A prospective open-label study of glatiramer acetate: over a decade of continuous use in multiple sclerosis patients.

A decade of continuous glatiramer acetate (GA) use by relapsing remitting multiple sclerosis (RRMS) patients was evaluated in this ongoing, prospective study, and the neurological status of 'Withdrawn' patients was assessed at a 10-year long-term follow-up (LTFU) visit. Modified intention-to-treat (mITT, n=232) patients received > or =1 GA dose since 1991; 'Ongoing' patients (n = 108) continued in November 2003. Of 124 patients, 50 Withdrawn patients returned for LTFU. Patients were evaluated every six months (EDSS). Mean GA exposure was 6.99, 10.1 and 4.26 years for mITT, Ongoing, and Withdrawn/LTFU patients, respectively. While on GA, mITT relapse rates declined from 1.18/year prestudy to approximately 1 relapse/5 years; median time to > or = 1 EDSS point increase was 8.8 years; mean EDSS change was 0.73 +/- 1.66 points; 58% had stable/improved EDSS scores; and 24, 11 and 3% reached EDSS 4, 6 and 8, respectively. For Ongoing patients, EDSS increased 0.50 +/- 1.65; 62% were stable/improved; and 24,8 and 1% reached EDSS 4, 6 and 8, respectively. For Withdrawn patients at 10-year LTFU, EDSS increased 2.24 +/- 1.86; 28% were stable/improved; and 68, 50 and 10% reached EDSS 4, 6 and 8, respectively. While on GA nearly all patients (mean disease duration 15 years) remained ambulatory. At LTFU, Withdrawn patients had greater disability than Ongoing patients.

Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group.

In a randomized, placebo-controlled, double-blind study, glatiramer acetate (Copaxone) reduced the relapse rate and slowed accumulation of disability for patients with relapsing - remitting multiple sclerosis. Of the original 251 patients randomized to receive glatiramer acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug. The majority of the original double-blind cohort continues to receive glatiramer acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse. The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg glatiramer acetate were well tolerated. The mean annual relapse rate of the patients who received glatiramer acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34 - 0.51). The rate per year has continued to drop and for the sixth year is 0.23. Of the group who have received glatiramer acetate without interruption for 5 or more years, 69.3% were neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS). Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out. This study demonstrates the sustained efficacy of glatiramer acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with relapsing forms of multiple sclerosis. Multiple Sclerosis (2000) 6 255 - 266

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.

When 251 relapsing-remitting patients with multiple sclerosis were randomized to receive daily subcutaneous injections of glatiramer acetate, previously called copolymer 1 (Copaxone; n = 125) or placebo (n = 126) for 24 months, there were no laboratory abnormalities associated with glatiramer acetate treatment and it was well tolerated with few side effects. Patients receiving glatiramer acetate had significantly fewer relapses and were more likely to be neurologically improved, whereas those receiving placebo were more likely to worsen. This study was extended for 1 to 11 months (mean of 5.2 months for the glatiramer acetate group and 5.9 months for the placebo group). The blinding and study conditions used during the core 24-month study were unchanged throughout the extension. The results of this extension study confirm the excellent tolerance and safety profile of glatiramer acetate for injection. The clinical benefit of glatiramer acetate for both the relapse rate and for neurologic disability was sustained at the end of the extension trial.

Concurrence of multiple sclerosis and brain tumor: clinical considerations.

We report a patient with multiple sclerosis (MS) who developed an oligodendroglioma 8 years after the initial diagnosis of MS. This is the first description of a neoplasm, suspected initially on brain MRI and subsequently confirmed by brain biopsy, in an MS patient. Our case emphasizes the need to evaluate atypical brain MRI lesions carefully, even in well-established MS patients, as well as to obtain a tissue diagnosis of such lesions whenever possible in order to determine their precise etiology.

Treatment with oral 3,4 diaminopyridine improves leg strength in multiple sclerosis patients: results of a randomized, double-blind, placebo-controlled, crossover trial.

To examine the efficacy and toxicity of oral 3,4 diaminopyridine (DAP) in dosages up to 100 mg/day, 36 patients with multiple sclerosis (MS) enrolled in a randomized, double-blind, placebo-controlled, crossover trial. The primary outcome measure was improvement of a prospectively defined neurologic deficit, which was leg weakness in 34 patients. Secondary outcome measures included the patient's subjective response, scored manual motor testing (MMT) of leg strength, scored leg strength from videotaped motor testing (VMT), quadriceps and hamstrings strength (QMT) measured by isometric dynamometry, neuropsychological testing (NPT), ambulation index (AI), and Expanded Disability Status Scale (EDSS) score. Paresthesias and abdominal pain were common and were dose limiting in eight patients. Three patients had episodes of confusion, and one patient had a seizure while on DAP. Eight patients withdrew from the study, leaving 28 evaluable patients for the efficacy analysis. The prospectively defined neurologic deficit improved in 24 patients-22 on DAP and 2 on placebo (p = 0.0005). All improvements were in leg weakness. Subjective response and measures of leg strength and function (MMT, VMT, QMT, and AI) improved on DAP compared with placebo. Neither NPT nor EDSS scores improved. DAP treatment can induce improvements in leg strength in MS patients, but toxicity is limiting in many patients.

Investigational drug therapies of treatment of multiple sclerosis.

The licensing of interferon beta-1b dramatically changed the treatment of multiple sclerosis (MS) in the United States. Although it was the first therapeutic agent shown to affect the natural course of the disease, interferon beta-1b is not appropriate for all patients and is far from being a cure. Several other promising therapies now under study include immunosuppressive and immunomodulatory drugs to limit inflammation; oral administration of myelin to induce tolerance; monoclonal antibodies designed to deliver targeted immunotherapy; potassium channel blockers to facilitate conduction along demyelinated axons; and glial growth factors to promote remyelination. Clinical trials of potential therapeutic agents have proliferated in the past decade in conjunction with rapid advances in our understanding of the immunologic basis of MS. Some investigational therapies are associated with problematic toxicities, others benefit only a minority of patients, and many are still in the early stages of development. Nevertheless, because current therapeutic options are limited, and because the history of MS therapy is one of disappointment and frustration, it is essential that legitimate, scientifically based advances be widely disseminated to the neurologic community. This article reviews some of the most promising current and investigational therapies for MS.

Interferon beta-1b serum levels in multiple sclerosis patients following subcutaneous administration.

Recombinant interferon beta-1b (rIFNbeta) reduces the frequency of exacerbations in relapsing-remitting MS when administered subcutaneously on alternate days. However, the pharmacokinetics of rIFNbeta are not well understood and there are scant data on the detectability of rIFNbeta in the serum of MS patients following subcutaneous administration. Moreover, existing assays for detecting IFNbeta are biologic, time-consuming, and require handling of infectious agents. We developed and standardized an ELISA specific for measuring rIFNbeta with a detection range of 40 to 1,000 IU/ml. The specificity of our ELISA was confirmed by the lack of cross-reactivity with other cytokines, including IFNalpha, IFNgamma, IFN Consensus-1, and TNFalpha. We screened serum from 34 MS patients drawn within 12-36 hours of treatment: 15 patients taking 8 MIU, four patients taking 1.6 MIU, and 15 patients taking placebo. Eleven of the 15 patients in the 8-MIU treatment group had measurable rIFNbeta serum levels ranging from 120 to 475 MIU/ml. Two of four patients in the 1.6-MIU treatment group, but none of the placebo group, had detectable serum rIFNbeta levels. A small prospective time-course study was carried out in four MS patients receiving rIFNbeta. Serial blood samples were obtained prior to and 4, 8, 24, and 48 hours after rIFNbeta injection. A peak serum rIFNbeta level was observed between 8 and 24 hours after rIFNbeta injection and tended to decline to near preinjection levels at 48 hours postinjection. These results are consistent with the rationale of alternate-day, subcutaneous administration of rIFN beta. In addition, the ELISA described might be a useful tool to study the pharmacokinetics and the relationship of rIFN beta serum levels to clinical efficacy.

The Brief Repeatable Battery of Neuropsychological Tests for Multiple Sclerosis: a preliminary serial study.

The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) for MS consisting of the selective reminding, 10/36 spatial recall, symbol digit modalities, paced auditory serial addition (PASAT) and word list generation tests is a sensitive measure of early cognitive impairment in MS patients. We administered it to 19 chronic stable MS patients every 60 days for 120 days to examine variability. The mean coefficient of variation for the tests ranged from 18% to 22%. A significant practice effect was seen in the PASAT results (P < 0.05) using the Wilcoxon signed rank test. These results suggest that cognitive fluctuations analogous to motor fluctuations may occur in MS patients and that the BRB-N may be useful in clinical trials of agents expected to alter cognitive function in MS patients if test-retest variability and practice effects are taken into account. Further study is warranted.

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.

We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving copolymer 1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Early treatment trials with interferon beta in multiple sclerosis.

Recent reports of the successful treatment of relapsing-remitting MS with interferon beta-1b (IFN-beta) have ushered in a new era of immunotherapy. In a sense, this was the result of a remarkable conjunction of molecular biotechnology, immunology and clinical research, resulting in the first therapeutic agent to alter the course of this previously untreatable disease. In more concrete terms, the use of IFN-beta in MS was the logical outcome of a series of clinical trials of natural and recombinant IFNs carried out over the past decade, and of concurrent laboratory research suggesting that the effects of the IFNs in MS are mediated by immunoregulatory rather than antiviral or antiproliferative mechanisms. It is now known that the proinflammatory cytokines IFN-gamma and tumor necrosis factor alpha (TNF-alpha) are probably involved in the pathogenesis of MS lesions. In contrast, type I IFNs (alpha and beta) tend to inhibit the activity of IFN-gamma and to prevent disease activity. The earliest controlled studies of natural IFN-alpha and IFN-beta, carried out in the early 1980s, led to the phase III clinical trial of systemic recombinant IFN-beta (Betaseron), recently completed in the United States and Canada. In patients treated with high-dose IFN-beta there were significant reductions in relapse rate and in the appearance of new lesions on magnetic resonance imaging (MRI). The US Food and Drug Administration approved Betaseron for treatment of relapsing-remitting MS in 1993, and it is now in widespread clinical use. A trial of another recombinant IFN-beta, given by intramuscular injection once a week, was also recently completed. The results of this study are awaited with great interest because the primary end point was progression of disability rather than relapse rate. Meanwhile, recombinant IFN-alpha was reported to prevent relapses and MRI changes in a small but well-designed trial. In this paper, the early clinical studies and some of the immunological developments leading to the use of IFN-beta in MS are reviewed.

The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial.

Because 4-aminopyridine (AP) improves residual deficits in some multiple sclerosis (MS) patients but has a narrow toxic-to-therapeutic margin, we compared the safety and efficacy of two target peak serum concentration ranges (low: 30 to 59 ng/ml and high: 60 to 100 ng/ml). We enrolled eight MS patients with temperature-sensitive visual and motor deficits in a randomized, placebo-controlled, double-blind, crossover trial of short-term oral AP treatment. We randomized patients to a sequence of three treatments on three separate days: placebo, low serum concentration, and high serum concentration. We determined dosing to achieve the desired steady-state peak serum concentration ranges from a test dose and population pharmacokinetic parameters using bayesian estimation. Contrast sensitivity, standard neurologic examination, ratings of videotaped neurologic examinations, and quantitative strength assessment all improved with treatment, but flicker fusion frequency, visual evoked response latencies, and Expanded Disability Status Scale scores did not. All patients experienced side effects during the high-serum-concentration arm. A grand mal seizure occurred at a serum AP level of 104 ng/ml, and an acute confusional episode occurred at 114 ng/ml. AP treatment produced improvements in residual deficits in MS patients, but the occurrence of significant toxicity suggests that AP serum levels should be monitored and peak levels above 100 ng/ml should be avoided. Concentration-control methodology may be useful in testing putative treatments for other neurologic diseases.

Increased cathepsin B activity in peripheral blood mononuclear cells of multiple sclerosis patients.

Proteinase levels are increased in multiple sclerosis (MS) lesions and are implicated in demyelination. The cellular origins of the activity are not known, but inflammatory cells of hematogenous origin are one possibility. We studied the levels of two lysosomal proteinases implicated in the proteolysis of myelin basic protein, cathepsin B (CB) and cathepsin D (CD), in peripheral blood mononuclear cells (PBMCs) of 20 stable relapsing-remitting MS patients. We prepared and assayed cell lysates of PBMCs from the MS patients, 10 patients with other neurologic diseases (OND), and 12 normal controls (NC). Mean CB activity expressed as milliunits of activity per million cells was significantly increased in MS patients (7.86 +/- 0.54) compared with OND (6.80 +/- 0.74) and NC (5.94 +/- 0.28) cells (p < 0.05). CD levels were not significantly increased. To determine whether the increase was generalized or limited to a subset of cells, PBMCs were fractionated by plate adherence. CB levels in the adherent fraction (AD) of the 20 MS patients were higher than in the nonadherent fraction (NA), and the AD:NA ratio of CB in MS was higher than that in controls. This would be consistent with an increase in CB levels in monocytes and macrophages, cells known to be activated in the peripheral blood of MS patients and implicated as effectors of demyelination.

Influence of infection on exacerbations of multiple sclerosis.

Exacerbations of multiple sclerosis (MS) are triggered by exogenous events, the best documented being viral upper respiratory infections (URIs), which can stimulate secretion of cytokines such as interferon-gamma (IFN-gamma) by immune cells. In conjunction with a recent clinical trial of systemic interferon-beta (IFN-beta) in relapsing-remitting MS, we studied the occurrence of viral infections and their correlation with MS attacks. Thirty patients kept daily logs, noting URI symptoms in themselves, family members, and co-workers. Patients were examined every 3 months, or whenever an attack of MS occurred, and were tested for antibodies to common upper respiratory pathogens. A strong correlation was found between MS attacks and URIs. There were 168 URIs in 2,792 patient-weeks, including 996 weeks at risk (the interval beginning 1 week before and ending 5 weeks after onset of URI symptoms) and 1,796 weeks not at risk. Nearly two-thirds of attacks occurred in periods at risk. Attack rates were 2.92 per year in weeks at risk compared to 1.16 per year in weeks not at risk, a significant difference (p < 0.001). High-dose interferon reduced the frequency of MS attacks, but had no effect on the number of URIs. Although a specific virus could not be incriminated, we concluded that URIs of presumed viral origin are an important trigger of MS attacks, and that treatment with IFN-beta reduces the attack rate, but not by preventing URIs. Rather, it may modulate responses to viral infection that would otherwise lead to immune activation and clinical symptoms.

Systemic recombinant human interferon-beta treatment of relapsing-remitting multiple sclerosis: pilot study analysis and six-year follow-up.

A pilot study was undertaken to test the safety and establish the side effect profile of recombinant human interferon-beta 1b (Betaseron, Berlex Laboratories, Richmond, CA), in patients with relapsing-remitting multiple sclerosis (RRMS). During the initial dose finding period (24 weeks), five groups of 6 patients each were treated by subcutaneous injection three times each week with either 0.8, 4, 8, or 16 million units (mU) of Betaseron or placebo (WHO Standard). Although some side effects were noted in all groups, a dose-related trend in reduction of exacerbation frequency and side-effect profile was noted. Patients given 16 mU had no exacerbations during the initial dosing period, but associated side effects led to dose reduction or dropout. An 8 mU dose was selected for further study after 24 weeks, and continuous dosing at 8 mU in 15 patients has now exceeded 6 years. Side effects abated over time. Neutralizing antibody developed in most patients, but titers were variable, fluctuated independently of clinical course, and tended to fall with prolonged treatment. A dose-dependent rise in neopterin levels was observed during the initial dosing period. This pilot study has demonstrated responsiveness to Betaseron, shown a stable safety profile over time, and established guidelines for a dosing regimen to evaluate and optimize further the efficacy of Betaseron in RRMS.

Clinical trials of interferons in multiple sclerosis. What have we learned?

Although multiple sclerosis (MS) is generally believed to be an immune-mediated disease, conventional therapy with ACTH, corticosteroids, or immunosuppressive drugs is unsatisfactory. Aside from their unpredictable therapeutic effects, these agents are potentially hazardous and can only be given for short periods of time. There is an urgent need for less toxic yet effective immunotherapy, that that can be administered early in the disease and continued indefinitely. Clinical trials of the interferons (IFNs) have not only led to a promising new approach to treatment, but have also stimulated basic research in the immunological mechanisms of underlying disease activity. Administration of IFN-gamma promotes exacerbations of MS, whereas recombinant IFN-beta has been shown, in controlled clinical trials, to suppress them. Other ongoing studies are likely to provide further information about its long-term therapeutic value. More importantly, laboratory studies performed in conjunction with these clinical trials have provided fresh insights into the pathogenesis of MS by revealing immunoregulatory mechanisms in which endogenous IFN-gamma, TNF-alpha, and other cytokines appear to play central roles. The 'Decade of the Brain' may therefore see answers both to the therapeutic dilemma of MS, and to more basic questions about the function of IFNs and other cytokines in activation and regulation of the disease process.