Introduction

Data presented during the 13th Meeting of the European Neurological Society (ENS) continue to evaluate and assess the efficacy of intramuscular interferon beta-1a (Avonex), subcutaneous interferon beta-1b (Betaseron), and subcutaneous interferon beta-1a (Rebif) in the treatment of multiple sclerosis (MS). Additional data was presented on the clinical impact of neutralizing antibodies on interferon beta efficacy.

An analysis of several interferon beta trials has shown an increase in annualized relapse rate and mean T2 active lesions in neutralizing antibody-positive patients compared to neutralizing antibody-negative patients.¹ But, these responses are not evident in the short-term and cannot be adequately assessed until at least 12 months, if not longer, after initiation of treatment. Although all interferons induce neutralizing antibodies, there are quantifiable differences between the available agents in the incidence of neutralizing antibodies. Data continues to indicate that Betaseron induces the highest incidence of neutralizing antibodies, followed by Rebif, and lastly by Avonex.

Prompted by a 30% treatment failure observed with Betaseron 250 mcg,² investigators presented preliminary data from a study designed to compare the efficacy of Betaseron 375 mcg to the conventional dose of 250 mcg.³ Using Mx protein as a biomarker for interferon beta bioavailability, investigators correlated increased levels of Mx protein to treatment response with Betaseron. Within 6 months, 22% of 250 mcg recipients developed neutralizing antibodies. Neutralizing antibody-positive patients were less likely to derive a full therapeutic response (eg, "suboptimal responders"). Further follow-up is planned to more fully elucidate the relationship between levels of Mx protein and the impact of neutralizing antibodies on Betaseron efficacy.

This Multiple Sclerosis Express Report will review these presentations in addition to the results of a study designed to create an extensive international epidemiological database and allow global comparison of long-term treatment data of Avonex, Betaseron, and Rebif.⁴

Neutralizing Antibodies-Factors in the Long-term Success of Disease Management

The issue of patient management, specifically, patients who become neutralizing antibody-positive, was extensively addressed by Hans-Peter Hartung, MD, from the Department of Neurology, Heinrich-Heine-University, Dьsseldorf, Germany.¹ The concept of neutralizing antibodies is not a recent phenomena and not limited to MS. Dr. Hartung first elaborated on the clinical impact of neutralizing antibodies in other diseases.

Development of neutralizing antibodies has been reported in patients treated with interferon alpha-2a for hairy cell leukemia and renal cell carcinoma, and with interferon alpha-2b for chronic myeloid leukemia with a resultant decline in efficacy. This decline in interferon alpha efficacy in these neutralizing antibody-positive patients⁵ is consistent with observations of decreased clinical efficacy of interferon beta in neutralizing antibody-positive patients with MS.

The key consideration according to Dr. Hartung in the development of neutralizing antibodies is that appropriate alternative treatment options need to be devised for neutralizing antibody-positive patients. For example, Factor VIII is used to treat Hemophilia A. Neutralizing antibodies inactivate Factor VIII by increasing proteolysis requiring costly and cumbersome alternative therapies. Alternative treatment options include induction of immune tolerance, Bonn protocol (high dose Factor VIII), Malmo protocol (Factor VIII, cyclophosphamide, intravenous IgG), Factor hrVIIa, and activated prothrombin complex concentrates (FEIBA).

Clinical Impact of Neutralizing Antibodies to Interferon Beta in Multiple Sclerosis

Treatment failures as a result of neutralizing antibody development may pose therapeutic consequences to the patient. Because of complexities and problems related to the specificity and sensitivity of assays for neutralizing antibodies, comparison of the incidence of neutralizing antibodies induced by one immunomodulatory agent to another immunomodulatory agent may be misleading. However, despite these complexities, data illustrate that Avonex has the lowest frequency of neutralizing antibody development in clinical trials of interferon beta in the treatment of MS (Figure 1).

To illustrate the clinical consequences of neutralizing antibodies, Dr. Hartung reviewed the results from the phase III trial of Betaseron⁶ from the IFNB MS Study Group. After three years of treatment with Betaseron, it was demonstrated that although neutralizing antibodies began to appear early in the treatment (3 to 6 months), the clinical effects were apparent after approximately 18 to 24 months. An examination of the relapse rates from Months 13 to 36 of treatment for placebo-treated, neutralizing antibody-positive and neutralizing antibody-negative patients, respectively, revealed an annual relapse rate of 1.06, 1.08, and 0.56 (P = 0.001). A similar association was demonstrated for mean number of enlarging T2 lesions between neutralizing antibody-positive and neutralizing antibody-negative patients.

A phase III study evaluating the clinical impact of neutralizing antibodies on magnetic resonance imaging (MRI) measures in patients receiving Avonex,⁷ showed an increase in mean gadolinium-enhancing lesions in neutralizing antibody-positive patients (1.7, n = 18) compared to neutralizing antibody-negative patients (0.6, n = 63) but this difference did not reach statistical significance (P = 0.062). An analysis of annualized relapse rates in neutralizing antibody-positive and neutralizing antibody-negative patients receiving Avonex 30 mcg, annualized relapse rates were higher in neutralizing antibody-positive patients in Years 1, 2, and 3 of treatment. Clearly, neutralizing antibody-positive patients do not realize the same therapeutic benefits from receiving interferon beta therapy as do neutralizing antibody-negative patients.

Similar findings were observed in patients receiving Rebif 44 mcg in PRISMS-4.⁸ The annualized relapse rate (Years 3 and 4) for neutralizing antibody-positive patients was 0.81 compared to 0.5 in neutralizing antibody-negative patients (P = 0.002). Furthermore, neutralizing antibody-positive patients showed a greater median burden of disease on T2 active lesions on MRI measures compared with neutralizing antibody-negative patients (1.4 vs 0.3, respectively; P<0.001).

In assessing the clinical impact of neutralizing antibodies on immunomodulatory agents, Dr. Hartung made an important observation: short-term clinical trials of MS treatments are incapable of detecting the clinical impact of neutralizing antibodies (Figure 2).

Consequently, Dr. Hartung strongly recommended to practicing neurologists that, when making treatment decisions, physicians should consider the long-term impact of neutralizing antibodies and choose a therapy with a sustained and proven long-term benefit.

In conclusion of his presentation, Dr. Hartung indicated the known incidence of neutralizing antibody formation is greatest with Betaseron, followed by Rebif, and lastly Avonex. High-titer neutralizing antibodies are recognized to weaken the efficacy of the interferons and this effect may be missed in short-term studies. Thus, cautioned Dr. Hartung, neutralizing antibody-positive patients may no longer gain therapeutic benefit from interferon beta therapy.

The QUASIMS Survey

Immunomodulatory agents have become the standard for the treatment of relapsing-remitting MS. However, a prospective comparator trial between Avonex, Betaseron, and Rebif is not available. Volker Limmroth, MD, Department of Neurology, University of Essen, Germany briefly described the ongoing Quality Assessment in Multiple Sclerosis Therapy (QUASIMS) Survey.⁴ QUASIMS is a retrospective data survey designed to compare Avonex (30 mcg), Betaseron (250 mcg), and Rebif (22 mcg and 44 mcg) with regard to disability progression, relapse rate, and tolerability. A total of 4121 patients with relapsing-remitting MS have been enrolled into the study (Avonex n = 1488, 36%; Betaseron n = 1510, 37%; Rebif n = 1123, 27%) and followed prospectively.

Inclusion criteria included interferon beta therapy for at least 2 years with complete documentation of relapses, disease progression (Expanded Disability Status Scale, EDSS) and adverse events. Baseline patient characteristics were comparable between all 4 treatment arms with mean duration of therapy ranging from 37.7 months to 51.4 months. Outcome parameters were efficacy (progression of disability as defined by change in EDSS) and annual relapse rate.

After 2 years of treatment with interferon beta, EDSS increased comparably in all treatment arms and the mean EDSS increased comparably with duration of disease. The progression of disability was similar for all treatment arms ranging from 0-0.1 in the first year and 0.2-0.3 in the second year. The mean number of annual relapses was comparable between all treatment arms (Figure 3).

Dr. Limmroth indicated the final results of the QUASIMS survey will result in an extensive international epidemiological database and will allow global comparison of long-term Avonex, Betaseron, and Rebif treatment data.

This type of data may further support the approach of combination therapy in patients in whom there is disease breakthrough. Up to 2 years of treatment, there appears to be little difference in the efficacy of the immunomodulatory agents used. Switching from a less to a more immunogenic agent may not be the best approach to managing these types of patients given the tendency of neutralizing antibodies to degrade efficacy over time. Using a platform therapy upon which to build (add) other medications, similar to the approach used in oncology, may prove to be the most effective management method.

Mx Protein and Neutralizing Antibodies: Correlation with Clinical Efficacy of Betaseron

Treatment with Betaseron 250 mcg has resulted in a 30% rate of treatment failure.² The Optimization of Interferon for MS (OPTIMS) study was designed to compare the efficacy of Betaseron 250 mcg and 375 mcg.² The study protocol called for patients to be treated with Betaseron 250 mcg every other day for 6 months. At 6 months, partially responding patients (persisting clinical/MRI signs of disease activity) would be randomized to either continue on the same dose or receive 375 mcg every other day. Assessment of interferon beta bioavailability was determined through the measurement of Mx protein, due to its high specificity for interferon beta. Preliminary immunological data from the first 23 patients completing the first 6 months (pre-randomization phase) of the study were presented by A. Ricci, MD, University of Turin, Turin, Italy.³

Eleven of the 23 patients responded to Betaseron 250 mcg while 12 patients displayed a partial response. Mx protein was increased in all patients after 3 months of treatment with Betaseron (P<0.01). The increase in Mx protein was 4-fold greater than baseline in the 12 partially-responding patients (P = 0.01) and 6-fold greater than baseline in the 11 responding patients (P<0.01). The difference between the two groups was statistically significant (P<0.05). After 6 months, the difference between responders and partial responders was not statistically significant. Five of the 23 patients (22%) had developed neutralizing antibodies (titer <60). Of those patients, only one responded well to treatment with Betaseron.

Investigators concluded that levels of Mx protein correlated with the response to treatment. Further follow-up is planned to fully evaluate the effect of increased levels of Mx protein and impact of neutralizing antibodies on the clinical efficacy of Betaseron.

References

1. Hartung HP. Neutralizing Antibodies-Factors in the Long-term Success of Disease Management. Presented in the Satellite Symposium "Multiple Sclerosis: Treatment Goals and Long-term Success Factors" during the 13th Meeting of the European Neurological Society (ENS), June 16, 2003, Istanbul, Turkey.
2. Durelli L, Oggero A, Verdun E, et al. Interferon-b dose and efficacy: the OPTIMS study. Neurol Sci. 2001;22:201-203.
3. Ricci A, Cucci MA, Verdun E, et al. Mx protein and neutralizing antibodies in relapsing remitting multiple sclerosis patients treated with interferon beta-1b: correlation with clinical and MRI efficacy. 13th Meeting of the European Neurological Society (ENS), June 14-18, 2003, Istanbul, Turkey. Poster 301.
4. Limmroth V, Kalski G, Richter A, et al. Quality assessment in multiple sclerosis therapy-the QUASIMS Survey. 13th Meeting of the European Neurological Society (ENS), June 14-18, 2003, Istanbul, Turkey. Poster 767.
5. Oberg and McKenna. In: Reder, ed. Interferon Therapy of Multiple Sclerosis. 1997:509.
6. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. IFNB MS Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277-1285.
7. Rudick RA, Simonian NA, Alam JA, et al. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group. Neurology. 1998;50:1266-1272.
8. PRISMS-4: long-term efficacy of interferon beta-1a in relapsing MS. PRISMS Study Group, University of British Columbia MS/MRI Analysis Group. Neurology. 2001;56:1628-1636.