Introduction

According to two studies presented at the 14^th Meeting of the European Neurological Society, currently available interferon beta agents demonstrate comparable clinical efficacy for the treatment of multiple sclerosis (MS). Results from a study of 214 patients with clinically definite MS found comparable clinical efficacy among intramuscular interferon beta-1a (Avonex), subcutaneous interferon beta-1a (Rebif), and subcutaneous interferon beta-1b (Betaseron).¹ These results were corroborated by similar findings from QUASIMS (Quality Assessment in Multiple Sclerosis Therapy), a large comprehensive analysis of nearly 5,000 patients with MS.² These data suggest that patients with MS derive similar clinical benefit from all interferon beta agents.

Comparable Benefits from Interferon Betas

According to Hossein H. Pakdaman, MD, Professor of Neurology at Shahid Beheshti University, Tehran, Iran, and President of the Iranian Neurological Association, the incidence of MS in Iran has been rapidly increasing. Current estimates place the number of individuals with MS at 40,000 - among a population of 75 million. Dr. Pakdaman reported the results of a long-term study evaluating Avonex, Rebif, and Betaseron in the treatment of clinically definite MS.

This single-blind (physician), direct comparison study evaluated 214 patients with clinically definite MS who received treatment with intramuscular Avonex 30 mg once weekly, subcutaneous Rebif 22 mcg three times weekly, or subcutaneous Betaseron 8 MIU every other day.¹ The three treatment arms were matched according to age, gender, age at diagnosis, and mean Expanded Disability Status Scale (EDSS) score. The primary outcomes of the study were relapse rate, disability progression, mean number of T2 active lesions, mean number of T1 lesions, and adverse events from treatment.

At the end of the first year of treatment, 76.3% of patients treated with Avonex were relapse-free compared with 73.5% for Rebif 22 mcg, and 71.2% for Betaseron (Table 1). Mean changes in EDSS (mean baseline EDSS 2.1) at the end of the first year of treatment were 0.6, 0.5 and 0.6 for Avonex, Rebif, and Betaseron, respectively. Mean changes in EDSS at the end of the second year were 1.3, 1.2, and 1.2, respectively, and at the end of the fifth year were 2.2, 2.0, and 2.35, respectively.

Throughout the study, patients were evaluated by magnetic resonance imaging (MRI). At the end of the first year of treatment, 79.0% of patients treated with Avonex were free from new T2 lesions, compared with 91.5% for Rebif 22 mcg, and 88.3% for Betaseron. After 5 years of treatment with Avonex, Rebif, and Betaseron, the percentage of patients free from new T2 lesions were 45.3%, 40.2%, and 41.4%, respectively.

“For years, the efficacy of disease-modifying agents used in treating multiple sclerosis was questioned by many physicians. Now there is no question they are effective, and this study shows that the agents we are using [interferon beta] offer comparable efficacy. The highlight of our study is that we have followed these patients for six years. This is not simply a matter of a one-year comparison,” advised Dr. Pakdaman.

The major adverse event associated with treatment was described as skin rash, which was observed in 56.2% of patients taking Betaseron, 45.4% taking Rebif, and 21.1% taking Avonex. Commenting on patient preferences, Dr. Pakdaman noted, “Although the long-term efficacy of these agents is comparable, I find that many patients prefer Avonex because fewer injections are required.”

Comparability among Interferon Betas Shown in QUASIMS

Similar efficacy results emerged from a much larger retrospective, controlled, observational study reported by Volker Limmroth, MD, PhD, from University Hospital Essen, Essen, Germany. The QUASIMS study involved 4,754 patients with clinically definite relapsing-remitting MS from 510 sites in Germany, Austria, and Switzerland, who received 2 years of uninterrupted therapy with intramuscular Avonex 30 mcg once weekly (36.3%), subcutaneous Betaseron 8 MIU every other day (35.9%), subcutaneous Rebif 22 mcg three times weekly (19.6%), or subcutaneous Rebif 44 mcg three times weekly (8.2%).² The QUASIMS database contains the largest cohort of MS patients ever assembled to compare the effectiveness of interferon beta agents.

“We believe this is the largest head-to-head study of treatment in multiple sclerosis patients,” remarked Dr. Limmroth, “and the first to address the question of whether patients benefit after being switched from one interferon beta agent to another.”

QUASIMS divided patients into two categories: those wh received immediate and sustained treatment (uninterrupted for 2 years) with interferon beta as initial therapy (initial therapy group), and those who received interferon beta for less than 2 years before switching to another interferon beta agent and continuing that agent for at least 2 years without interruption (follow-up therapy group). The initial therapy group consisted of 3,991 patients while the follow-up therapy group consisted of 662 patients. The majority of patients received interferon beta treatment for 3 to 4 years.

The results of this study revealed two key findings: interferon beta agents are essentially equivalent in their clinical efficacy (judged by relapse rates and disease progression), and patients in the follow-up therapy group (who had switched agents prior to 2 years of uninterrupted treatment) fared significantly worse compared with those receiving interferon beta for 2 uninterrupted years as their initial strategy. According to Dr. Limmroth, these findings suggest that interferon beta agents are equally efficacious, and that there is no additional clinical benefit from switching from one interferon beta agent to another.

Annualized relapse rates over 2 years of treatment were similar among the interferon beta agents (with the exception of Rebif 44 mcg, which was higher), and were more favorable in the initial therapy group than in the follow-up therapy group. In the initial therapy group, the percentages of relapse-free patients over 2 years were significantly higher for patients treated with Avonex (48.5%) and Betaseron (45.7%), than for those treated with Rebif 22 mcg (39.8%), and Rebif 44 mcg (34.6%) (Figure 1). In the follow-up therapy group, the 2-year relapse-free percentages were 38.9%, 36.2%, 37.5%, and 22.3%, respectively.

In the initial therapy group, the percentage of progressionfree patients over 2 years was significantly greater in patients treated with Avonex (P <0.001) and Rebif 22 mg (P = 0.001) compared with Rebif 44 mcg, and significantly greater for Avonex than for Betaseron (P = 0.001).

Dr. Limmroth noted that although comparable, there were subtle differences in favor of Avonex. These included patients more likely to remain relapse-free at one and two years and progression-free at two years.

Approximately 19% of patients switched therapies; 18% changed from Avonex; 20% from Betaseron; 21% from Rebif 22 mcg; and 12% from Rebif 44 mcg. The predominant reason was a perceived lack of efficacy, which was reported more commonly for patients taking Rebif 22 mcg than for those taking Avonex or Betaseron. Therapy changes due to flu-like symptoms were reported significantly less often for Rebif 22 mcg than Betaseron, while changes due to injection-site reactions were reported significantly less often for Avonex than Rebif 22 mcg.

While the interferon beta agents were comparable in efficacy throughout the QUASIMS analyses, patients treated with Rebif 44 mcg performed significantly worse in most categories. The EDSS score and duration of disease in the Rebif 44 mcg group suggested there may have been higher disease activity in this group at baseline [at treatment initiation], according to Dr. Limmroth.

An analysis of patients who progressed ≥1 EDSS point during the study, showed highly significant differences between Rebif 44 mcg and an average percentage of Avonex, Betaseron, and Rebif 22 mcg for all baseline EDSS scores (P >0.0001). For patients with baseline EDSS <3, an EDSS progression of at least 1 point was seen in 24.3% of patients treated with Rebif 44 mcg, compared with 19.9% of patients treated with Avonex, Betaseron, and Rebif 22 mcg; for baseline EDSS 3-4, progression was seen in 39.5% of patients treated with Rebif 44 mcg versus 23.0% of patients treated with Avonex, Betaseron, and Rebif 22 mcg; and for baseline EDSS >4, progression was seen in 51.9% of patients treated with Rebif 44 mcg versus 22.2% of patients treated with Avonex, Betaseron, and Rebif 22 mcg (Table 2).

Dr. Limmroth stated that a significantly higher percentage of patients taking Rebif 44 mcg advanced at least one point in their EDSS score, compared to Avonex, Betaseron, and Rebif 22 mcg.

The results of QUASIMS also found that early initiation of treatment with interferon beta is important; the longer the time between diagnosis and treatment initiation, the greater the mean change in EDSS during the first 2 years of treatment.

“This finding reinforces the importance of early and sustained use of disease-modifying treatment,” advised Dr. Limmroth. “QUASIMS clearly showed that patients benefit from two years of treatment with interferon beta, regardless of the agent, and benefit most when started on treatment within the first year of diagnosis.”

The results of QUASIMS complement the results of other open-label comparisons^3-6 Dr. Limmroth noted, suggesting there are no real differences in clinical efficacy among interferon beta agents.

Conclusion

Two studies presented at the 14^th Meeting of the European Neurological Society demonstrated comparable clinical efficacy between interferon beta agents. Moreover, the results of QUASIMS suggest that early and sustained treatment with one interferon beta agent yields greater benefit than switching between interferon beta agents over the course of the disease.

References

1. Pakdaman H, Shahbeigi S, Pakdaman R. Direct comparison study of the effect of beta-interferons in Iranian patients with multiple sclerosis: results of a 6-year therapy. Presented at the 14^th Meeting of the European Neurological Society, June 26-30, 2004, Barcelona, Spain. P230.
2. Limmroth V, Malessa R, Kalski G, Wernsdцrfer C. A comparison of the efficacy and tolerability of interferonbeta products used as initial or follow-up therapy for the treatment of relapsing multiple sclerosis: results from the QUASIMS study. Presented at the 14^th Meeting of the European Neurological Society, June 26-30, 2004, Barcelona, Spain. Abstract 192.
3. Haas J, Firzlaff M, Schmidt M. Comparisons of new immunomodulatory treatments in the early stages of MS. Mult Scler. 2001;7(suppl 1):S15. Platform Presentation O-28.
4. Milanese C, La Mantia L, Palumbo R, et al. A postmarketing study on interferon beta 1b and 1a treatment in relapsing-remitting multiple sclerosis: different response in drop-outs and treated patients. J Neurol Neurosurg Psychiatry. 2003;74:1689-1692.
5. Miralles A, Fuentes B, Barreiro P, Diez-Tejedor E. Comparative clinical efficiency analysis between interferon beta-1b and interferon beta-1a. J Neurol. 2000;247(Suppl 3):III/139.Poster 556.
6. Öztekin N, Öztekin MF. An open label trial comparing the effects of IFNβ-1a (Rebif), (Avonex), and IFNβ-1b (Betaferon) on the relapse rate, lesion load on MRI and disease progression in patients with relapsing-remitting multiple sclerosis: results of 24 months of therapy. Mult Scler. 2001;7(suppl 1):S96. Poster Presentation P-312.

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