J Neuroophthalmol 2001 December;21(4):284-291
Richard A. Rudick, MD
From the Department of Neurology, Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland, Ohio.
JOURNAL OF NEURO-OPHTHALMOLOGY 2001;21:284-291
Multiple sclerosis (MS) is no longer considered an unmanageable disease. Five drugs have obtained regulatory approval to safely and effectively modify the course of MS. Three preparations of interferon b Avonex (interferon b-1a), Betaseron (interferon b-1b), and Rebif (interferon b 1a)have shown efficacy in relapsing-remitting MS and show promise in slowing the course of secondary progressive MS. Glatiramir acetate (Copaxone) has demonstrated efficacy in relapsing-remitting MS, and is being tested for the management of primary progressive disease. Mitoxantrone (Novantrone) has been approved for secondary progressive and progressive relapsing MS. There is a tendency toward early diagnosis and treatment based on the hypothesis that treatment effectiveness declines with advancing disease.
Several immunomodulatory drugs have become available for disease management in relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) during the past 7 years. There is a new emphasis on early therapy based on evidence that the disease process is continuously active, even during clinically quiescent phases of early MS, and that therapy will prevent irreversible tissue injury and diffuse axonal pathology.
AVAILABLE DRUGS FOR RELAPSING-REMITTING MULTIPLE SCLEROSIS
Recombinant interferon b-1b (Betaseron (Berley Labs, Richmond, CA)), b-1a (Avonex (Biogen, Inc., Cambridge, MA) and Rebif (Serono, S.A., Lausanne, Switzerland)), and glatiramer acetate (Copaxone (Teva Marion, Partners, Kansas City, MO)) (Table 1) have been shown to be safe and effective in the management of RR-MS. Avonex and Rebif are recombinant interferon b preparations that are glycosylated and have amino acid sequences identical to natural human interferon b. Betaseron is produced by Escherichia coli and, unlike interferon b-1a, is nonglycosylated. The drug has a serine-for-cysteine substitution at the 17-amino acid position. Copaxone is a polymer of four basic amino acids that was originally synthesized as a mimic of myelin basic protein. These drugs were tested in separate multicenter, placebo-controlled, double-masked clinical trials (Table 2).
TABLE 1. Available disease-modifying drugs for relapsing-remitting MS
TABLE 2. Pivotal double-blind, randomized controlled clinical trials for relapsing-remitting MS
Betaseron was tested in 372 patients given 250 mg (9 MIU), 50 mg (1.8 MIU), or placebo by subcutaneous injection every other day for up to 5 years (1). The primary outcome measure was relapse rate. Treatment with the higher interferon dose reduced the relapse rate by 33%, increased the proportion of relapse-free patients from 16% to 31%, and reduced by twofold the number of patients with moderate or severe relapses of MS. Beneficial effects were maintained for patients who elected to remain in the blinded trial for up to 5 years (5). A statistically nonsignificant trend suggested that patients in the 250-mg arm were less likely to experience worsening by at least one point from the baseline Expanded Disability Status Scale (EDSS) sustained for at least 3 months.
Avonex was tested in 301 patients given weekly intramuscular injections (6 MIU, 30 mg) or placebo for up to 2 years (2,6). The primary outcome measure was time to onset of sustained disability progression, defined as deterioration from baseline by at least one point on the EDSS persisting for at least 6 months. Treatment with Avonex resulted in a significantly lower probability of sustained disability progression, and significantly fewer interferon b-1a recipients became severely disabled, defined as 6-month sustained worsening at least to the EDSS 4.0 or EDSS 6.0 levels (7). Patients at EDSS 6.0 require assistance to walk, and at this EDSS score, SP-MS has evolved in most patients. This finding suggests that interferon b therapy can prevent or delay transition from RR-MS to SP-MS in some patients. Treatment with Avonex also reduced the relapse rate by 32% in the cohort of patients treated for 2 years, and by 18% in all patients regardless of the study period (2).
Rebif was tested in 560 patients given 44 mg, 22 mg, or placebo by subcutaneous injection three times weekly for 2 years (3). The primary outcome measure was relapse rate. Treatment with the lower dose reduced the relapse rate by 29%, and treatment with the higher dose reduced the relapse rate by 32% after 2 years. Treatment with Rebif increased the proportion of relapse-free patients from 16% to 27% (lower dose) and 32% (higher dose). Treatment with Rebif also reduced the number of severe relapses, steroid courses, and hospital admissions for MS. There were statistically significant benefits in terms of EDSS change between baseline and 2 years and in the time to 3-month sustained worsening.
Both interferon b-1b and b-1a had beneficial effects on the disease process measured by cranial magnetic resonance imaging (MRI) scans. Betaseron resulted in significantly fewer new or enlarging T2 lesions in 52 patients studied at one of the clinical sites with MRI scans every 6 weeks, and significantly less annual accumulation of T2 lesions in the entire study group (8). In a separate study, Betaseron reduced the frequency of gadolinium-enhanced brain lesions (9). In the phase III trial, Avonex significantly reduced gadolinium brain lesions after 1 and 2 years of treatment, and decreased the number of new and enlarging T2 lesions after 1 and 2 years (2,10). These studies indicate that interferon b inhibits new brain lesion formation. Rebif also has prominent beneficial effects on MRI parameters, and particularly enhancing lesions and new and enlarging T2 lesions.
The significance of the prominent effects of interferon b on enhancing MRI abnormalities remains uncertain because of the lack of a documented relation between these abnormalities and subsequent neurologic disability (14). This may be clarified as studies focus more on the effects of interferon b on destructive pathologic process, as measured by the volume of T1 holes or brain atrophy. Nevertheless, the prominent effect of interferon b preparations on enhancing lesions suggests that interferon b therapy reduces brain inflammation. This conclusion was supported by the Avonex study, which found significantly reduced cerebrospinal fluid pleocytosis among Avonex recipients after 2 years of therapy (15).
Two studies tested the efficacy of interferon b in patients experiencing a first clinical demyelinating episode and with MRI signal abnormalities, which have predicted a high likelihood of future MS-like neurologic events. These studies enrolled patients with optic neuritis, transverse myelitis, or brainstem syndromes who had at least two periventricular T2 lesions. Avonex decreased the probability of conversion to clinically definite MS by 50%, and markedly reduced MRI disease progression (16). Rebif was also effective at the dose used, but the results were more modest.
All three interferon b preparations cause transient flulike symptoms. Headache, myalgia, fever, or malaise, commonly last 24 to 48 hours after each injection, but the severity of these symptoms typically lessen after 6 to 12 weeks of therapy. Betaseron causes redness and swelling at the injection site and skin necrosis in 5% of the patients.
In the phase III clinical trials, neutralizing antibodies to interferon b were observed in 38% of Betaseron recipients (13), 22% of Avonex recipients (2), 23.8% of low-dose Rebif recipients, and 12.5% of high-dose Rebif recipients (3). The presence of neutralizing activity in the Betaseron study was associated with reduced clinical and MRI efficacy. In an open-label study, a single biologic assay was used to determine titers of neutralizing antibodies in patients treated clinically with Betaseron or Avonex (12). After 12 to 18 months of treatment, neutralizing antibodies were observed in 35% of patients treated with Betaseron, and in 7% of patients treated with Avonex. This finding raises the likelihood that interferon b-1b is more immunogenic than interferon b-1a. In a Danish national study (17) of 754 patients starting treatment with interferon , blood samples were collected at frequent intervals and analyzed using well-standardized assays in a central laboratory. Neutralizing antibodies varied in frequency from 7% to 42%. The frequency and titers of antibodies were considerably higher with interferon b-1b treatment than with interferon b-1a preparations. This finding may relate to immunochemical differences between interferon b-1b and b-1a. Additional variables that might be important are route and frequency of administration. The relative frequency of interferon b-1a products used as recommended is not known.
TABLE 3. Features of pivotal trials in relapsing-remitting MS
Because interferon b induces expression of many genes, the mechanisms of action in MS are likely complex (18). Putative mechanisms include: 1) inhibition of autoreactive T cells (19), 2) inhibition of major histocompatibility complex class II expression (20) with reduced antigen presentation within the central nervous system, 3) inhibition of metalloproteases (21,22) or altered expression of cell-associated adhesion molecules leading to reduced cellular migration to the central nervous system (23), 4) induction of immunosuppressive cytokines (24) and inhibition of proinflammatory cytokines (25), leading to resolution of the inflammatory process.
Glatiramer acetate (Copaxone) is a polypeptide consisting of a random arrangement of four basic amino acids. The drug is thought to mimic myelin basic protein, and is postulated to induce myelin-specific suppressor T cells and to inhibit myelin-specific effector T cells. Copaxone was tested in 251 patients given daily subcutaneous injections (20 mg) or placebo for 2 years (4). The primary outcome measure was drug effect on the relapse rate. In the original 2-year study, Copaxone reduced the relapse rate by 29%. At the end of 2 years of therapy, patients were offered entry to an extension study, which was continued in a double-masked manner for approximately 1 additional year. The majority of patients continued in the extension study, and the beneficial effect on relapse rate was maintained (26). No significant effect was observed on sustained changes on EDSS, either in the original study or in the extension study. Although Copaxone was well tolerated, mild swelling and redness occurred at each injection site, and 15% of patients experienced brief episodes of flushing, chest tightness, palpitations, dyspnea, and anxiety.
MRI scans were not included as part of the Copaxone phase III study, but 27 patients underwent serial MRI scans at one of the sites (27). There was a trend toward reduced gadolinium lesions favoring Copaxone, and a significant benefit in favor of Copaxone on a measure of brain volume loss (28). A similar trend in favor of Copaxone enhancing MRI lesions was found in a small study in 10 patients (29). A large study was recently completed to determine the effect of glatiramer acetate on MRI disease activity. Patients with RR-MS were required to have at least one enhancing lesion to enroll, and 239 of 485 patients screened were eligible to participate in the study. After a baseline MRI scan, patients were randomly assigned to glatiramer acetate or placebo, and followed in a double-blind protocol with monthly MRI scans for 9 months. During the 9-month double-blind phase, there was a statistically significant 35% reduction in the total number of gadolinium-enhancing lesions in the glatiramer group compared with the placebo group (30). Interestingly, the therapeutic effect was first observed 3 to 4 months after treatment was initiated. This effect is considerably slower than the rapid-onset inhibitory effect of interferon b on enhancing brain lesions.
Direct comparisons across trials are not an accurate means of comparing drug efficacy because patient populations differ and outcome measures are subjective, poorly standardized, and used differently by different investigators. Nevertheless, Table 4 shows key outcomes from the pivotal trials of drugs for the management of RR-MS. The Table shows a similar treatment effect on relapse-rate reduction in RR-MS patients across studies. There is somewhat more between-study difference in sustained EDSS worsening, and it is unclear whether this represents a difference in treatment effect on MS-related disability or a difference in the way the EDSS measure was used. Nevertheless, considering all treatments together, the treatment effect on relapse rate appears to be roughly comparable with the treatment effect on sustained EDSS worsening. The effect of treatment on enhancing and T2 MRI lesions is greater than the effect on relapse rate, but the significance of this discrepancy is not yet clear.
TABLE 4. Key findings from pivotal trials in relapsing-remitting MS
AVAILABLE DRUGS FOR SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS
Interferon b-1b (Betaseron), b-1a (Rebif), and b-1a (Avonex) have been tested for efficacy in patients with SP-MS (Table 5). The European Study Group conducted a randomized, double-blind, placebo-controlled trial of subcutaneous Betaseron 8 MIU every other day versus placebo (31). Patients at 32 centers in 12 European countries were randomized to Betaseron (n = 360) or placebo (n = 358). Participants had confirmed SP-MS, two relapses, or a 1-point EDSS progression in the 2 years before study entry, and an EDSS score between 3.0 and 6.5. The primary endpoint was time to confirmed progression, defined as an increased EDSS score, sustained for 3 months. Time to confirmed progression was significantly prolonged in the Betaseron-treated arm (P < 0.001). The time until 40% of the cases progressed on the primary endpoint was delayed for 12 months. In this study, there was a significant effect on disability progression in patients with or without relapses during the study. A significant benefit was observed in a number of secondary endpoints, including progression to EDSS 7.0 (32% reduction), relapse rate (32% reduction), change in T2 lesion volume between baseline and year 1 and 2, and the number of newly enhancing lesions.
TABLE 5. Pivotal double-blind, randomized controlled clinical trials for secondary progressive MS
Another study of interferon b-1b enrolled 939 patients in 35 centers in the United States and Canada. Patients were randomized to receive subcutaneous Betaseron 8 MIU every other day (n = 317), 5 MIU/m2 (n = 314), or placebo (n = 308). Participants had confirmed SP-MS with at least one documented relapse during the course of MS, entry EDSS between 3.0 and 6.5, and 1 EDSS-point progression in the 2 years before study entry. The primary outcome measure was time to confirmed progression, defined as sustained increase in EDSS score lasting at least 6 months. The study showed no difference between study arms on the primary study outcome, though significant benefits were observed in some of the secondary outcomes. Relapse rate was decreased by 43% (P < 0.01) in the 8-MIU arm, and by 29% (P < 0.05) in the 5-MIU/m2 arm. There was no significant difference between the doses on relapse rate. Change in T2 lesion area from baseline was significantly decreased in both treatment arms (P < 0.001), and again there was no dose effect. Newly enhancing lesions were reduced by 64% in the 8-MIU arm and by 76% in the 5-MIU/m2 arm. Although both reductions were statistically significant, there were no significant dose effects.
In a randomized European controlled trial of interferon b-1a (Rebif) (31), 618 patients with confirmed SP-MS were randomized to receive m22 g Rebif subcutaneously three times per week (n = 209), 44 mg three times per week (n = 204), or placebo (n = 205). Patients had an EDSS between 3.0 and 6.5, and had worsened by at least one EDSS point during the previous 2 years. The primary outcome was time to confirmed progression in disability, defined as EDSS worsening for at least 3 months of 1 point for patients entering at 5.0 or below or 0.5 points for patients entering at 5.5 or above. Time to sustained disability progression did not differ significantly between the study arms. As with the North American Betaseron study, there were significant benefits of treatment in a number of secondary endpoints. Both the low-dose and high-dose groups showed a 30% reduction in relapse rate (P < 0.01) and there was no dose effect. There were significant benefits in favor of either arm in number of steroid courses and hospital stays for relapses. There were also significant reductions in new and enlarging T2 lesions, enhancing lesions, and T2 lesion volume. The beneficial MRI effects were greater at the higher dose. A post-hoc analysis showed that women benefited more than men. In contrast to the European Betaseron study, the presence of prestudy relapses was associated with greater therapeutic effect during the clinical trial.
A recently completed randomized controlled trial of interferon b-1a (Avonex) for the management of SP-MS enrolled 436 patients with confirmed SP-MS to receive weekly intramuscular injections of 60 mg Avonex or placebo for 2 years. The primary outcome measure was 2-year change in the MS Functional Composite (MSFC), a new outcome measure for MS clinical trials (3335). The MSFC consists of quantitative tests of arm function, walking speed, and cognitive function, expressed as a standardized score along a continuous scale. Avonex treatment was associated with a statistically significant benefit on MSFC z score change (median change from baseline, 0.10 for Avonex group vs. 0.16 in the placebo group, P = 0.033). There were also significant benefits on numerous other secondary outcome measures, including a 33% reduction in relapse frequency, reduced new or enlarging T2 lesions, enhancing MRI lesions, and significant benefits on 8 of 11 scales in the MS Quality of Life Inventory. Interestingly, there was no benefit observed on time to worsening on EDSS, or on EDSS change from baseline to 24 months. This may be better understood by analysis of the individual MSFC components. The overall benefit on the MSFC was driven by the upper-extremity score and the cognitive score. Consistent with the EDSS result, there was not a significant benefit of treatment on the ambulation score of the MSFC. This finding suggests that ambulation (which is the principal dimension captured by EDSS at this range of disability) is not as favorably affected by treatment as are other dimensions of the disease. The Avonex SP-MS trial result may help explain discrepant findings in the other SP-MS interferon studies. It also suggests that the MSFC is a more sensitive and probably more informative disability-related outcome measure than the EDSS.
The results of interferon b trials in patients with SP-MS have thus been mixed. This is particularly striking with the two Betaseron studies, which appear superficially similar and use an identical interferon b product administered with the same dose schedule. The European study showed a highly significant, though modest, benefit on disability progression, whereas the North American Study showed no differences. This discrepancy has led to comparison between the two study populations. The North American population was significantly older at entry, had a longer disease duration, fewer relapses in the previous 2 years, greater change in EDSS in the 2 years before study entry, and fewer MRI enhancing lesions at study entry. These differences suggest that the North American population showed less inflammation and possibly more noninflammatory axonal degeneration. Although speculative, this analysis would conclude that interferon b therapy is most effective in the earlier inflammatory stage of MS, and increasingly less effective in later stages characterized by progressive disability.
Mitoxantrone (Novantrone (Immunex, Seattle, WA)), an anthracenedione derivative introduced in 1979 for the treatment of patents with cancer, was recently approved for SP and progressive relapsing MS at an intravenous dose of 12 mg/m2 every 3 months to a maximum cumulative dose of 140 mg/m2. Novantrone has cytotoxic and immunosuppressive effects and has been used for the management of acute myeloid leukemia and symptomatic hormone-resistant prostate cancer. Approval for MS management was based on results of a placebo-controlled, double-blind, randomized, multicenter trial conducted in Europe. In that trial, 194 patients with EDSS scores ranging from 3.0 to 6.0 were randomized to receive 12 mg/m2 mitoxantrone, 5 mg/m2 mitoxantrone, or placebo. Treatment was given intravenously every 3 months for 24 months, and patients were then followed up for 36 months. The primary outcome was a multivariate composite consisting of EDSS change, Ambulation Index change, the number of treated relapses, the time to the first treated relapse, and the change in the Scripps Neurologic Rating Scale. There were statistically significant benefits on each of these composite outcome components in favor of the 12-mg/m2 dose compared with placebo. At that dose, mitoxantrone decreased EDSS worsening confirmed at 3 months by 64%, and reduced relapses by 69%. Less significant benefits were observed for the 5-mg/m2 dose. Patients commonly experienced nausea and alopecia, had more frequent urinary tract infections, and many of the women experienced amenorrhea that persisted in approximately 20%. One patient was withdrawn from the study because of decreased left ventricular function, but generally there were no other serious adverse events. Because of the known cardiac toxicity with this class of drug, the recommended cumulative dose has been limited to less than 140 mg/m2. The long-term impact of mitoxantrone on cardiac function in patients with MS remains an area of significant interest.
Table 6 shows a relapse-rate reduction of approximately 30% with active treatment in most studies. There is more variability in these studies than in the RR-MS studies shown in Table 4. The effect of treatment on EDSS worsening appears more modest when the studies are viewed in aggregate. This discrepancy between treatment effect on relapse and treatment effect on EDSS progression at this disability level is of great theoretical and practical interest. The Avonex SP-MS study, which used the MSFC as the primary end-point, suggests that the limited benefit on EDSS is not based entirely on EDSS scale limitations because there were similar findings using the timed 25-ft walk (a component of the MSFC). The limited effect of interferon b treatment on measures of ambulation compared with larger effects on relapse rate suggests the possibility of a progressive component of MS that is not responsive to antiinflammatory intervention. Despite that possible explanation, beneficial effects on relapse rate, MRI lesions, and quality-of-life measures suggest a significant beneficial effect of interferon b in patients with SP-MS. A relatively greater therapeutic effect with mitoxantrone is also notable. However, the result derives from one relatively small study that enrolled patients at a somewhat earlier stage of SP-MS.
TABLE 6. Key findings from pivotal trials in secondary progressive MS
PROMISING NEW APPROACHES FOR IMMUNOMODULATORY THERAPY
Altered peptide ligands
Productive interaction between antigens and T cells necessitates an major histocompatibility complex class II molecules on the surface of an antigen-presenting cell, together with a cognate antigen and T-cell receptor. All three elements contribute to the specificity of the immune response, and also to the downstream events resulting from T-cell activation. The nature of costimulatory molecules may determine whether a T cell develops into a memory cell or becomes tolerant to that particular antigen. Considerable work in experimental autoimmune encephalomyelitis (EAE) has defined immunodominant epitopes of myelin basic protein and the therapeutic potential of altered peptides that fail to induce EAE and protect treated animals from active or passive EAE induction. One such altered peptide ligand is CGP77116, an altered peptide of Myelin basic protein 8399.
In one study, patients with confirmed MS were randomized in a placebo-controlled, double-blind, phase II study (36). The study was discontinued by a safety monitoring committee because 9% of patients developed hypersensitivity reactions. There were no increases in clinical relapses or new enhancing lesions in any patient, and a secondary analysis suggested that the volume and number of enhancing lesions was reduced at the highest dose tested (5 mg). A second study of this altered peptide ligand also was discontinued early (37). In this study, three patients had relapses of MS, two of whom also had markedly increased reactivity to myelin basic protein. The study raised a concern about the risk of antigen therapy.
At the present time, the future of antigen-specific immunotherapy is uncertain for a number of reasons. There is significant variability in myelin recognition between patients (38,39), significant change in myelin recognition within patients over time (40), and inadequate information about reliable methodologies to induce protective rather than inflammatory T-cell responses.
Movement of cells across endothelial barriers and into tissues requires molecular interactions between selectins and their receptors, integrins on leukocytes and their immunoglobulin-family receptors on endothelial cells, chemokines and their receptors, and various enzymes such as metalloproteinases. Inhibition of leukocyte trafficking is an attractive therapeutic strategy. The future of chemokine-based therapy is bright, but has not yet emerged in the MS field. Inhibition of very-late antigen 4, an a4b1 integrin, has emerged as a potential therapeutic strategy in MS. A randomized, double-blind, placebo-controlled trial of Antegren (Elan Pharmaceuticals, Dublin Ireland), a humanized monoclonal antibody to very-late antigen 4, was conducted in 72 patients with active RR-MS or SP-MS (41). Each patient received two infusions of Antegren or placebo 4 weeks apart, and was followed up for 6 months with serial MRI and clinical assessments. The treated group exhibited significantly fewer new enhancing lesions than did the placebo group during the first 12 weeks of the study. There was no effect of treatment on relapses, but the study was not designed to look at a clinical outcome. Inhibition of leukocyte integrins, such as Antegren, represents an appealing therapeutic strategy, and further studies are ongoing.
Two reagents targeting costimulatory molecules are in the planning stages. The first molecule that is being targeted is CD40 ligand (CD154), and the reagent is a humanized monoclonal anti-CD40L (IDEC Pharmaceuticals, San Diego CA; and Biogen Inc., Cambridge MA). The IDEC-produced molecule has been tested in a phase I dose-finding study, and will be tested in a phase II trial with gadolinium enhancement as the target. Biogen has planned a phase II trial of anti-CD40L in MS patients, but the trial has not started because of concerns about thrombotic complications of anti-CD40L that have arisen in other studies.
Another promising target of immunomodulatory therapy is CTLA4 immunoglobulin. This fusion protein binds CD28 and may make T cells tolerant. Bristol Myers Squibb and Repligen have plans to test CTLA4 immunoglobulin in RR-MS.
Address correspondence and reprint requests to Richard A. Rudick, MD, Area U100, Mellen Center, Cleveland Clinic Foundation, Cleveland, OH 44195; E-mail: firstname.lastname@example.org
Copyright © 2001 Lippincott Williams & Wilkins