studies have found an association between achieving NEDA in the first 2 years of treatment and favorable longer-term outcomes, others have failed to do so

CONFIRM, Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis study; GALA, Glatiramer Acetate Low-frequency Administration study; OLE, open-label extension.

^c Effective n.
^d NEDA analysis used 2:1 PSM with PLEGRIDY ADVANCE patients and GA patients in the MRI subcohort of CONFIRM. Patients assessed for NEDA were required to have 2 years of follow-up. Patients followed for <2 years, regardless of disease outcomes, were not counted as achieving NEDA. Missing data for NEDA assessments were treated using an observed-only approach.

A matching-adjusted comparison of PLEGRIDY SC 125 mcg every 2 weeks (PLEGRIDY Q2WK) versus SC interferon beta-1a 44 mcg 3 times per week (IFNb1a TIW) over 2 years using data from 4 clinical trials that used pooled aggregate data. PLEGRIDY-treated patients were weighted to match the aggregate baseline characteristics of SC interferon beta-1a; after matching, the key baseline characteristic values were identical for both groups. Patients were matched based on age, sex, EDSS score, years since symptom onset, and number of relapses in the prior year. 

• The use of aggregated data for the comparator and smaller sample sizes after matching
  • The results should be interpreted with caution, as there is still the potential for some residual bias; matching-adjusted (indirect/cross-trial) comparisons should be considered as observational studies
• Inherent biases from included patient populations
  • Because patients are weighted based on select baseline characteristics, the interpretation of the results after matching should be limited to patients whose baseline profile is similar to that of the analyzed patients
• The exclusion of historic studies may be a source of selection bias
• Due to the variability in adverse-event reporting across trials, the safety of PLEGRIDY and SC interferon beta-1a was not compared in this study

OPERA, A Study of Ocrelizumab in Comparison with Interferon Beta-1a (Rebif) in Participants with Relapsing Multiple Sclerosis; CARE-MS, Comparison of Alemtuzumab and Rebif® (SC interferon beta-1a TIW) Efficacy in Multiple Sclerosis.

^e Protocol-defined objective relapses were used for PLEGRIDY.
^f ARR for PLEGRIDY was analyzed with a negative binomial regression model adjusted for baseline EDSS score (<4 versus ≥4), baseline ARR (the number of relapses in the 3 years prior to study entry divided by 3), and age (<40 versus ≥40).
^g Effective n.