Efficacy and safety

AVONEX has been the subject of multiple studies. The clinical effects of AVONEX in patients with relapsing forms of multiple sclerosis (MS) were studied in the MSCRG clinical trial (Study 1) and the CHAMPS clinical trial (Study 2).1-3 Its clinical effects were further analyzed in the long-term follow-up studies, CHAMPIONS (10 years) and ASSURANCE (15 years).4,5 These 4 studies are presented below.

Abbreviations: MSCRG, Multiple Sclerosis Collaborative Research Group; CHAMPS, Controlled High-Risk AVONEX Multiple Sclerosis Prevention Study; CHAMPIONS, Controlled High-Risk AVONEX Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance; ASSURANCE, ASSessment of Drug Utilization, EaRly TreAtmeNt, and Clinical Outcomes; IM, intramuscular.

AVONEX pivotal trials

AVONEX MSCRG pivotal study design (Study 1)1,2

A 2-year, randomized, double-blind, placebo-controlled study of 301 patients with relapsing MS in which
282 patients completed 1 year on study, and 172 (AVONEX, n=85; placebo, n=87) patients completed 2 years on study.

Randomization

AVONEX

n=158
AVONEX 30 mcg
by IM injection
once weekly

Placebo

n=143
Placebo
by IM injection
once weekly

Primary

Time to progression in disabilitya

Additional

  • Mean confirmed change in Expanded Disability Status Scale (EDSS) score from study entry (baseline) to the end of the study
  • Rate and frequency of relapses
  • MRI measures including number and volume of gadolinium-enhanced (Gd+) lesions and volume of T2-weighted lesions

aDisability progression was defined as a ≥1-point increase in EDSS score sustained for at least 6 months, to help distinguish permanent increase in disability from a transient (due to an exacerbation) increase.

  • Had a diagnosis of clinically definite multiple sclerosis (CDMS) for at least 1 year

AND

  • A baseline EDSS score of 1.0 to 3.5
  • Chronic progressive MS

Neurological evaluations
Performed at baseline and every 6 months

MRI evaluations
Performed at baseline, at year 1, and at year 2

In the MSCRG (Study 1) pivotal trial, AVONEX significantly reduced the risk of sustained disability progression at 2 years (P=.02)1,2,a

78% of patients taking AVONEX had no sustained disability progression at 2 years compared with 65% of placebo-treated patients.

The percentage of patients progressing in disability by the end of 2 years was 22% in the AVONEX group and 35% in the placebo group.

Not all enrolled patients were assessed at 2 years.

AVONEX-treated patients were 37% less likely to have sustained disability progression at 2 years compared with placebo

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Primary

Time to second relapse

Additional

  • MRI measures, including:
    • Cumulative increase in the number of new or enlarging T2 lesions
    • T2 lesion volume at baseline compared to results at 18 months
    • Number of Gd+ lesions at 6 months
  • Had recently experienced an isolated demyelinating event involving the optic nerve, spinal cord, or brainstem/cerebellum

AND

  • Had lesions typical of MS on brain MRI
  • Prior neurologic or visual event consistent with the occurrence of demyelination that lasted longer than 48 hours

Neurological evaluations
At baseline, at month 1 (and again at month 2, if the patient’s condition was not considered to be stable or improving at month 1), at month 6, and every 6 months thereafter

MRI evaluations
Performed at baseline and at months 6, 12, and 18

bWho had recently experienced an isolated demyelinating event involving the optic nerve, spinal cord, or brainstem/cerebellum, and who had lesions typical of MS on brain MRI.

cPatients were enrolled into the study over a 2-year period and followed for up to 3 years or until they developed a second relapse in an anatomically distinct region of the central nervous system.

In the CHAMPS (Study 2) pivotal trial, time to second relapse was significantly delayed in AVONEX-treated patients compared to placebo-treated patients (P=.002)1,3

79% of patients taking AVONEX were relapse free at 2 years compared with 61% of placebo-treated patients.

The percentage of patients developing a second relapse within 2 years was 21% in the AVONEX group and 39% in the placebo group.

The relative rate of developing a second relapse in the AVONEX group was 0.56 of the rate in the placebo group (95% CI, 0.38-0.81).

Adverse reactions1

AVONEX has a well-understood safety profile

In placebo-controlled studies, adverse reactions observed at an incidence ≥20% on AVONEX and at least 2% more frequently on AVONEX than placebo were:

Other adverse reactions that occurred in the placebo-controlled studies with AVONEX-treated patients (n=351) at an incidence of at least 2% more than that observed in the placebo-treated patients (n=333) included:

  • Chills: 19% AVONEX-treated versus 5% placebo-treated patients
  • Abdominal pain: 8% AVONEX-treated versus 6% placebo-treated patients
  • Injection site pain: 8% AVONEX-treated versus 6% placebo-treated patients
  • Infection: 7% AVONEX-treated versus 4% placebo-treated patients
  • Injection site inflammation: 6% AVONEX-treated versus 2% placebo-treated patients
  • Chest pain: 5% AVONEX-treated versus 2% placebo-treated patients
  • Injection site reaction: 3% AVONEX-treated versus 1% placebo-treated patients
  • Toothache: 3% AVONEX-treated versus 1% placebo-treated patients
  • Depression: 18% AVONEX-treated versus 14% placebo-treated patients
  • Dizziness: 14% AVONEX-treated versus 12% placebo-treated patients
  • Upper respiratory tract infection: 14% AVONEX-treated versus 12% placebo-treated patients
  • Sinusitis: 14% AVONEX-treated versus 12% placebo-treated patients
  • Bronchitis: 8% AVONEX-treated versus 5% placebo-treated patients
  • Arthralgia: 9% AVONEX-treated versus 6% placebo-treated patients
  • Urinary tract infection: 17% AVONEX-treated versus 15% placebo-treated patients
  • Urine constituents abnormal: 3% AVONEX-treated versus 0% placebo-treated patients
  • Alopecia: 4% AVONEX-treated versus 2% placebo-treated patients
  • Eye disorder: 4% AVONEX-treated versus 2% placebo-treated patients
  • Injection site ecchymosis: 6% AVONEX-treated versus 4% placebo-treated patients
  • Anemia: 4% AVONEX-treated versus 1% placebo-treated patients
  • Migraine: 5% AVONEX-treated versus 3% placebo-treated patients
  • Vasodilation: 2% AVONEX-treated versus 0% placebo-treated patients

Long-term follow-up studies: CHAMPIONS

Explore CHAMPIONS, a 10-year follow-up of the CHAMPS pivotal trial4

CHAMPIONS extension study design

CHAMPIONS was a 10-year open-label, prospective follow-up of the pivotal phase 3 CHAMPS study (Study 2) and the CHAMPIONS 5-year follow-up.1,3,4,6

In the CHAMPIONS prospective 10-year follow-up study,
patients randomly assigned in CHAMPS to receive 30 mcg of IM interferon beta-1a once a week were characterized as the immediate treatment (IT) group (n=81), and those randomly assigned to receive placebo were characterized as the delayed treatment (DT) group (n=74).4

For the IT group, treatment with AVONEX was initiated early (within a month) after onset of clinically isolated syndrome (CIS), and for the DT group treatment was initiated a median of 30 months (interquartile range, 24-35 months) after CHAMPS randomization.4

All patients were offered, but not required to take, 30 mcg of IM interferon beta-1a once a week at enrollment. All MS-related disease-modifying therapies (DMTs) and symptomatic therapies (with the exclusion of investigational therapies) were prescribed at the discretion of the study investigator and in accordance with local practices.4

dAlternative (other) therapies included SC interferon beta-1b and interferon beta-1a, glatiramer acetate, intervals of high-dose corticosteroid treatment, mitoxantrone hydrochloride, and natalizumab.

Study limitations4

  • The study was an open-label extension study
  • Long-term study design includes the possibility of selective attrition of patients with greater levels of disease activity
  • The study protocol did not include the measurement of neutralizing antibodies against interferon beta
  • At the end of the study, individual patients (n=10 of 127) may no longer have met the criteria for relapsing MS based on retrospective assessment
  • As with all sampling, there is a possibility of significant nonrandom differences between cohorts. The CHAMPIONS 10-year cohort reflects a sampling of the CHAMPIONS 5-year cohort, which in turn was only a sampling of the original CHAMPS cohort
  • Further studies are needed to determine whether there are particular high-risk groups that require immediate initiation of DMTs

Disclosure4
CHAMPIONS was funded by Biogen.

CHAMPIONS 10-year extension results4

Early treatment with AVONEX reduced rate of progression to CDMS at 10 years4

At 10 years, the cumulative probability of developing clinically definite multiple sclerosis (CDMS)e was significantly lower in the IT group (58% [95% CI, 48%-68%]) than the DT group (69% [95% CI, 61%-78%]) (unadjusted hazard ratio, 0.64 [95% CI, 0.48-0.87]; P=.004). The treatment effect was comparable when adjusting for age, CHAMPS qualifying event, number of CHAMPS baseline T2 lesions, and baseline number of Gd+ lesions (adjusted hazard ratio, 0.61 [95% CI, 0.45-0.82]; P=.001).

eDefined as development of a second exacerbation in an anatomically distinct region of the central nervous system in patients with CIS.

fKaplan-Meier rates for the development of CDMS calculated using timing from the first month. Patients not meeting the criteria for CDMS were censored on the date of their last neurologic examination.

81% (103 of 127) of all patients had an EDSS score below 3.0 at 10 years4

  • 9% (n=12) of all patients and 16% of CDMS patients reached an EDSS score of 4.0 or greater
  • 6% (n=7) of all patients and 10% of CDMS patients reached an EDSS score of 6.0 or greater

Additional efficacy results4

  • Annualized relapse rate (ARR) in the DT group was double that of the IT group from years 5 to 10 (0.31 vs 0.14; P=.03), even though use of interferon beta-1a was comparable during that time. A similar trend was observed during the first 5 years (0.36 vs 0.18; P=.04) and over the entire 10 years (0.33 vs 0.16; P=.02), but these differences did not meet the 0.01 threshold for statistical significance
  • There were no significant differences between the IT and DT groups for any of the MRI measures conducted in the study

No changes to the well-understood safety profile of AVONEX were identified in CHAMPIONS out to 10 years1,4

  • Over the course of the entire 10-year follow-up, there were 34 serious adverse events in 25 patients, including 2 deaths (metastatic breast cancer and an automobile accident)4
  • Serious adverse events were similar by treatment group (16 patients in the IT group and 18 patients in the DT group had serious adverse events)4
  • Please see Adverse Reactions from clinical trials
  • In placebo-controlled studies, adverse reactions observed at an incidence ≥20% on AVONEX and at least 2% more frequently on AVONEX (n=351) than placebo (n=333) were headache (58% vs 55%), flu-like symptoms (49% vs 29%), myalgia (29% vs 22%), asthenia (24% vs 18%), nausea (23% vs 19%), pain (23% vs 21%), and fever (20% vs 9%)1

56% (45 of 81) of patients who started on AVONEX (IT group) were on AVONEX 10 years later4

Long-term follow-up studies: ASSURANCE

Discover ASSURANCE, a 15-year follow-up of the MSCRG pivotal trial5

ASSURANCE follow-up study design5

ASSURANCE, a multicenter, observational, single-time-point evaluation of patients conducted 15 years after the MSCRG pivotal trial (Study 1), evaluated the impact of AVONEX treatment on long-term disability in patients who completed 2 years in the MSCRG study.

The primary endpoints of ASSURANCE were change in EDSS score from baseline (start of MSCRG study) and percentage of patients with EDSS scores of at least 4, at least 6, and at least 7. Physician-measured EDSS scores were obtained during the original MSCRG study. Patient-reported EDSS scores were used for the 15-year time point.

In the ASSURANCE 15-year follow-up study,
patients were eligible regardless of current treatment or treatment assignment in the MSCRG study. Deceased patients were included if they were deceased at the time of the 8-year follow-up and/or if they were listed in a public database as deceased. A total of 172 patients from the MSCRG study were eligible, and 122 living patients (71%) were enrolled in ASSURANCE. An additional 14 patients (8%) were deceased. Thus, we were able to determine the status of 79% (136/172) of the eligible patients. The analysis focused on the 122 living patients.5

Propensity scores were calculated to estimate the probability of current AVONEX treatment given the observed baseline covariates. Propensity score analysis is a rigorous statistical technique used in observational studies to correct for any measured baseline differences between nonrandomized groups.5

gPatients not currently taking AVONEX were either not on any therapy or were using different medications, including natalizumab, glatiramer acetate, SC interferon beta-1b, SC interferon beta-1a, and methotrexate.

Study limitations5

  • Incomplete ascertainment, a problem inherent in long-term follow-up studies, lowers power and may skew the results because of informative censoring
  • As no randomization to treatment existed beyond the MSCRG core study, it is assumed that unmeasured factors contributed to treatment decisions during the follow-up interval. While not a replacement for randomization, the use of propensity score weightings results in more equivalent comparison groups
  • There may be inherent biases in nonrandomized observational studies. Despite the use of propensity score weightings to adjust for baseline differences between comparison groups and to reduce bias that could arise from the lack of randomization in AVONEX use after the 2-year clinical trial, multiple unobserved factors may have influenced the beneficial outcomes for those currently on AVONEX. Such possible biases include the presence of less aggressive disease, better adherence to therapy over time, and better overall health and symptom management
  • Although these data show that a subgroup of patients do well on AVONEX over the long term, the reason for this result (therapeutic effect vs different natural history) cannot be fully addressed by these data. It is impossible to draw causal inferences between either the continued use of AVONEX or a fundamentally benign natural history in the group of patients with better long-term outcomes
  • The group of patients described is relatively small and initially was enrolled based on select criteria for disease activity; therefore, extrapolating the results of this study to the entire population without confirmation in additional patient samples is hazardous
  • Patients continuing to use AVONEX at the 15-year time point were more likely to have been randomized to AVONEX during the clinical trial (38 current users originally randomized to AVONEX vs 18 originally randomized to placebo) and had slightly lower EDSS scores at study entry (2.1±0.77 vs 2.4±0.85)
  • Presumably, the magnitude of benefit for active versus placebo treatment in this patient sample was not sufficiently large to overcome the effects of small patient numbers and inconsistent treatment patterns over the long follow-up interval
  • The self-reported EDSS used in this trial has been shown to have a strong correlation between patient and physician reports. As such, we believe that any discrepancies between patient and physician EDSS scores are more than counterbalanced by the higher ascertainment rate possible by the self-report method, particularly at the higher EDSS levels, when patients are less likely able to travel to the site for a physician-derived EDSS

Disclosure5
ASSURANCE was supported and funded by Biogen.

ASSURANCE 15-year follow-up study results5

At 15-year follow-up, patients on AVONEX experienced less disability compared with patients not currently taking AVONEX5

  • The mean EDSS score for patients on AVONEX was 4.4 versus 5.7 for patients not on AVONEX (median, 5.0 vs 6.0; range, 0-8.5 vs 0-9.0)
  • Patients currently on AVONEX had a smaller mean change from baseline EDSS score versus those not currently on AVONEX (2.3 vs 3.3; median, 2.5 vs 4.0; range, –1.5 to 6.5 vs –2.0 to 6.5)
  • 27% of patients currently on AVONEX had a stable disability score since enrollment into the MSCRG trial versus 17% of patients not currently on AVONEX
  • Patients on AVONEX at 15-year follow-up reported:
    • 64% reached an EDSS milestone of 4.0 versus 83% of patients not on AVONEX
    • 32% reached an EDSS milestone of 6.0 versus 62% of patients not on AVONEX
    • 9% reached an EDSS milestone of 7.0 versus 33% of patients not on AVONEX

Patient use over 15 years5

Nearly half the patients enrolled in ASSURANCE were taking AVONEX at 15-year follow-up

  • 46% (56 of 122) of patients were on AVONEX at 15-year follow-up
  • 13.3 years was the median duration of use among patients currently taking AVONEX (mean, 12.1; range, 3-15 years)
    • Of these 56 patients, 80% used AVONEX for at least 10 years
  • AVONEX was the only DMT that had been used by 42 of 56 patients (75%) currently on AVONEX

No changes to the well-understood safety profile were identified over 15 years of use5

In placebo-controlled studies, adverse reactions observed at an incidence of ≥20% on AVONEX and at least 2% more frequently on AVONEX (n=351) than placebo (n=333) were headache (58% vs 55%), flu-like symptoms (49% vs 29%), myalgia (29% vs 22%), asthenia (24% vs 18%), nausea (23% vs 19%), pain (23% vs 21%), and fever (20% vs 9%).1

Please see Contraindications and Warnings and Precautions in the Important Safety Information below.