Understanding Dose Response in Multiple Sclerosis Treatment Regimens
In relapsing multiple sclerosis, 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, in an extension of the European Interferon Beta-1a Dose-Comparison Study reported at this meeting.1
"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 four 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.
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 multiple sclerosis (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 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, Dr. Radue reported.
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 while 14% and 13% had progressive relapsing 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 resulting outcomes:
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 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% in the 30 mcg group and 5.8% in the 60 mcg group.
The MRI findings corroborated the clinical results.4 Substantial reductions from baseline were seen in each group for all MRI measures (number and volume of gadolinium-enhanced lesions, T2-hyperintense lesion accrual, T1-hypointense lesion accrual, and brain parenchymal fraction).
The results of the study, both the clinical and MRI outcomes, concur with the effects of interferon beta-1a observed in the pivotal phase III trial by Jacobs et al5, Dr. Radue stated.
EVIDENCE Data Reported
Also presented at this meeting were 48-week results of the EVIDENCE (Evidence of Interferon Dose Response: European-North American Comparative Efficacy Study) trial, which assessed differences based on dose of interferon and treatment regimen.6 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 to 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), 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 although 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 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 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 EDSS.
Higher Doses Yield Higher Percentage of Neutralizing Antibodies
If additional benefits do exist with the higher dose, there was some trade-off in terms of toxicity, Dr. Panitch noted in his presentation. Injection site reactions, elevated liver enzymes, and leukopenia were more prevalent with Rebif, though these were manageable.
More importantly, NAB were markedly more common with Rebif 44 mcg, occurring (any titer) in 35% versus 5% of patients on Avonex 30 mcg; NAB > 20 NU/ml were observed in 24% and 2%, respectively. "This was considerably higher than in any previous studies with this drug," noted Dr. Panitch.
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 agreed. "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.
"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," Dr. Greenstein advised.
1. Kappos L, Clanet M, for the European Interferon Beta-1a (Avonex) Dose-Comparison Study Group: Sustained Efficacy of Interferon Beta-1a in Relapsing Multiple Sclerosis: 4-Year Results from the European Dose-Comparison Study. 54th Annual Meeting of the American Academy of Neurology, Denver, Colorado, April 13-20, 2002. Poster #P06.085.
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.
3. Clanet M, Radue EW, Kappos L, et al. A Randomized, Double Blind, Dose Comparison Study of Interferon Beta-1a (Avonex) in Relapsing MS. Neurology (Submitted).
4. Radue EW, Kappos L. MRI Results of the European Interferon Beta-1a (Avonex) Dose-Comparison Study. 54th Annual Meeting of the American Academy of Neurology, Denver, Colorado, April 13-20, 2002. Poster #P03.069.
5. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular Interferon Beta-1a for Disease Progression in Relapsing Multiple Sclerosis. Ann Neurol 1996;39(3):285-294.
6. 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, Denver, Colorado, April 13-20, 2002. Presentation #S13.006.