ABSTRACT
Four major disease-modifying therapies are dis-cussed within the context of relapsing and remitting multiple sclerosis. The major trials leading to approval by the US Food and Drug Administration (FDA) for these medications (interferon beta-1a; Avonex, Biogen Idec, Cambridge, Mass; interferon beta-1a; Rebif, Serono, Geneva, Switzerland; interferon beta-1b; Betaseron, Berlex, Montville, NJ; and glatiramer acetate; Copaxone, Teva Neuroscience, Kansas City, Mo) are compared, examining various endpoints, including relapse rate, disease progression, time to next exacerbation, and magnetic resonance imaging findings. There is also discussion of natalizumab (Tysabri, Biogen Idec, Cambridge, Mass, and Elan, New York, NY), which is currently being evaluated by the US FDA and may become available again soon. An analysis of comparative data and side-effect pro-files are among the issues discussed in an effort to guide clinicians to work with individual patients in making the best possible treatment decisions.
(Adv Stud Med. 2006;6(7D):S694-S700)
T
here are currently 4 US Food and DrugAdministration (FDA)-approved im-munomodulatory drugs for the treat-ment of relapsing-remitting multiple sclerosis (RRMS). Three are interferons (Avonex, Biogen Idec, Cambridge, Mass [interferon beta-1a]; Rebif, Serono, Geneva, Switzerland [interfer-on beta-1a]; and Betaser[interfer-on, Berlex, M[interfer-ontville, NJ [interferon beta-1b]), and the fourth is glatiramer acetate (Copaxone, Teva Neuroscience, Kansas City, Mo). Table 1 lists the major controlled clinical trials that have evaluated these medications. These trials dif-fer in their design: early treatment trials have examined the role of various medications in the setting of a sin-gle clinical event, whereas other trials have looked at an individual drug’s activity throughout the course of multiple sclerosis (MS). A relatively few number of tri-als have been comparative, during which 2 different medications are evaluated in 1 patient population. A variety of endpoint measures have also been used, including the number of relapses or the annual relapse rate; magnetic resonance imaging (MRI) findings including new lesion counts/enhancing lesions; the percentage of patients who remained exacerbation-free; and disease progression as measured by the Kurtzke Expanded Disability Status Scale (EDSS). Let us consider some of these pivotal trials in detail.
INTERFERONBETA-1B(BETASERON)
The first medication to be US FDA approved for the treatment of RRMS was Betaseron in 1993, based on a multicenter, randomized, double-blind, placebo-controlled trial of interferon beta-1b in 372 patients
with RRMS.1Patients enrolled in the trial had to have
an EDSS score of 0 to 5.5 and had to have had 2 or more exacerbations in the previous 2 years. They were
randomized to 175 µg/week or 875 µg/week of
DISEASE-MODIFYING THERAPIES IN
RELAPSING-REMITTING MULTIPLE SCLEROSIS*
—
Benjamin M. Greenberg, MD, MHS†
*This article by Dr Greenberg is based on a symposium held on February 25, 2006, in New York City.
†Instructor in Neurology, Department of Neurology,
Johns Hopkins Hospital, Baltimore, Maryland.
Address correspondence to: Benjamin M. Greenberg, MD, MHS, Instructor in Neurology, Department of Neurology, Johns Hopkins Hospital, 600 North Wolfe Street, Pathology 627C, Baltimore, MD 21287.
Betaseron or placebo—all by subcutaneous injection. The primary endpoint was differ-ences in exacerbation rates. After 2 years, the annualized exacerbation rates were 1.27 for patients receiving placebo and 1.17 and 0.84 for those in the low-dose and high-dose Betaseron groups, respectively (Figure 1). Exacerbation rates were significantly lower in both treatment groups compared to the
placebo group (875 µg vs placebo [P =
.0001]; 175 µg vs placebo [P = .0101]; and
875 µg vs 175 µg [P = .0086]). There was a
2-fold reduction in the frequency of
moder-ate and severe attacks in the 875-µg
treat-ment group (n = 36) at 2 years compared to the placebo group (n = 18; P = .007). Patients treated with Betaseron were also sig-nificantly more likely to have inactive MRIs (16% vs 35%; P = .001). EDSS scores changed little from baseline in the placebo
and treatment arms.1
INTERFERONBETA-1A(AVONEX)
The pivotal Avonex trial was designed to determine if weekly intramuscular injections of interferon
beta-1a (30 µg) could affect the progression of physical
dis-ability associated with MS. This was a randomized, double-blinded, placebo-controlled, multicenter phase III trial involving 301 patients with RRMS. The pri-mary outcome was time to sustained disability pro-gression of at least 1.0 point on the EDSS, sustained for 6 months. The authors found that interferon beta-1a treatment produced a significant delay in time to sustained EDSS progression (P = .02). The proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the inter-feron beta-1a-treated group. Patients treated with interferon beta-1a also had significantly fewer exacer-bations (P = .03) and a significantly lower number and volume of gadolinium-enhancing brain lesions on MRI (P values ranging between .02–.05). Over 2 years, the annual exacerbation rate was 0.90 in place-bo-treated patients versus 0.61 in interferon
beta-1a–treated patients.2 Interestingly, in those patients
who only completed 1 year of the study, those who received Avonex actually had a higher relapse rate than patients taking placebo (Figure 2). One possible expla-nation for this has been that the patients who entered
Figure 1. Relapse Rate for Patients Taking Betaseron
1.4 1.2 1 0.8 0.6 0.4 0.2 0 P = .0001 P = .0101 P = .0086 1.27 1.17 0.84 Placebo 1.6 MIU 8 MIU
Placebo 1.6 MIU 8 MIU
Annualized
exacerbation
rate
Reprinted with permission from Neurology. 1993;43:655-661.1
Table 1. Representative Major Therapeutic Trials in RRMS Individual Drugs Early Treatment Trials Comparative Trials IFN-beta MS Study Group CHAMPS (Avonex) EVIDENCE (Rebif
(Betaseron) vs Avonex)
Copolymer-1 MS Study ETOMS (Rebif) INCOMIN (Betaseron
Group (Copaxone) vs Avonex)
MS Collaborative BENEFIT (Betaseron) BEYOND and BECOME
Research Group (Betaseron-2 doses vs
(Avonex) Copaxone) PRISMS (Rebif)
IFN = interferon; BENEFIT = Betaseron in Newly Emerging MS for Initial Treatment; CHAMPS = Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study; ETOMS = Early Treatment of Multiple Sclerosis; EVIDENCE = Evidence of Interferon Dose-Response: European North American Comparative Efficacy; INCOMIN = Independent Comparison of Interferon; PRISMS = Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis; RRMS = relapsing-remitting multiple sclerosis.
the study late or who exited the study early represent-ed a biasrepresent-ed cohort, a different patient population than those who remained in the trial for 2 years. The find-ing may also be representative of the heterogeneous nature of MS; some patients were drug responders and others were nonresponders.
GLATIRAMERACETATE(COPAXONE)
In one of the pivotal Copaxone studies, Johnson et al conducted a multicenter, randomized, phase III trial
of patients (n = 251) with RRMS.3Fifty percent of the
subjects received glatiramer acetate at a dosage of 20 mg subcutaneously daily for 2 years; 50% received placebo. The primary endpoint was the difference in relapse rate, which was 1.19 ± 0.13 for patients ing glatiramer acetate and 1.68 ± 0.13 for those receiv-ing placebo. There was a statistically significant 29% reduction in favor of the study medication (P = .007; annualized rates = 0.59 for Copaxone and 0.84 for placebo; Figure 3). Trends in the proportion of relapse-free patients, median time to first relapse, and indica-tors of disability (as measured by the EDSS) all favored Copaxone, but were not always statistically significant. In terms of MRI results, those on Copaxone had fewer new lesions versus placebo-treated patients, again
sup-porting the efficacy of glatiramer acetate (P = .01).3
INTERFERONBETA-1A(REBIF)
In the Prevention of Relapses and Disability by Interferon Subcutaneously in Multiple Sclerosis study, 560 patients with RRMS were randomized to receive placebo or subcutaneous interferon beta-1a 22 or 44
µg 3 times weekly for 2 years. Patients who had been
receiving placebo were then rerandomized to 1 of the 2 doses of interferon beta-1a for an additional 2 years. Patients taking the original study medication contin-ued at the same dose. As with prior studies, relapse rate was the primary endpoint, and investigators also want-ed to determine if so-callwant-ed “delaywant-ed therapy” would
have any effect on overall disease progression.4
Looking at the data from the first 2 years (patients on drug or placebo without crossover), there was a sta-tistically significant difference (P <.005) between placebo and drug in terms of the relapse rate. However, there was no significant difference between the 2 doses of Rebif; they were both better than placebo (Figure
4).5When investigators looked at that same data at the
4-year mark, taking the placebo arm and crossing them
over to a 44-µg dose (the higher dose of Rebif ), the
patients now had a benefit that mirrored the long-term–treated patients in terms of relapse rate. These data suggest that if therapy is delayed in a patient with clinically definite MS, their relapse rate is still compa-rable to patients who have been on the drug all along. However, these data do not determine whether long-term disability is worse in patients with a delay in
treatment (Figure 5).6
Figure 2. Exacerbation Rate at 1 and 2 Years
1.2 1 0.8 0.6 0.4 0.2 0
Annualized exacerbation rate
0.8 1.03 1.01 0.72 0.78 0.54 Placebo Interferon 1-Year Patient Subset 2-Year Patients During Year 1 2-Year Patients During Year 2
Figure 3. Relapse Rates on Copaxone
Placebo Glatiramer acetate 0.84
0.59
Annualized relapse rate
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 P = .007
Reprinted with permission from Johnson et al. Neurology. 1995;45:1268-1276.3
When investigators looked at disease progression, which in this study was defined as a 1-point change in EDSS scale over 3 months, there was a trend in favor of Rebif therapy with not a statistically significant
differ-ence between the 2 doses in terms of the 2-year data.7
The same trend was noted at 4 years, and it is clear that over 4 years, MS symptoms progressed despite therapy. Although disease progression did slow significantly compared to placebo, the medication did not entirely
stop disability from occurring.7In terms of MRI data,
100% of patients on placebo developed new T2 lesions within the first 2 years of study. In contrast, approxi-mately 66% of patients on the lower dose of Rebif and 33% of patients on the higher dose developed new lesions; there was a statistically significance difference between the 2 doses. After 2 years, when the placebo arm was crossed over to the higher dose of medication, the rate of new T2 lesions dropped among this group— only 50% of the scans obtained in this crossover arm had new T2 lesions over years 3 and 4, a significant
improvement from years 1 and 2.7
COMPARINGTHERAPIES
Ideally, clinicians would be able to evaluate the evi-dence from these 4 major trials of immunomodulato-ry drugs and determine which therapy is best for any given patient. In practice, this becomes very complex. Comparing trials using reduction of relapse rate or dis-ease progression, we find that there is no significant statistical difference between the medications. Even more importantly, these trials should not and cannot be compared; they differ in study design, primary end-points, and patient populations (in terms of disease activity and EDSS baselines). Some of the studies had extensions and potential design biases cannot be con-trolled for when trying to compare data between dif-ferent studies. Head-to-head trials comparing individual therapies are the only method by which we can begin to answer, with some certainty, whether there is a distinct difference between the available dis-ease-modifying MS drugs.
Two such trials were the EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) trial, which compared Rebif and Avonex, and the INCOMIN (Independent Comparison of Interferon) trial, which involved Betaseron and Avonex. The EVIDENCE trial
demon-strated that interferon beta-1a 44 µg administered
subcutaneously 3 times weekly (Rebif ) was signifi-cantly more effective than intramuscular interferon
beta-1a 30 µg administered once weekly (Avonex) in
reducing clinical relapses and MRI activity in patients with RRMS. This was true at 24 and 48 weeks of
ther-apy.8 Follow-up studies revealed that the efficacy of
Rebif depended to some extent on whether patients were neutralizing antibody positive or negative, but a difference between Rebif and Avonex persisted even
Figure 4. Two-Year Relapse Rates for Patients in the PRISMS Study
Placebo Rebif 22 µg Rebif 44 µg 3 2.5 2 1.5 1 0.5 0 Number of relapses per patient 2.56 1.82 1.73 P <.005.
PRISMS = Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis.
Reprinted with permission from Lancet. 1998;352:1498-1504.5
Figure 5. Four-Year Relapse Rates for Patients in the PRISMS Study Placebo Changeover Rebif 22 µg Rebif 44 µg 3 2.5 2 1.5 1 0.5 0 Number of relapses per patient 2.56 1.2 1.82 1.3 1.73 1.04 P <.001.
PRISMS = Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis.
when this was taken into account. Whether this appar-ent difference will be retained throughout the duration of therapy remains to be proven.
When we compare another set of high- versus low-dose interferon data (Betaseron vs Avonex) from the INCOMIN trial, we see that there is still a difference, although not quite as robust in this study, in terms of the patients who are relapse-free—51% in the Betaseron-treated group (administered interferon
beta-1b 250 µg on alternate days) versus 36% in the
Avonex-treated group (administered once-weekly
interferon beta-1a 30 µg; P = .03). In addition, 55%
of patients compared to 26% on Betaseron versus Avonex, respectively, had no new T2 lesions at MRI at
24 months (P <.0003).9In both groups, the differences
between the 2 treatment groups increased during the second year of study, suggesting that, at least in short-term trials (1–2 year data), higher-dose interferon may be more effective. The question remains as to whether there will any differences between these dosing regi-mens over the long term.
NATALIZUMAB
Although not currently available for the treatment of RRMS, natalizumab (Tysabri, Biogen Idec, Cambridge, Mass, and Elan, New York, NY) is currently under con-sideration by the US FDA for a return to the market after an investigation of safety concerns. Natalizumab is a monoclonal antibody that prevents leukocytes from infiltrating the brain and causing myelin disruption. In early trials by Miller et al, this drug did have a statisti-cally significant impact in terms of decreasing the per-centage of patients with relapses, and an even stronger
impact on MRI data.10At a dose of 3 or 6 mg per
kilo-gram, 19% of natalizumab-treated patients experienced relapses, compared to 38% of patients receiving
place-bo.10 Treated patients had a median number of new
gadolinium-enhancing MRI lesions of zero, compared
to 2 new lesions in the placebo group.10These results
were seen after only 6 months of the study.
TOTREAT ORNOT TOTREAT
Evidence from CHAMPS (Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study) and ETOMS (Early Treatment of Multiple Sclerosis) trials demonstrate that early treatment of a clinically isolated syndrome appears to delay progression to
clin-ically definite MS. However, whether early treatment makes a difference in the ultimate outcome is still an unanswered question. In other words, are patients less disabled over the long run if treatment is begun imme-diately after their first episode? Thus, although ETOMS and CHAMPS provide evidence of benefit for early treatment in demyelinating disease, there are several caveats. First, some patients who are never going to progress to MS may be started on therapy unnecessarily, with its associated costs and adverse effects. Second, there is no long-term data to show that early treatment makes a difference in disability (but there is some evidence to suggest that prevention of relapses may prevent disability). Lastly, longer expo-sure to interferon may increase the risk of developing neutralizing antibodies, which may limit efficacy later. These issues must be balanced against the potential to prevent disability by starting treatment early. Early therapy should be routinely offered, but these complex issues need to be discussed with every patient, thus they can make a well-informed decision.
CLINICALTRIALS INMULTIPLESCLEROSIS
There are many challenges in designing and inter-preting clinical trials in MS. For example, how do we define treatment failure? If the population studied at the onset has clinically isolated syndromes, treatment failure may be defined as conversion to clinically defi-nite MS or as the development of disability. How do we determine the proper endpoint for a study, how do we decide if the treatment has been a success or a fail-ure? Do we select disease progression as the endpoint? Do we look at the occurrence of relapses within a given length of time? MS is a disease that by its very nature has relapses and remissions with fluctuations in symp-tomatology. What evidence of disease progression should we utilize? Should we examine patient-defined symptoms or confirmed test results, such as MRI data? And, how do we effectively blind our study popula-tion, when adverse events from the medications under investigation are common? Finally, there is the issue of “regression to the mean” (ie, the inherent probabilities within patient populations with MS that there are going to be changes over time). When we look at a regression to the mean analysis, even among the place-bo arms from previous trials, there is great variability in the relapse rates (Figure 6). Ultimately, the most useful data would be measures of disability over time.
ADVERSEEFFECTS
This leaves us with the challenge of making diffi-cult decisions with our patients regarding the risks and benefits of various treatments. Often, patients will look at the side-effect profiles of medications to choose the best drug for them. With the interferons, injection site reactions are most common (although less com-mon with Avonex because it is an intramuscular, not a subcutaneous injection), along with flu-like symp-toms, depression, headaches, leukopenia, and elevated liver function tests (Table 2). Patients taking Copaxone may have site reactions and an idiopathic reaction within minutes after an injection, with flush-ing, palpitations, chest pain, and shortness of breath (Table 3). This is still not understood, but is usually a 1-time event that resolves within 20 to 30 minutes. It is not an allergy, and it is not a contraindication to continuing Copaxone therapy. However, it is impor-tant to warn patients about this reaction because it can be a cause for alarm, and for inappropriately discon-tinuing the medication. It is important for patients to have careful instruction in appropriate injection tech-nique for all 4 medications, thus minimizing side effects such as site reactions.
CONCLUSIONS
As researchers continue to search for a cure for MS, clinicians continue to attempt to select the best thera-py for their patients based on the available clinical trial
evidence. There are 3 major aspects to counseling patients about MS treatment and improving their adherence to therapy. The first key is to communicate a clear understanding of goals. The goal of MS treat-ment is a reduction in disease activity—not a cure. Frequently, patients may discontinue therapy if they have an exacerbation. They need to understand that the goal is to reduce the number of relapses; unfortu-nately, we cannot yet prevent all of them. The second key is the management of side effects, with careful attention to lifestyle issues. Finally, it is critical to have a clear long-term plan, especially in patients with clin-ically isolated syndromes. Patient education and coun-seling are essential as we work with them to treat this disease with our, at best, imperfect tools to date. Figure 6. Annualized Relapse Rates Among Placebo
Groups
Avonex 1.01
1.3
Annualized relapse rate
1.4 1.2 1 0.8 0.6 0.4 0.2 0 0.8
Rebif Betaseron Copaxone 0.78
1.27
0.84
Data from Neurology. 1993;43:655-6611; Jacobs et al2; Johnson et al3; Oger
et al.6
Table 2. Adverse Effects of Interferon Medications
Side Effect Avonex Betaseron Rebif
Site reactions 3/1 85/29 92/39 Flu symptoms 49/29 60/41 59/51 Depression 18/14 – – Headache 58/55 48/57 70/63 Leukopenia 18/5 36/14 Elevated LFTs 10/4 27/4
LFT = liver function test.
Data from Avonex package insert. Research Triangle Park, NC: Biogen Idec; Betaseron package insert. Montville, NJ: Berlex Laboratories; and Rebif package insert. Rockville, Mass: Serono, Inc; New York, NY: Pfizer Inc.
Table 3. Adverse Effects of Copaxone
Side Effect Copaxone (%) Placebo (%)
Site reaction 66 19 Chest pain 21 11 Palpitations 17 8 Vasodilatation 27 10 Nausea 22 17 Fever 8 7 Syndrome 10 –
Data from Copaxone package insert. Kansas City, Mo: Teva Pharmaceutical Industries, Ltd.
REFERENCES
1. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, dou-ble-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology. 1993;43:655-661. 2. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular
inter-feron beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39:285-294. 3. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces
relapse rate and improves disability in relapsing-remitting multi-ple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45:1268-1276.
4. Gold R, Rieckmann P, Chang P, et al. The long-term safety and tolerability of high-dose interferon beta-1a in relapsing-remitting multiple sclerosis: 4-year data from the PRISMS study. Eur J Neurol. 2005;12:649-656.
5. Randomised double-blind placebo-controlled study of inter-feron beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet. 1998;352:1498-1504.
6. Oger J, Francis G, Chang P, et al. Prospective assessment of changing from placebo to IFN beta-1a in relapsing MS: the PRISMS study. J Neurol Sci. 2005;237:45-52.
7. PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group. PRISMS-4: long-term efficacy of interferon-beta-1a in relapsing MS. Neurology. 2001;56:1628-1636.
8. Panitch H, Goodin D, Francis G, et al. Benefits of high-dose, high-frequency interferon beta-1a in relapsing-remitting multiple sclerosis are sustained to 16 months: final comparative results of the EVIDENCE trial. J Neurol Sci. 2005;239:67-74. 9. Durelli L, Verdun E, Barbero P, et al. Every-other-day
interfer-on beta-1b versus interfer-once-weekly interferinterfer-on beta-1a for multiple sclerosis: results of a 2-year prospective randomised multi-centre study (INCOMIN). Lancet. 2002;359:1453-1460. 10. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial
of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2003;348:15-23.