Satellite Symposium: Toward the Optimal Management of Multiple Sclerosis: Treating a Lifelong Disease

Introduction

Careful selection of immunomodulatory agents is important to the optimal management of multiple sclerosis (MS). The available agents differ in ways that may impact their therapeutic efficacy, including mechanism of action and the potential for the development of neutralizing antibodies.

Importance of Neutralizing Antibodies

In order to ensure that patients receive the most from therapy, it is critical for physicians to look at what factors may be mitigating or improving the long-term efficacy of immunomodulating therapy. "One of those (factors) is the concept of neutralizing antibodies. Do they really make a difference? If neutralizing antibodies do abrogate the effects of interferon-beta, we as clinicians need to know that," stated Frederick E. Munschauer, III, MD, Professor of Clinical Neurology, State University of New York, Buffalo, New York and Chairman of the Jacobs Neurological Institute.¹

According to pivotal Phase III trial data for the beta-interferons, the emergence of neutralizing antibodies can be associated with an attenuation of therapeutic effect. Furthermore, not all beta-interferons are equal in this regard, and it is the clinician's responsibility to select agents that pose the least risk.

The suggestion of a diminution in efficacy in association with neutralizing antibodies is supported by in vivo evidence of a loss of inducible biological markers (indicating biological response) and loss of an effect on decreasing natural killer cells, he said.

Clinically, diminished efficacy in the face of neutralizing antibody emergence was demonstrated in both the Phase III trial of interferon beta-1b (Betaseron, Berlex Laboratories, Inc.)² and the PRISMS-4 study of interferon beta-1a (Rebif, Serono, Inc.).³ In the Phase III Betaseron trial, neutralizing antibody-positive patients had a significantly higher relapse rate than neutralizing antibody-negative patients during the second and third years of therapy.²

Similarly, in the PRISMS-4 study, the relapse rate of neutralizing antibody-positive patients was 62% higher than for negative patients during the third and fourth years of therapy.³ In addition, the presence of neutralizing antibodies to Rebif was associated with magnetic resonance imaging (MRI) evidence of loss of efficacy, as measured by a significant 17.6% increase in lesion burden in neutralizing antibody-positive patients versus an 18.5% decrease in neutralizing antibody-negative patients.³

Incidence of Neutralizing Antibodies Lower With Avonex

The development of neutralizing antibodies formation has been associated with a reduction in clinical efficacy in a number of other diseases including hepatitis and cancer.^4,5 Although neutralizing antibodies develop to all interferon-beta preparations, their incidence with interferon beta-1a (Avonex, Biogen, Inc.) is lower than with Betaseron and Rebif. This was most recently demonstrated in the EVIDENCE trial comparing Rebif and Avonex.⁶ After 48 weeks, neutralizing antibodies were markedly more common with Rebif, occurring (any titer) in 35% versus 5% of patients on Avonex. Neutralizing antibodies ≥ 20 NU/ml were observed in 24% and 2% of patients, respectively.

The differences in neutralizing antibody incidence among the three beta-interferons was also demonstrated in the large Danish Multiple Sclerosis Study Group.⁷ In this study, 754 patients' neutralizing antibodies were measured by high-sensitivity assay every 6 months by blinded observers. After 2 years of therapy, neutralizing antibodies were detected in 25% of patients on Avonex, 50-85% on Rebif, and over 95% on Betaferon (Betaseron), Dr. Munschauer remarked.

It has been suggested that interferon beta-1b is more immunogenic than interferon beta-1a and that subcutaneous injections may be more immunogenic than intramuscular injections. Frequency and route of administration may also be factors.

"In the EVIDENCE trial, a higher dose of beta-interferon with a higher frequency of dosing and a subcutaneous site contributed to a ten-fold increase in neutralizing antibodies with Rebif," Dr. Munschauer pointed out.

He added that neutralizing antibodies might not emerge for a year or longer after initiation of therapy. In studies with less than 2 years follow-up, their clinical effects could be missed.

When asked to put neutralizing antibodies into a patient-care context, Dr. Munschauer said he has concluded that neutralizing antibodies have a "negative clinical impact on relapse rate, MRI findings and probably disability. With high neutralizing antibody titers (≥ 20 NU/ml), efficacy of beta-interferon is compromised, but low titers are probably without clinical significance," he stated.

"Once you develop neutralizing antibodies to beta-interferon, they cross-react with all other preparations of beta-interferon," he said. "In the long-term, we need higher vigilance for neutralizing antibodies. Maybe we should select the drug with the lowest probability of developing neutralizing antibodies in the first place."

Exploring the Mechanism of Action of Immunomodulators

Rather than target a single pathway in the inflammatory cascade, beta-interferons demonstrate pleiotropic immunomodulatory effects, as seen in both in vitro and in vivo studies, said J. Theodore Phillips Jr., MD, PhD, Director of the Multiple Sclerosis Center at Texas Neurology, Dallas, Texas.⁸

In addition to reducing T-cell activation, beta-interferons act in multiple other ways: they reduce antigen presentation, inhibit the pro-inflammatory effects of interferon gamma, and induce immunodeviation whereby the Th1 pro-inflammatory response slowly evolves into a more protective, counter-regulatory Th2 response. Moreover, beta-interferons inhibit blood brain barrier transgression by affecting the expression of adhesion molecules and by suppressing the secretion of matrix metalloproteases.

"With beta-interferon, a single event at the cell surface translates into a complex cascade at the nuclear level," Dr. Phillips observed. "With these agents you have a multifactorial, multilocational interference with the cascading events of MS."

Glatiramer acetate also works presumably by inducing immune deviation, shifting the process from a prolonged Th1 response into a more protective Th2 response. Glatiramer acetate reduces antigen-presenting cells, however, the mechanism of action is not clear.

These differences between beta-interferon and glatiramer acetate may have clinically relevant consequences. While all immunomodulators reduce relapse rates, only Avonex and Rebif yielded sustained, statistically significant improvements in disability in the Phase III trials. In terms of brain atrophy, glatiramer acetate showed a trend toward a lower atrophy rate at 9 months, one that disappeared at 18 months.⁹ In the Rebif study, atrophy progressed at 2 years in all treatment groups; however, a higher rate of brain atrophy was seen in the Rebif 44 mcg 3 times weekly treatment group.¹⁰ In the Avonex studies, a significant difference in atrophy emerged in year 2, pointing to a neuroprotective effect of Avonex.¹¹

"There are clear differences in long-term disability progression, and I think there are some differences in long-term atrophy. This is important, because MS is a long-term disease," Dr. Phillips said.

Investigators have been intrigued, he said, by laboratory and clinical differences observed between the two interferon beta-1a molecules. The question is whether the differences are related to dose, schedule, and route of administration, or to other factors.

One such factor could be the temporary desensitization of T cells seen upon beta-interferon stimulation in recent studies¹², he said. "Even with vanishingly small amounts of exposure to interferon, one day later you lose almost all responsivity, which only gradually returns to baseline," Dr. Phillips reported. "One hit at one point causes downstream events, activity and suppression of genes, that are refractory to further stimulation with interferon for up to 7 days, before the response normalizes again."

In addition, increasing exposure to interferon-beta gradually depletes the levels of the signal transduction molecule STAT3, upon which many immunosuppressive cytokines are dependent.

This in vitro effect suggests that since cells are desensitized, more frequent exposure to interferon would produce a "null event," he pointed out. "Over-aggressive, over-frequent and over-abundant exposure to interferon-beta may affect the system by depleting it of necessary molecules...beneficial effects may be confounded with higher doses," Dr. Phillips said.

MRI and Neuropathology Correlates of MS

New MRI techniques can demonstrate the extent of demyelination, axonal loss, and brain atrophy that is taking place in a given individual. These methods have revealed abnormalities, especially in the normal-appearing white matter, that are occurring in advance of the development of actual lesions. They also provide an improved means of assessing the efficacy of disease-modifying therapy.

In her presentation on the value of MRI in MS, Nancy Richert, MD, PhD, of the Laboratory of Diagnostic Radiology Research, National Institutes of Health, Bethesda, Maryland emphasized the growing recognition that MRI findings correlate with clinical outcomes.¹³ "We now believe that gadolinium-enhancing lesions are ten times more sensitive than relapses in determining disease activity," she said. "Gadolinium-enhancing lesions evolve into T2 hyperintense lesions, and some of these evolve into black holes, which are the most damaging lesions and the ones that correlate best with clinical disability."

Magnetic resonance spectroscopy imaging quantifies N-acetyl aspartate (NAA), found exclusively in neurons in MS patients. Decreases in NAA are demonstrated in both lesions and normal-appearing white matter, suggesting axonal loss is not limited to lesions. Magnetization transfer ratio is another non-invasive and very sensitive method of tracking lesions, revealing changes in areas not detected by MRI. The changes seen by these two methods include Wallerian degeneration, pre-lesion pathology, and metabolic dysfunction.

"Now we know there is diffuse disease in the normal-appearing white matter, accumulating over time, which is confirmed by pathology studies," she said. "Cerebral atrophy is the permanent tissue damage that is the end result of these processes."

References

1. Munschauer FE. Controversies in MS Therapy: Do NAbs Matter? Satellite Symposium: Toward the Optimal Management of Multiple Sclerosis: Treating a Lifelong Disease. Held June 6, 2002 during the Annual Meeting of the Consortium of Multiple Sclerosis Centers, June 5-9, 2002, Chicago, Illinois.
2. The IFNB Multiple Sclerosis Study Group Neutralizing Antibodies during Treatment of Multiple Sclerosis with Interferon Beta-1b: Experience during the First Three Years. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology 1996;47(4):889-894.
3. The PRISMS Study Group PRISMS-4: Long-Term Efficacy of Interferon Beta-1a in Relapsing MS. The PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology 2001;56(12):1628-1636.
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5. Itri LM, Campion M, Dennin RA, et al. Incidence and Clinical Significance of Neutralizing Antibodies in Patients Receiving Recombinant Interferon Alfa-2a by Intramuscular Injection. Cancer 1987;59(3 Suppl):668-674.
6. Panitch H, Coyle P, Francis G, Goodin D, O'Connor P, Weinshenker B and the Evidence Study Group. The Evidence of Interferon Dose Response: European-North American Comparative Efficacy (EVIDENCE) Study: 48 Week Data. Neurology 2002;58(suppl 3):A86.
7. Ross C, Clemmesen KM, Svenson M, et al. Immunogenicity of Interferon-Beta in Multiple Sclerosis Patients: Influence of Preparation, Dosage, Dose Frequency, and Route of Administration. Danish Multiple Sclerosis Study Group. Ann Neurol 2000;48(5):706-712.
8. Phillips JT. How and Why Immunomodulatory Agents Work. Satellite Symposium: Toward the Optimal Management of Multiple Sclerosis: Treating a Lifelong Disease. Held June 6, 2002 during the Annual Meeting of the Consortium of Multiple Sclerosis Centers, June 5-9, 2002, Chicago, Illinois.
9. Rovaris M, Comi G, Rocca MA, Wolinsky JS, Filippi M and the European/Canadian Glatiramer Acetate Study Group. Short-Term Brain Volume Change in Relapsing-Remitting Multiple Sclerosis: Effect of Glatiramer Acetate and Implications. Brain 2001;124(Pt 9):1803-1812.
10. Jones CK, Riddehough A, Li DKB, Zhao G, Paty DW for the PRISMS Study Group and University of British Columbia MS/MRI Research Group. MRI Cerebral Atrophy in Relapsing-Remitting MS: Results from the PRISMS Trial. Neurology 2001;56(suppl 3):A379.
11. Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L. Use of the Brain Parenchymal Fraction to Measure Whole Brain Atrophy in Relapsing-Remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology 1999;53(8):1698-1704.
12. Dupont SA, Goelz S, Goyal J, Green M. Mechanisms for Regulation of Cellular Responsiveness to Human IFN-Beta-1a. J Interferon Cytokine Res 2002;22(4):491-501.
13. Ostrow PT, Richert ND. Neuropathology and MRI Correlates of Multiple Sclerosis. Satellite Symposium: Toward the Optimal Management of Multiple Sclerosis: Treating a Lifelong Disease. Held June 6, 2002 during the Annual Meeting of the Consortium of Multiple Sclerosis Centers, June 5-9, 2002, Chicago, Illinois.