Rebif in the treatment of MS

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David de Monteverde-Robb MRPharmS IPresc ADA MSc
Lead Pharmacist: Neurosciences,
Critical Care and Peri-operative Services,
Addenbrooke’s Hospital,
Cambridge, UK

Rebif (IFNβ1a; Merck Serono) is a purified 166-amino acid glycoprotein produced through recombinant DNA technology in genetically modified Chinese Hamster Ovary cells. It is licensed for the treatment of patients with a single demyelinating event with an active inflammatory component where they are deemed to be at a high risk of developing definite multiple sclerosis (MS), and for the treatment of patients with relapsing–remitting MS, characterised by two or more exacerbations in the previous two years. The recommended dose of Rebif is 44μg given three times a week by subcutaneous injection. A 22μg dose is recommended for patients who cannot tolerate the higher dose and for patients aged between 12 and 16 years.

Rationale for IFNβ therapy in MS
The Cochrane meta-analysis(1) of studies evaluating IFNβ in relapsing–remitting MS shows a reduction in the occurrence of exacerbations (95%CI 0.73–0.88; p<0.001) and progression of disease (95%CI 0.55–0.87; p=0.002). However, there are limitations in reported studies for this indication in that if active treatment dropouts were discovered to have disease progression, the significance of the effect of the interferon is lost (p=0.5). Magnetic resonance imaging (MRI) technologies, standardisation of reporting and MRI diagnostic criteria for MS have developed since many of the original studies were published, which have made meta-analysis of the existing data problematic.

The use of interferon for delaying conversion of the first demyelinating event to multiple sclerosis is also subject to a Cochrane meta-analysis.(2) The review found that IFNβ is effective in preventing the conversion of the first demyelinating event to clinically definite MS after one and two years of follow-up.

Summary of key clinical trials
EVIDENCE
The original EVIDENCE study compared Rebif 44μg subcutaneously three times per week with Avonex (IFNβ1a; Biogen Idec) 30μg intramuscularly once weekly over 24 weeks (primary endpoint). Rebif-treated patients were more likely to remain relapse-free than the Avonex patients and had fewer active lesions on MRI (p<0.001).  Interestingly in the extension to the EVIDENCE study, patients who had been given Avonex and were converted to Rebif therapy improved on clinical measures (annualised relapse rate fell from 0.64 to 0.32; p<0.001) and identified MRI lesions (p=0.02) compared with previous therapy.(3,4)

PRISMS
The phase III, randomised, double-blind, placebo-controlled PRISMS trial (Prevention of Relapses and Disability by Interferon β1a Subcutaneously in Multiple Sclerosis)(5)  assessed efficacy of IFNβ1a 22 and 44μg sc tiw in relapsing-remitting MS patients. The study demonstrated a beneficial effect for all major outcomes with either drug dose regimen. The relapse rate in both IFNβ1a 22μg and 44μg groups was reduced significantly compared with the placebo group (1.82 and 1.73 respectively for treatment groups vs 2.56 in the placebo group; p<0.005). A 27% (p<0.05) and a 32% (p<0.005) reduction in relapse rate was achieved in the 22μg group and in the 44μg group, respectively, compared with the placebo group. The median time to first relapse was significantly delayed by three months in the lower dosage group, and by five months in the higher dose treatment group versus placebo (statistical significance not reported). A significant reduction in moderate to severe types of relapses (p<0.005) and in corticosteroids courses (p<0.05 for the 22μg group; p<0.005 for the 44μg group) was also observed in the active arms compared with placebo. Number of hospitalisations decreased significantly in the 44μg group (p<0.005 vs placebo).

REFLEX and REFLEXION
The REFLEX study,(6) published in 2011, has regenerated interest in the role of IFNβ in early demyelinating disease, concluding with the revision of the licensed indications in the marketing authorisation in November 2011 by the European Medicines Agency.(7) As mentioned previously, IFNβ is now authorised to be used in patients after a single demyelinating event in those deemed at high-risk of developing MS. Patients included in the REFLEX study were 18–50-year-old adults from 80 participating centres in 28 countries. These patients had expanded disability status scale (EDSS) scores of 0.0–5.0 (up to moderately severe disablement) without a firm diagnosis of MS and at least two clinically silent lesions identified on T2-weighted MRI of the brain. Randomisation placed these patients into three groups: IFNβ1a 44μg three-times a week, IFNβ1a once a week, or placebo in a 1:1:1 ratio. Each patient received three weekly subcutaneous injections, with the number of placebo injections dictated by the study group assigned, for a period of two years. Withdrawal rates were similar across the groups at 15%: 11%: 15% respectively. Power calculations required at least 150 patients in each study arm and a minimum of 171 were recruited to each arm; however, only 146 patients completed the study in two of the study arms. The primary and secondary endpoints of the study were: time to 2005 McDonald diagnostic criteria; and time to clinically definite multiple sclerosis according to Poser criteria.

The results of the study show a highly significant reduction in the risk of developing McDonald 2005(8) criteria diagnosis of MS (p=0.0004 in the 44μg three-times weekly; p=0.0023 in the 44μg once-weekly groups vs placebo).

Adverse events were also higher in the interferon groups, but interestingly the rate of influenza-like illness was lower in the three-times weekly group compared with the once-weekly group. Some commentators have suggested that the greater exposure to interferon in the three times weekly group may help increase tolerance to this side-effect, but the discrepancy is not yet fully understood. The greatest difference seen between the groups was injection site reactions, which is to be expected and flu-like symptoms which were two or three times more common in the active treatment groups. Cytopaenia (11%: 5%: 2%) and thyroid disorders (6%: 3%: 1%) were two of the most serious untoward effects identified where there were significant differences between study groups. These results replicate the findings of previous studies.

Trial limitations include potentially insufficient time to detect real differences between the once- and thrice-weekly dosing on clinical relapses. The delay of a definite diagnosis of MS at two years does not help us understand the effect of early intervention on ultimate disease progression.

REFLEX is the first trial to be published which compared two different dosing schedules of IFNβ in patients with a first demyelinating event, and it is the first study to use McDonald diagnostic criteria as the primary endpoint of the study, in line with common clinical diagnostic practice. It appears from this trial, and previous trials looking at IFNβ and glatiramer acetate that early intervention can delay progression after a demyelinating event to a diagnosis of MS or further demyelinating events. This supports the strategy of early intervention with these disease-modifying agents.
There is much that remains unknown, but the first step to progress from our current knowledge would be to understand if the benefits of early intervention with IFNβ1a translate into longer-term benefits. The results from an ongoing double-blind extension study called REFLEXION are eagerly awaited. This study will follow the outcomes for existing patients for three years after the REFLEX study representing five years of data in total.

Conclusions
There has been mounting excitement in neurology conferences around the world in recent years owing to a number of new therapies that open new treatment pathways for people who have definite, probable or relapsing–remitting MS. Rebif, an immunomodulatory, disease‑modifying therapy, is one such drug. While it is important that new therapeutic options are brought to market and that these new medicines are fully evaluated so they can be made available to treat people with this debilitating disease appropriately, it is also important not to lose sight of the proven mainstays of treatment for MS and how these medicines can be used more effectively.

Current treatment guidelines(9) in the UK were published in 2004 and are out of step with current evidence. The mainstay treatment recommendation for acute episodes in the guidelines is oral or intravenous methylprednisolone. It is heartening to note that at the time of writing the National Institute for Health and Clinical Excellence is conducting scoping exercises leading to a review of the current guidance.

References

1. Rice GPA et al. Interferon in relapsing-remitting multiple sclerosis. Cochrane Database of Systematic Reviews, Issue 4. 2001. Art. No:CD002002. DOI: 10.1002/14651858.CD002002.
2. Clerico M et al. Recombinant interferon beta or glatiramer acetate for delaying conversion of the first demyelinating event to multiple sclerosis. Cochrane Database of Systematic Reviews, Issue 2. 2008. Art. No: CD005278. DOI: 10.1002/14651858.CD005278.pub3.
3. Panitch H et al. Randomized, comparative study of IFNβ1a treatment regimens in MS. The EVIDENCE trial. Neurology 2002;59:1496–506.
4. Schwid SR et al. Enhanced benefit of increasing interferon beta-1a dose and frequency in relapsing multiple sclerosis: the EVIDENCE study.  Arch Neurol 2005;62(5):785–92.
5. PRISMS Study Group. Randomized double-blind placebo-controlled study of IFNβ1a in relapsing/remitting multiple sclerosis. Lancet 1998;352:1498–504.
6. Comi G et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol 2012;11:33–41.
7. Committee for Medicinal Products for Human Use Summary of opinion (post authorisation) – Rebif (interferon beta-1a). 2011. European Medicines Agency EMA/900110/2011. www.ema.europe.eu/.
8. Polman CH et al (2005). Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald criteria. Ann Neurol 2005;58:840–6.
9. The (United Kingdom) National Collaborating Centre for Chronic Conditions (Multiple sclerosis: national clinical guideline for diagnosis and management in primary and secondary care. 2004. London: Royal College of Physicians.