Pharmacology

Interferons are cytokines that mediate antiviral, antiproliferative, and immunomodulatory activities in response to viral infections and other biological inducers.

Pharmacodynamics. Interferon beta exerts its effect by binding to specific receptors on human cells. This leads to a complex chain of events that, in turn, lead to expression of various interferon-induced gene products that are believed to be the mediators of the biological actions of interferon beta 1b. The exact mechanism of action is not fully understood, but it may decrease the synthesis of inflammatory cytokines interferon gamma and tumor necrosis factor alpha.

Interferon beta 1b stabilizes the blood-brain barrier, which is damaged in multiple sclerosis. This might help improve the management of multiple sclerosis. Interferon beta 1b achieves this by blocking apoptosis of the endothelial cells of the blood-brain-barrier that is induced by serum from multiple sclerosis patients (15). Measurement of immunological biomarkers such as cytokines and neurotrophic factors in patients treated with interferon beta 1b for 1 year indicate their usefulness as indicators of clinical response (08).

Pharmacokinetics. Because serum concentrations of interferon beta 1b are low or undetectable following subcutaneous administration of 0.25 mg or less, pharmacokinetic information in patients with multiple sclerosis receiving the recommended dose of the drug is not available. In healthy volunteers, serum interferon beta 1b concentrations are generally below 100 IU/mL following single and multiple daily subcutaneous administrations of 0.5 mg of the drug. Peak serum interferon beta 1b concentrations occur between 1 and 8 hours. The pharmacokinetic profile is similar after intravenous administration. In patients receiving single intravenous doses up to 2.0 mg, increases in serum concentrations are dose proportional. Mean terminal elimination half-life values ranged from 8.0 minutes to 4.3 hours. Prolonged treatment does not result in accumulation of interferon beta 1b in the serum of patients.

Formulations. A refrigeration-free formulation of interferon beta 1b, based on mannitol, is stable at room temperature for up to 2 years. The safety and efficacy of the refrigeration-free formulation of interferon beta 1b is comparable with that of the original glucose.

Pharmacogenetics/pharmacogenomics. Nonresponder and responders to interferon beta differ in their ex vivo gene expression profile as determined by cDNA microarrays, longitudinal gadolinium-enhanced MRI scans, and clinical disease activity. These findings will help to better understand the mechanism of action of interferon beta in relation to different disease patterns and enable optimized therapy. Several differentially regulated genes have been identified in healthy volunteers in response to interferon beta 1b, and this biomarker panel may become a valuable tool for assessment of clinical drug effects.

Clinical trials

Several clinical trials have been conducted with interferon beta 1b. Some of these are shown in Table 1.

Table 1. Clinical Trials for Interferon beta 1b

Modest but beneficial effects of interferon beta 1b on clinical variables and brain atrophy development were observed 5 years after termination of a 2-year clinical trial of interferon beta 1b for the treatment of primary progressive multiple sclerosis (41).

In the BENEFIT study, the impact of interferon beta-1b on cognitive performance at the clinically isolated stage of multiple sclerosis was evaluated by Paced Auditory Serial Addition Test-3 scores (31). IFNβ-1b treatment had a sustained positive effect on the test scores over the 5-year duration of the study. A 16-year longitudinal study has shown beneficial effects of interferon beta-1b on cognition outcomes in multiple sclerosis (23). In a randomized placebo-controlled trial of clinically isolated syndrome with follow-up of 5 years, interferon beta-1b was shown to reduce the number of black holes (ie, persisting T1 hypointensities on MRI) (28).

Regression analysis of patients with relapsing-remitting multiple sclerosis from BEYOND clinical trial has examined the predictive value of patient characteristics at baseline and after 1 year of treatment with interferon beta-1b 250 μg every other day (16). Higher number of relapses in year 1 predicted the future occurrence of relapses, whereas age, MRI activity, and the presence of neutralizing antibodies in the first year were mainly predictive of future MRI activity.

A 2-year prospective cohort study assessed serum 25-hydroxyvitamin D levels to determine association of interferon beta-1 treatment with the course of multiple sclerosis in participants of BEYOND clinical trial because low 25-hydroxyvitamin D levels indicate increased disease activity and rate of progression (10). Results showed that in patients treated with interferon beta-1b, higher 25-hydroxyvitamin D levels were associated with lower rates of disease activity observed on MRI.

A 2-year longitudinal study was conducted to estimate the prevalence of growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in clinically isolated syndrome (CIS) patients and their correlation with conversion to multiple sclerosis in interferon beta 1b treated patients (24). GH/IGF-1 axis function was found to be frequently altered in CIS patients, but this was not related to conversion to multiple sclerosis despite improvement of growth hormone deficiency during interferon therapy.

Indications

Interferon beta 1b is indicated for use in ambulatory patients with relapsing-remitting multiple sclerosis. An extension of the indication to include the treatment of patients with a first clinical event suggestive of multiple sclerosis has been approved in all 27 European member states, as well as in Iceland and Norway.

Off-label uses

A multicenter, prospective, open-label, randomized, phase 2 trial in adults with COVID-19 showed that triple antiviral therapy (interferon beta-1b, lopinavir-ritonavir, and ribavirin) was safe and superior to lopinavir-ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19 (17). A randomized clinical trial showed that interferon-beta 1b was effective in shortening the time to clinical improvement without serious adverse events in patients with severe COVID-19 (34).

Contraindications

Interferon beta 1b is contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, human albumin, or other components of the formulation.

Goals and duration of treatment

The aim is to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations. It is not a curative treatment. The therapy can be continued for an indefinite period. A 21-year follow-up of multiple sclerosis patients treated with interferon beta-1b has reported better life (22).

An MRI study has shown that lack of size decrease of contrast enhancing lesions, which represent inflammatory events during interferon beta 1a therapy, suggests a limited therapeutic effect of the drug due to increased severity of brain tissue damage associated with blood-brain barrier breakdown (12).

In an observational extension study of the BENEFIT clinical trial, 8-year results provide further evidence supporting early initiation of treatment with interferon beta 1b in patients with a first event suggestive of multiple sclerosis (09). Patients originally randomized to interferon beta 1b had a reduced risk of developing clinically definite multiple sclerosis by 32.2% over the 8-year observation period.

A study on patients with relapsing-remitting multiple sclerosis showed that serum neutralizing antibodies (Nabs) were more frequent in patients receiving interferon beta 1b treatment than in those treated with subcutaneous or intramuscular interferon beta 1a, supporting Nabs as a biomarker to identify multiple sclerosis patients with a high probability of showing an optimal response to interferon beta 1b (01).

Predictive validity for negative disability outcomes at 16 years and survival at 21 years postrandomization were assessed in a follow-up of a randomized trial of interferon beta 1b for no evidence of disease activity (13). Clinical assessment of no disease activity predicted long-term disability outcome, whereas MRI variables did not increase the predictive validity.

The goal of a digital observational study, which was a mixed prospective and retrospective study, conducted among users of autoinjector BETACONNECT^® (80% of the patients) was to establish a method that enables the collection of medication usage data on a medical app (myBETAapp) and to assess medication usage among patients with multiple sclerosis treated with interferon beta 1b (ClinicalTrials.gov NCT03134573). This study provides important information on interferon beta 1b usage among patients with multiple sclerosis as well as on the consenting behavior of patients in digital studies, and in future clinical studies, this approach may enable patients' feedback to be rapidly implemented in existing digital solutions (26).

Following the introduction of BETACONNECT^® (an electronic autoinjector), an exploratory study suggested that persons with multiple sclerosis taking interferon beta 1b were more adherent compared with those taking interferon beta 1a, with higher persistence (06). More than 90% reached a medication possession ratio of 80%, a threshold commonly used to define good adherence.

Dosing

The recommended dose of interferon beta 1b for the treatment of ambulatory relapsing-remitting multiple sclerosis is 0.25 mg injected subcutaneously per day. Higher doses have been given on alternate days in clinical trials, and this was found to be more effective than once weekly interferon beta 1a.

Special considerations

All patients should have blood chemistry and hematology tests prior to initiating interferon beta 1b therapy and at periodic intervals thereafter: hemoglobin, complete and differential white blood cell counts, platelet counts, and blood chemistries including liver function tests. In the controlled clinical trials, patients were monitored every 3 months. The study protocol stipulated that interferon beta 1b therapy should be discontinued in the event the absolute neutrophil count fell below 750/mm3. When the absolute neutrophil count had returned to a value greater than 750/mm3, therapy could be restarted at a 50% reduced dose. Similarly, if hepatic transaminase levels exceeded 10 times the upper limit of normal or if the serum bilirubin exceeded 5 times the upper limit of normal, therapy was discontinued. In each instance during the controlled trials, hepatic enzyme abnormalities returned to normal following discontinuation of therapy.

Caution should be exercised in giving interferon beta 1b to patients with depression and patients with seizure disorders. Patients with cardiac disease should be closely monitored.

Anesthesia. No relevant information is available.

Pregnancy. Interferon beta 1b is contraindicated for pregnant women. It is not known if interferon beta is excreted in human milk. Nursing mothers should either discontinue nursing or interferon beta treatment. The rates of spontaneous abortions and birth defects in a study with the largest number of interferon beta 1bexposed pregnancies do not differ from available population estimates, and no pattern of specific birth defects was observed (36). However, the number of cases is not large enough to make a final assessment of the safety of interferon beta 1b during pregnancy.

Pediatric. Safety and efficacy in patients below the age of 18 years has not been established. A retrospective study, however, supports the safety and tolerability of interferon beta 1b in children with multiple sclerosis and related diseases, but regular monitoring of liver function is recommended (03).

Geriatric. No relevant information is available.

Interactions

There are no clinically significant interactions.

Adverse effects

Adverse events reported during clinical trials and postmarketing experience are listed in the Physicians Desk Reference. Some of the adverse reactions are: