Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Pharmacotherapeutic group: Immunostimulants, interferons
ATC Code: L03AB08
Interferons belong to the family of cytokines, which are naturally occurring proteins. Interferons have molecular weights ranging from 15,000 to 21,000 Daltons. Three major classes of interferons have been identified: alpha, beta, and gamma. Interferon alpha, interferon beta, and interferon gamma have overlapping yet distinct biological activities. The activities of interferon beta-1b are species-restricted and therefore, the most pertinent pharmacological information on interferon beta-1b is derived from studies of human cells in culture or human in vivo studies.
Interferon beta-1b has been shown to possess both antiviral and immunoregulatory activity. The mechanisms by which interferon beta-1b exerts its actions in multiple sclerosis are not clearly understood. However, it is known that the biological response-modifying properties of interferon beta-1b are mediated through its interactions with specific cell receptors found on the surface of human cells. The binding of interferon beta-1b to these receptors induces the expression of a number of gene products that are believed to be the mediators of the biological actions of interferon beta-1b. A number of these products have been measured in the serum and cellular fractions of blood collected from patients treated with interferon beta-1b. Interferon beta-1b both decreases the binding affinity and enhances the internalisation and degradation of the interferon-gamma receptor. Interferon beta-1b also enhances the suppressor activity of peripheral blood mononuclear cells.
No separate investigations were performed regarding the influence of Extavia on the cardiovascular system, respiratory system and the function of endocrine organs.
One controlled clinical trial was performed with Extavia in patients with relapsing-remitting multiple sclerosis and able to walk unaided (baseline EDSS 0 to 5.5). In patients receiving Extavia there was a reduction in the frequency (30%) and severity of clinical relapses and in the number of hospitalisations due to disease. Furthermore, there was a prolongation of the relapse-free interval. There is no evidence of an effect of Extavia on the duration of relapses or on symptoms in between relapses, and no significant effect was seen on the progression of the disease in relapsing-remitting multiple sclerosis.
Two controlled clinical trials were performed with Extavia involving a total of 1,657 patients with secondary progressive multiple sclerosis (baseline EDSS 3 to 6.5, i.e. patients were able to walk). Patients with mild disease and those unable to walk were not studied. The two studies showed inconsistent results for the primary endpoint time to confirmed progression, representing delay of disability progression:
One of the two studies demonstrated a statistically significant delay in the time to disability progression (Hazard Ratio = 0.69, 95% confidence interval (0.55, 0.86), p=0.0010, corresponding to a 31% risk reduction due to Extavia) and in the time to becoming wheelchair-bound (Hazard Ratio = 0.61, 95% confidence interval (0.44, 0.85), p=0.0036, corresponding to a 39% risk reduction due to Extavia) in patients who received Extavia. This effect continued over the observation period of up to 33 months. The treatment effect occurred in patients at all levels of disability investigated and independent of relapse activity.
In the second trial of Extavia in secondary progressive multiple sclerosis, no delay in the time to disability progression was observed. There is evidence that the patients included in this study had overall less active disease than in the other study in secondary progressive multiple sclerosis.
In retrospective meta-analyses including the data of both studies, a statistically significant overall treatment effect was found (p=0.0076; 8.0 million IU Extavia versus all placebo patients).
Retrospective analyses in subgroups showed that a treatment effect on disability progression is most likely in patients with active disease before treatment commences (Hazard Ratio 0.72, 95% confidence interval (0.59, 0.88), p=0.0011, corresponding to a 28% risk reduction due to Extavia in patients with relapses or pronounced EDSS progression, 8.0 million IU Extavia versus all placebo patients). From these retrospective subgroup analyses there was evidence to suggest that relapses as well as pronounced EDSS progression (EDSS >1 point or >0.5 point for EDSS ≥6 in the previous two years) can help to identify patients with active disease.
In both trials there was a reduction (30%) in frequency of clinical relapses in patients with secondary progressive multiple sclerosis patients receiving Extavia. There is no evidence of Extavia having an effect on the duration of relapses.
One controlled clinical trial with Extavia was performed in patients with a single clinical event and Magnetic Resonance Imaging (MRI) features suggestive of multiple sclerosis (at least two clinically silent lesions on the T2-weighted MRI). Patients with monofocal or multifocal onset of the disease were included (i.e. patients with clinical evidence of a single or at least two lesions, respectively, of the central nervous system). Any disease other than multiple sclerosis that could better explain signs and symptoms of the patient had to be excluded. This study consisted of two phases, a placebocontrolled phase followed by a pre-planned follow-up phase. The placebo-controlled phase lasted for 2 years or until the patient developed clinically definite multiple scleroiss (CDMS), whichever came first. After the placebo-controlled phase, patients entered a pre-planned follow-up phase with Extavia to evaluate the effects of immediate versus delayed start of Extavia treatment, comparing patients initially randomised to Extavia (“immediate treatment group”) or to placebo (“delayed treatment group”). Patients and investigators remained blinded to the initial treatment allocation.
In the placebo-controlled phase, Extavia delayed the progression from the first clinical event to clinically definite multiple sclerosis (CDMS) in a statistically significant and clinically meaningful manner, corresponding to a risk reduction of 47% (Hazard Ratio = 0.53, 95% confidence interval (0.39, 0.73), p<0.0001). Within the study period of two years, CDMS occurred in 45% of the placebo group compared to 28% of the Extavia group (Kaplan-Meier estimates). Extavia prolonged the time to CDMS by 363 days, from 255 days in the placebo group to 618 days in the Extavia group (based on the 25th percentiles). This treatment effect was still evident after the additional year of follow-up at which stage the risk reduction was 41% (Hazard Ratio = 0.59, 95% confidence interval (0.42, 0.83), p=0.0011). Within the study period of three years, CDMS occurred in 51% of the delayed treatment group compared to 37% of the immediate treatment group (Kaplan-Meier estimates). The persistence of the treatment effect was observed although the majority of patients from the placebo-group was treated with Extavia in the third year of the study.
The robustness of the treatment effect was also shown by the delay of progression to multiple sclerosis according to the McDonald criteria. In two years, the risk was 85% in the placebo group and 69% in the Extavia group (Hazard Ratio = 0.57, 95% confidence interval (0.46, 0.71), p<0.00001).
After 3 years, a pre-planned interim analysis showed EDSS progression (confirmed increase in EDSS of greater than or equal to 1.0 compared to baseline) occurred in 24% of the patients in the delayed treatment group compared to 16% in the immediate treatment group [Hazard Ratio = 0.6, 95% confidence interval (0.39, 0.92), p=0.022]. There is no evidence for benefit in terms of confirmed disability progression in the majority of patients receiving “immediate” treatment. Follow-up of patients is continuing in order to provide additional data. No benefit, attributable to Extavia, in quality of life (as measured by FAMS – Functional Assessment of MS: Treatment Outcomes Index) was seen.
Subgroup analyses according to baseline factors demonstrated evidence of efficacy in all subgroups evaluated. Significant effects were also obtained in patients with less disseminated and less active disease at the time of the first event. The risk for progression to CDMS within two years in patients with monofocal onset was 47% for placebo and 24% for Extavia, without gadolinium (Gd-) enhancement 41% and 20%, with less than 9 T2 lesions 39% and 18%. Further subgroup analyses indicated a high risk for progression to CDMS within 2 years in monofocal patients with at least 9 T2- lesions (55% risk for placebo, 26% for Extavia) or Gd-enhancement (63% versus 33%). In multifocal patients, the risk for CDMS was independent from MRI findings at baseline, indicating a high risk for CDMS because of the dissemination of the disease based on clinical findings. However, the long-term impact of early treatment with Extavia is unknown even in these high risk subgroups as this study was mainly designed to assess the time to CDMS rather than the long-term evolution of the disease. Furthermore, for the time being there is no well established definition of a high risk patient, although a more conservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at least one new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after the initial scan. In any case, treatment should only be considered for patients classified as high risk.
Therapy with Extavia was well accepted in the study of patients with a single clinical event as indicated by a high rate of trial completion (92.8% in the Extavia group). To increase tolerability of Extavia in the study of patients with a first clinical event, a dose titration was applied and nonsteroidal anti-inflammatory medicinal products were administered at start of therapy. Moreover, an autoinjector was used by the majority of patients throughout the study.
In all multiple sclerosis studies Extavia was effective in reducing disease activity (acute inflammation in the central nervous system and permanent tissue alterations) as measured by magnetic resonance imaging (MRI). The relation of multiple sclerosis disease activity as measured by MRI and clinical outcome is currently not fully understood.
Extavia serum levels were followed in patients and volunteers by means of a bioassay that was not completely specific. Maximum serum levels of about 40 IU/ml were found 1-8 hours after subcutaneous injection of 500 microgram (16.0 million IU) interferon beta-1b. From various studies mean clearance rates and half-lives of disposition phases from serum were estimated to be at most 30 ml·min-1 ·kg-1 and 5 hours, respectively.
Administration of Extavia injections every other day does not lead to serum level increase, and the pharmacokinetics do not seem to change during therapy.
The absolute bioavailability of subcutaneously administered interferon beta-1b was approximately 50%.
No acute toxicity studies have been performed. As rodents do not react to human interferon beta, repeated dose studies were carried out with rhesus monkeys. Transitory hyperthermia was observed, as well as a significant rise in lymphocytes and a significant decrease in thrombocytes and segmented neutrophils.
No long-term studies have been conducted. Reproduction studies with rhesus monkeys revealed maternal toxicity and an increased rate of abortion, resulting in prenatal mortality. No malformations have been observed in the surviving animals.
No investigations on fertility have been conducted. No influence on the monkey oestrous cycle has been observed. Experience with other interferons suggest a potential for impairment of male and female fertility.
In one single genotoxicity study (Ames test), no mutagenic effect has been observed. Carcinogenicity studies have not been performed. An in vitro cell transformation test gave no indication of tumorigenic potential.
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