Nearly 12,000 neurologists and investigators convened in New Orleans in April to present findings at the American Academy of Neurology’s annual meeting. Over 500 scientific presentations and display posters focused on research to stop multiple sclerosis (MS), restore function, and end MS forever. The MS sessions were often standing-room only, and appear to get bigger every year. Among these were the latest results from pivotal clinical trials of emerging MS therapies, possible risk factors, underlying disease mechanisms, rehabilitation approaches, CCSVI, and much more. For free access to the conference abstracts (brief summaries), go to the American Academy of Neurology’s Website.
In most cases, studies presented are considered preliminary. Many of the results will be analyzed more thoroughly, and usually published in peer-reviewed science and medical journals. Confidence in a study’s findings grows when it is repeated by others, with similar results.
• STOP: Among studies reported were these first results from late-phase clinical trials. If these treatments are found to be safe and beneficial, some of them may come on the market in 2012 and 2013. Other studies focused on understanding benefits, risks, and modes of action of available and emerging therapies.
• RESTORE: Rehabilitation to address cognitive changes was explored. In addition, several presentations focused on imaging techniques and pathology findings related to Chronic Cerebrospinal Vascular Insufficiency (CCSVI) and MS.
• END: Understanding risk factors that influence who gets MS, and also what course their MS will take, is crucial for finding ways to prevent MS and progression of symptoms. Among the presentations were studies that looked at interactions of genes, gender, and vitamin D levels.
Research toward stopping MS in its tracks
Among studies reported were these first results from late-phase clinical trials. If these treatments are found to be safe and beneficial, some of them may come on the market in 2012 and 2013. Other studies focused on understanding benefits, risks, and modes of action of available and emerging therapies.
• BG-12 (Biogen Idec) – The phase 3 CONFIRM trial of this oral therapy in 1430 people with relapsing-remitting MS – tested at 2 or 3 times a day against placebo over 2 years – achieved statistical significance on the primary endpoint of reducing average annual relapses by 44% to 51% over placebo. Both BG-12 groups and a group given glatiramer acetate (Copaxone®) were compared to the placebo groups, but not to each other. Both doses of BG-12 reduced disease activity on MRI. Disability progression was not reduced significantly by BG-12. The most common adverse events in the BG-12 groups were flushing and gastrointestinal events. (Abstract S01.003) A small study in 56 healthy volunteers treated with BG-12 showed that pretreatment with aspirin (325 mg for 4 days) decreased the incidence and severity of flushing, without increasing gastrointestinal upset. Whether long-term use of aspirin with BG-12, if approved, in people with MS will be as effective and well tolerated is not known. (Abstract P04.136) Biogen Idec has applied to the FDA for marketing approval of BG-12 for MS.
• Alemtuzumab (Genzyme/Sanofi) – The 2-year CARE-MSII phase 3 trial compared intravenous alemtuzumab against standard dosing of Rebif® in 840 people with relapsing-remitting MS who had relapsed while on prior therapy. Alemtuzumab was infused once each year, on 5 consecutive days the first year, and on 3 consecutive days the second year. The relapse rate was reduced by 49% compared to Rebif, and the risk of disability progression was reduced by 42%. Several aspects of MRI-detected disease activity also showed benefit, and alemtuzumab reduced brain atrophy. Adverse events of alemtuzumab included autoimmune thyroid-related problems in 15.9%, ITP (a rare blood disorder) in 0.9%, and infusion-related reactions. The most common infections were upper respiratory and urinary tract infections, sinusitis, and herpes simplex infections; serious infections occurred in 3.7% of the alemtuzumab group and 1.5% of the Rebif group. (Abstract S01.004) Genzyme has publicized plans to file for FDA approval of alemtuzumab in the second quarter of 2012.
• Gilenya® (fingolimod) – In a phase 3 "FREEDOMS II” study, a daily dose reduced the relapse rate by 48% compared with placebo in 778 people with relapsing-remitting MS, the primary endpoint of the study. (Abstract 5LB00.015) A registry of 500 pregnant women has been established by Novartis, collecting information on maternal, fetal, and infant outcomes associated with accidental exposure to Gilenya during pregnancy; this is an FDA requirement that helps to determine whether therapies are safe for pregnant women. (Abstract P06.189)
• CombiRx trial – First results from a clinical trial that tested a combination of Copaxone and Avonex® were presented by Fred Lublin (Mount Sinai College of Medicine, New York City) and Jerry Wolinsky MD (University of Texas Health Science Center at Houston). This 3-year trial was funded by the NIH, with trial drugs donated by Teva Pharmaceuticals and Biogen Idec. Although there was some evidence from MRI that the combination was better than either therapy alone, there was little evidence that the combination was superior in terms of reducing clinical relapses or progression. (Abstracts S11.002 and PL02.003)
• Green tea extract – Alexander Ramos (Louisiana State University, New Orleans) and colleagues at LSU and Oregon Health Science University administered 400 mg of Polyphenon E – a green tea extract – twice daily to 10 people with relapsing-remitting or secondary-progressive MS; the major component of this extract is an antioxidant that may help to protect nerve cells from damage. One person discontinued therapy after mild elevation of liver enzymes, but no serious adverse events occurred. Treatment resulted in a 13% increase in average levels of a molecule that reflect nerve tissue integrity (N-acetyl-aspartate). (Abstract P03.050) The team is now conducting a phase 2 study to determine safety and neuroprotective effects in 48 people. Read more about this study.
• Predicting response to therapy – An international team analyzed DNA from individuals who had participated in a clinical trial of Copaxone (FORTE trial), looking for signposts that might indicate in advance whether a person will or will not respond well to treatment with this disease-modifying therapy. Rather than looking at over 1100 participants, they selected ones who did very well—having no MRI lesions or relapses during the trial -- and for high contrast, ones who did not do well—having signs of high disease activity during the trial. Using advanced technology, in preliminary results they were able to identify an array of gene signals that could predict high response to Copaxone. This study is an example of a growing trend to seek ways to optimize treatment choices for people with MS. (Abstract IN3-2.003)
• Treating acute relapses – A multicenter trial by Cristina Ramo-Tello MD (Pujol Hospital, Badalona, Spain) and colleagues reported that intravenous and oral methylprednisolone were equally effective in treating acute relapses in 49 people with MS who were given either dosing regimen or inactive placebo after a relapse. At least one other larger-scale study is underway which should help clarify whether the more convenient oral treatment is equally effective as IV. (Abstract P01.128)
Research toward restoring what's been lost
Understanding how MS damages the nervous system and how symptoms impact daily life can help to take full advantage of the variety of rehabilitation and exercise regimens that may restore function to people with MS.
• Cognitive rehabilitation – Letizia Panicari (San Raffaele University, Milan) and team used functional MRI – which provides pictures of changes in brain activity – to compare 10 people with MS who completed a course of computer-assisted cognitive rehabilitation compared with 10 who did not undergo rehabilitation. After 12 weeks, the treatment group showed increases in brain activity relating to the functions being tested (attention/information processing) while activity decreased in the control group. (Abstract S51.003)
• MS impact on taste – Corey McGraw MD and colleagues (Mount Sinai School of Medicine, New York) described a series of case reports of people with MS whose sense of taste was affected by the disease (dysgeusia). The issue was brought to their attention by a prominent food and wine critic who developed a decrease in taste on the left side of his tongue. In all seven cases, MRI revealed lesions – areas of tissue damage – in a small area of the brainstem (the back of the brain). Fortunately, taste function was recovered within 2 weeks to 3 months. In some cases this symptom was the first symptom indicating MS. Since brain stem lesions can be associated with more severe disease activity, this may be an important signal for people with MS and healthcare providers to pick up. (Abstract P06.178)
Several platform and poster display presentations focused on nervous system repair, finding ways to better track MS disease activity and progression, and CCSVI and MS, including:
• Ultrasound study: CCSVI – Andrew Barreto MD, Jerry Wolinsky MD, and colleagues (University of Texas Health Science Center at Houston) reported on preliminary results from a National MS Society-supported study investigating CCSVI. This team has been conducting ultrasound to evaluate venous drainage in a blinded fashion in 206 people with different types of MS and 70 people who were healthy or had other diseases. So far, they reported finding that 3.88% of people with MS met at least 2 criteria for CCSVI, in contrast to 7.14% of people who did not have MS – a difference that was not statistically significant. The prevalence of CCSVI using this team’s rigorous techniques is less than previously reported by other groups. (Abstract S10.005)
• Pathology study: CCSVI – Preliminary results were presented in a poster from an ongoing study of vein structure in autopsy specimens (by Claudiu Diaconu, Dr Robert Fox, and colleagues, Cleveland Clinic, Ohio) from 10 people who had MS in their lifetimes, compared to 10 people who did not. In this unblinded study, funded by the National MS Society, they have identified abnormalities inside the vein tubes (lumen) that drain the brain and found a variety of structural abnormalities and anatomic variations in both groups. They reported 9 abnormalities in 6 out of 10 people who had MS and 5 abnormalities in 4 out of 10 controls. They noted that ultrasound CCSVI studies should include evaluation of intraluminal abnormalities. (Abstract P05.125)
• BIIB033 (anti-LINGO-1, Biogen Idec) – Blocking the nervous system molecule LINGO-1 increases myelin repair in mice, so the next step was to evaluate safety in humans. In the first human trial of this approach, a team administered test doses of BIIB033, an immune antibody that inhibits LINGO-1, to 64 healthy adult volunteers and 42 people with relapsing or secondary-progressive MS. There were no serious adverse events; headache was the most frequently adverse event reported. The authors conclude that the results support advancing this myelin repair strategy into a phase 2 clinical trial. (Abstract P02.021)
• Smartphone to track MS progression – Sashank Prasadd MD (Brigham and Women’s Hospital, Boston) and team presented a new series of studies that will evaluate whether smartphones can actually monitor MS disease progression. A consortium has been established of clinicians and scientists with expertise in MS, cognitive psychology, computer science, ethics, and regulatory issues to build smartphone technology that tracks clinical changes in MS. The consortium has created 21 custom applications for the Android smartphone platform, including MS-related questionnaires and specific tests of vision and cognition. Each is completed in 10 minutes or less. Fifty people with MS and 50 controls are being enrolled for a phase 1 study of the effectiveness of this method of tracking MS disease progression. This type of research aims at outcome measures that more accurately track MS and MS progression, especially for use in clinical trials. (Abstract P01.144)
Research toward ending MS forever
Understanding risk factors that influence who gets MS, and also what course their MS will take, is crucial for finding ways to prevent MS and progression of symptoms.
• Gender differences and vitamin D – Men with low blood levels of vitamin D (less than 30 ug/mg) may be more susceptible to MS disability, according to a study of 500 people with different types of MS, conducted by John Rose MD and colleagues (University of Utah, Salt Lake City). They also found that women with vitamin D deficiency (less than 20 ug/mg) had significantly higher MRI-detected active brain lesions if they had a genetic marker that is common in people with MS (HLA-DR2). This study adds to growing information about the role of vitamin D in MS, and possible gene and gender influences. (Abstract S50.004)
• Clue to benign MS? Some people have an unusually mild course of MS, sometimes called “benign” MS. Researchers in Israel (Sheba Medical Center, Tel-Hashomer) took blood samples from 31 people with very mild MS and 36 people with relapsing remitting MS. Genes were looked at with microarray, or “gene-chip” technology, which can identify hundreds of thousands of variations of thousands of genes at once. The activity of 406 genes differed between the 2 disease groups. Genes that were more active in people with milder MS courses were related to suppression of immune T cells. The most significant difference was seen in the gene that instructs the RNA-Polymerase-I pathway – a key player in causing inflammation. This study may provide an important clue for tracking and improving the prognosis of MS. (Abstract S20.005)
• Influence of virus on relapses – The Epstein-Barr virus (which causes infectious mononucleosis and other disorders) has been associated with a higher risk of MS. Jennifer Graves MD (National MS Society Sylvia Lawry Physician Fellow, University of California, San Francisco) and colleagues evaluated whether the immune antibody response against Epstein-Barr virus, cytomegalovirus, and herpes simplex virus was associated with relapse rate in children or adolescents with MS. There was no statistically significant association. (Abstract P02.096) Investigators nationwide are recruiting 640 children with early MS or at high risk for MS to study whether such risk factors make children susceptible to developing MS. Read more about this study.
These and many other presentations reflect the rapid pace of MS research focusing on stopping MS, restoring function, and ending MS forever.
Source: News Release
National Multiple Sclereosis Society
May 15, 2012