Results from the 5-year, phase IV RENEW (Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis) study.

BACKGROUND: Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis (RENEW) was a 5-year, phase IV study in which the safety of Mitoxantrone was monitored in a patient cohort from the United States (US). The objective of the study was to evaluate the long-term safety profile of Mitoxantrone in patients with secondary progressive multiple sclerosis (SPMS), progressive relapsing multiple sclerosis (PRMS), and worsening relapsing-remitting multiple sclerosis (RRMS). METHODS: Overall, 509 patients (395 SPMS, 81 worsening RRMS, 33 PRMS) were enrolled and treated at 46 multiple sclerosis (MS) treatment centers located in the US. Patients received Mitoxantrone in accordance with the package insert every 3 months. During the treatment phase, patients received laboratory workups and cardiac monitoring every 3 months and then annually for a total of 5 years. RESULTS: Five hundred and nine subjects were enrolled in this trial and received at least one infusion of Mitoxantrone. Overall, 172 (33.8%) completed the 5-year trial (i.e., participated for 5 years ± 3 months [treatment + follow-up]); 337 (66.2%) did not complete the 5-year trial. Annual follow-up data were available for 250 of 509 enrolled patients. Left ventricular ejection fraction reduction under 50% was reported in 27 (5.3%) patients during the treatment phase (n = 509) and 14 (5.6%) patients during the annual follow-up phase (n = 250). Signs and symptoms of congestive heart failure were observed in 10 (2.0%) patients (six during treatment phase and four during the annual follow-up phase). Post-hoc analyses of the risk for cardiotoxicity outcomes revealed that cumulative dose exposure is the primary risk factor associated with the risk of cardiac toxicity with Mitoxantrone. Therapy-related leukemia was reported in three (0.6%) patients who received total cumulative Mitoxantrone doses of 73.5 mg/m², 107.3 mg/m², and 97.1 mg/m² respectively. During the treatment phase, persistent amenorrhea developed in 22% (28/128) of women with regular menses and 51% (25/49) of women with irregular menses at baseline. During the annual follow-up phase, persistent amenorrhea developed in 5% (4/73) of women with regular menses at baseline. CONCLUSION: RENEW results are consistent with the known safety profile of Mitoxantrone, and provide additional long-term safety data for Mitoxantrone in MS patients.

Variability in detection and quantification of interferon ß-1b-induced neutralizing antibodies.

BACKGROUND: Interferon-beta (IFNB) therapy for multiple sclerosis can lead to the induction of neutralizing antibodies (NAbs) against IFNB. Various methods are used for detection and quantification of NAbs. METHODS: Blood samples from 125 IFNB-1b-treated patients, which were tested NAb negative or NAb positive after conclusion of a clinical study, were retested three years after first being assessed in four different laboratories that offer routine NAb testing to practicing neurologists. The myxovirus protein A (MxA) induction assay, the cytopathic effect (CPE) assay (two laboratories), or the luciferase assay were used. Intra- and inter-laboratory agreement between assays with respect to NAb detection and NAb titer quantification were evaluated. RESULTS: High agreement for NAb detection (kappa coefficient, 0.86) and for titer levels was observed for the intra-laboratory comparison in the laboratory using the MxA induction assay performed three years ago and now. A similarly high agreement for NAb detection (kappa coefficient, 0.87) and for titer quantification was noted for the MxA assay of this laboratory with one of two laboratories using the CPE assay. All other inter-laboratory comparisons showed kappa values between 0.57 and 0.68 and remarkable differences in individual titer levels. CONCLUSIONS: There are considerable differences in the detection and quantification of IFNB-induced NAbs among laboratories offering NAb testing for clinical practice using different assay methods. It is important that these differences are considered when interpreting NAb results for clinical decision-making and when developing general recommendations for potentially clinically meaningful NAb titer levels.

Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial.

BACKGROUND: Interferon beta-1a and glatiramer acetate are commonly prescribed for relapsing-remitting multiple sclerosis (RRMS), but no published randomised trials have directly compared these two drugs. Our aim in the REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) study was to compare interferon beta-1a with glatiramer acetate in patients with RRMS. METHODS: In this multicentre, randomised, comparative, parallel-group, open-label study, patients with RRMS diagnosed with the McDonald criteria who had had at least one relapse within the previous 12 months were randomised to receive 44 mug subcutaneous interferon beta-1a three times per week or 20 mg subcutaneous glatiramer acetate once per day for 96 weeks to assess the time to first relapse. A subpopulation of 460 patients (230 from each group) also had serial MRI scans to assess T2-weighted and gadolinium-enhancing lesion number and volume. Treatments were assigned by a computer-generated randomisation list that was stratified by centre. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00078338. FINDINGS: Between February and December, 2004, 764 patients were randomly assigned: 386 to interferon beta-1a and 378 to glatiramer acetate. After 96 weeks, there was no significant difference between groups in time to first relapse (hazard ratio 0.94, 95% CI 0.74 to 1.21; p=0.64). Relapse rates were lower than expected: 258 patients (126 in the interferon beta-1a group and 132 in the glatiramer acetate group) had one or more relapses (the expected number was 460). For secondary outcomes, there were no significant differences for the number and change in volume of T2 active lesions or for the change in the volume of gadolinium-enhancing lesions, although patients treated with interferon beta-1a had significantly fewer gadolinium-enhancing lesions (0.24 vs 0.41 lesions per patient per scan, 95% CI -0.4 to 0.1; p=0.0002). Safety and tolerability profiles were consistent with the known profiles for both compounds. The overall number and severity of adverse events were similar between the treatments and were not an important cause for discontinuation of the trial during the 96 weeks. INTERPRETATION: There was no significant difference between interferon beta-1a and glatiramer acetate in the primary outcome. The ability to predict clinical superiority on the basis of results from previous studies might be limited by a trial population with low disease activity, which is an important consideration for ongoing and future trials in patients with RRMS.

Fingolimod: a review of its mode of action in the context of its efficacy and safety profile in relapsing forms of multiple sclerosis.

Fingolimod is an orally administered, first-in-class therapy for the treatment of relapsing forms of multiple sclerosis. Data from pivotal clinical trials show that fingolimod has a robust, significant effect on annualized relapse rates and MRI outcomes. Fingolimod has a novel, well-characterized mechanism of action. It acts through a specific set of receptors, sphingosine 1-phosphate receptors, present on the surface of a wide range of human cells and tissues, including neural cells, neurons and lymphocytes. Here we review the current literature to describe the mechanism of action of fingolimod in the context of its well-established clinical efficacy and safety profile. Understanding of the mechanisms behind any non-therapeutic effects of fingolimod facilitates their prediction and management in the clinical setting.

The relationship between the rate of brain volume loss during first 24 months and disability progression over 24 and 48 months in relapsing MS.

Clinical evidence in patients with relapsing-remitting multiple sclerosis suggests an association between MRI outcome measures and disability progression (DP). Post hoc analysis to investigate the association and potential predictive value of brain volume loss (BVL) with long-term DP in FREEDOMS. Patients were categorized into quartiles by SIENA-calculated percent brain volume change from baseline to month (M) 24. Patient characteristics at baseline were determined for each quartile, as were the proportions of patients at M24 and M48 reaching Expanded Disability Status Scale (EDSS) scores of ≥4.0 or ≥6.0 or DP confirmed at 3 months (CDP3) or 6 months (CDP6), and change in EDSS and Multiple Sclerosis Functional Composite. MS disease activity and severity as well as brain volume at baseline were predictive of subsequent BVL over 24 months. The quartiles of patients with greater BVL at 24 months were at highest risk (odds ratio, p value) for reaching EDSS ≥4 (2.8, p = 0.001) or ≥6 (5.73, p = 0.0005) and experienced more DP at M24 (CDP3 2.13, p = 0.002; CDP6 2.17, p = 0.003) and M48 (CDP3 1.98, p = 0.006; CDP6 1.87, p = 0.018) compared to the quartile of patients with the least amount of BVL. These findings confirm the clinical relevance of early brain volume changes for long-term DP.

Incidence and course of depression in multiple sclerosis in the multinational BEYOND trial.

Early experience in MS generated concerns that interferon beta treatment might provoke onset or worsening of depression. The objective of the study was to compare depression incidence in relapsing-remitting MS patients receiving interferon beta-1b (IFNB-1b) or glatiramer acetate (GA) in the BEYOND trial. 891/897 (99 %) of English, French, Spanish and Italian speakers among 2244 patients randomized (2:2:1) to receive either IFNB-1b 500 µg, 250 µg, or GA 20 mg QD for 2-3.5 years submitted Beck Depression Inventory Second Edition (BDI-II) scores at screening and serially thereafter, in which scores ≥14 indicated depression. Baseline BDI-II scores ≥14 were reported in 232/891 patients (26.3 %), with no meaningful difference among the three treatment arms noted at this or at any other time during the study including trial end. Percentages of patients depressed by BDI-II scores deviated little in any arm at any time (IFNB-1b 500 µg: 24.7 %, IFNB-1b 250 µg: 24.4 %, GA: 32.4 %). Antidepressant usage was likewise similar among the three treatment arms (IFNB-1b 500 µg: 33.7 %, IFNB-1b 250 µg: 31.8 %, GA: 28.8 %) as was depression severity and the frequency with which non-blinded treating physicians recorded depression as an adverse event (IFNB-1b 500 µg: 17.2 %, IFNB-1b 250 µg: 17.0 %, GA: 14.4 %). Treating physicians attributed depression to IFNB-1b 250 µg therapy in 53.6 % and to GA in 21.9 % of instances. This large, prospective, randomized-controlled MS dataset showed no increased risk of depression above baseline values with standard or double-dose IFNB-1b or GA QD treatment.

Association of Vitamin D Levels With Multiple Sclerosis Activity and Progression in Patients Receiving Interferon Beta-1b.

IMPORTANCE: Low serum 25-hydroxyvitamin D (25[OH]D) levels are associated with an increased risk of multiple sclerosis (MS) as well as with increased disease activity and rate of progression in clinically isolated syndromes and early MS. OBJECTIVE: To assess the association between 25(OH)D and disease course and prognosis in patients with relapsing-remitting MS treated with interferon beta-1b. DESIGN, SETTING, AND PARTICIPANTS: We conducted a prospective cohort study assessing 25(OH)D levels and subsequent MS disease course and progression characterized by magnetic resonance imaging (MRI) and clinical end points. The study took place between November 2003 and June 2005; data analysis was performed between June 2013 and December 2014. The study was conducted among participants in the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) study, a large, phase 3, prospective, multicenter, blinded, randomized clinical trial. Patients were monitored for at least 2 years. Clinic visits were scheduled every 3 months, and MRI was performed at baseline and annually thereafter. Eligible patients included 1482 participants randomized to receive 250 µg or 500 µg of interferon-1b with at least 2 measurements of 25(OH)D obtained 6 months apart. EXPOSURES: Serum 25(OH)D measurements were performed at baseline, 6 months, and 12 months. MAIN OUTCOMES AND MEASURES: Main outcomes included cumulative number of new active lesions (T2 lesions and gadolinium acetate-enhancing lesions), change in normalized brain volume, relapse rate, and progression determined by the Expanded Disability Status Scale (EDSS). Statistical analyses were adjusted for age, sex, randomized treatment, region, disease duration, and baseline EDSS score. RESULTS: Overall, average 25(OH)D levels in 1482 patients were significantly inversely correlated with the cumulative number of new active lesions between baseline and the last MRI, with a 50.0-nmol/L increase in serum 25(OH)D levels associated with a 31% lower rate of new lesions (relative rate [RR], 0.69; 95% CI, 0.55-0.86; P = .001). The lowest rate of new lesions was observed among patients with 25(OH)D levels greater than 100.0 nmol/L (RR, 0.53; 95% CI, 0.37-0.78; P = .002). No significant associations were found between 25(OH)D levels and change in brain volume, relapse rates, or EDSS scores. Results were consistent following adjustment for HLA-DRB1*15 or vitamin D-binding protein status. CONCLUSIONS AND RELEVANCE: Among patients with MS treated with interferon beta-1b, higher 25(OH)D levels were associated with lower rates of MS activity observed on MRI. Results for brain atrophy and clinical progression were more equivocal.

Early intervention with immunomodulatory agents in the treatment of multiple sclerosis.

Multiple sclerosis (MS) is a lifelong neurologic disease leading to moderate or severe disability in the majority of affected patients. Studies of the natural history of MS suggest that 90% of patients with relapsing-remitting MS eventually develop secondary progressive (SP) disease. Magnetic resonance imaging (MRI) studies have consistently shown a high frequency of new T2 lesions and new gadolinium enhancing lesions even in the absence of clinical relapse. Lesion burden on T2 MRI increases by 5% to 10% per year and both axonal transection and cerebral atrophy are present at the earliest stages of RR MS. A wealth of evidence suggests that MS is a disease process that is continuously active, and that irreversible damage occurs early in the disease. Despite knowledge of the natural history and the availability of treatments that reduce relapse rates, decrease the accumulation of disability, and decrease surrogate measures of disease activity, only 60% of eligible patients have been treated with immunomodulating agents. This paper reviews the available evidence suggesting that immunomodulatory therapy modifies the natural history of MS and presents an argument for early intervention in the treatment of MS.

The argument against the use of cyclophosphamide and mitoxantrone in the treatment of multiple sclerosis.

Mitoxantrone (MITX) and cyclophosphamide (CPM) are potent immunosuppressive agents with efficacy in the treatment of multiple sclerosis (MS). Both agents appear effective in those patients with active inflammatory disease but are probably less effective in patients with a secondary progressive (SP) course dominated by a degenerative component. Given these agents are effective patients with active inflammation the question arises as to whether they are more effective than high dose interferon therapy. Interferon beta administered at high dose and high frequency suppresses enhancing lesions by as much as 90% and brings about a 35% decrease in relapse rates in addition to decreasing the progression of disability. Interferons have an excellent safety profile even after years of administration. What then is the advantage of immunosuppressive agents such as cyclophosphamide and mitoxantrone over safer and still effective treatments? The answer lies in the magnitude of effect in those with the most active and aggressive disease states. While interferons are safe and effective in those with mild or moderate inflammatory disease states, they are probably not sufficient to bring about control in disease that is highly active and resilient. Both mitoxantrone and cyclophosphamide have the ability to suppress inflammation that may be resistant to therapy with more conservative agents. Given the safety profile of these agents their use should be restricted to those patients with aggressive disease resistant to treatment with more conservative agents.

Treatment of Marburg variant multiple sclerosis with mitoxantrone.

Marburg variant multiple sclerosis (MS) is a severe, sometimes monophasic, form of MS leading to advanced disability or death within a period of weeks to months. No consistently successful treatment for Marburg variant MS has been described. The case reported here is that of a 34-year-old woman with Marburg variant MS whose magnetic resonance imaging scan showed extensive brainstem, periventricular white matter, subcortical, and cortical involvement, giving the appearance of an "MS cerebritis." The patient had no response to treatment with methylprednisolone but improved and recovered after treatment with mitoxantrone (MITX). Because MITX has potent anti-inflammatory effects and demonstrated efficacy in worsening MS, it may be an appropriate agent for the treatment of Marburg variant MS.

Recent advances in treating multiple sclerosis: efficacy, risks and place in therapy.

The development of new pharmacologic agents for the treatment of multiple sclerosis (MS) and advances in testing for exposure to the JC virus have led to changes in the treatment of MS. In addition several new agents are in late stage development for MS and their entry onto the market will provide additional treatment options. In 2012 and in early 2013, it is likely that both terifunomide and BG-12 will be approved by the United States Food and Drug Administration (FDA) for the treatment of relapsing forms of MS. The therapeutic environment has already changed and is likely to change rapidly over the next several years. Fingolimod was the first oral agent approved for the treatment of MS and this agent is now widely used in patients intolerant of injections and the side effects associated with the older platform therapies. In many settings it is also used a first-line agent. Owing to the risk of progressive multifocal leukoencephalopathy, natalizumab had previously been reserved for patients with active disease who were intolerant of first-line agents or patients who were worsening despite standard therapy. With the availability of JC virus antibody testing, natalizumab is now being used as a first-line agent in patients negative for JC virus antibodies. Teriflunomide and BG-12 will become available in the next year. Both agents have suitable efficacy and a favorable safety and tolerability profile. There are advantages and disadvantages associated with all of the oral agents. In this article we summarize the clinical trial results regarding the efficacy and safety of the oral agents and discuss the changes that are already taking place in the therapeutic landscape for MS.

Interleukin 17F level and interferon ß response in patients with multiple sclerosis.

IMPORTANCE: High serum levels of interleukin 17F (IL-17F) at baseline have been associated with suboptimal response to interferon beta in patients with relapsing-remitting multiple sclerosis. OBJECTIVE: To further investigate the role of IL-17F in predicting treatment response to interferon beta-1b in patients with relapsing-remitting multiple sclerosis using the Singulex Erenna IL-17F immunoassay. DESIGN, SETTING, AND PATIENTS: Serum samples were analyzed from 239 randomly selected patients treated with interferon beta-1b, 250 µg, for at least 2 years in the Betaferon Efficacy Yielding Outcomes of a New Dose Study. EXPOSURE: Treatment with interferon beta-1b, 250 µg, for at least 2 years. MAIN OUTCOME MEASURES: Levels of IL-17F at baseline and month 6 as well as the difference between the IL-17F levels at month 6 and baseline were compared between the following: (1) patients with less disease activity vs more disease activity; (2) patients with no disease activity vs some disease activity; and (3) responders vs nonresponders. RESULTS: Levels of IL-17F measured at baseline and month 6 did not correlate with lack of response to treatment after 2 years using clinical and magnetic resonance imaging criteria. Relapses and new lesions on magnetic resonance imaging were not associated with pretreatment serum IL-17F levels. When patients with neutralizing antibodies were excluded, the results did not change. All patients with levels of IL-17F greater than 200 pg/mL were associated with poor response with some clinical or radiological activity. CONCLUSIONS AND RELEVANCE: An increase of IL-17F before and early after treatment with interferon beta-1b was not associated with poor response. These data do not support the value of IL-17F as a treatment response indicator for therapy of patients with multiple sclerosis with interferon beta, although high levels of IL-17F greater than 200 pg/mL may predict nonresponsiveness.

The changing face of multiple sclerosis clinical trial populations.

BACKGROUND: Since the commercial introduction of disease-modifying drugs (DMDs) for the treatment of multiple sclerosis (MS), there have been numerous randomized placebo-controlled and head-to-head clinical trials assessing the efficacy and safety of these agents in relapsing-remitting MS (RRMS). SCOPE: Recent trials in the past 10 years demonstrate that the characteristics and behavior of clinical trial populations in RRMS have changed. Here we review evidence from key published clinical trials of DMDs in RRMS that highlights the general shift in trial populations, and examine the implications of this shift for future trial design. FINDINGS: Populations in recent studies are characterized by lower clinical disease activity. This difference is apparent with regards to baseline patient characteristics and on-study behavior in terms of outcomes (e.g., relapse rates). The reasons for this shift are probably multifactorial and include study design, current treatment options, patient selection, and a possible change in the natural history of MS. CONCLUSIONS: The variation among study designs makes it difficult to draw more extensive conclusions about changes in clinical trial populations. However, these recent changes undoubtedly will affect interpretation of recent study results, some of which based clinical and statistical assumptions on earlier trials. Furthermore, the shift in populations has major implications for the design of future studies: (1) assumptions regarding effect size and statistical powering must be based on comparable patient populations; (2) larger trials of longer duration may be needed, possibly with stopping criteria based on the number of actual events rather than a preset, fixed time point for the end of study; (3) the use of biomarkers to facilitate identification of subpopulations may be considered; and (4) enhanced measures of disease activity (e.g., composite outcomes) may help to identify effects in multiple relevant MS outcomes. Furthermore, trial design may need to be modified to study the effects of a medication in patients who are representative of the anticipated patient population. To ensure that the clinical trial experience of a drug is reflected in its eventual clinical use, 'real-life' observation study programmers should be conducted to continuously monitor its effects in relevant populations and in comparison with available therapies.

Fingolimod for the treatment of relapsing multiple sclerosis.

Fingolimod is the first oral agent approved in the USA for the treatment of relapsing forms of multiple sclerosis. Fingolimod is a sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phosphate receptors on lymphocytes, resulting in a downregulation of the receptor and a reversible sequestration of lymphocytes in lymphoid tissue. Effector memory T cells are not sequestered so that immune surveillance may be minimally affected. Two large-scale Phase III clinical trials have demonstrated the efficacy of fingolimod compared with placebo and intramuscular interferon ß-1a in relapsing-remitting multiple sclerosis. Due to its mechanism of action, fingolimod administration may be associated with first-dose bradycardia and macular edema. Therefore, patients should be observed for 6 h at the time of their first dose and undergo ophthalmologic evaluation prior to treatment initiation and at 3-4 months after initiation.

Efficacy of natalizumab therapy in patients of African descent with relapsing multiple sclerosis: analysis of AFFIRM and SENTINEL data.

BACKGROUND: Patients with multiple sclerosis (MS) who are of African descent experience a more aggressive disease course than patients who are of white race/ethnicity. In phase 3 clinical trials (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]), natalizumab use significantly improved clinical and magnetic resonance imaging outcomes over 2 years in patients with relapsing MS. Because patients of African descent may be less responsive to interferon beta treatment than patients of white race/ethnicity, the efficacy of natalizumab therapy in this population is clinically important. OBJECTIVE: To evaluate the efficacy of natalizumab use in patients of African descent with relapsing MS. DESIGN: Post hoc analysis. SETTING: Academic research. PATIENTS: Patients of African descent with relapsing MS who received natalizumab or placebo in the phase 3 AFFIRM study and those who received natalizumab plus intramuscular interferon beta-1a or placebo plus intramuscular interferon beta-1a in the phase 3 SENTINEL study. MAIN OUTCOME MEASURE: Efficacy of natalizumab use in patients of African descent with relapsing MS who participated in the AFFIRM or SENTINEL trial. RESULTS: Forty-nine patients of African descent participated in AFFIRM (n = 10) or SENTINEL (n = 39). Demographic and baseline disease characteristics were similar between patients treated with natalizumab (n = 21) or placebo (n = 28). Natalizumab therapy significantly reduced the annualized MS relapse rate by 60% (0.21 vs 0.53 in the placebo group, P = .02). Compared with placebo use, natalizumab therapy also significantly reduced the accumulation of lesions observed on magnetic resonance imaging over 2 years: the mean number of gadolinium-enhancing lesions was reduced by 79% (0.19 vs 0.91, P = .03), and the mean number of new or enlarged T2-weighted lesions was reduced by 90% (0.88 vs 8.52, P = .008). CONCLUSION: Natalizumab therapy significantly improved the relapse rate and accumulation of brain lesions in patients of African descent with relapsing MS.

Chemotherapeutics in the treatment of multiple sclerosis.

The likely pathogenic mechanisms of multiple sclerosis (MS) provide a sound rationale for investigating the efficacy of drugs possessing immunosuppressive or immunomodulatory properties. With proven efficacy, safety and tolerability, interferon beta formulations and glatiramer acetate have become the mainstay of initial treatment for patients with relapsing forms of MS. More recently, natalizumab, a humanized monoclonal antibody (mAb) against the cellular adhesion molecule α4-integrin, has been employed for patients with an inadequate response or lack of tolerability to an alternate MS therapy, or as initial therapy for patients with severe disease. Various agents initially developed for oncological indications, either as chemotherapeutics or mAbs, may also have current or future uses in MS treatment. Mitoxantrone is currently the only chemotherapeutic agent approved for treatment of MS in the United States, while in parts of Europe azathioprine is approved and widely used for MS treatment. Other chemotherapeutics that have been tested in MS to date include cyclophosphamide, methotrexate, cladribine, and the mAbs alemtuzumab and rituximab. While there has been varying evidence of efficacy for these compounds, each appears to be associated with serious risks that require careful consideration and management. Given the risks that have been demonstrated for available chemotherapeutic agents and while long-term postmarketing safety data are still not available for those agents in development, it seems prudent to carefully assess the possible use of chemotherapeutics in the treatment of MS. A thorough risk-benefit analysis is becoming increasingly important in the assessment of therapeutic options for this disabling disease.

Dalfampridine sustained-release for symptomatic improvement of walking speed in patients with multiple sclerosis.

Dalfampridine sustained-release (SR) is a time-release formulation of 4-aminopyridine, recently approved by the Food and Drug Administration to improve walking in patients with multiple sclerosis (MS). In Phase II trials, walking speed and lower extremity muscle strength was increased in patients with MS, but the increase in walking speed did not reach statistical significance. A responder analysis revealed that approximately 35% of treated patients had a statistically significant and clinically meaningful increase in walking speed. When treated responders were compared with treated nonresponders, walking speed significantly increased in the responder group, but not in the nonresponder or placebo groups. This result was duplicated in two larger Phase III trials. The optimal dose to maximize the risk-benefit ratio was 10 mg twice daily. Higher doses were associated with a greater risk of seizure, but no further improvement in walking speed or in the proportion of responders. Dalfampridine SR is eliminated by renal clearance and undergoes only limited metabolism (<10%). It is contraindicated in patients with moderate or severe renal insufficiency and in those with a history of seizures or epileptiform activity on electroencephalography. The development of time-released 4-aminopyridine represents a major advance in symptomatic therapy for MS.

A pilot test of pioglitazone as an add-on in patients with relapsing remitting multiple sclerosis.

The peroxisome proliferator-activated receptor gamma agonist pioglitazone is FDA-approved for treatment of type-2 diabetes due to insulin sensitizing effects. However pioglitazone has anti-inflammatory and neuroprotective effects, reduces glial and T-cell activation, and reduces signs in an animal model of multiple sclerosis (MS). We tested the effects of daily treatment with pioglitazone in a small cohort of relapsing remitting MS patients. RRMS patients taking IFNbeta-1alpha and having an EDSS score <6.5 were randomized to treatment with pioglitazone (30 mg daily, p.o.) or placebo and monitored clinically and by MRI for 1 year. Primary outcomes were safety and tolerability, secondary outcomes included changes in neurological outcome, lesion burden, and gray matter volume. After 1 year 11 patients in the pioglitazone arm and 10 in the placebo arm completed the trial. Pioglitazone was well tolerated with a similar incidence of non-serious adverse events in placebo and treatment groups. After 1 year there were no significant differences in clinical symptoms as assessed by EDSS; however MRI showed a significant reduction in gray matter atrophy, and a trend for reduced lesion burden in the treatment group. These results show that pioglitazone was well tolerated in RRMS patients with indications of beneficial effects, warranting further trials to establish clinical efficacy.

A pilot trial of combination therapy with mitoxantrone and interferon beta-1b using monthly gadolinium-enhanced magnetic resonance imaging.

OBJECTIVE: To examine the safety of combination therapy with mitoxantrone (MITX) and interferon beta-1b (IFNbeta-1b) in patients with multiple sclerosis (MS) and a high on-therapy relapse rate and enhancing lesions on baseline magnetic resonance imaging (MRI) scan. METHODS: Ten patients with worsening relapsing remitting or secondary progressive MS were studied using monthly MRI with triple-dose gadolinium contrast. All patients must have been on IFNbeta-1b for at least six months, have at least one enhancing lesion on a screening MRI, at least one relapse on IFNbeta-1b in the six months prior to study entry and be neutralizing antibody negative. Monthly MRI scans using triple dose contrast and a 30-minute delay between contrast administration and scanning were carried out three times over two months to obtain baseline numbers of enhancing lesions each month. At the end of the baseline phase, MITX was administered at 12 mg/m2 (month 3), and 5 mg/m2 at months 4 and 5. Dosing was continued at 5 mg/m2 every third month. Monthly MRI scanning was continued throughout the duration of MITX dosing. The primary outcome measure was the frequency of new enhancing lesions. Secondary outcome measures included relapse rate, and T1 hypointense and T2 lesion burden. RESULTS: Following the addition of MITX to IFNbeta-1b mean enhancing lesion frequency decreased 90% at month 7 (P = 0.008) and enhancing lesion volume decreased by 96% (P = 0.01). Relapse rates decreased 64% (P = 0.004). T2 lesion burden and T1 hypointense lesion burden increased slightly during the baseline phase and decreased following MITX but the difference did not reach statistical significance. There were no serious adverse events on combination therapy and no drop-outs due to toxicity. Total white blood cell count was reduced at 14 days post-MITX infusion but returned to normal levels by day 21. There were no neutropenic fevers and there was no clinically significant elevation of liver function tests. CONCLUSIONS: While the number of patients in this study was small, the results suggest that the combination is safe and well tolerated. Disease activity was substantially reduced following the addition of MITX to IFNbeta-1b.