Efficacy and tolerability of intramuscular interferon beta-1a compared with subcutaneous interferon beta-1a in relapsing MS: results from PROOF

ABSTRACT

Objective: Benefits from interferon beta (IFNβ) treatment in patients with multiple sclerosis are affected by many factors, including sustained clinical efficacy, acceptable tolerability, adherence to therapy, and the development of neutralizing antibodies (NAbs). The Prospective and Retrospective Long-Term Observational Study of Avonex and Rebif (PROOF) was designed to compare the relative efficacy and tolerability of the two IFNβ-1a products for up to 5 years.

Methods: PROOF compared the relative efficacy and tolerability of intramuscular (IM) IFNβ-1a (Avonex) 30?µg once weekly (n= 69) and subcutaneous (SC) IFNβ-1a (Rebif) 44?µg three times per week (n= 67). The duration of the retrospective portion of the study was 12–24 months. Due to slow enrollment, PROOF ended earlier than planned and the final duration of the prospective portion of the study was 6 months. Therefore, between 18 and 30?months of efficacy and tolerability data were available for analysis.

Results: After controlling for baseline disability level, Expanded Disability Status Scale (EDSS) scores revealed no statistically significant differences between the treatment groups during the prospective portion of the study, with sustained disability progression similar in both groups (25.8% IM IFNβ-1a 30?µg once weekly vs. 26.7% SC IFNβ-1a 44?µg three times per week). Relapse rates were similar in the groups, as were MRI endpoints of brain parenchymal fraction, T1 lesion volume, T2 lesion volume, number of new/enlarging T2 lesions, and gadolinium-enhancing (Gd+) lesion volume and count. Treatment groups differed in frequency of NAbs, with 19% of patients treated with SC IFNβ-1a 44?µg three times per week NAb+ compared with none treated with IM IFNβ-1a 30?µg once weekly. More NAb+ patients compared with NAb– patients had disability progression (40.0% vs. 27.8%, p= NS), new or enlarging T2 lesions at the end of treatment (63.6% vs. 40.7%, p= 0.003), and Gd+ lesions after 12–24 months of treatment (36.4% vs. 15%, p= 0.001). The IFNβ-1a products had comparable tolerability. However, fewer patients treated with IM IFNβ-1a 30?µg once weekly had injection-site reactions (2.9% vs. 6.0%). Limitations of this study include its design and sample size, both of which hinder detection of differences in efficacy between IFNβ-1a treatments.

Conclusions: The results of the present study show that the two IFNβ-1a products have comparable efficacy and differing immunogenicity.     

Long-term adherence of patients with relapsing-remitting multiple sclerosis to subcutaneous self-injections of interferon β-1a using an electronic device: the RIVER study

ABSTRACT

Objectives: The BRIDGE study has previously shown a high short-term (12 weeks) adherence rate (>85%) of patients with relapsing-remitting multiple sclerosis (RRMS) to subcutaneous self-injections of interferon β-1a using an electronic auto-injection device (RebiSmart®). The primary goal of the RIVER study was to investigate in a real-life setting the long-term adherence to the use of RebiSmart among patients enrolled in the parent BRIDGE study.

Methods: The RIVER study was designed as a real-life extension study of the BRIDGE trial. RRMS patients who completed BRIDGE and still had an indication for treatment were included. Data were collected prospectively through the RebiSmart device, and analyzed retrospectively. Long term adherence (administration of ≥ 80% of injections) to and safety of RebiSmart were assessed. The expected follow-up period ranged from 19 to 26 months.

Results: A total of 57 RRMS patients participated in the follow-up study. The mean observation period was 20.5 ± 5.7 months. The overall adherence to the use of RebiSmart in the entire study cohort was 79.8% (median = 85.2%, range = 16–100%). There were 36 patients (63.2%) who completed at least 80% of the scheduled injections. No statistically significant differences were found between adherent and non-adherent patients in terms of age, sex, duration of the observation period, and occurrence of relapses. No serious treatment-related adverse events occurred.

Conclusions: This study showed a high level of long-term adherence to the use of RebiSmart, with 63.2% of participants meeting the criterion for adherence to treatment.     

Pharmacokinetics and pharmacodynamics of peginterferon beta-1a in patients with relapsingremitting multiple sclerosis in the randomized ADVANCE study

AimsTo evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of subcutaneous peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS) in the phase 3 ADVANCE study (n = 1512).MethodsDuring year 1, patients were randomized (1:1:1) to placebo or peginterferon beta-1a 125 μg every 2 or 4 weeks. After year 1, patients randomized to placebo were re-randomized to 125 μg peginterferon beta-1a administered every 2 weeks or every 4 weeks for year 2. Patients randomized to peginterferon beta-1a in year 1 remained on the same dosing regimen in year 2. Intensive blood samples for PK and PD (neopterin elevation; a biomarker of pharmacological activity induced by interferon beta-1a) measurements were collected from 44 patients pre-dosing and at intervals over 240 h post-dosing at weeks 4 and 24. Sparse samples were collected from all patients after each dosing at weeks 4, 12, 24, 56 and 84.ResultsThe PK profile of peginterferon beta-1a did not change over time or between dosing regimens. No accumulation was observed. Peak serum concentrations were reached 1–1.5 days post-dosing, with a mono-phasic decline and a median half-life of approximately 2–3 days. Dosing every 2 weeks provided approximately two-fold greater monthly cumulative area under the curve than every 4 weeks. Neopterin elevation was sustained for 10−14 days following each dose, indicating doubled cumulative duration of pharmacological activity for dosing every 2 weeks vs. every 4 weeks.ConclusionsThese PK/PD profiles potentially explain the enhanced efficacy of dosing every 2 weeks in patients with RRMS.     

Results from the single-use autoinjector for self-administration of subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis (MOSAIC) study

Background: Patients with multiple sclerosis (MS) often receive long-term injectable therapy, and difficulties associated with self-injection can affect treatment adherence and efficacy.

Objective: The objective of this study was to evaluate an investigational, ready-to-use, single-use autoinjector for self-injection of subcutaneous (sc) interferon beta-1a (IFNβ-1a).

Methods: In this multicenter, open-label, single-arm study, patients with relapsing MS who were receiving IFNβ-1a sc 44 μg three times weekly for ≥ 12 weeks continued therapy using a single-use autoinjector and completed a user trial questionnaire at baseline and weeks 6 and 12. The primary endpoint was the proportion of patients rating the autoinjector as easy or very easy to use at week 12.

Results: At 12 weeks, 86% of 109 patients included in the intent-to-treat population rated the autoinjector easy or very easy to use (95% confidence interval, 80% ? 93%), and the most important perceived benefit was its overall convenience. The majority (74%) of patients reported the device as somewhat or extremely convenient to use, and most (83%) agreed or strongly agreed that the device made injections simple.

Conclusion: The single-use autoinjector was well received and supported by favorable ratings for simplified injections and convenience. The results suggest that the device may improve overall injection experience in patients with relapsing MS.     

High-dose,high-frequency recombinant interferon beta-1a in the treatment of multiple sclerosis

Background: There is at present no cure for multiple sclerosis (MS), and existing therapies are designed primarily to prevent lesion formation, decrease the rate and severity of relapses and delay the resulting disability by reducing levels of inflammation. Objective: The aim of this review was to assess the treatment of relapsing MS with particular focus on subcutaneous (sc) interferon (IFN) beta-1a. Method: The literature on IFN beta-1a therapy of MS was reviewed based on a PubMed search (English-language publications from 1990) including its pharmacodynamics and pharmacokinetics, clinical efficacy in relapsing MS as shown in placebo-controlled studies and in comparative trials, efficacy in secondary progressive MS, safety and tolerability, and the impact of neutralizing antibodies. Conclusion: The literature suggests that high-dose, high-frequency sc IFN beta-1a offers an effective option for treating patients with relapsing MS, with proven long-term safety and tolerability, and has a favourable benefit-to-risk ratio compared with other forms of IFN beta.     

Good results for early treatment of clinically isolated syndrome prior to multiple sclerosis with interferon beta-1b and glatiramer group

The first sign of developing multiple sclerosis is a clinically isolated syndrome that resembles a multiple sclerosis relapse. Objective/methods: The objective was to review the clinical trials of two medicines in clinically isolated syndromes (interferon β and glatiramer acetate) to determine whether they prevent progression to definite multiple sclerosis. In the BENEFIT trial, after 2 years, 45% of subjects in the placebo group developed clinically definite multiple sclerosis; the rate was lower in the interferon β-1b group. All subjects were then offered interferon β-1b, and the original interferon β-1b group became the early-treatment group and the placebo group became the delayed-treatment group. After 5 years, the number of subjects with clinical definite multiple sclerosis remained lower in the early-treatment than in the late-treatment group. In the PreCISe trial, after 2 years, the time for 25% of the subjects to convert to definite multiple sclerosis was prolonged in the glatiramer group. Interferon β-1b and glatiramer acetate slow the progression of clinically isolated syndromes to definite multiple sclerosis. However, it is not known whether this early treatment slows the progression to the physical disabilities experienced in multiple sclerosis.     

Single-use autoinjector for peginterferon-β1a treatment of relapsing-remitting multiple sclerosis: safety,tolerability and patient evaluation data from the Phase IIIb ATTAIN study

Objectives: A sub-study to evaluate safety, tolerability, ease-of-use and patient satisfaction with a single-use autoinjector administering subcutaneous peginterferon-β_1a (a pegylated interferon-β_1a in clinical development) in a subset of relapsing-remitting multiple sclerosis (MS) patients participating in ATTAIN, a long-term dose-frequency blinded extension of the Phase III randomized ADVANCE study.

Methods: Over 8 weeks, patients self-administered peginterferon-β_1a 125 µg or placebo every 2 weeks (two injections via manual pre-filled syringe [PFS]; two injections via single-use autoinjector). Primary end points were incidence of adverse events (AEs), patient assessment of injection pain score (10-point Visual Analog Scale), and clinician assessment of injection site reactions (ISRs). Secondary objectives included patient assessment of ease-of-use and satisfaction with the autoinjector and evaluation of autoinjector training materials.

Results: In 39 patients, the safety profile of peginterferon-β_1a was similar when delivered via autoinjector or PFS; AEs were mostly mild or moderate in severity. Clinicians and patients reported a similar tolerability profile using both PFS and autoinjector, and pain scores were low (< 1), with no reports of clinician-assessed ISRs after administration with the autoinjector. Patients perceived the single-use autoinjector to be easy to use and convenient; overall patient satisfaction with the autoinjector and accompanying training materials was high.

Conclusion: The safety and tolerability profile of peginterferon-β_1a delivered via autoinjector was similar to delivery via PFS. Patients found the autoinjector easy to use and convenient; this device may simplify the injection process for MS patients who require long-term therapy, thereby potentially improving patient’s quality of life and adherence.