Editorial

William H. Stuart, MD, Medical Director, MS Center of Atlanta, Georgia

Interferon Dosing

The dosing issue with interferons in the treatment of MS in my opinion has been a "smoke and mirrors" issue for some length of time. This often emotional discussion between individuals of academic "will" has detracted from the more important issue at hand for the MS patient, which is: "What else can you do for me to give me a 30%-40% benefit above and beyond my ABC drug?"

Several facts seem evident about interferon therapy in MS:

1. Interferons are effective in MS, varying between individuals but producing an advantage to the MS patient that is less than perfect. Better therapies and/or add-on therapies were always going to be needed if control of disease progression was to be accomplished.

2. Higher interferon doses are associated with increased side effects and increased antibody levels.

3. Skin reactions are increased with subcutaneous dosing.

4. Long-term and extensive clinical experience with other drugs has not shown that increasing the dosage results in significant clinical benefit for the majority of patients. This step in the algorithm of clinical treatment often delays more effective treatment. A similar comment would apply to changing from one drug to another. It is encouraging to see from studies in progress and reported by Dupont et al. at the ENS meeting that this clinical and experience-based observation is being confirmed by laboratory measures. An immunologic and subsequent ceiling effect clinically is almost certainly present.

Valuable time has been lost in our ongoing vigorous and too often vituperative discussion of this issue. It is time for all interested parties in MS care to begin a more cohesive approach to the "next step."

Clinical Trial Design

As a practicing clinician not prone to or having the time to write often for journal publication, I have long admired and held in esteem those who do.

Medicine through the last 40 years has advanced from "descriptive" publication and nonrandomized/unblinded case series presentations to highly controlled, randomized, and double-blinded phase III studies. While this will be increasingly difficult in the years to come for multidrug regimens, it has been disappointing to see the ready acceptance of poorly designed "personal experience" papers being accepted by industry, our academic community, journals, and subsequently cleverly included in marketing data presented to the busy clinician who doesn't always have time to carefully assess all of the study design and outcomes. The use of long-term, open-label extension studies, which had traditionally been to further assess long-term toxicity, to "create" invalid outcome data is another example of this breakdown in academic discipline. No non-academic practicing neurologist would have been allowed to present this type of dubious data.

Dr. Jeffrey Greenstein in his careful analysis and critique of study design has refocused all of us in the discipline needed for correction of this insidious move toward pseudoscience.

MS patients are at the center of this entire conflict. Their welfare is our primary interest. We should band together with single-mindedness to develop those facts that will benefit them. We are not in competition with one another, rather we are in competition with the terrible demographic of untreated and partially treated MS.

Interferon beta-1a Dose-Comparison: Understanding the Latest Evidence-Based Medicine

Michel Clanet, MD, CHU Purpan Hospital, Toulouse, France

The US phase III study of Avonex (interferon beta-1a, Biogen Inc.) (Jacobs et al. Ann Neurol 1996;39:285) found that at the currently available 30-µg dose once a week intramuscularly, Avonex slowed disability progression, reduced relapse, and decreased lesion activity on magnetic resonance imaging (MRI) in patients with relapsing-remitting multiple sclerosis (RRMS). Recently, the Controlled High Risk Multiple Sclerosis Prevention Study (CHAMPS) (Jacobs et al. N Engl J Med 2000;343:898) showed that treatment with Avonex after a single demyelinating event delayed the risk of conversion to clinically definite MS (CDMS) in the treated group by about half.

Dosing and the frequency of administration of interferon beta-1a has been a subject of recent debate, and it has been suggested that higher doses administered three times a week might be more effective in the treatment of MS.

The results of a dose comparison study, the first specifically designed to address whether a higher dose of interferon beta-1a is more effective than a lower dose, were presented at the 11th Meeting of the European Neurological Society (April 21-25, 2001, Paris). The study found that the 60 µg/wk dose was not more effective than the 30 µg/wk dose.

Michel Clanet, MD (CHU Purpan Hospital, Toulouse, France), the principal investigator, said that the dose-comparison study of Avonex is the largest randomized, controlled, double-blind, parallel-group trial to date in RRMS, involving 38 centers in 10 European countries and a total of 802 patients. Patients between the ages of 18 and 55 years with an Expanded Disability Status Scale (EDSS) score of 2 to 5.5 were randomized to receive either 30 or 60 µg intramuscularly once a week for 3-4 years. Patients were excluded from the study if they had experienced a relapse in the previous 2 months.

Two neurologists at each center participated in the study; one provided clinical treatment, and the other evaluated the EDSS in a blinded manner. The EDSS score of the patients and the nine-hole peg test were assessed every 3 months for disability progression and upper-arm function. Steroid use was also noted and administered under strict guidelines by the treating neurologist; patients were self-reporting their relapses. Almost 50% of the patients had an annual MRI at baseline and at years 1, 2, and 3. Half of these patients had more frequent MRIs (pre-treatment; baseline; at months 4, 5, 6, 10, 11, and 12; then annually).

The two groups were well balanced in terms of demographic characteristics. In each group, 85% had RRMS and 15% had relapsing progressive MS. At baseline, the mean number of exacerbations per year was 1.3 for both groups. A similar percentage of both groups had EDSS scores of І3.5 and і4.0.

The primary end point of the study was the effect of the 30- and 60-µg doses of interferon beta-1a on the time to sustained progression of disability. For patients with baseline EDSS І4.5, sustained progression of disability was defined as a 1-point increase in EDSS from baseline (maintained for 6 months). For patients with baseline EDSS і5.0, sustained progression of disability was defined as reaching EDSS і6.0 (maintained for 6 months).

The results reported by Dr. Clanet were based on more than 80% of the patients who completed 3 years of follow-up. On 19 of 20 parameters studies and analyzed, no difference was found between the two doses. Overall, a similar percentage of patients in the two groups (30 and 60 µg Avonex) progressed at 2 years, and no dose differences were found between the two groups.

Clinical Results

EDSS score. No difference was seen between the two dosage groups in any EDSS subgroup. The patient group with EDSS І3.5 progressed at the same rate as the Avonex-treated group in the phase III study (Jacobs et al. Ann Neurol 1996;39:285) (22% Avonex and 35% placebo). Time to a sustained 1.5-point progression in EDSS and the extent of change in EDSS were similar in the two groups.

Relapse. Although relapse rate was not a predefined end point, it was analyzed based on patients' self-reports. The annualized relapse rates were noted to be decreasing at the same frequency for both the lower- and higher-dose groups at years 1, 2, and 3.

Use of intravenous steroids was similar between the two groups at years 1, 2, and 3.

MRI data. Both groups had decreased MRI lesions compared to baseline; the number of gadolinium-enhancing lesions, the volume of gadolinium-enhancing lesions, and the change in lesion load over 1, 2, and 3 years were similar in the two groups.

Brain atrophy. No difference in brain parenchymal fraction (BPF), a measure of brain atrophy, was evident between the two groups.

The incidence of adverse events was similar between the two active treatment groups. Frequency of headache was somewhat greater in the 30-µg group, and more flu-like symptoms occurred in the 60-µg group.

The presence of neutralizing antibodies (NAbs) has been shown to compromise the efficacy of interferon beta-1a treatment. The incidence of NAb positivity in previous studies has been very low with Avonex. In the dose-comparison study, NAbs were identified in 2.3% of the 30-µg group and 5.8% of the 60-µg group. No clinically relevant laboratory abnormalities were found in either group. "These data emphasize the low immunogenicity of Avonex," Dr. Clanet said.

"We have a reliable result that there is no additional benefit with a higher dose of interferon beta-1a after 3 years, and there is no hint that higher doses would make a difference over a longer period of time," said Dr. Clanet. "We conclude that Avonex 30 µg intramuscularly once a week is the appropriate dose in RRMS."

Interferon Dose Escalation In Vitro

S. Dupont, Biogen Inc., Cambridge, Massachusetts

The above results and the frequency of administration were reinforced by a poster presentation (Dupont et al. Poster abstract 425) at the ENS meeting discussing the effect of different courses of treatment and various concentrations of interferon beta-1a on the signal transduction pathway.

According to the researchers, the data suggest that increasing the amount or frequency of interferon administration may not yield desired biological effects and that the dosage and frequency of interferon beta-1a administration deserves careful consideration.

The biological activity of interferons is exerted after binding to a multicomponent cell surface receptor (IFNAR-1) that activates STATs (signal transducers and activators of transcription) and transcribes new genes. To investigate whether the cell has mechanisms to modulate interferon activity in response to excessive or prolonged interferon exposure, Jurkat T cells were exposed to interferon beta-1a in vitro.

This study, using escalating doses of interferon beta-1a, showed reduction in IFNAR-1 cell surface expression and associated attenuation of STAT1 activation when interferon beta-1a was given in higher doses or for a longer time. The cells recovered IFNAR-1 density only slowly, and the recovery was slower when interferon beta-1a exposure was more frequent.

These reductions in receptor expression started at interferon beta-1a concentrations less than 100 IU/mL; STAT1 phosphorylation and cellular responses were reduced by 80% to 90% when the dose reached 500 IU/mL every 48 hours. Measures of interferon gamma phosphorylation were not affected.

Clinical Trial Design

Jeffrey I. Greenstein, MD, Director, MS Center, Temple University School of Medicine, Philadelphia

With the advent of effective, disease-modifying therapy for MS, the number of clinical trials in MS has escalated dramatically. Not all of these trials have been well-designed, however, and even some prospective, randomized, controlled trials (the gold standard) have used weak end points, said Jeffrey I. Greenstein, MD, Director, MS Center, Temple University School of Medicine, Philadelphia. Dr. Greenstein told listeners that rigorously controlled trials are needed to provide reliable data on therapeutic benefit and make evidence-based decisions about managing patients.

"For therapeutic claims to be valid, trials need to be well designed, with appropriate outcome measures and necessary controls," he said. "Efficacy can only be demonstrated in large, randomized, phase III trials, and it may be suggested in phase II trials."

Pivotal trials of MS treatments should include three major outcome measures, according to Dr. Greenstein: physical disability, MRI parameters, and measures of cognitive function. He argued that the occurrence and/or severity of relapses, which has been used to measure physical outcomes in some MS trials, may not be a reliable measure.

"Relapse rate is widely used as an outcome measure in clinical trials because it is easy to quantify, but it is a measure seemingly independent of both underlying disease activity and the clinical course of MS," he said. "Reduction of sustained disability-and that means reduced disability progression for at least 6 months-is now acknowledged to be a better outcome measure than relapse rate in terms of a patient's physical status."

The EDSS has been commonly used to measure disability, but it has become clear that this instrument has limitations. The MS Functional Composite (MFSC) score, which measures time to walk 25 meters in seconds, 9-hole peg test performance in seconds, and number of correct answers on the Paced Auditory Serial Addition Test (PASAT), seems to be sensitive to change, has predictive ability, and is amenable to statistical analysis, noted Dr. Greenstein. Experts involved in the development of the MSFC are also planning to incorporate a vision test, so as to identify MS-associated optic neuritis.

Gadolinium-enhanced T1 images on MRIs provide a measure of inflammation. Also, MRI scans can show a composite of inflammation, demyelination, gliosis, and axonal loss through T2-weighted images. Tissue destruction is assessed on MRI by T1 images and measures of brain atrophy, such as the brain parenchymal fraction. Dr. Greenstein noted, however, that MRI changes do not always correlate with the clinical picture.

Dr. Greenstein discussed the interferon beta-1a (Avonex, Biogen Inc.) trials that meet his criteria for being well designed with appropriate end points, including the phase III study of Avonex in RRMS (Jacobs et al. Ann Neurol 1996;39:285), which demonstrated a 37% reduction in the risk of disease progression. The outcome measure used in that trial was a 6-month period of sustained disability. The frequency of exacerbations was significantly less in the group treated with interferon beta-1a compared with placebo (p = .03), and the volume of gadolinium-enhanced lesions was significantly better in the interferon beta-1a group at year 1 (p = .02) and year 2 (p = .05) compared with placebo. A significant treatment effect of interferon beta-1a was also seen on the number of new and enlarged T2 lesions (p = .002) at year 1.

A post hoc analysis of data from the phase III trial (Rudick RA et al. Neurology 1999;53:1698) showed that BPF accurately reflected change in the pathological processes over time, showed a relationship with severe disease progression, and was capable of demonstrating therapeutic effects. The same analysis showed that brain atrophy did not correlate with number of relapses or EDSS scores. In addition, the analysis showed that interferon beta-1a resulted in a significant reduction of measurable brain atrophy during the second year of the trial (p = .03), while patients in the placebo group continued to have worsening brain atrophy. Interestingly, the rate of brain atrophy was not strongly related to baseline clinical and MRI abnormalities.

The value of early initiation of disease-modifying therapy in high-risk MS patients was demonstrated in both CHAMPS (Jacobs et al. N Engl J Med 2000;343:898) and the Early Treatment of MS (ETOMS) study (Comi et al. AAN 2001, San Diego, Scientific Session 17.003). CHAMPS showed that initiation of interferon beta-1a treatment significantly reduced the rate of development of clinically definite MS by 44% (p = .002) in high-risk patients (i.e., patients who had sustained one MS-like attack and had two or more lesions on brain MRI) compared with placebo. In CHAMPS, patients who developed clinically definite MS dropped out, explained Dr. Greenstein; MRI data were obtained from high-risk patients who continued in the study. In that group, MRI showed that interferon beta-1a treatment substantially reduced the burden of disease, with a 57% reduction in the number of new T2 lesions, 67% reduction in the number of gadolinium-enhanced lesions, and 91% reduction in T2 lesion volume.

The interferon beta-1a dose-comparison study (discussed by Dr. Clanet earlier in this report) showed similar effectiveness for two doses of interferon beta-1a (30 or 60 µg intramuscularly once a week) and a low incidence of neutralizing antibodies (NAbs) associated with treatment. "This is important, because NAbs can confound the assessment of clinical outcome," said Dr. Greenstein.

For Further Reading

Jacobs L et al. Extended observations on MS patients treated with IM interferon-beta1a (Avonex): implications for modern MS trials and therapeutics. J Neuroimmunol 2000;107:167

Kalvakolanu DV. Interferons and cell growth control [review]. Histol Histopathol 2000 15:523

Marshall FJ et al. Clinical research in neurology: from observation to experimentation [review]. Neurol Clin 1996;14:451

Noseworthy JH. Multiple sclerosis clinical trials: old and new challenges [review]. Semin Neurol 1998;18:377

Pfeffer LM et al. Biological properties of recombinant alpha-interferons: 40th anniversary of the discovery of interferons [review]. Cancer Res 1998;58:2489

Reder AT (ed). Interferon Therapy of Multiple Sclerosis. New York: Marcel Dekker, 1997

Tilg H, Kaser A. Interferons and their role in inflammation [review]. Curr Pharm Des 1999;5:771

Wills RJ. Clinical pharmacokinetics of interferons [review]. Clin Pharmacokinet 1990;19:390