CNS Drugs. 2004;18(8):521-546
McCormack PL, Scott LJ.
Adis International Limited, Auckland, New Zealand.
Interferon-beta-1b (Betaseron((R)), Betaferon((R))) is a non-glycosylated recombinant human interferon-beta approved for high-frequency, subcutaneous (SC) administration in the treatment of multiple sclerosis (MS).
Its mechanism of action is unknown, but may involve modulation of the autoimmune pathogenic processes of MS.
In a randomised, double-blind trial in patients with relapsing-remitting MS (RRMS), SC interferon-beta-1b 250 micro g (8 million International Units [MIU]) every other day reduced the annual relapse rate and increased the proportion of relapse-free patients compared with placebo.
It also reduced relapse severity, hospitalisations, and disease activity assessed by magnetic resonance imaging (MRI), and increased the time to first relapse.
Progression of disability showed a trend towards reduction relative to placebo and baseline, but did not reach statistical significance.
SC interferon-beta-1b 250 micro g every other day was shown in a randomised trial to be superior to intramuscular (IM) interferon-beta-1a 30 micro g (6 MIU) once weekly with respect to reductions in relapse-related parameters, disability progression and MRI-assessed disease activity.
In patients with secondary progressive MS (SPMS), SC interferon-beta-1b 250 micro g every other day slowed progression of the disease relative to placebo in one randomised, double-blind trial, but not in another.
In both studies, interferon-beta-1b 250 micro g recipients had fewer relapses and less MRI-assessed disease activity than placebo recipients.
The difference in primary outcome may reflect differences in patient entry criteria.
Interferon-beta-1b is generally well tolerated and the common adverse events (e.g. injection site reactions, asthenia and an influenza-like symptom complex) are clinically manageable.
In a randomised trial, the tolerability of SC interferon-beta-1b 250 micro g every other day was generally similar to that of IM interferon-beta-1a 30 micro g once weekly, except for higher incidences of injection site reactions and neutralising anti-interferon-beta antibodies with SC interferon-beta-1b.
In conclusion, SC interferon-beta-1b 250 micro g every other day reduces the frequency and severity of relapses and MRI measures of disease activity and may delay the progression of disability in RRMS.
The drug appeared to be more effective than, and as well tolerated as, IM interferon-beta-1a 30 micro g once weekly.
Interferon-beta-1b also has positive effects on relapse rates and disease activity in patients with SPMS, although its effects on disease progression remain uncertain.
The drug is generally well tolerated, and the common adverse events are clinically manageable.
Thus, interferon-beta-1b is a valuable first-line therapy for patients with RRMS and a potentially useful option in those with SPMS.
The mechanism of action of interferon-beta-1b in multiple sclerosis (MS) is not known and could involve any of the known actions of interferon-beta, which include antiviral, anti-inflammatory, antiproliferative and immunomodulatory activities.
Owing to the autoimmune nature of MS, current hypotheses favour the immunomodulatory actions of interferon-beta-1b as those responsible for its therapeutic efficacy in MS.
Interferon-beta-1b is thought to interfere with T-cell activation, cytokine production and cellular activities responsible for the inflammatory and destructive processes occurring within the CNS.
Interferon-beta-1b may also be instrumental in maintaining the integrity of the blood-brain barrier and preventing the penetration of activated autoimmune T-cells into the CNS.
Interferon-beta-1b is immunogenic and many patients develop binding antibodies to interferon-beta.
A proportion of these are neutralising antibodies (NAB) that inhibit the biological activity of interferon-beta.
The reported prevalence of NAB is variable (28-38% in pivotal clinical trials) since it is highly dependent on the assay method used.
NAB develop early after initiation of therapy; titres peak at 1.5-2 years, and then decline with continued tres peak at 1.5-2 years, and then decline with continued therapy.
Many patients initially positive for NAB to interferon-ß-1b revert to an NAB-negative status.
A recent consensus statement suggests that NAB-related loss of clinical efficacy of interferon-ß may occur, depending on the duration and severity of decreased bioactivity.
However, current data on the clinical impact of NAB in trials of interferon-ß-1b, as with other interferon-ß products, are conflicting.
NAB are cross-reactive between interferon-ß-1b and interferon-ß-1a.
In the absence of guidelines on how to manage the NAB-positive patient, it is appropriate to base treatment decisions on clinical, rather than NAB, status.
The pharmacokinetic properties of interferon-ß-1b are not well characterised as a result of technical difficulties in quantifying serum concentrations of the drug.
Following single-dose subcutaneous (SC) administration of 500µg (16 million International Units [MIU]) in 12 healthy adult volunteers, peak serum concentrations were attained at 1-8 hours.
The bioavailability was 51%.
There was no serum accumulation following SC administration of 500µg once daily for 8 days in healthy volunteers.
Peak serum concentrations of interferon-ß-1b in three patients with MS receiving long-term therapy with SC interferon-ß-1b 250µg every other day were 260-290 IU/mL at 8-24 hours; they declined to near pre-injection levels (75-90 IU/mL) by 48 hours.
Following intravenous administration in 9 healthy volunteers, the elimination half-life was 4.29 hours, the clearance was 0.76 L/h/kg, and the steady state volume of distribution was 2.88 L/kg.
Blood levels of biological response markers (BRMs) induced by interferon-ß, such as neopterin, ß(2)-microglobulin and human myxovirus protein A (MxA), are more frequently used to assess the kinetics of interferon-ß-1b activity.
After single-dose administration of SC interferon-ß-1b 250µg in 5 healthy volunteers, peak blood levels of the BRMs occurred at 24-48 hours and then declined to baseline levels by 120-168 hours.
Blood levels of BRMs increased in a dose-dependent manner with SC interferon-ß-1b 62.5-375µg.
During multiple-dose SC administration of interferon-ß-1b 250µg every other day in healthy volunteers, maximum blood levels of various BRMs were attained after 40-123 hours.
A small dose-finding study in 30 patients with relapsing-remitting MS (RRMS) indicated that SC interferon-ß-1b 250µg every other day was an appropriate dosage regimen based on efficacy and tolerability.
The pivotal multicentre, randomised, double-blind trial in 338 patients with RRMS demonstrated that SC interferon-ß-1b 250µg every other day significantly reduced the mean annual relapse rate and increased the proportion of relapse-free patients compared with placebo (primary endpoints assessed at 2 years).
In addition, interferon-ß-1b was more effective than placebo for other endpoints (measured over 2 or 3 years), with a longer median time to first relapse, reductions in relapse severity and MS-related hospitalisations, and improvement in all magnetic resonance imaging (MRI) measures of disease activity.
Improvements in relapse rates and annual activity monitored by MRI were maintained throughout the 5-year study period.
Interferon-ß-1b did not significantly reduce disease progression over 5 years, relative to placebo or baseline, as assessed by changes in Kurtzke's Expanded Disability Status Scale (EDSS) scores, although the trial was not sufficiently powered to show such an effect.
In the only head-to-head, randomised, active comparator trial of interferon-ß-1b, the Independent Comparison of Interferons (INCOMIN) trial in patients with RRMS, SC interferon-ß-1b 250µg every other day for 2 years (n = 96) was superior to intramuscular (IM) interferon-ß-1a 30µg (6 MIU) once weekly (n = 92) for all efficacy parameters, including the primary endpoint of proportion of patients remaining relapse free after 2 years (51% vs 36%, p < 0.05).
Mean annual relapse rates, progression of disability (assessed using EDSS) and MRI measures of disease activity were all significantly lower in the interferon-ß-1b group.
In the randomised, double-blind European study of SC interferon-ß-1b 250µg every other day for 3 years in patients with secondary progressive MS (SPMS), interferon-ß-1b significantly delayed the time to confirmed disease progression according to changes in the EDSS scores, and reduced the proportion of patients with confirmed progression by 21.7% and the proportion of patients becoming wheelchair bound by 32% relative to placebo.
In addition, interferon-ß-1b increased the time to first relapse and reduced the annual relapse rate, the proportion of moderate or severe relapses, MS-related hospital admissions and corticosteroid use, and MRI-assessed newly active lesions and total lesion volume.
The relative difference in EDSS scores between placebo and interferon-ß-1b recipients observed at 36 months was maintained during open-label treatment in a subset of patients assessed at 96 months.
In contrast, a randomised, double-blind study conducted in North America in patients with SPMS showed that SC interferon-ß-1b 250µg or 160 µg/m(2) (5 MIU/m(2)) every other day for 3 years had no significant effect on disease progression, as measured by changes in EDSS scores, compared with placebo, although at the fixed 250µg dosage the annual relapse rate was significantly reduced, and both dosages significantly reduced MRI-assessed lesions, relative to placebo.
Neither dosage affected the proportion of moderate or severe relapses, MS-related hospitalisations or the number of patients requiring corticosteroids (although there were fewer corticosteroid courses with the 250µg dosage).
Patients with SPMS treated with SC interferon-ß-1b 250µg every other day for up to 3 years had mean total Sickness Impact Profile scores not significantly different from those in placebo recipients.
Between-group differences in favour of interferon-ß-1b for the physical dimension components of this health-related quality of life (HR-QOL) assessment scale reached statistical significance at 6 and 12 months and at the last visit, while those for the psychosocial dimension were significant only at 18 months.
HR-QOL in patients with RRMS treated for >2 years (mean duration approximately 5 years) with interferon-ß-1b 250µg every other day (n = 80) was assessed using the Short-Form Health Survey (SF-36) questionnaire.
Relative to historical control patients, those with an EDSS score <3.0 had significant improvements in 4 of 8 SF-36 domains, those with an EDSS score 3.0-6.0 had no improvement, and those with an EDSS score >6.0 had improvement in the physical function domain.
Using a £30000/quality-adjusted life year (QALY) threshold and a 20-year time frame, interferon-ß-1b approached a 50% probability of being cost effective for both RRMS and SPMS, a level of cost effectiveness less likely to be achieved by three other interferon-ß products or glatiramer acetate.
Relative to no treatment, interferon-ß-1b appeared cost effective over 10 years (cost/QALY, euro7800) and cost saving over 15-25 years when progression from RRMS to SPMS, and costs and utilities at all disease/disability levels, were considered.
The cost/QALY over 20 years for a patient starting treatment at EDSS level 3.0 had a >80% probability of being below euro50000.
Nonetheless, uncertainty over the cost-utility of interferon-ß-1b remains and firm conclusions cannot be drawn at this time.
SC interferon-ß-1b is generally well tolerated at the recommended dosage of 250µg every other day in patients with MS.
The most frequent adverse events, occurring in >=30% of patients, are injection site reaction, asthenia, influenza-like symptoms, headache, pain, hypertonia, myasthenia, fever and arthralgia.
Injection site necrosis occurred in 5% of patients.
Lymphopenia is the most common laboratory abnormality, but is generally mild and intermittent.
Elevated liver enzymes occur in 3% (AST) and 10% (ALT) of patients.
Autoimmune disease and/or autoantibodies may occur in a small proportion of patients and most commonly manifest clinically as thyroid or liver dysfunction.
Although depression may increase with therapy with interferon-ß, the incidence of depression with interferon-ß-1b was similar to that with placebo in clinical trials.
Interferon-ß-1b at dosages higher than those currently recommended appears to have acceptable tolerability in ongoing trials.
In the 2-year INCOMIN trial in 186 patients with RRMS, the tolerability profile of SC interferon-ß-1b 250µg every other day was similar to that of IM interferon-ß-1a 30µg once weekly, except for significantly higher incidences of injection site reactions and NAB with interferon-ß-1b.
A randomised, rater-blinded, 4-week study in 64 healthy volunteers indicated that SC interferon-ß-1b 250µg every other day caused approximately one-third less injection site pain than SC interferon-ß-1a 44µg (12 MIU) three times weekly (p < 0.0001), as well as almost one-half the number of injection site reactions (p < 0.0001), which were of lower severity (p < 0.01).
Dosage and Administration
Interferon-ß-1b is approved in the US for the treatment of relapsing forms of MS to reduce the frequency of clinical relapses, and in Europe for the treatment of active RRMS and SPMS; the difference in indications reflects the disparate results of the two pivotal trials in SPMS conducted in the US and Europe.
The recommended dosage in both the US and Europe is 250µg injected SC every other day; in the US, the dosage should be titrated to this level over a 6-week period.
The duration of therapy is undefined, but consensus guidelines recommend that therapy be continued indefinitely where possible.
Therapy should be restricted to adult patients (aged 18-64 years).Interferon-ß-1b is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon-ß, pregnant women and breast-feeding mothers.
Special caution should be exercised in patients with active depression.
There are no known interactions between interferon-ß-1b and other drugs.