Understanding the Long-Term Benefits of Interferon Beta-1a Treatment
William H. Stuart, MD, Medical Director, Multiple Sclerosis Center of Atlanta, GA
At the 54th Annual Meeting of the American Academy of Neurology in Denver, CO, updated findings from several major clinical trials in multiple sclerosis (MS) bolstered confidence that disease-modifying therapies can, indeed, affect the clinical course of our MS patients. The best results from individual clinical trials, whether past studies or new reports, show convincing treatment effects with the four available MS agents (Avonex, Betaseron, Rebif and Copaxone). To varying degrees, depending on the drug, we see reductions in attack rate (whether measured clinically or by MRI) and disease severity, as measured by EDSS progression, T2 disease burden, or brain atrophy.
The question we now grapple with is no longer whether to prescribe these agents to the majority of our patients, but which agents to use. Close examination of clinical trials, not only efficacy outcomes but also trial designs, will offer some guidance in this regard.
Clearly, the most important therapeutic aim of the immunomodulators is to prevent or postpone long-term disability. However, long-term disability in MS often evolves slowly over many years. Most clinical trials, by contrast, study patients for only short periods of time and therefore use only short-term outcome measures to assess efficacy. Often, when trials are extended long-term, they are open-label studies and inherently suffer from treatment biases and other design flaws.
The cumulative 4-year results (one year extension of 3-year study) of the European Interferon Beta-1a Dose-Comparison Study were reported at this meeting, satisfying the need for long-term treatment efficacy data from a large, double blind, multicenter trial. This study found efficacy of Avonex maintained for four years in both the 30 mcg and 60 mcg once-weekly doses, with improvement in multiple outcomes and over half the subjects remaining progression-free at 4 years. The fact that higher doses do not impart greater efficacy allows us to treat patients with less drug, thus enhancing safety and reducing the likelihood of developing neutralizing antibodies.
Neutralizing antibodies, in fact, developed in only 2.3% of patients treated with Avonex in the European Interferon Beta-1a Dose-Comparison Study. This is a remarkably low rate, given their common occurrence in patients treated with interferon beta-1b (IFNB Multiple Sclerosis Study Group. Neurology 1996;46:647-650). Neutralizing antibodies were found, for example, in 35% of patients treated with Rebif in the EVIDENCE trial (also reported at the AAN) but in only 5% of Avonex-treated patients in that same study. Neutralizing antibodies interfere with receptor-mediated functions of interferon beta and have been associated with a loss of biological activity. In fact, evidence or results from two interferon beta trials (PRISMS-4; Interferon Beta-1b 3-Year Results) have shown a direct link between neutralizing antibody-positive patients and loss of biological activity and clinical efficacy.
Apart from the development of neutralizing antibodies at 48 weeks, the EVIDENCE trial showed efficacy for Rebif in a short-term study. Data should continue to be collected from this study in order to determine the long-term clinical effectiveness of these agents in addition to the relevance of neutralizing antibodies.
A cohort of patients from the Phase III glatiramer acetate study who elected to stay on an open-label extension study was reviewed and continues to show stability. This study's unblinded and nonrandomized structure continues to raise issues regarding clinical relevance apart from the long-term toxicity of glatiramer acetate.
This Forum Report describes the encouraging results from these trials. It also summarizes several studies evaluating the immunologic changes that occur with interferon beta-1a therapy, including the potential for greater immunologic impact by combining interferon beta-1a with corticosteroids (prednisone), azathioprine, or glatiramer acetate. The Forum Report also looks at encouraging data on mitoxantrone for rapidly worsening MS. Despite the efficacy of immunomodulators in relapsing-remitting MS patients, too many of our patients rapidly spiral downward, and there is a true need for treatments that will halt this course.
I invite you to review these highlights from this meeting. It is my hope that you will find this information both promising and useful in your care of patients with MS.
Efficacy of Current Disease-Modifying Agents
Sustained Efficacy of Interferon Beta-1a in Relapsing Multiple Sclerosis: Four-Year Results from the European Dose-Comparison Study
Ludwig Kappos, MD, Professor of Neurology, and Ernst-Wilhelm Radue, MD, Professor of Neuroradiology, University Hospitals, Basel, Switzerland
In relapsing multiple sclerosis (MS), treatment efficacy was sustained for at least 4 years with a 30 mcg once weekly dose of interferon beta-1a (Avonex, Biogen, Inc.) and levels of neutralizing antibodies (NAb) remained low during long-term use of this agent.1 These findings are from an extension of the European Interferon Beta-1a Dose-Comparison Study reported at this meeting.
"In our extension of the [European Interferon Beta-1a] Dose-Comparison Study, the good clinical effect in respect to EDSS, relapse rate, and neutralizing antibodies was maintained over 4 years. This is one of the longest studies we have that shows a positive effect," said Ernst-Wilhelm Radue, MD, Professor of Neuroradiology at the University Hospitals, Basel, Switzerland. He presented the study on behalf of the principal investigator, Ludwig Kappos, MD, Professor of Neurology at University Hospitals, Basel, Switzerland.
The double blind, parallel-group, 34-center European Interferon Beta-1a Dose-Comparison Study is the largest long-term study ever conducted (n = 802) in MS without patient re-randomization.2 Previous analysis of 608 evaluable patients showed sustained efficacy in delaying disease progression during 3 years of treatment with Avonex in doses of 30 mcg or 60 mcg once weekly.3
The current extension analysis, involving 491 patients who continued double blind treatment for one additional year, demonstrated strong maintenance of this benefit with the 30 mcg once-weekly dose with similar benefit from the 60 mcg dose.
Sustained efficacy was demonstrated in multiple outcomes, including cumulative rate of sustained disability progression, extent of change in Expanded Disability Status Scale (EDSS) score, relapse rate, percentage of relapse-free patients, and intravenous steroid use, Dr. Radue reported.
Disability Progression Delayed With Both Doses
Over the entire 4-year treatment period, 215 patients received Avonex 30 mcg and 231 received Avonex 60 mcg. For the 30 mcg and 60 mcg doses respectively, patient mean age was 37.6 (range 18-55) and 36.9 (range 18-55), and 86% and 87% had relapsing-remitting MS (RRMS) while 14% and 13% had relapsing progressive MS.
At the end of the 4-year treatment period, both doses yielded a similarly high percentage of progression-free subjects: 52% in the 30 mcg group and 57% in the 60 mcg group (p = 0.32). Thirty percent in each group progressed to an EDSS score of ≥ 4.0 (p = 0.93) and 22% in each group progressed to an EDSS of ≥ 6.0 (p = 0.46). There were similar differences in the mean changes in EDSS scores at months 12, 24, 36, or 48 between groups.
Avonex therapy maintained its efficacy on relapse rate at 4 years, as demonstrated by the following outcomes:
• Reduction in relapse rate from baseline was 43% with the 30 mcg dose and 42% with the 60 mcg dose.
• Mean relapse rate was reduced from 1.3 at baseline to 0.74 with 30 mcg and from 1.3 at baseline to 0.75 with 60 mcg.
• Percentage of relapse-free patients was 18% with 30 mcg and 19% with 60 mcg (p = 0.850).
• Median time to first relapse was 402 days with 30 mcg and 347 days with 60 mcg (p = 0.83).
Furthermore, the rates of intravenous steroid use, a surrogate marker for severe relapses, were similar as well, with 0.66 courses/patient/year for 30 mcg and 0.67 courses/patient/year for 60 mcg after 4 years of treatment (p = 0.960).
NAb formation, recognized as a possible factor in treatment efficacy, was low in both treatment groups. The proportion of patients with NAb titers ≥ 20 at any time during the study were only 2.3% with 30 mcg group and 5.8% with 60 mcg.
The long-term clinical outcomes [of the extension analysis] concur with the effects of Avonex observed in the pivotal Phase III trial by Jacobs et al.4 They are also similar to benefits seen with other agents in other studies, with the additional advantage of lacking NAb formation, Dr. Radue pointed out.
Disease Activity Reduced on MRI
In 386 of the patients followed for 3 years by annual magnetic resonance imaging (MRI) scans, the MRI outcomes corroborated the clinical results, showing similar benefit with both doses. Substantial reductions from baseline were seen in each group for all MRI measures at all time points [12, 24, and 36 months], Dr. Radue reported.
There were no statistically significant differences or trends observed between 30 mcg and 60 mcg dosed once weekly with regard to change in T2 [hyperintense] lesion volume, change in T1 [hypointense] lesion volume, number and volume of gadolinium-enhancing lesions, and number of new or enlarging T2 lesions, advised Dr. Radue.
After 3 years of therapy, the mean number of gadolinium-enhancing lesions was reduced by 78% with 30 mcg and 64% with 60 mcg (p = 0.76), while mean volume of gadolinium-enhanced lesions was reduced by 75% and 68% (p = 0.58), respectively. No significant differences were observed between 30 mcg and 60 mcg in change from baseline in T1 hypointense lesion volume at 3 years; the median change was 190 mm3 with 30 mcg (19% increase) and 85 mm3 with 60 mcg (10% increase) (p = 0.004).
Dr. Radue noted that, as with the clinical outcomes, the effect of Avonex on disease activity by MRI5 essentially mirrored the MRI results from the Phase III Avonex trial by Simon et al.6
The Evidence of Interferon Dose Response: European-North American Comparative Efficacy (EVIDENCE) Study: 48-week Data
Hillel Panitch, MD, Professor of Neurology, University of Vermont, Burlington, VT
Also presented at this meeting were 48-week results of the EVIDENCE trial (Evidence of Interferon Dose Response: European-North American Comparative Efficacy Study) that assessed differences based on dose of interferon and treatment regimen.7 Of the initial 677 patients enrolled, the 48-week data included 314 of 339 (93%) randomized to Rebif (interferon beta-1a, Serono, Inc.) 44 mcg subcutaneously three times weekly and 317 of 338 (94%) randomized to Avonex (interferon beta-1a, Biogen, Inc.) 30 mcg once weekly.
Hillel Panitch, MD, Professor of Neurology at the University of Vermont, Burlington, VT reported that Rebif provided greater benefit than Avonex. Kaplan-Meier curves at 48 weeks showed a reduced probability of relapse during treatment with Rebif, with exacerbations occurring in 38% compared with 48% of patients receiving Avonex with an absolute difference of 10%. The relative reduction in relapse rate over baseline was 26% and 16%, respectively (not statistically significant), and the relative risk of relapsing was 0.81 with Rebif, Dr. Panitch reported.
Frederick Munschauer, MD, Interim Chairman of Neurology at the State University of New York at Buffalo, Buffalo, NY pointed out in the discussion period that the first 24-week analysis showed an 11.8% difference in relapses favoring Rebif, the second 24 weeks of the study showed a 1% difference favoring Avonex among the remaining cohort of relapse-free subjects.
In response, Dr. Panitch agreed, "The differences become less pronounced [over time]."
Jeffrey I. Greenstein, MD, Matthew T. Moore Professor and Director of the Multiple Sclerosis Center at Temple University, Philadelphia, PA also expressed concerns about the study design and the interpretation of the data. "If you look at the actual relapse rate at 48 weeks, there is no statistically significant difference between the two agents. So what you are seeing is a relatively small effect that may be of relatively short duration...In other Phase III studies, the number of patients who have reductions in exacerbations is pretty much the same between Avonex and Rebif."
EVIDENCE investigators also reported that magnetic resonance imaging (MRI) activity was improved with the higher dose. Gadolinium-enhanced scans were performed monthly during the first 6 months, but the final scan at 48 weeks was not contrast-enhanced (i.e., PD/TD only). The MRI outcome measure was the combined unique (CU) activity (T1 plus T2 abnormalities).
Rebif was associated with less CU activity, however, Dr. Radue pointed out that the definition of disease activity in the study was inconsistent between the 24 and 48 week time points, and, lacking a final gadolinium-enhancing scan, conclusions cannot be drawn, he said.
In addition, Dr. Panitch reported that there was no significant difference between the agents in sustained progression of disability as measured by Expanded Disability Status Scale (EDSS).
Higher Doses Yield Higher Percentage of Neutralizing Antibodies
If additional benefits do exist with the higher dose of interferon beta-1a, there was some trade-off in terms of toxicity, Dr. Panitch noted in his presentation. Injection site reactions were common, with 44% of Rebif patients experiencing inflammation and 35% demonstrating other injection side effects. These occurred in only 4% and 12%, respectively, of Avonex-treated patients (p < 0.001). Elevated liver enzymes were seen in 18% and 9% of Rebif and Avonex groups, respectively (p < 0.002); leukopenia in 11% and 5%, respectively (p < 0.003); and flu-like symptoms in 42% and 49%, respectively (p < 0.089).
More importantly, neutralizing antibodies (NAb) were markedly more common with Rebif, occurring (any titer) in 35% versus 5% of patients on Avonex 30 mcg; NAb > 20 NU/ml were observed in 25%7 and 2%, respectively. "This was considerably higher than in any previous studies with this drug," Dr. Panitch observed.
During the discussion, Donald Goodkin, MD, Medical Director of Immunex Corporation raised concerns about the development of antibodies and its impact on the EVIDENCE trial interpretation. "The treatment effect on the Kaplan-Meier curve favors Rebif, but the chance of having neutralizing antibodies is far greater. And everything we have learned would suggest that they would neutralize the benefits of the drug," he commented.
The EVIDENCE investigators reported that the presence or absence of NAb made no difference on relapses. However, Dr. Goodkin pointed out that the effect of NAb occurs months after they appear; therefore, their influence can only be judged at a longer duration than was possible in this short-term study.
"To me, this would mean the benefits of Rebif over Avonex are probably confined to the initial 24-week period," he said. "The issue is whether the difference at 24 weeks is clinically meaningful, and this deserves discussion."
Dr. Munschauer added, "You may prevent relapses in one out of ten patients, but on the other hand, one out of four patients will develop neutralizing antibodies with Rebif and this is associated with a loss of therapeutic effect. I think there was an 11.8% benefit to Rebif in the first 6 months, but it disappears in the second 6 months and the emergence of neutralizing antibodies may cause further deterioration in disease control in subsequent years."
Dr. Greenstein echoed comments made by Dr. Elliott Frohman, MD, PhD, Director of the Multiple Sclerosis Program and Eye Movement Clinic at the University of Texas, Southwestern Medical School, Dallas, TX during the presentation. "The PRISMS-4 study, which continued for 4 years, showed a statistically significant impact of neutralizing antibodies on relapses, progression of disease, and MRI activity. There is real coherence of data showing that on all parameters, you lose benefit."
Furthermore, he continued, with such a short-term study it is not possible to demonstrate a sustained effect on progression of disability, which is the primary concern of the patient and their physicians. EDSS changes were similar between the two agents in the EVIDENCE trial; in previous studies9,10 progression of disability was slowed by 31% with Rebif and by 37% with Avonex. Maintenance of this effect with Avonex was further demonstrated in the European Interferon Beta-1a Dose-Comparison study.1
"The issue with EVIDENCE is whether it is scientifically valid enough to change our treatment decisions. What we need is not short-term but long-term data, because we want to know what will happen to patients several years from now," said Dr. Greenstein.
Results of the Long-Term (8-Year) Prospective, Open-Label Trial of Glatiramer Acetate for Relapsing Multiple Sclerosis
Kenneth P. Johnson, MD, Professor and Chair, Department of Neurology, University of Maryland, Baltimore, MD
A continuation of the prospective open-label trial of glatiramer acetate (GA) (Copaxone, Teva Neuroscience, Inc.) treatment of relapsing-remitting multiple sclerosis (RRMS) patients demonstrates continued effects on relapse rate, according to a report at this meeting.11
The trial began in 1991-92 with 251 RRMS patients randomized to GA 20 mg/day (n = 125) or placebo (n = 126).12 After approximately 30 months, placebo-treated patients crossed-over to GA, which initiated the current open-label study that now includes 148 remaining patients (original GA patients n = 72; original placebo patients currently on GA n = 70).
At 8 years, the yearly relapse rate is 0.16 for original GA patients and 0.23 for patients who received placebo for the first 3 years. Prior to randomization, the yearly relapse rates were 1.49 and 1.45, respectively. The relapse rates during the entire 8 years are 0.43 for original GA patients and 0.52 for the placebo/GA treatment group, reported Kenneth P. Johnson, MD, Professor and Chair, Department of Neurology, University of Maryland, Baltimore, MD.
Relapse rates were significantly better for the original GA patients versus those receiving placebo during the first 2-3 years, then fell to low levels for both groups by year 8, when all patients had been on GA for 5 or more years. Patients who received placebo at randomization, thus delaying active GA treatment, were more likely to have worsened by at least one Expanded Disability Status Scale (EDSS) step, compared to patients who originally received GA.
"The relapse rate is now at a very low level. At the same time, the patients are not necessarily getting worse: 65% are at the same level as when they entered 8 years earlier. For patients who were on placebo for the first 30-36 months, however, 50% are at the same level," Dr. Johnson noted.
"This 15% difference is due to a delay in therapy," he continued. "This is one of the first studies to really show there is a price to pay when therapy is delayed."
One concern with these and previous findings in this open-label GA study12-14 has been that, over the long-term, patients with the poorest response, [increases of EDSS ≥ 1.5] or outcomes were the ones who dropped out. Sixty-three percent of poorest responders dropped out by 6 years.
Dr. Johnson commented, "We are cognizant of that kind of criticism and we are interested in these patients. This is certainly something that is a problem with any open label trial. You don't have a comparison group."
John Noseworthy, MD, Consultant in Neurology, Mayo Clinic, Rochester MN commented in the MS Therapy Educational Session that patients in the original cohort who chose not to continue GA treatment in the extension study were clearly shown to have higher annual relapse rates and greater worsening of their disease as study participants. "Without doubt, the group continuing in the prolonged extension phase of the study were doing well, and were perhaps destined to do well," he stated. "Either way one looks at it, they were a selected group of patients who had a more benign course, and their considerable stability thereafter could at least, in part, be related to that."
Patients dropped out or were lost to follow-up for a variety of reasons, Dr. Johnson continued, but in order to obtain details about these patients the investigators must develop a means of locating and surveying the patients who discontinued the study. "We want to find out exactly what has happened to them to be able to answer this question," Dr. Johnson stated.
Efficacy of Combination Therapy: Emerging Data
Effects of Combination Therapy of Beta Interferon-1a and Prednisone on Serum Immunologic Markers in Patients with MS
Hassan H. Salama, MD, MS Research Unit, Baylor-Methodist Center, Houston, TX
Combination therapy with Avonex and prednisone (Deltasone, Pharmacia Corp.) may have an additional treatment effect on the inflammatory processes in multiple sclerosis (MS) by further lowering the production of pro-inflammatory cytokines and the T-cell activation state, reported Hassan Salama, MD of the MS Research Unit at Baylor-Methodist Center, Houston, TX at the meeting.15
The two agents were studied in combination based on their immunomodulatory properties. Avonex presumably exerts a regulatory effect on T-cell activation and cytokine production while prednisone has an immunosuppressive effect in high doses.
The multicenter study included 55 clinically definite MS patients with relapsing-remitting MS (RRMS) or secondary progressive MS and a control group of 27 healthy subjects. Patients were randomized to receive Avonex 30 mcg once weekly (n = 22) or Avonex plus prednisone at a daily oral dose of 15 mg (n = 33). Serum specimens were collected at baseline and 3, 6, 9, and 12 months during treatment. The blood specimens were assayed for concentrations of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-12, IL-2R (receptor), and IL-10; CD95; Intercellular Adhesion Molecule-1 (ICAM-1; CD54) and binding antibodies to Avonex using ELISA. Patients were monitored for clinical exacerbation and EDSS.
Avonex alone significantly reduced TNF-α and ICAM-1 but not IL-12 and IL-2R. The production of IL-10 and CD95 was increased.
Combination therapy inhibited IL-12, IL-2R, TNF-α, and ICAM-1 more profoundly than did monotherapy. However, combination therapy appeared to antagonize the up-regulatory effect of Avonex on IL-10 (potent anti-inflammatory cytokine produced by Th2 cells) and soluble CD95 (natural inhibitor for Fas/Fas ligand-mediated T-cell apoptosis) by suppressing the production of both serum markers. Reduction in serum levels of soluble CD95 induced by the addition of prednisone may provide some additional benefit, because CD95 may be associated with aberrant T-cell regulation, Dr. Salama explained.
"Combination therapy worked well in suppressing the inflammatory cytokines, but at the same time it suppressed IL-10 and CD95. Avonex alone had an effect on CD95, which has an important role in apoptosis of harmful Th1 cells," he explained.
Results revealed the same occurrence of binding antibodies in both treatment groups (2/22 vs. 3/33) at 6 and 12 months, suggesting that the addition of prednisone had no effect on the production of binding antibodies. Three patients on Avonex monotherapy and 5 patients on combination therapy had a single relapse during treatment. Avonex monotherapy patients had a slight 0.1-point reduction in EDSS (p < 0.05) after 12 months of therapy.
Dr. Salama stated the low doses of prednisone used in the study were well tolerated by the patients. Definitive conclusions cannot be drawn at this time as to whether one therapy or the other is more clinically beneficial, due to the small number of patients and short follow-up. Future studies will address the clinical efficacy and the usefulness of monitoring immunologic markers.
Interferon Beta-1a In Combination with Azathioprine and Low-Dose Steroids for Relapsing-Remitting MS: Preliminary Clinical and MRI Data from a Two-Year, Double-Blind, Randomized, Placebo-Controlled Study
Eva Havrdova, MD, Department of Neurology, Charles University, Prague, Czech Republic
Interferon beta-1a efficacy may be improved by combining the agent with classical immunosuppressant agents, according to a European study presented here.16
The study in 105 relapsing-remitting multiple sclerosis (RRMS) patients combined Avonex with azathioprine (Imuran, Prometheus Labs) and low-dose prednisone. The patients were randomized into three groups: Avonex 30 mcg once weekly plus placebo A (azathioprine) and placebo S (steroid); Avonex 30 mcg once weekly plus azathioprine 50 mg daily plus placebo S (steroid); or Avonex 30 mcg once weekly plus azathioprine 50 mg daily plus prednisone 10 mg every other day. Magnetic resonance imaging (MRI) scans were done every 8 weeks, providing T1, T2 and PD weighted images; magnetic transfer ratio (MTR); automatic measurement of lesion load; and measurement of atrophy.
The study is still blinded, but preliminary data in 55 patients who completed the first year of the study and 40 patients who completed 2 years of treatment indicate there is a significant benefit to combined therapy, reported Eva Havrdova, MD, Department of Neurology, Charles University, Prague, Czech Republic.
"Before the introduction of interferon beta in the Czech Republic, immunosuppression consisted mainly of azathioprine, and sometimes low-dose oral steroids were used in patients with active disease. After the introduction of interferon, a lot of patients were still treated with both immunosuppressive drugs and interferon beta. This group showed greater reductions in relapse rate than expected by published studies," Dr. Havrdova explained.
By way of background, Dr. Havrdova recounted that azathioprine was retrospectively studied in a 1997 study and showed the ability to decrease MRI activity in MS.17 After 2.5 years, the lesion load in patients receiving azathioprine was approximately half what it was in untreated patients. Furthermore, preliminary MRI data support the likelihood that combination immunosuppressive therapy markedly influences MS, she reported.
Baseline MRI data concerning the initial lesion load were divided into three groups (A = entry lesion load 4 cm3, B = 4-10 cm3, and C = >10 cm3). The increase in atrophy differed in these three groups at 2 years. Patients in group A with minimal entry lesion load progressed by 0.4%; patients in group B progressed by 3.25%; and patients in group C with the highest entry lesion load progressed by 2.5%. The increase in lesion load has not been correlated with the progression in atrophy, but may support high variability in the pathogenetic mechanisms underlying the development of hyperintense MRI lesions, Dr. Havrdova observed.
"Patients with a lesion load of 4-10 cm3 had the greatest atrophy increase, while the least atrophy increase was observed in patients whose initial lesion load was less than 4 cm3, though they had a substantial increase in lesions. In 70% of patients, the brain volume has decreased by approximately 1% every year," she observed.
The overall relapse rate diminished from 1.9 at baseline to 0.6, for a 68% reduction, the greatest reduction being at 2 years. In this mildly affected study population, Expanded Disability Status Scale (EDSS) did not change significantly. Eight patients withdrew from the study due to ongoing disease activity and switched to more aggressive therapy but remained in follow-up.
There appears to be a correlation between increased lesion load and attacks. Patients with a stable lesion load experienced no attacks, Dr. Havrdova added.
The MTR ratio had high predictive value in patients whose MS had clinically worsened. MTR changes preceded clinical worsening by at least 6 months and also the development of typical T2 lesions.
Results of the Extension of a Trial to Assess the Longer Term Safety of Combining Interferon Beta-1a and Glatiramer Acetate
Fred Lublin, MD, Professor of Neurology, Mt. Sinai Medical Center and Corinne Goldsmith Dickenson Center for MS, New York, NY
The combination of interferon beta-1a (Avonex) and glatiramer acetate (GA; Copaxone) is safe and potentially of greater efficacy than immunomodulating monotherapy, according to an extension of a trial that is evaluating this combination.18 The primary outcome of the trial is safety, but the study also assessed gadolinium-enhancing lesion load, relapse rates, Expanded Disability Status Scale (EDSS) change, and the development of neutralizing antibodies (NAb).
The study included 33 patients with relapsing-remitting multiple sclerosis (RRMS) who had been using Avonex for 6 or more months. The initial 6-month data from this trial was reported at the 2001 AAN annual meeting19; the current report was based on the extension of the study to 12 months.18
After a run-in period of 3 months on Avonex monotherapy, 31 patients received additional treatment with GA; 26 patients completed 6 months of combination therapy and 16 patients completed 12 months of combination therapy. Patients underwent magnetic resonance imaging (MRI) scans at each monthly follow-up visit for the first 6 months, then again at months 9 and 12.
In the extension study, the combination continued to demonstrate activity and safety. The findings reject the null hypothesis, that the addition of GA would block the effect of interferon, demonstrated by increasing the average number of gadolinium-enhanced MRI lesions by 1 (p < 0.001).
"When patients are on interferon-beta therapy, gadolinium-enhancing lesions are at a low level. We assumed that patients coming in on interferon-beta were at this low level, and if these agents interfered with one another, a sensitive measure of safety would be an increase in gadolinium-enhancing lesions. So we compared the number of gadolinium-enhancing lesions between months 1 and 6 versus those in the run-in period (monotherapy)," explained Fred Lublin, MD, Professor of Neurology, Mt. Sinai Medical Center and Corinne Goldsmith Dickenson Center for MS, New York, NY.
In fact, there was a suggestion of increased efficacy, as a decline in lesion volume and numbers was shown, Dr. Lublin reported. There was no increase in gadolinium-enhanced lesions either as a group or individually. There were no serious adverse events related to combination therapy, except one seizure after interferon therapy (reported last year), and no increased production of neutralizing antibodies.
There were two relapses in two patients during the run-in period, four relapses in three patients during the initial 6 months, and no new relapses in the following 6 months of the extension.
There is a suggestion of increased effectiveness of combination therapy, as a downward trend in gadolinium lesion numbers and volumes over time was found. Eight of the 11 patients (73%) with any gadolinium lesions at baseline showed a decline in lesion number and volume at 6 months. Of the 16 patients completing 12 months of follow-up, only 2 patients had lesions present during the final 6 months. In both cases, there was a decrease from the previous 6 months in lesion number and volume. "As the study continued, lesions tapered off to almost nothing," advised Dr. Lublin.
"We think we have established the safety of this combination, by the absence of any new gadolinium activity or unexpected or adverse events contributable to therapy," Dr. Lublin said. "And we have some tantalizing efficacy data, though the numbers are small."
To evaluate the efficacy of Avonex and GA combination therapy, a Phase III multicenter clinical trial is being planned, which will randomize 750-1000 patients to Avonex, GA, or the combination of the two.
Induction Treatment with the Monthly Combination Mitoxantrone-Methylprednisolone for Six Months Followed by a Maintenance Therapy in Worsening Relapsing-Remitting MS: The Clinical Benefits Last at Least Four Years
Emmanuelle Le Page, MD, and Gilles Edan, MD, CHU Pontchaillou, Rennes, France
Several reports at this meeting suggested that relapsing-remitting multiple sclerosis (RRMS) patients who are rapidly worsening might benefit from mitoxantrone (Novantrone, Immunex Corp.) in combination with either steroids or interferon beta.
In France, mitoxantrone has been used in MS [induction therapy] for more than a decade. In a study reported here by French investigators, mitoxantrone 20 mg plus methylprednisolone 1000 mg was given as a monthly infusion for 6 months to 100 worsening RRMS patients.20 After mitoxantrone induction, 25 patients received mitoxantrone every 3 months; 53 patients received another long-term modifying agent (azathioprine (19), methotrexate (9), interferon beta (21), or glatiramer acetate (4)); and 22 received no maintenance therapy up to the next relapse.
The median duration of MS before starting mitoxantrone treatment was 3.7 years. Within the 12 months before initiation of treatment, the annual relapse rate was 2.8, the mean worsening of Expanded Disability Status Scale (EDSS) was 2.2, and gadolinium-enhanced lesions were detected in 77 of 95 patients.
After mitoxantrone induction, disease activity declined dramatically. The mean number of relapses diminished to 0.3, 0.4, and 0.4 at years 1, 2, and 3, respectively. This constituted a reduction of 88.3%, 84.5% and 84.5% compared with the annual relapse rate prior to treatment (p < 0.0001), reported Emmanuelle Le Page, MD, CHU Pontchaillou, Rennes, France.
The percentage of relapse-free patients was, respectively, 78%, 63%, 48%, and 42.5% at years 1, 2, 3, and 4. EDSS was improved [from induction baseline] by ≥ 1 point in 58%, 50%, 50% and 40.5% at year 1, 2, 3 and 4 (p < 0.0001). Only 7 out of 80 patients had a gadolinium-enhanced lesion after mitoxantrone induction, equating to a 90% reduction compared with MRI baseline levels (p < 0.0001). Fifteen of the 100 patients evolved to secondary progressive MS.
"The clinical benefit and reduction of disease activity supports our belief that mitoxantrone, as administered in this study, may be an effective induction treatment before initiating other long-term disease-modifying therapies for worsening relapsing-remitting MS patients," Dr. LePage remarked.
Mitoxantrone Safety Profile
Gilles Edan, MD, CHU Pontchaillou, Rennes, France, one of the investigators in the aforementioned study, reported on the safety profile of mitoxantrone based on a cohort of 802 MS patients from 12 French MS centers (1992-2001) in a separate study.21 The median and the mean cumulative dose of mitoxantrone was 70 mg/m2. There was no evidence of clinical heart failure in any patient; 12 patients (1.8%) experienced asymptomatic reduction of left ventricular ejection fraction to < 50% (persisting in 3 patients for follow-up range of 4.5-7.0 years). Other adverse events included: 1 case of acute myelogenous leukemia detected 22 months after initiating mitoxantrone, 6 patients with infection associated with absolute neutrophil count (ANC) < 500, and 10% of women at risk to lose menses experienced amenorrhea persisting more than 6 months. There were no treatment-related deaths, he reported.
Mitoxantrone Plus Interferon Beta-1b
In another presentation, Douglas R. Jeffery, MD, Department of Neurology, Wake Forest University, Winston-Salem, NC examined the safety and efficacy of combined therapy with mitoxantrone and interferon beta-1b (Betaseron, Berlex Laboratories, Inc.) in 10 relapsing-remitting or secondary-progressive patients with worsening MS and a suboptimal therapeutic response to interferon beta-1b alone.22 The mitoxantrone regimen was administered intravenously at 12 mg/m2 for the first month, 5 mg/m2 at months 2 and 3, continuing with maintenance dosing at 5 mg/m2 every third month.
The combination was well tolerated and there were no serious adverse events. There was some short-term neutropenia at 14 days, but this normalized by day 21.
Both clinical and MRI measures of disease activity suggested efficacy. Relapse rates were reduced 64% following the addition of mitoxantrone from 2.86 to 1.05 (p < 0.004). There was no significant change, however, in EDSS.
There was also a significant decrease in the frequency and volume of new enhancing lesions. The mean number of these lesions was reduced by 93% [from baseline], and volume was reduced by 96% [from baseline], he reported. "By the time of the last scan only two patients had new enhancing lesions and lesion volume was very small," Dr. Jeffery observed.
"The data are limited by the small number of patients and the short duration of the study, but it suggests this combination might be effective in patients with suboptimal responses to interferon," concluded Dr. Jeffery.
New Laboratory Findings in Interferon Therapy
Repeated Treatment with Interferon Beta-1a: in Vitro Results in the Attenuation of Cellular Responsiveness
Susan E. Goelz, PhD, Biogen, Inc., Cambridge, MA
Frequent treatment with interferon beta can make cells refractory to further interferon beta treatment. Thus, Susan E. Goelz, PhD, Biogen, Inc., Cambridge, MA hypothesizes that in the context of using interferon beta as a therapeutic agent, increasing the amount or frequency of interferon beta may not yield desired biological effects. Issues concerning dosage and frequency of interferon beta administration deserve careful consideration, according to Dr. Goelz, who presented an in vitro study at this meeting.23
The objective of her study was to examine how different dosing regimens can affect biological responses to interferon beta in the laboratory.
Interferons exert their biological effects by binding to multicomponent cell surface receptors (IFNAR1 and IFNAR2). The activated receptors, in turn, induce signaling molecules [Signal Transducers and Activators of Transcription, (STATs)] as well as genes. Since interferons are potent pleiotropic cytokines, it is likely that cells have mechanisms to modulate interferon activity in response to excessive or prolonged interferon exposure, she pointed out.
It is of interest to determine what regulatory mechanisms might be induced in cells with excess and/or chronic exposure to interferon, Dr. Goelz explained. The study, therefore, investigated the regulation of the interferon receptor, signaling molecules, and interferon-induced gene expression in response to high or repeated doses of interferon beta-1a using Jurkat T-cells and fresh human peripheral blood mononuclear cells (PBMCs) in vitro.
The study revealed the following:
• Effect on interferon receptor expression: increasing the dose of interferon beta-1a reduces interferon receptor levels.
• Effect on cellular responsiveness: even when receptor levels are high, interferon-dependent gene expression is blocked; therefore, there must be another level of control.
• Duration of desensitization to further interferon treatment: cells remain desensitized to further interferon treatment for up to 6 days. After 48-96 hours of initial treatment, cells are only partially responsive to retreatment with interferon beta-1a but gain full responsiveness by 168 hours. This data suggests that the current once-weekly dose of Avonex is correct.
• Effect of interferon on normal human PBMCs: Fresh PBMCs also become desensitized by frequent interferon treatment.
Dr. Goelz concluded that cell surface expression of the interferon receptor is reduced by relatively low doses of interferon beta. Interferon-dependent activation of signaling molecules and gene expression is decreased when cell surface levels of the receptor are reduced. Pretreatment of cells with interferon beta can result in alterations in the signal transduction pathway that reduce biological responses to the drug, even when receptor levels are normal.
Increasing the amount or frequency of interferon beta may not yield the desired biological effects, although this is not yet linked to clinical outcome, she said.
"This study shows there are unexpected ways in which cells can modulate a response to interferon, for example, through the signal transduction pathway," she explained.
Binding Antibodies to Interferon Beta During Treatment of MS Are Biologically and Clinically Relevant
Ebrima Gibbs, MS, and Joel Oger, MD, University of British Columbia, Vancouver, Canada
Post-marketing surveillance of patients receiving interferon beta-1b demonstrate marked development of binding antibodies (BAb) and neutralizing antibodies (NAb), which correlate with reduced drug bioavailability and reduced clinical efficacy, Canadian researchers reported.24
There has been suggestive evidence that NAb reduce the effectiveness of injected interferon beta-1b in relapsing multiple sclerosis (MS); as shown by relapse rates and magnetic resonance imaging (MRI) activity. NAb neutralize the biologic effects of interferon beta, and their presence correlates with decreasing levels of interferon-induced surrogate markers such as neopterin, B2 microglobulin, and myxovirus protein. Additionally, it has been demonstrated that high levels of NAb completely inhibit the bioavailability of interferon beta, and that natural killer cells return to pre-treatment levels when NAb emerge.
NAb are a subset of BAb. Generally, only samples that are positive for BAb are assayed for NAb, but BAb and NAb develop in different patterns and the potential exists for BAb to also interfere with the effects of interferon, the investigators explained.
"We decided to correlate BAb with therapeutic responsiveness, and we are beginning to see that they are important. Previously, we only recognized neutralizing antibodies," stated Ebrima Gibbs, MS, University of British Columbia, Vancouver, Canada.
The post-marketing study included 100 patients with relapsing MS who had received interferon beta-1b for up to 2 years. The study was initiated to examine the incidence, the effect on bioavailability, and the effect on clinical efficacy of BAb. Patients were followed immunologically by binding antibody assay (sandwich ELISA) and clinically by repeated examinations (48 prospectively and 52 retrospectively). Monthly BAb titers were obtained and samples from 16 randomly chosen patients were also assayed for NAb.
Assays revealed that 67 of 100 treated patients developed BAb. Most BAb appeared during the first 6 months of treatment, and reached a maximum (78.7% of maximal normalized level) at 5 months. Thereafter, the titers fell to an average of 39% at 24 months, and 45 of 67 patients became BAb-negative, probably because the patients developed tolerance, Dr. Oger, Professor of Neurology at the University of British Columbia, Vancouver, Canada explained.
In 16 randomly chosen patients, 9 were positive for BAb and 5 of these 9 developed NAb at well. None of the 7 patients who were negative for BAb developed NAb. BAb-positive patients destined to become NAb-positive had higher BAb titers than BAb-positive patients who did not develop NAb.
Bioavailability of interferon beta-1b, determined by measuring myxovirus protein content of lymphocytes, was compromised by the appearance of BAb. Myxovirus protein levels rose following interferon beta-1b therapy in all patients. The levels remained high in BAb-negative patients but fell following the appearance of BAb. With the disappearance of BAb, myxovirus protein levels rose again.
Clinical efficacy appeared to be significantly affected by the development of BAb. Data on 92 patients showed 43 "successes" (no relapse or increase in disability over 2 years) and 49 failures. BAb segregated with failure: 36/59 failures were BAb-positive and 20/33 successes occurred in BAb-negative patients (p < 0.05).
Dr. Oger commented on the temporal relationship between the development of antibodies and their clinical impact. "No one has yet determined the time lag between the point when the antibody appears--where there is reduced action of the interferon--and the time when the clinical effect appears. Will the antibody appearing at 5 months change the course at 5 months or later at 18 months? We don't know," he said.
New Neuropsychological Assessment Instrument Facilitates Screening
Neuropsychological Assessment of Multiple Sclerosis Patients: The Predictive Validity of Computerized Testing
Jeffrey A. Wilken, PhD, Clinical Neuropsychologist, VA Medical Center, Washington, DC and the University of Maryland, College Park, MD
Neuropsychological assessment using a new brief computerized battery reliably predicts future cognitive functioning as measured by traditional paper-and-pencil measures reported Jeffrey A. Wilken, PhD and Clinical Neuropsychologist at the VA Medical Center in Washington, DC, and the University of Maryland, College Park, MD.25
The instrument, the Automated Neuropsychological Assessment Metrics (ANAM), which was developed by the Department of Defense, takes the patient 20-30 minutes to complete and covers many of same areas as traditional cognitive testing. The brief battery was tested on a sample of 36 relapsing-remitting multiple sclerosis (RRMS) patients. The same patients completed the traditional battery 6 months later, and the results of the two instruments were correlated.
"For MS patients, it is very important to have cognitive function measured because it declines over the years, and because it can help in the differential diagnosis of other neurological states, such as depression. But there are drawbacks to traditional neuropsychological testing," Dr. Wilken pointed out.
With the traditional battery of cognitive tests, the lack of timing precision makes it difficult to accurately measure psychomotor slowing, a central cognitive symptom of MS. These instruments also lack multiple alternate forms necessary to control for practice effects when following cognitive changes over time. They are lengthy and expensive; therefore, many persons with MS are denied access to neuropsychological assessment.
Computerized neuropsychological testing addresses many of these shortcomings, according to Dr. Wilken. Computerized batteries measure response time more precisely, require significantly less administration time, include numerous alternate forms, and are ideal for rapid screening and triage. The ANAM can be self-administered in the neurologist's office, with patients obtaining assistance as needed from a nurse, he said.
The ANAM could be administered before the initiation of immunomodulating therapies so that patients can be followed over time. Dr. Wilken envisions ANAM as a screening tool to identify patients who will require the more comprehensive battery of tests.
The reliability and validity of this brief test appears to be very good. In 38 RRMS patients, the ANAM reliably predicted how patients would perform 6 months later on traditional neuropsychological testing. On several measures, the correlations between the baseline ANAM testing and 6-month traditional testing were very high. Logistic regression analysis indicated that baseline performance on the computerized battery correctly classified patients as cognitively impaired or not impaired at 6 months, he reported.
"Across a lot of the measures we have correlations between 0.4 and 0.7, and in behavioral science research these are considered to be moderate to high," he said.
For example, in the area of motor functioning, the correlation for the two tests of traditional finger tapping was 0.743. In the area of attention/processing speed, the Paced Auditory Serial Addition Test (PASAT) correlated with math accuracy on the ANAM at 0.68; it correlated with running memory continuous performance test at 0.668 and 0.735, Dr. Wilken reported.
"We found high correlations between our test and the traditional tests in the areas of motor functioning, problem solving, verbal fluency, attention, and delayed recall," he said.
The study also evaluated whether the PASAT performance could be predicted by the ANAM test. "With two of the parameters (math accuracy and running memory throughput), we were able to predict 64.6% of the variance in PASAT," he said. "These two components predicted PASAT with a very high degree of accuracy."
The study further determined overall impairment of patients. The ANAM predicted the observed impairment index on the traditional test with 97.2% accuracy. "We only missed one person who was impaired on the traditional test, but who was judged by ANAM to be intact. The rest of the time the ANAM was correct," he noted.
Again, two tests--the running memory throughput and math accuracy--predicted 59.4% of the variance in the impairment index.
"We are able to follow patients, to get accurate measurements 6 months later. The hope is that the neurologist and staff can administer it in their offices to patients without having to consider insurance issues," he said. "I'm not trying to put myself out of business. Some patients will need the further testing. But this addresses the needs of the large majority of patients who are falling through the cracks right now-the patients who are having trouble that nobody recognizes. The test is cost-effective, fast, and easy on the patients."
Dr. Wilken and colleagues will continue to follow these patients and look for cognitive changes over time by the ANAM. Another component will compare ANAM-tested patients to a control group of patients with other neurological disorders, which will help determine the impact of practice effect.
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2. [no authors listed] Double Blind, Randomized Multicenter Dose Comparison Study of Interferon Beta-1a (Avonex): Rationale, Design and Baseline Data. Mult Scler 2001;7(3):179-183.
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5. Radue EW, Kappos L, Simonian N, et al. MRI Results of the European Interferon Beta-1a Dose-Comparison Study. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002, Denver, CO. Poster #P03.069.
6. Simon JH, Jacobs LD, Campion M, et al. Magnetic Resonance Studies of Intramuscular Interferon Beta-1a for Relapsing Multiple Sclerosis. Ann Neurol 1998;43:79-87.
7. Panitch H, Coyle P, Francis G, Goodin D, O'Connor P, Weinshenker B. The Evidence of Interferon Dose Response: European-North American Comparative Efficacy (EVIDENCE) Study. 54th Annual Meeting of the American Academy of Neurology, April 13-20, Denver, CO. Presentation #S13.006.
8. [no authors listed] 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 2201;56(12):1628-1636.
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11. Johnson KP, Brooks BB, Ford CC, et al. Results of the Long-Term (8-Year) Prospective, Open-Label Trial of Glatiramer Acetate for Relapsing Multiple Sclerosis. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002, Denver, CO. Poster #P06.79.
12. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 Reduces Relapse Rate and Improves Disability in Relapsing-Remitting Multiple Sclerosis: Results of a Phase III Multicenter, Double Blind Placebo-Controlled Trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995;45(7): 1268-1276.
13. Johnson KP, Brooks BR, Cohen JA, et al. Extended Use of Glatiramer Acetate (Copaxone) is Well Tolerated and Maintains Its Clinical Effect on Multiple Sclerosis Relapse Rate and Degree of Disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998;50(3):701-708.
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15. Salama HH, Kolar OJ, Zang YCQ, Zhang J. Effects of Combination Therapy of Beta-Interferon 1a and Prednisone on Serum Immunologic Markers in Patients with MS. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002, Denver, CO. Poster #P04.123.
16. Havrdova E, Horakova D, Krasensky J, et al. Interferon Beta-1a in Combination with Azathioprine and Low-Dose Steroids for Relapsing-Remitting Multiple Sclerosis: Preliminary Clinical and MRI Data from a Two-Year, Double Blind, Randomized, Placebo-Controlled Study. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002, Denver, CO. Poster #P06.078.
17. Cavazzuti M, Merelli E, Tassone G, Mavilla L. Lesion Load Quantification in Serial MR of Early Relapsing Multiple Sclerosis Patients in Azathioprine Treatment. A Retrospective Study. Eur Neurol 1997;38(4):284-290.
18. Lublin F, Baier M, Cutter G, et al. Results of the Extension of a Trial to Assess the Longer Term Safety of Combining Interferon Beta-1a and Glatiramer Acetate. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002, Denver, CO. Session #S13.003.
19. Lublin F, Cutter G, Elfont R, et al. A Trial to Assess the Safety of Combining Therapy with Interferon Beta-1a and Glatiramer Acetate in Patients with Relapsing MS. 53rd Annual Meeting of the American Academy of Neurology, May 5-11, 2001, Philadelphia, PA. Session #S20.002.
20. LePage E, Coustans M, Taurin G, Chaperon J, Edan G. Induction Treatment with the Monthly Combination of Mitoxantrone-Methylprednisolone for Six Months Followed by a Maintenance Therapy in Worsening Relapsing-Remitting MS: The Clinical Benefits Last at Least Four Years. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002, Denver CO. Poster #P03.023.
21. Edan G, Brochet B, Brassat D, et al. Safety Profile of Mitoxantrone in a Cohort of 802 Multiple Sclerosis Patients. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002, Denver, CO. Session #S23.005.
22. Jeffrey DR, Chepuri NB, Rosenburg J. Safety and Efficacy of Combination Therapy with Interferon Beta-1b and Mitoxantrone in Worsening Multiple Sclerosis Using Monthly Gadolinium-Enhanced MRI. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002. Denver, CO. Session #S23.004.
23. Goelz SE, Dupont S, Goyal J, Green M. Repeated Treatment with Interferon Beta-1a in Vitro Results in the Attenuation of Cellular Responsiveness. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002, Denver, CO. Poster #P06.049.
24. Gibbs E, MacDonnell G, Deisenheimer F, Oger J. Binding Antibodies to Interferon Beta during Treatment of MS Are Biologically and Clinically Relevant. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002, Denver, CO. Poster #P01.139.
25. Wilken JA, Kane RL, Sullivan CL, Wallin MT, Usiskin JB. Neuropsychological Assessment of Multiple Sclerosis Patients: The Predictive Validity of Computerized Testing. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002, Denver, CO. Poster #P03.084.