Research RoundUp 37

as at 2 November 2007

Research Progress Reported at International ECTRIMS Meeting

Multiple sclerosis research took centre stage at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held October 10-14, 2007, in Prague. Results were presented from numerous clinical trials, indicating the potential within the MS pipeline. Key findings also were reported on the development of disease.

Here is just a sample of these presentations. The full list of presentations and their summaries (abstracts) are available online at http://www.akm.ch/ectrims2007/.

Trials of experimental therapies in the pipeline:

• Dr. H. Garren (Bayhill Therapeutics) and colleagues reported preliminary data from a phase II study of BHT-3009 (one of two doses (.5 mg or 1.5 mg) vs. inactive placebo) in 289 people with relapsing-remitting MS. BHT-3009 is a vaccine containing genetic material that instructs cells to produce myelin basic protein (MBP), a component of myelin, an immune target in MS. It is given by periodic injections into the muscle. The primary goal was to determine differences in the rate of new, active brain lesions (areas of inflammation or active damage to nerve fibre insulating myelin) as shown on MRI scans. Dr. Garren focused this presentation on safety data, reporting that BHT-3009 was well tolerated, and also reported that the agent altered immune responses to MBP and several other myelin proteins.  According to a company press release, preparations are underway to conduct a larger-scale, phase III trial.
• A new formulation of Rebif® (interferon beta-1a) proved more tolerable than the original formulation in a two-year study reported by Dr. Gavin Giavannoni and colleagues in a poster presentation (48-week data) and also in a special satellite meeting (96-week data). The new formulation is designed to reduce the development of neutralising antibodies (Nabs), which are immune system proteins that may reduce effectiveness of interferon treatments. At 96 weeks, 17.4% of patients treated with the new formulation were Nab positive compared with 21.4% of patients in the former EVIDENCE study at 48 weeks. The new formulation of Rebif was approved for release in Europe, and according to company press releases, it has also applied to the U.S. FDA for approval.
• Dr. I. Catz and colleagues (University of Alberta) reviewed the safety of MBP8298 (BioMS), a synthetic fragment of myelin basic protein (MBP, a component of myelin), which reduces the production of spinal fluid antibodies that react against MBP. MBP8298 is currently under study in two studies in secondary-progressive MS and one study in 218 people with RRMS. )
• Dr. G. Mancardi (University of Genoa) provided an update on the status of hematopoietic stem cell transplantation (in which blood or bone marrow stem cells, usually the patient’s own, are used to reconstitute the immune system in hopes of stopping immune attacks in MS). From 1995 to 2007, more than 300 people have been treated. According to a survey of patients in the database of the Europe Blood and Transplantation Group, 63% of people have improved or stabilised. The results were best in rapidly evolving, severe MS. Among 58 cases in Italy, 63% of people with SPMS improved or stabilised, versus 95% of those with RRMS. Dr. Mancardi pointed out that this therapy has not yet been proven to be clinically effective.
• Dr. M. Freedman and the Canadian Bone Marrow Transplantation Study Group reported on 25 patients enrolled in this study who have active, relapsing MS with high risk of disease progression; 15 have received full treatment (hematopoietic stem cell transplantation, described above). No patient has experienced relapses or has any new disease activity on MRI.
• Dr. X. Montalban (University of Barcelona) and colleagues reported on preliminary results of the phase II “CHOICE” study of daclizumab in 230 people with relapsing forms of MS who were taking an interferon beta. Ninety percent of people completed the study and the investigators found the addition of daclizumab to interferon beta generally well tolerated. The primary endpoint of the study – number of new or enlarged areas of active damage on MRI – was significantly reduced by 72% in the high-dose group compared with placebo.
• Dr. J. Drulovic (University of Belgrade) and colleagues reported on a study of MN-166 (MediciNova), an experimental oral drug, in 292 people with RRMS (93%) or SP MS (7%). People were randomly assigned to receive MN-166 at low or high dose (30 or 60 mg) or placebo. MN-166 was associated with a significant reduction in loss of brain tissue volume over one year, and also with a significant increase in time to first relapse. Gastrointestinal events – mostly mild – occurred in 22% of the high-dose group, 15% of the low-dose group, and in 8% of those on placebo.

Studies of approved MS therapies

• In a head-to-head comparison trial, Dr. D. Mikol and researchers from the REGARD Study Group compared Rebif® (interferon beta-1a, EMD Serono and Pfizer) against Copaxone® (glatiramer acetate, Teva Pharmaceutical Industries) in RRMS. In this study, 386 participants were randomly assigned to receive the current formula of Rebif and 378 received Copaxone for 96 weeks. The primary goal was to determine differences in the time to first relapse, but these findings were not statistically different between the two drugs.
• Dr. M. Panzara (Biogen Idec) and colleagues presented updates on its TOUCH™ prescribing program in the U.S. and TYGRIS global observation program for Tysabri® (natalizumab, Biogen Idec and Elan Pharmaceuticals), a treatment approved for relapsing forms of MS given by IV infusion every four weeks. The TOUCH program is designed to track opportunistic infections and to understand their risk factors. As of September 2007, approximately 17,000 people are currently being prescribed Tysabri or are involved in clinical trials, 10,500 of those in the U.S. No new cases have been confirmed of PML (progressive multifocal leukoencephalo­pathy), a brain disease that occurred in three people (two of whom died) who had been in earlier clinical trials of Tysabri. Funded by Biogen Idec, Inc and Elan Pharmaceuticals. All told, about 26,200 people in the world have been exposed to Tysabri in clinical trials and post-marketing settings.
• In recent years, continued research on Copaxone (glatiramer acetate, Teva Pharmaceutical Industries) has uncovered more information about how it fights MS inflammation and more recently, researchers have suggested that it may influence brain repair mechanisms. Along these lines, Dr. C. Silva and colleagues presented work showing that Copaxone generates immune T cells that are anti-inflammatory. Future studies will focus on whether the elevation of repair cells results in increased myelin repair.
• Dr. D. Langdon and colleagues in the Betaseron® (interferon beta-1b, Bayer Healthcare Pharmaceuticals Inc) 16-Year Long-term Follow-up Study Group administered cognitive tests to 179 people who had originally participated in the pivotal North American clinical trial of Betaseron that led to its approval. The investigators attempted to correlate the cognitive test results with the MRI and EDSS (a disability measure) data obtained for the clinical trial 16 years earlier. They found that people with higher EDSS scores (worse disability) and greater amounts of disease evidence on MRI scans had significantly lower cognitive test scores 16 years later.
• Dr. K. Hawker (University of Texas Southwestern Medical Center, Dallas) and colleagues reported on an ongoing study of  ® (rituximab, Genentech and Biogen Idec) in 439 people with primary progressive MS. The primary goal of the study is to determine the treatment’s effect on time to disease progression as measured by the EDSS disability scale.

Findings on MS development

• In late-breaking news, Dr. F. Martinelli Boneschi (Ospedale Maggiore, Milan) and colleagues reported having completed a scan of the genome (all genetic material) in a group of 197 people with primary-progressive MS, a course experienced by about 10% of those diagnosed with the disease. They selected 20 genetic variations for further study, and compared them with genetic material from 234 controls. One variation in the HLA region (immune system genes associated with MS) was more than twice as common in primary progressive MS as in controls. They are now comparing the results with scans of RR and SPMS, and doing other analyses of their findings.
• Dr. R. Zivadinov (SUNY Buffalo) and colleagues reported on a study of 759 people with MS, of whom 198 had a family history of MS. Evaluating MRI scans, the group found more severe disease activity in those with a family history of MS, particularly those with first-degree relatives with the disease. Further study is necessary to determine exactly how genetics affect MS severity.
• Dr. Zivadinov also reported on cigarette smoking and MRI findings in 368 people with MS, of whom 96 were active smokers and 32 were former smokers. Measures of brain tissue volume indicate significantly lower volumes in smokers, and a significant relationship between lower volume and higher average use of packs per day.
• Recent studies have debated the association between smoking and MS progression: A 2005 Harvard University study showed an association between smoking and risk of MS progression, but a recent report from the Netherlands found no such connection.
• Dr. R. Magliozzi and colleagues in London and Rome recently identified B-cell follicles, sack-like structures, in the membrane that surrounds the outer layer of the brain (cerebral meninges) of people with secondary progressive MS, providing further insights into the role of  B cells in the immune attack. They found that these abnormal structures were associated with a younger age of diagnosis and onset of disability, and a more aggressive disease course. They found increased damage to the cerebral cortex, the outer layer of the brain, in people who had SPMS and B-cell follicles—including decreases in nerve cells and myelin-producing cells, in association with a marked increase in immune activity of cells called microglia. Identifying these follicles in people with SPMS may help predict a more aggressive course of MS.
• During a special session, Dr. F. Aloisi  (Rome) described further work exploring B cell follicles and the possibility that their formation could be linked to an infection of B cells with Epstein-Barr virus (EBV, the virus linked to infectious mononucleosis—glandular fever—and other disorders). Using techniques to unravel the presence of EBV in brain tissue samples from people with MS, they showed possible signs of accumulation of EBV-infected B cells and plasma cells in the follicles and in MS lesions. They also showed evidence of an immune attack toward EBV-infected cells in the MS brain. Although previous studies have suggested that exposure to EBV increases the risk of developing MS, possible evidence of the virus’s presence in brain lesions was lacking. 

Eye scanning device detects MS nervous system damage

Using a new machine called an optical coherence tomography scanner, or OCT, investigators have reported that thinning of the nerve layer at the back of the eye echoes evidence of brain shrinkage in MS, detected with magnetic resonance imaging (MRI). The study, funded by the USA National MS Society’s Promise:2010 initiative on Nervous System Repair and Protection, suggests that OCT may detect global information about disease progression in the brains of people with MS, and may ultimately prove useful for measuring the success of clinical trials aiming to protect or repair the nervous system.

Researchers Eliza Gordon-Lipkin, Dr. Peter Calabresi (Johns Hopkins University, Baltimore) and other collaborators published their results in the October 16, 2007 issue of Neurology (2007;69:1603-1609).

Although MRI scanning of the brain or spinal cord is commonly used to detect MS disease activity and tissue damage, there is not yet a sensitive measure that can detect damage to axons, the wire-like nerve fibers that extend from nerve cell bodies. Having such a measure is key to determining whether current or future therapies can successfully protect or repair the nervous system in people with MS. 

OCT is a relatively new technique that has been under investigation by Dr. Calabresi’s team and others to determine its potential for tracking the health of nerve fibers in MS. It utilizes a small, easy-to-use device that can be used in a doctor’s office. It measures the thickness of the nerve layer at the back of the eye (retinal nerve fiber layer), and can detect thinning of that layer in people with all types of multiple sclerosis.

For this study, 40 people with different forms of MS, and 15 healthy control subjects, underwent OCT eye scanning and MRI brain scanning. The MRIs allowed investigators to measure brain volume to detect shrinkage, or atrophy, which frequently occurs in people with MS over time. They compared atrophy in individuals with their OCT scans, and found that in MS, thinning of the retinal nerve fiber layer strongly correlated with brain atrophy.   

Further testing of OCT, which is ongoing, should map out its potential usefulness as a tool for tracking disease progression and as a much-needed outcome measure for clinical trials aiming to protect or repair the nervous system. As pointed out in an accompanying editorial by Drs. Stephen G. Waxman and Joel A. Black (Yale University School of Medicine), OCT may also turn out to be a useful tool for studies aimed at understanding how axons become targets of MS. 

“This is just one example of the important progress being made by more than 50 investigators collaborating in our Nervous System Repair and Protection initiative,” said John R. Richert, MD, Executive Vice President of the Society’s Research and Clinical Programs. “The goal is to pave the way for clinical testing of therapies to protect and restore function in people with MS; I’m happy to say that the pace of this vital endeavor is accelerating.” 

Researchers report findings on antibody that stimulates myelin repair

Researchers funded in part by the USA National MS Society report that an antibody can stimulate repair of myelin in mice with MS-like disease. Myelin is the insulating coating on nerve fibres that is attacked and damaged during the course of MS. They also report that the antibody, called rHIgM22, remains effective in mice when combined with methylprednisolone, a corticosteroid used to treat relapses in people with MS. Moses Rodriguez, MD, and Art Warrington, PhD (Mayo Clinic and Foundation, Rochester, MN) presented their findings at the annual meeting of the American Neurological Association in Washington, DC, late last month.

Although the body naturally repairs some damage to myelin that occurs in MS, this repair is insufficient. One strategy under study encourages internal "repair" capabilities by immune-system proteins called antibodies. Dr. Rodriguez and colleagues have identified human antibodies that target and attach to cells in the brain and spinal cord that make myelin (oligodendrocytes), and have found a way to produce these antibodies in the lab. With funding from National MS Society research grants, including a Collaborative MS Research Center Award, Dr. Rodriguez assembled a team of investigators to explore this therapeutic opportunity further.

The Mayo team tested the repair strategy in a mouse model with chronic, progressive disease similar to MS. The mice received a single dose of different amounts of the antibody. Myelin repair occurred at a low dose (23 mcg) and stabilized after five weeks. When combined with daily methylprednisolone, which is used to treat MS attacks in people, the antibody still promoted repair and the mice did not worsen.

Although these findings warrant confirmation in further animal and human studies, the results take us one step further in efforts to stimulate myelin repair in people with MS.