http://www.nationalmssociety.org/Research-2003Apr15.asp

April 15, 2003
Research Programs Department

Neurologists and neuroscientists from around the world gathered to share their research findings at the American Academy of Neurology’s 55th Annual Meeting in Honolulu March 29-April 5, 2003. Following are selected highlights from over 200 presentations that had relevance to multiple sclerosis.
 
HOPEFUL FINDINGS FROM EARLY CLINICAL TRIALS

Investigators reported promising findings from small-scale, early phase studies testing the safety and possible benefits of several experimental treatments.

New Drugs with Potential for Altering Disease
 

• A small pilot study found that the cholesterol-lowering pill Zocor® (simvastatin) safely reduced the number of new MRI-detected lesions in 30 people with relapsing-remitting MS. Dr. Timothy Vollmer (formerly of Yale University, now at Barrow Neurological Institute, Phoenix) and colleagues also reported that immune responses also suggested a positive shift away from inflammation. Larger, well-controlled studies, which will be necessary to determine whether Zocor or other cholesterol-lowering statins are safe and effective against MS, are currently in planning stages. (See Research/Clinical Update dated April 4, 2003, “Early Study Finds Oral Cholesterol Drug Zocor Safe for MS.”)

• Campath-1H (Alemtuzumab) is a powerful, laboratory-created monoclonal antibody that removes immune T cells from the body and has been used to treat forms of cancer and other diseases. Dr. Alastair Compston (Cambridge University, United Kingdom) presented the experience of his collaborators in using Campath to treat individuals with secondary-progressive MS and relapsing-remitting MS in tests spanning 10 years. Initially the team focused on later-stage secondary-progressive MS and found that while a single infusion could suppress immune activity, it did not alter disease progression. Their experience to date in treating individuals with aggressive relapsing-remitting disease has been more positive, not only reducing or stopping relapses and disease progression, but in some, even improving disability (EDSS) scores. Unfortunately, many of those treated develop an acute flare-up of MS symptoms that has to be treated with steroids, and one-third of MS patients treated with a single dose of Campath develop Graves’ disease, a serious but treatable thyroid condition. Dr. Compston reported that the group is now focusing on individuals within the first few years of disease onset, when inflammation appears to be the most active component of the underlying disease. A large-scale, international clinical trial testing Campath-1H in combination with Rebif is now getting started. (See “Trials Recruiting Patients,” at http://www.nationalmssociety.org/Research-trialsrecruiting.asp, for further information.)

• Dr. L.M. Metz (University of Calgary, AL, Canada) and colleagues reported results of a small, nine-month safety study of minocycline (an oral antibiotic in the tetracycline family) in 10 individuals with relapsing-remitting MS who were not taking any proven therapy. The drug was well tolerated and showed positive benefits on MRI scans. The group is still analyzing other data, such as immune studies, but suggested that further testing of this drug is warranted.

• Two teams reported preliminary results from small studies testing Zenapax® (daclizumab), a laboratory-created monoclonal antibody that blocks the activity of a key immune activator in MS. Dr. John W. Rose (University of Utah, Salt Lake City) presented findings from monthly intravenous infusions of the drug in 11 individuals with relapsing-remitting and secondary-progressive MS, alone or in combination with interferon beta. Dr. Rose reported that his patients’ disability stabilized or improved, and a few studied thus far with MRI have shown no new brain lesions. Dr. Bibiana Bielekova (National Institutes of Health, Bethesda, MD) described her group’s study of immune responses in 10 participants of a clinical trial of Zenapax in combination with interferon beta. Although the full results are still being analyzed, Dr. Bielekova reported that Zenapax therapy reduced MRI-detected disease activity in relapsing-remitting and secondary-progressive MS by over 70% without profoundly suppressing immune cell responses. A larger-scale trial of this drug is under way.

• Dr. Andrew D. Goodman (University of Rochester, NY), and colleagues reported on a small, placebo-controlled study of oral fampridine (4-aminopyridine) in a slow-release formula. This drug – which has been tested in small studies and uncontrolled use – is a potassium channel blocker that has shown some promise for improving nerve conduction and thus some symptoms of MS, but has had a tendency to cause seizures. This study involved 36 individuals who received gradually higher doses. While higher doses were not well tolerated, at lower doses those on fampridine tended to show improvement in walking speed and leg strength, but no benefit was seen for fatigue. Side effects included dizziness, insomnia, numbness/tingling, and on higher doses, two participants had seizures. A larger study, which is needed to fully determine safety and effectiveness, is now under way.

• A small, placebo-controlled study involving 69 individuals with MS with mild to moderate cognitive impairment was conducted by Dr. Lauren B. Krupp (State University of New York, Stony Brook) and colleagues. Their results suggested that the oral drug Aricept® (donepezil hydrochloride) modestly improved performance on a memory test. Larger studies are needed to confirm the safety and benefits of this medication, and to determine whether the drug would have a positive impact on everyday activities. (See Research/Clinical Update dated April 4, 2003, “Aricept Shows Potential to Improve Memory in MS.”)

Investigators reported on several studies attempting to understand and treat primary progressive MS, which, unlike other forms of the disease, causes worsening symptoms from disease onset without any initial relapses or remissions.
 

• A preliminary study using Novantrone® (mitoxantrone), a powerful chemotherapy that is approved for treating worsening MS, in 64 individuals with primary progressive MS suggested that monthly intravenous treatment might be of benefit in slowing progression, especially in persons with only moderate disability (EDSS 5 or under). This was an open-label study by Dr. Marc Coustans and others (Université de Rennes, France), over two years. Because it was not a controlled study, no definite conclusions can be drawn, but the investigators suggest that a larger-scale, controlled study is warranted. Additional studies with mitoxantrone in primary progressive MS are ongoing.

• A small-scale study by Dr. Xavier Montalban and others (Vall d'Hebron University Hospital, Barcelona, Spain) tested the safety and early signs of treatment benefit of Betaseron® (interferon beta-1b) in 73 individuals with progressive forms of MS, including primary progressive MS, over two years. Although there was no sign of slowing disease progression using the traditional EDSS disability measure, the study did suggest that the treatment had clinical benefits using another clinical measure, the MS Functional Composite, and also showed beneficial differences in MRI-detected brain lesions, including lower numbers of standing lesions and new lesions. Larger studies are under discussion.

• Dr. Helene Zephir (INSERM, Lille, France) and colleagues set out to determine whether they could identify clinical characteristics that might predict whether an individual with progressive MS would respond favorably to immune-system suppression with the chemotherapeutic agent cyclophosphamide (in the U.S., brand name Cytoxan®). They looked backward at the past treatment experience of 490 individuals with primary progressive MS and secondary-progressive MS (which begins with a relapsing-remitting course and then changes over time to a progressive course with or without relapses) who had been treated with monthly doses of cyclophosphamide for at least one year. While they failed to find a clinical predictor of response, they did find – at least in this uncontrolled study – that for many, the drug appeared to stabilize the course of disease, and that those who did not respond well after 6 months were unlikely to respond after one year.

Several investigative teams weighed in with results from ongoing efforts to determine whether killing individuals’ immune cells and reconstituting them with immune stem cells derived from their own blood or bone marrow (a procedure called autologous hematopoietic stem cell transplantation, or bone marrow transplantation) can stop MS. Further trials, which are ongoing, will hopefully sort out issues such as which is the safest protocol and who might best benefit from this high-risk and expensive procedure.

• Dr. Mark Freedman (University of Ottawa, ON, Canada) and others involved in the Canadian MS/Bone Marrow Transplant Study Group are conducting a trial in 32 patients with early, aggressive forms of MS. This group used chemotherapy to kill immune cells before transplant. Results from the first 6 suggested that most experienced clinical stabilization or improvement of symptoms, and MRI results from three of the earliest participants who have been followed for one year after treatment, also showed stabilization of disease.

• In contrast, Dr. Johnny Samijn and colleagues (Academisch Ziekenhuis Rotterdam,  Netherlands) used both chemotherapy and total body irradiation to kill immune cells before transplantation. Of 8 patients who have been followed beyond one year after the procedure, two have improved disability scores, one is stable, and five have experienced disease progression.

• Similarly, Dr. Richard Burt (Northwestern University, Chicago, IL) and colleagues presented findings in 28 individuals, most of whom had secondary-progressive MS that was worsening. They used chemotherapy and total body irradiation to kill immune cells before the stem cell transplants. They reported that those whose with mild to moderate disability scores (EDSS less than 6) before the procedure tended to stabilize, while those with higher disability scores tended to continue to progress after the procedure. Dr. Burt also voiced concern that the use of radiation to kill immune cells may also be causing harm to brain tissue, and may be detrimental to long-term outcomes.

• A study by Dr. Barry Oken and colleagues (Oregon Health Sciences University, Portland, OR) compared a six-month regimen of adaptive yoga or exercise (stationary bicycle and home exercise) to a non-exercising control group in over 50 individuals with different forms of MS. The study found significant improvement in fatigue over the control group, but no impact on cognitive function.

Is there an increased risk of birth defects when a woman becomes pregnant while she is taking Copaxone® (glatiramer acetate)? Since the potential effects of this drug have only been studied in animal pregnancies, Copaxone is not recommended for use during pregnancy. Dr. Patricia Coyle (State University of New York, Stony Brook, NY) and others reviewed past clinical trials and postmarketing surveillance records for information about outcomes from such pregnancies. In most cases, women were exposed to Copaxone only during the first trimester before going off the drug. The good news is, of the 215 pregnancies with known outcomes, the risk of congenital abnormalities was not higher than that observed in the general population, nor was the risk of spontaneous abortion. This study does NOT change recommendations that Copaxone be stopped before a woman begins trying to become pregnant. It may, however, relieve worries of some who accidentally become pregnant before stopping the drug.

RACIAL DIFFERENCES IN MS

MS occurs less frequently in African Americans than in Caucasian Americans, but there appear to be other differences as well. A study comparing the clinical characteristics of MS between these groups, conducted by Dr. Bruce Cree (University of California, San Francisco) and others, found that African Americans tended to have a more aggressive course, and are at higher risk for developing disability and for transitioning into the secondary-progressive form of MS. The investigators also found that African Americans tended to develop MS two years later than Caucasian Americans, but were more quickly diagnosed.

In a separate study, Dr. Cree reported on an analysis of disease activity of African Americans who had participated in a clinical trial comparing Rebif and Avonex over 48 weeks of therapy (“EVIDENCE” trial). Based on a small number of participants (36), the team found suggestions that African Americans in this study responded less to interferon beta therapy than Caucasian participants.

ON THE HORIZON: POSITIVE RESULTS FROM THE LAB

Several reports focused farther on the horizon to new approaches that may ultimately lead to better understanding and treatment of MS.

• Seeking preliminary evidence that they could repair nervous system tissues in MS, investigators transplanted immature brain cells into the brains of rats that were then induced with the MS-like disease EAE. Dr. Tamil Ben-Hur and colleagues (Hadassah Hebrew University Medical Center, Jerusalem, Israel) reported that the rats receiving transplants had milder disease, and their brains showed fewer signs of inflammation, than rats that did not receive the transplants. They also showed that the transplanted cells migrated to inflamed areas and matured into two types of replacement cells. Further work in the exciting field of nerve tissue repair is ongoing.

• In a study partially supported by the National MS Society, Dr. Halina Offner and colleagues (Oregon Health & Science University, Portland) found further evidence that oral estradiol, a form of the female sex hormone estrogen, was able to protect mice from developing EAE, and, when given after the development of disease, reduced its severity. The hormone inhibited the recruitment of immune cells into the brain and decreased messenger chemicals that ordinarily spur inflammation in the disease. Further studies of estrogen in women with MS are planned.

• Dr. Michael K. Racke and colleagues (University of Texas Southwestern Medical Center) offered further evidence that EAE in mice could be ameliorated with oral compounds known as “PPAR-gamma ligands,” some of which are currently used to treat diabetes. The team also found that the treatment reduced inflammation and changed the behavior of aggressive immune T cells. This study was supported in part by a research grant from the National MS Society and could lead the way to a new class of agents that might prove useful in treating MS, alone or in combination with other proven treatments.

• Can nerve fibers be protected in MS? That was the question posed by Dr. Albert C. Lo (Yale University, New Haven, CT) and colleagues when they treated mice with phenytoin, an agent that blocks the tiny pores, called sodium channels, on the surface of nerve fibers which facilitate nerve conduction. In this study, supported in part by the National MS Society, mice with the MS-like disease EAE that were treated with phenytoin showed considerably less nerve fiber injury than those that did not receive phenytoin. Further lab and clinical research will help determine whether blocking sodium channels has a place in the future of MS treatment.

© 2003 The National Multiple Sclerosis Society