Application of Interferon Beta-1b in Multiple Sclerosis
RCTs led to the approval of IFNβ-1b by regulatory agencies for medical drugs and devices worldwide. They were subsequently slightly modified by substituting the placebo with another approved disease-modifying therapy. This type of ‘active comparator’ study allows the superiority of IFNβ-1b versus other standard-of-care or experimental compounds to be measured.
Baseline versus Therapy Studies
A BVT study is where each patient receives exposure to the drug after a natural history evaluation period. The main advantages offered by this type of study versus the RCTs are:
• •
each patient serves as his/her own control, thus minimizing the effect of inter-patient variability in measuring drug effect; and it generally requires a smaller number of subjects.
However, at the same time, BVT studies eliminate the blinding component of the RCT, thus potentially introducing the so-called Pygmalion type of bias. In MS, studies of this led to the initial identification of IFNβ-1b’s efficacy in decreasing the number of active lesions or CELs within individual patients.
Presently, in patients with MS, placebo-controlled trials can still ethically be prepared, but with restrictions. Specifically, for MS patients for whom established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the patients refuse any of the existing therapies, have not responded to them, or if these treatments are not available for other reasons, such as cost.19
Interferon Beta-1b Effects on Clinical and Imaging Disease Parameters This section discusses the effects of IFNβ-1b on clinical and imaging measures of disease seen in the main clinical trials. Clinical and imaging findings will be presented separately. For each type of finding, evidence obtained in each patient subgroup, i.e. CIS, RRMS and SPMS with and without superimposed relapses and PPMS, is discussed.
In the majority of clinical trials and post-marketing studies, IFNβ-1b has been administered at a dosage of 8 million international units, equivalent to 250 µg, subcutaneously, every other day (EOD). For the purpose of this review, this dosage is always referred to as the as standard dose unless otherwise indicated. In addition, when specifying that the effects of the drug were found to be significant, a p-value ≤0.05 is always referred to. Readers are advised to consult the individual papers referred to for additional details regarding the magnitude of alpha error of each study.
Clinical Measures Frequency and Severity of Clinical Relapses
When looking at differences in clinical relapse rate between patients treated with IFNβ-1b and patients in the placebo group, a statistically significant reduction was seen and maintained over the course of two-year observational periods in patients with CIS,20 and SPMS with superimposed relapses.22 RRMS21
RRMS21 On average, one in every seven or one in every nine CIS20 patients will remain relapse-free for two years if treated with 250 µg IFNβ-1b. It is important to highlight that US NEUROLOGY
when a greater proportion of CIS patients remain relapse-free, ultimately a greater proportion have a delay in time to conversion to MS.20
Such reductions, to some extent dose-dependent,21 are attributable
to an average two-fold decrease in the frequency of moderate and severe attacks in treated versus untreated patients. Subcutaneous administrations of 250 µg IFNβ-1b EOD had greater efficacy than 50 µg EOD.21
On clinical relapse, 250 µg IFNβ-1b was not inferior to:
• 500 µg subcutaneous IFNβ-1b EOD;23 • 22 µg IFNβ-1a subcutaneously once weekly;24 • 44 µg IFNβ-1a subcutaneously three times per week; or25 •
20 mg subcutaneous glatimerar acetate (GA) daily23
or EOD.26
The greater efficacy of standard doses of IFNβ-1b over 30 µg IFNβ-1a given intramuscularly once weekly has been proven.25,27
In SPMS patients
without superimposed relapses, IFNβ-1b 250 µg or 160 µg/m2 body surface area administered EOD significantly decreased the number of clinical attacks over a time period of up to two years.28
Observational periods longer than two years have provided controversial results. In CIS patients, early treatment with 250 µg IFNβ-1b maintained a reduced annualized relapse rate for only one additional year, but not from year four of therapy onwards versus patients starting therapy two years later.29
In RRMS patients, a one-third reduction in exacerbation rate was maintained for up to five years versus placebo.30
Differences in mean
yearly exacerbation rate between patients treated with a standard dose of IFNβ-1b and those treated with either 50 µg subcutaneous IFNβ-1b EOD or placebo only remained statistically significant until the end of the second year of therapy.30
Conversely, a lower rate of severe versus
In SPMS patients with superimposed relapses, a statistically relevant decrease in mean relapse rate was sustained for up to four years in treated patients.31
Disability Progression
When one looks at the effect of a given drug in reducing disability progression, two important considerations need be kept in mind. First, disability changes during therapy might be linked to the indirect effect of a given drug in reducing the number and severity of clinical relapses, thereby leading to slower or lower accumulation of disability over time. Second, changes in disability might be due to a direct effect of the drug in promoting faster and more efficient remyelination or relenting demyelination. This will favor slower and less pronounced disability accumulation independently from the effect of reducing clinical relapse.
Compared with placebo, 250 μg subcutaneous IFNβ-1b EOD over a two-year time period significantly reduced the proportion of patients experiencing a sustained progression in disability among those with CIS, RRMS and SPMS with superimposed relapses.20,21,22 rate, 250 µg was superior to 50 µg administered EOD21
As seen with relapse but was not
inferior to the following subcutaneous regimens for remaining free from disability progression or having relevant beneficial changes in EDSS during therapy: 500 µg IFNβ-1b EOD,23 44 µg IFNβ-1a three times per week.25
22 µg IFNβ-1a once weekly24 Interestingly, on measures of
and disability progression by EDSS scores, 250 µg subcutaneous IFNβ-1b EOD 49
moderate relapses was seen throughout five years in the standard-dose group.30
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76