Highlights from the ECTRIMS 29th Congress International Meeting

Highlights on Several of the FDA-Approved Medications for MS

Aubagio® (teriflunomide) proven helpful in early MS (CIS) as well as in relapsing MS for up to nine years in studies. Aubagio is an oral medication taken once daily and is approved for the treatment of relapsing forms of MS. Results were reported from TOPIC, a double-blind, placebo-controlled parallel-group study to evaluate the safety and effectiveness of Aubagio in patients experiencing their first clinical episode suggestive of MS (clinically isolated syndrome or CIS). The study was ended early as revised diagnostic criteria enabled earlier diagnosis of MS. Results of the study were consistent with safety and efficacy of other Phase III Aubagio studies and highlighted the ability of early treatment with this disease-modifying therapy (DMT) to delay the onset of MS symptoms.

The higher of the two approved dosages of Aubagio (14 mg) significantly reduced the occurrence of severe relapses, including relapses with lasting effects and those requiring healthcare resources in this analysis of the pooled TEMSO and TOWER datasets. The analysis suggests that Aubagio may reduce relapse-related healthcare costs. Aubagio’s positive effects are maintained with treatment over the long term. Measured clinical and MRI disease activity remained low in patients remaining on Aubagio therapy. Aubagio has a well-characterized and manageable safety profile. No new or unexpected adverse events (AE) were associated with long-term (up to nine years) exposure to Aubagio in the TEMSO extension trial. AEs were consistent with the two-year core trial. Incidence of first AE generally decreased and remained low over time.

Copaxone® (glatiramer acetate) continues to demonstrate effectiveness in relapsing forms of MS. Copaxone is administered subcutaneously (under the skin) daily and is recommended for the treatment of relapsing forms of MS and clinically isolated syndrome (CIS). Copaxone use resulted in a complete treatment response (no disability progression or relapses) in 45 percent of patients with relapsing-remitting MS (RRMS) during the two years of this retrospective observational study. Patients who had been treated with another disease-modifying therapy prior to Copaxone treatment did not demonstrate this response. The authors conclude that Copaxone should be considered in patients with low to medium disease activity.

Gilenya® (fingolimod, FTY720) reduces brain atrophy and is generally safe and effective over a five-year period. Gilenya is an oral medication taken once daily and is approved for the treatment of relapsing forms of MS. Patients on Gilenya who remained disease free over 48 months experienced less brain-volume loss over the four-year study than those who were not disease free. In addition, reduced brain-volume loss was associated with better clinical outcomes at month 48.

Results of an Italian study confirm that the first-dose administration of Gilenya is generally safe and well tolerated; these results are consistent with results from previous clinical trials. Data was collected from 812 Italian patients who were undergoing the required six-hour first-dose observation period following administration of Gilenya. Most patients (95.2 percent) did not have any adverse events during the six hours. Cardiovascular adverse events occurring in 18 patients were all self-limiting, and did not require intervention.

Clinical disease activity remained low for up to five years in patients treated with Gilenya, an interim data analysis indicates. Interim data was presented from LONGTERMS, a single-arm, open label extension study that began in June 2010 and will continue with annual interim analyses through June 2016. Most patients remained relapse free and disability remained stable for up to five years. As a side note, individuals dropping out may have caused a selection bias.

The new injection system for Rebif® (interferon beta-1a) is shown to be very satisfactory. Mean cumulative adherence to treatment with Rebif using the RebiSmart® device was 96.6 percent at month 12. Rebif is administered three times weekly subcutaneously (under the skin) and is recommended for individuals with relapsing forms of MS. The RebiSmart® device, not yet approved in the United States, is an electronic autoinjector that stores several doses of Rebif at a time, and provides an interactive interface to help make injections more tolerable and to remind patients to stay on schedule with the medication. No unknown safety issues were detected in the study.

Tecfidera® (dimethyl fumarate) shows consistent efficacy in different subpopulations. Tecfidera is an oral medication taken two times per day and is recommended for the treatment of relapsing forms of MS. Looking at both of the Phase III DEFINE and CONFIRM studies with Tecfidera in patients from Europe, a more exact estimate can be made of the effectiveness of this treatment in RRMS. This integrated analysis looked at relapse rates, MRI lesions, and disability progression. This post-study analysis found that both groups on active treatment (those given twice-per-day or
three-times-per-day dosing) experienced benefits in comparison to the placebo group across all measures. These include: reductions in annual relapse rates of more than 50 percent (52 and 54 percent
respectively for the twice-per-day or three-times-per-day dosing); a mean reduction in the number of gadolinium-enhancing lesions of 85 and 77 percent respectively; and 12-week confirmed disability progression reductions of 32 and 30 percent, respectively. Tecfidera is approved in the United States, Australia, and Canada; these results support the effectiveness of this disease-modifying therapy in subpopulations of patients in European countries.

Tysabri® (natalizumab) continues to demonstrate remarkable effectiveness over periods of more than four years. Tysabri is administered by IV infusion once every four weeks and is generally recommended for individuals with RRMS who have not responded adequately to or cannot tolerate other MS medications.

Final results of the Tysabri 24 PLUS study were presented. In this observational study, the clinical course of patients with RRMS receiving Tysabri 300 mg intravenously every four weeks for more than two years was assessed. Patients experienced reductions in relapse rates of more than 90 percent compared to their status before treatment. Eighty percent of patients experienced no relapses during the entire observation period after baseline. The mean Expanded Disability Status Scale (EDSS) scores remained stable at the level observed before the start of treatment. Safety data, including the number of cases of progressive multifocal leukoencenphalopathy (PML) were consistent with the known safety profile of Tysabri. (For more information on PML, please see the section on Tysabri from MSAA’s MS Research Update.

Interim results from TOP (Tysabri Observational Program) indicate that disease activity was significantly reduced with increasing Tysabri treatment duration. TOP is an ongoing, open-label 10-year prospective study of patients receiving Tysabri. Patients enrolled for at least four years were included in this analysis. Approximately 90 percent of patients who experienced disability progression in months 0-24 had no disability progression in months 25-48.

Switching Disease-Modifying Therapies

Switching therapies appears to be safe and effective. Patients switching from Tysabri to Gilenya with a shorter washout period had a lower risk of clinical and MRI disease recurrence without increased risk of infections or other treatment related adverse events. (A “washout period” refers to the time needed after discontinuing one medication and beginning a new medication.) Patients were randomized to receive their first dose of Gilenya at either eight, 12, or 16 weeks following their last infusion of Tysabri. The percentage of patients who were relapse free at 24 weeks in the 8-week, 12-week, and 16-week treatment groups were 96 percent, 95.2 percent, and 47.5 percent respectively, suggesting that a shorter washout period and earlier intervention with another treatment may be beneficial.

Results were reported from the COPTIMIZE study, a two-year observational survey of patients with RRMS switching to Copaxone (glatiramer acetate) due to a lack of efficacy or treatment intolerability with a different disease-modifying therapy. Patients who switched to Copaxone from other disease-modifying drugs generally improved in measures of fatigue, cognition, quality of life, and depression; mobility remained stable and EDSS increased slightly from baseline.

Pregnancy While Taking DMTs

While no disease-modifying therapies are approved by the FDA for pregnancy, healthy babies are being born. Women of childbearing age taking disease-modifying therapies (DMTs) are encouraged to use a reliable form of birth control since (as noted) none of these drugs have been approved for use in pregnancy. While the drugs have not been tested in pregnancy, the FDA requires the manufacturers of DMTs to develop pregnancy registries to monitor women who have taken one of these drugs within a week of becoming pregnant or while they were pregnant. The purpose of the registries is to identify pregnancy outcomes.

Pregnancy outcomes with women on interferon beta-1b (Betaseron® and Extavia®) resulted in healthy births. The authors conclude that the data do not suggest an effect of interferon beta-1b on pregnancy outcomes after review of 1,045 pregnancy outcomes of women with an ongoing pregnancy at the time of reporting. Most pregnancies exposed to interferon beta-1b in utero resulted in healthy live births, and the spontaneous abortion rate was consistent with the rate seen in the general population.

Symptomatic Treatments

Ampyra™ (fampridine-SR) may help more symptoms than just walking speed. Ampyra has been shown to improve walking speed and muscle strength in the lower extremities for individuals with MS. It is the first drug to be approved by the FDA to improve walking speed for this population. Amprya’s effects on upper extremities and cognition have not been fully investigated. This study evaluated these functions and showed that Amprya has a positive effect on hand function and cognition, as well as on lower body functions related to muscle strength, according to a study of 108 people with MS and with an EDSS of between 4 and 7.

New Treatments under Review by the FDA

Lemtrada® (alemtuzumab, formerly Campath) may improve disability. This medication is administered in one course yearly by intravenous infusion over three-to-five consecutive days and is being studied in RRMS. According to the authors of this study, “Reversal of disability was significantly more likely with [Lemtrada] than with [Rebif] in CARE MS II… This suggests that whatever impairment a patient may have developed as a result of prior MS attacks, [Lemtrada treatment] increases the odds that it will improve and lead to a meaningful recovery of neurological function.”

Education about adverse events with Lemtrada and close monitoring for these events are important. Adverse events in year three of Lemtrada therapy were similar to those in year one and two. The purpose of this study was to examine the safety in the CARE-MS studies in patients who continued in the ongoing extension study, whether they received an additional dose of Lemtrada or not. (The 18-29 percent of patients who had evidence of clinical or MRI disease activity were eligible for a third course of Lemtrada.) Sixty-six percent of patients who received a third dose experienced infusion-associated reactions, while 50.3 percent of those not receiving a third dose experienced infections, most of which were mild to moderate and responded to standard treatment. One death occurred in year three from sepsis (infection). The incidence of secondary autoimmune disorders (thyroid disease, immune thrombocytopenia, and nephropathy) increased in comparison to year two. For this reason, patient education and monitoring are important for early detection and treatment of these disorders.

Laquinimod reduces MS disability. The results of two separate analyses of pooled data from the Phase III ALLEGRO and BRAVO trials studying Laquinimod were presented. Laquinimod, an oral medication taken once daily, is under investigation in subjects with RRMS. The first analysis compared the expected risk of disability progression (given a particular relapse rate) with that seen in the pooled data. In this analysis, the effect of laquinimod on reducing the risk of disability progression was larger than predicted. The second analysis examined the relationship between relapses and disability by looking at disability progression in both relapsing and relapse-free patients in the two trials. About one third of the patients who progressed were relapse-free, suggesting that these two outcome measures are mediated through different pathways.

Plegridy™ (peginterferon beta-1a) shows encouraging results. New data analyses from year one of the two-year, pivotal, Phase III ADVANCE study of Plegridy were presented. The purpose of this placebo-controlled, double-blinded study is to investigate the safety, tolerability, and efficacy of two different dose regimens of Plegridy (125 mcg administered subcutaneously every two weeks or every four weeks) compared to placebo. Compared with placebo, Plegridy significantly reduced the annualized relapse rate, risk of relapse, and risk of 12-week disability at one year. The proportion of disease activity-free patients over one year was significantly higher in the two treatment groups compared to placebo. The incidence of serious adverse events (SAE) was similar across all treatment groups. Flu-like illness was reported in 47 percent of both treatment groups compared to 13 percent in the placebo group. These safety data are consistent with the established safety profile of interferon beta-1a therapies for MS.

Experimental Therapies

High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (HSCT) appears to be a safe procedure for individuals with MS. Safety and efficacy results from an observational study that followed nine patients who received treatment were reported. Although a short-term benefit was seen, the procedure was not sufficient to produce a long-term reduction in disease activity. No serious or late adverse events were reported, suggesting that this procedure, which uses a patient’s own stem cells, has a good safety profile.

A high proportion of patients with aggressive, relapsing forms of MS were free from disease activity following hematopoietic stem cell transplantation (HCST). A group of 41 Swedish patients participated in this study. They had a mean annualized relapse rate of 4.1 in the year preceding treatment, which means that on average, these individuals with very active disease were each experiencing four relapses in one year. With a mean average follow-up time of nearly four years (47 months) after receiving this procedure, 89 percent of the participants were relapse-free and 77 percent of the participants had no disability progression, as measured by the EDSS. In addition to the expected side effects of sepsis and fever, a small number of patients experienced other adverse events, such as a reactivation of herpes zoster in seven patients and thyroid disease in four patients; no deaths occurred.

Treatment with daclizumab high yield process (DAC HYP) may result in a reduction in the rate of brain atrophy in patients with RRMS receiving two years of this therapy. DAC HYP (also known as Zenapax®) is administered subcutaneously once every four weeks, rather than via intravenous infusion every four weeks. Patients who received two years of treatment with DAC HYP in the SELECT one-year trial and its one-year extension study, SELECTION, were evaluated to determine the rate of brain atrophy (brain-volume loss). During the second year of treatment, the percentage of brain-volume loss was 27-percent lower in the treated groups compared with the placebo group at year one, and 24-percent lower than year one of the treated groups. The authors of the study note that this reduction in the rate of brain atrophy in MS patients may be consistent with long-term neuroprotection.

Results with Rituxan® (rituximab) are encouraging. Administered by intravenous infusion, treatment with Rituxan appears safe and effective in some patients with RRMS and SPMS who have failed to respond to first and second-line therapies. A total of 15 patients began the study and two dropped out due to a lack of efficacy. No serious adverse events leading to discontinuation were observed in any of the patients. Of the remaining 13 patients, no clinical relapses or MRI activity were observed throughout the duration of the study. In the seven patients with RRMS, the EDSS remained stable in four patients and improved in three. In the SPMS group, EDSS improved in one patient and remained stable in the other five.

The combination of Rebif with high-estrogen containing birth control pills improves cognitive impairment in patients with RRMS. When compared to women on Rebif alone or on Rebif and low-estrogen dose oral contraceptives, women who took both high estrogen containing oral contraceptives and Rebif showed a higher reduction in cognitive impairment as compared to baseline.

Studies in Progressive MS

Tysabri trial with secondary-progressive MS (SPMS) patients is now underway. Baseline characteristics for those enrolled in ASCEND, a randomized, placebo-controlled study of Tysabri’s affects on disability progression in patients with SPMS, were presented. As of March, 2013, 717 of the planned total of 856 patients had been enrolled. The level of disability of those already enrolled is consistent with this SPMS population.

Recent studies suggest that it may be possible to slow the disease progression in progressive MS.Preliminary trials for progressive forms of MS are encouraging but not yet conclusive. It is still uncertain whether facilitating the regenerative process will improve function in this patient population.

Treatment with statins slowed the development of brain atrophy and EDSS progression
A study of amiloride indicated a neuroprotective effect in a small number of patients with primary-progressive MS (PPMS)
A study of mesenchymal stem cell treatment showed promising results in SPMS
A subgroup of patients with PPMS may respond to B-cell depletion with Rituxan
Treatment with Tysabri reduced both cerebrospinal fluid and MRI measures of neurodegeneration in PPMS and SPMS

Immunosuppressive therapy with Novantrone® or Rituxan reduces ongoing axonal damage and B-cell activity in progressive MS.Biomarkers for axonal injury, B-cell activity, and astrogliosis (indicating CNS nerve damage) were measured in 35 progressive MS patients treated with Novantrone or Rituxan. Fifteen of the 35 were also treated with interferon beta or Copaxone. Age-matched blood donors served as healthy controls. The analysis found that immunosuppressive therapies reduce ongoing axonal destruction and B-cell activity in progressive MS, but did not affect astrogliosis. The analysis also found that first-line disease-modifying therapies may influence the rate of axonal damage in this population.

Lifestyle Factors and MS

Study supports the benefits of exercise on cognition. The objective of this study was to determine if improved fitness was associated with improvement in cognition over time. Twenty-five of the 82 participants improved in fitness (PI), while 57 did not show improvement (PNI). Compared to the PNI group, the PI group improved on more cognitive measures. The results of this study provide additional support to the hypothesis that fitness is associated with improved executive functioning in people with MS.

Physical exercise resulted in improvement in cognition by some measures and not others in 17 people with MS (three male;14 female) who participated in 22.5 exercise sessions over an eight-week time period. Assessment of cognitive function through the administration of several screening cognition tests was undertaken before and following the eight-week exercise period. The exercise resulted in significant improvement in some of the cognitive assessments but not in others. More research on this important topic is needed.

High-salt intake may increase MS damage. Higher salt consumption is associated with increased clinical and MRI disease activity in people with MS. Salt has been reported to worsen disease activity in an experimental model of MS. Seventy patients with RRMS were followed over two years, tracking sodium intake, in conjunction with clinical and radiological assessment every three to six months or at the time of relapse. Researchers found that individuals with high-sodium intake had three-point-four times greater odds of developing a new lesion on the MRI and on average had eight more T2 lesions on MRI. Exacerbation rates were higher among those with high-sodium intake as well.

Smoking increases MS risk regardless of age at exposure and the detrimental effect slowly decreases following smoking cessation. Smoking habits were compared using two Swedish population-based studies. There was a clear association between the cumulative dose of smoking with both the duration and intensity of smoking contributing independently to the increased risk of MS. The negative effects of smoking slowly diminish after a decade of not smoking.

Smoking worsens MS prognoses through several different pathways. The time to progression to clinically definite MS in smokers with a clinically isolated syndrome (CIS) is shorter in smokers than non-smokers. Smokers were also more likely to develop secondary-progressive MS in a shorter time period compared to non-smokers.

More encouraging news was presented about vitamin D and MS treatment. Researchers looked at how vitamin D (25-hydroxyvitamin D) may play a role in MS development and disease activity on a molecular level. The BENEFIT trial studied the effects of interferon beta-1b (Betaseron) in patients with CIS. Blood samples were taken at various intervals, along with MRIs. This study found that individuals with higher vitamin D levels had lower numbers of gadolinium-enhancing lesions. These individuals generally experienced less disease activity, and genes associated with these higher vitamin D levels appear to be involved. Studies indicate that roughly 350 genes are “significantly associated” with MS activity, and of these 350 genes, 155 are associated with vitamin D regulation. The authors of this study explain that vitamin D “directly and indirectly may regulate gene expression in a manner that reduces MS activity” and that the analysis provides “a systematic model of the molecular mode of action of vitamin D in MS.”

We hope that you found these highlights from the 2013 ECTRIMS 29th Congress international meeting to be of great interest. As mentioned earlier, please watch for MSAA’s upcoming MS Research Update, due to be available in late December. As noted, all major disease-modifying therapies and experimental medications for the long-term treatment of MS will be updated with the latest information presented at this conference. Please watch for the announcement of this new publication on MSAA’s website (at mymsaa.org) and via email notification. If you do not already receive email updates from MSAA, please sign up for this free service.