Written by Jack Burks, MD
Edited by Susan Wells Courtney
The American Academy of Neurology’s (AAN) 65th Annual Meeting took place in San Diego, California in March. This large medical conference presents the latest findings in research and treatments for neurological conditions, including multiple sclerosis (MS). While covering all of the studies relating to MS would not be possible in this issue of The Motivator, to follow are some important highlights.
Adherence to a disease-modifying therapy (DMT) medication reduces the risk of MS relapses by 50 percent while increasing the number of individuals who are relapse-free at two years.
Women with MS who have had children may experience a slower rate of disability progression than women who have never been pregnant. More studies are needed to confirm these findings, and other disease factors may play a role in whether or not a patient becomes pregnant.
The herpes zoster vaccine (HZV) effect in MS was studied in 19 MS patients. These patients suffered no increase in MRI damage, nor had any clinical indication of increased MS symptoms at three months after the vaccination. This study suggests that the HZV is safe to use in MS patients.
FDA-Approved Disease-Modifying Therapies for MS
PEGylated Interferon beta-1a (peginterferon beta-1a) is a chemical modification of the interferon beta-1a (Avonex) molecule that allows it to be given subcutaneously (under the skin) every two or four weeks, in contrast to the current once-a-week, deeper, intramuscular injection. Studies are testing this experimental therapy for safety and effectiveness. If approved by the FDA, this would give patients the option of using a single-dose auto-injector with a prefilled syringe less frequently.
In a previous study (BENEFIT trial), patients with clinically isolated syndrome (CIS) were treated with Betaseron® (interferon beta-1b) or placebo for two years or until they were diagnosed with clinically definite MS (CDMS), at which time everyone was switched to Betaseron. A follow-up extension study at eight years showed both groups had stable or low disability levels, although the patients treated immediately with Betaseron following CIS had fewer relapses than those with delayed treatment.
The FDA-approved dose of Copaxone® (glatiramer acetate) is 20 mg given daily via subcutaneous injection. In this GALA study, patients received either a 40-mg dose three times per week subcutaneously, or a placebo. This experimental dose reduced relapses and MRI lesions compared to placebo. If FDA approved, a less-frequent treatment option for Copaxone may become available.
Rebif® (interferon beta-1a) is being studied with the use of the RebiSmart™ injection device, which is an electronic autoinjector that monitors drug adherence through an electronic dosing log. In a German study, it was found to have a 97-percent adherence rate at three months from the initiation of auto-injector use.
Data on small numbers of women who became pregnant within 90 days of taking Tysabri® (natalizumab) did not suggest any adverse effects on pregnancy outcome. The “C” recommendation (potential harm during pregnancy) stands. Women are not recommended to get pregnant while on Tysabri.
The higher dose (14 mg) of oral Aubagio®(teriflunomide) reduced both relapse rate and disability, while the 7-mg dose reduced relapses but not disability. Patients with fewer relapses prior to treatment had less disability while taking Aubagio.
A four-year patient-safety study with
oral Gilenya® (fingolimod) showed no unexpected safety concerns, as well as a suggestion that disability may improve at four years on treatment. Those who switched to Gilenya prior to 12 weeks of discontinuing Tysabri, had a lower risk of relapsing than those who began therapy with Gilenya after 12 weeks of stopping Tysabri.
A combined analysis of the two Tecfidera™ (dimethyl fumarate, BG-12) clinical trials showed that when given twice per day, Tecfidera reduced relapses and disability, while also having an acceptable safety profile. A higher number of patients were free of disease activity versus placebo-treated patients over the two-year trial periods.
Experimental MS Therapies
In a three-year extension study of the oral drug Laquinimod, treated patients continued to have less risk of disability compared to placebo. Also, no new safety issues occurred.
Lemtrada® (alemtuzumab), a drug infused intravenously only three-to-five consecutive days for the entire first year, was more effective than Rebif in reducing overall disease activity. Adverse events, including thyroid and platelet problems, were consistent with previous studies.
Daclizumab (also known as Zenapax®), a monoclonal antibody given by injection, was shown to have less disease and MRI activity compared to placebo at one year. In the SELECT study, participants who were given a 24-week washout period (without treatment), and then reinitiated the drug, showed no evidence of rebound disease activity following the washout period.
MS patients on Ocrelizumab, a B-cell targeted monoclonal antibody, had low disease and MRI activity, which lasted at least 72 weeks after the last dose. No new safety concerns were experienced.
Vitamin D continues to be linked to MS and optic neuritis. Treatment with Vitamin D demonstrates positive immune-system changes with decreased inflammation and demyelination. African Americans with MS tend to have lower Vitamin D levels and more MS disability.
Studies in Progressive Types of MS
Fourteen primary-progressive MS (PPMS) patients were involved in clinical trials with the oral drug Amiloride, a potassium-sparing diuretic that may have neuroprotective activity. Preliminary results suggest positive effects on MRI and disability.
INFORMS is a double-blind, multicenter, study that will evaluate Gilenya® (fingolimod) 0.5 mg versus placebo in PPMS patients, over a flexible duration of three-to-five years. It will measure the time-to-sustained disability progression. The enrollment of 969 PPMS patients was completed in 2011.
A preliminary study with secondary-progressive MS (SPMS) patients evaluated
the effectiveness of the oral statin drug, simvastatin. Preliminary results showed a positive influence on MRI and clinical disability outcomes. Further studies are necessary to confirm these results.
Siponimod (BAF312) is an oral drug that is in the same class of drugs as Gilenya, but it is not identical. A large study designed for SPMS patients is underway. A smaller study in relapsing-remitting MS (RRMS) was encouraging, based on relapse and MRI results.
Other Interesting Papers
High dietary salt was implicated in increased autoimmune neuro-inflammation by markedly boosting a Th17 helper T-cell driven autoimmune response in EAE (an experimental disease similar to MS in mice). Th17 is an immune-system cell (lymphocyte) involved with the inflammation that causes damage to the myelin and nerves with MS. This Th17-boosting property of dietary salt is also seen in humans. The theory that salt may increase MS inflammation has far reaching practical dietary implications for MS patients.
Glucose levels (sugar levels in the blood) were found to be a predictor of the level of disability in MS patients. Further studies are needed to prove a causal relationship.
MS patients who smoke have an increased severity of MS. Reasons include the fact that smoking causes damaging changes in the immune system and blood pressure regulating system.
MS patients with certain genetic patterns (HLA-DRB1) have an increased level of spinal cord damage compared to MS patients without HLA-DRB1. This highlights the value of examining the brain and spinal cord with a microscope and linking findings to genetic factors.
Chronic Cerebrospinal Venous Insufficiency(CCSVI) has been proposed to cause MS damage due to blocked venous drainage from the brain. In this study, no difference was found in the proportion of MS patients with CCSVI compared to healthy people without MS. This study suggests that CCSVI is not more common in MS patients than in the general population.
Walking and gait were measured in MS patients on Ampyra™ (dalfampridine) while first taking Ampyra, then while not on the drug, and again after the drug was reinstated. Researchers found that walking became worse for patients when not taking the drug, and improved when Ampyra was reinstated.
Written by Susan Wells Courtney
Reviewed by Jack Burks, MD
The United States Food and Drug Administration (FDA) announced on March 27, 2013 that it approved Tecfidera™ (dimethyl fumarate, BG-12) as a first-line therapy for the long-term treatment of relapsing forms of multiple sclerosis (MS). Tecfidera is manufactured by Biogen Idec and is the 10th drug (and third oral medication) to be approved as a disease-modifying therapy (DMT) for the long-term treatment of MS. The approved dosage is 240 mg, taken in pill form twice daily.
Tecfidera may have a distinct dual mechanism of action. First, it is an immunomodulator (modulating or affecting how the immune system functions and exhibiting anti-inflammatory properties), and second, Tecfidera may have neuro-protective effects (potentially protecting the nerves [axons] and their myelin covering from damage).
The Phase III DEFINE placebo-controlled study enrolled 1,200 patients. Results showed a 49 to 50-percent reduction in the proportion of patients who relapsed during the study period compared to placebo, and a 34 to 38-percent reduction in the risk of sustained disability progression (for at least 12 weeks). The Phase III CONFIRM placebo-controlled study enrolled 1,232 patients. Results showed a reduction in relapse rates of 44 to 51 percent for Tecfidera compared to placebo. In both studies, compared to placebo, individuals given Tecfidera had significantly reduced disease activity as shown on magnetic resonance imaging (MRI) scans.
The most commonly reported side effects were flushing and gastrointestinal events, such as diarrhea, nausea and vomiting, and abdominal pain. These occurred more often at the beginning of treatment, decreasing in frequency after the first one-to-two months on this medication.
Reduced white-blood cell (lymphocyte) counts were seen during the first year of treatment (lymphocytes are disease-fighting cells). The FDA recommends that prior to starting Tecfidera, and annually thereafter while still on the treatment, patients are given a complete blood count to monitor their ability to fight infection.
For More Information
Please see mymsaa.org/news/tecfidera-approved/ for MSAA’s full article on the approval of Tecfidera. Additional information on Tecfidera may be found by visiting www.tecfidera.com and or through Biogen Idec’s patient assistance program at www.msactivesource.com or (800) 456-2255. In addition to MSAA’s website (mymsaa.org), individuals may call MSAA at (800) 532-7667 for more information about MS and its treatments. Questions to MSAA’s Client Services Department may be emailed to MSquestions@mymsaa.org.