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Progress on Experimental Therapies for MS, and Much More, Reported at the American Academy of Neurology Meeting


Originally Posted May 11, 2007 -- Revised June 21, 2007

More than 10,000 researchers and practicing neurologists from around the world gathered at the 59thAnnual Meeting of the American Academy of Neurology in Boston from April 28-May 4. Well over 200 presentations were about multiple sclerosis.National MS Society grantees were among those presenting novel findings on many different aspects of MS research. (For free access to the abstracts of presentations given at this year’s meeting, go to:www.abstracts2view.com/aan2007boston/)

Here are a few highlights:


John Dystel Prize Presentation

“I do not think it is too bold to think about curing MS,” stated Dr. Howard Weinerwinner of the 2007 John Dystel Prize for MS Researchawarded by the National MS Society and the AAN during a presentation in which he talked about how far MS research had come since he started treating people with MS in 1972. “Enormous progress has been made.”

Dr. Weiner, of Harvard’s Brigham and Women’s Hospital, spoke of a multifaceted cure that would address the diverse, chronic nature of multiple sclerosis: administering immunotherapy early, to halt disease progression; employing stem cells to reverse neurological damage; and finding MS biomarkers predictive hallmarks with an end goal of developing methods of prevention.

Dr. Weiner also reported on the scope of research conducted at the Partners MS Center that he founded at Brigham & Women’s Hospital, including the Comprehensive Longitudinal Investigation of MS at Brigham (CLIMB). This study involvesfollowing 1000 people with MS (760have been enrolled as of this writing) from disease onset using yearly imaging, clinical, immunologic, cognitive and quality of life measures.

At this year’s AAN meeting,Dr. Weiner’s team including National MS Society grantee Dr. Rohit Bakshi reported on the use of the Magnetic Resonance Disease Severity Scale (MRDSS), a method of tracking MS disease activity that combines assessments of tissue damage with tissue volume loss. The group used the MRDSS to track 103 people over three years, and found this scale to more closely predict disease progression than MRI or clinical measures. (Abstract #P02.042)


Promising Results from MS Clinical Trials

Many presentations focused on new data analyzed from ongoing or completed clinical trials in multiple sclerosis. Following are a few examples of the exciting work being done by investigators and pharmaceutical and biotechnology companies around the world.


Experimental oral therapies:

·Dr. Giancarlo Comi (Scientific Institute and University Ospedale San Raffaele, Milan) and others administered 0.3 mg or 0.6 mg doses of oral laquinimod (Teva Pharmaceutical Industries, Ltd., Active Biotech AB) daily for 36 weeks to 306 people with RR MS. The primary goal was to determine if the immune-modulating drug would reduce the number of active MRI brain lesions. In those taking 0.6 mg, active lesions decreased significantly, by 38%, compared with the placebo group, but not in those on the lower dose. Participants tolerated both doses, experiencing transient increases in liver enzymes.

According to a press release from the companies, the majority of people who participated in the study continued treatment in an ongoing, blinded, 9-month extension study, to be followed by an open-label study in which patients will receive .6 mg for an additional 24 months (Abstract #S02.002)

·Dr. Claudia Kaiser (Universityof Illinois, Chicago)and colleagues studied whether oral pioglitazone (Actos®, Takeda Pharmaceuticals) a drug approved for diabetes that has anti-inflammatory effects was safe to use in people with MS already taking Avonex® (interferon beta-1a, Biogen Idec, Inc.). Secondary goals of the study were to determine the effect on disease activity and brain tissue loss as observed using advanced imaging technology.

In a small study, pioglitazone (30 mg/day) or placebo was administered for one year to 22 people with RR MS. The drug was well tolerated. There was no increase in clinical measures of disease activity, and disease activity observed on imaging scans decreased significantly in the pioglitazone group, as did brain tissue volume loss.The authors note that further study of this drug is warranted by these findings. (Abstract #S02.006)

·Dr. Andrew Goodman (University of Rochester) presented detailed results of a phase 3, placebo-controlled study of oral Fampridine-SR (sustained-release formula of 4-aminopyridine, Acorda Therapeutics) in 301 individuals with all types of MS. Fampridine blocks tiny pores, or potassium channels, on the surface of nerve fibers. This blocking ability may improve the conduction of nerve signals in nerve fibers whose insulating myelin coating has been damaged by MS.

Thirty-five percent of those on active therapy experienced an average of 20% improvement in walking speed (in the timed 25-foot walk), which was maintained over the 14 weeks of therapy. Improvement was also noted in the “MS Walking Scale 12,” a measure designed to assess how meaningful the improvement was. Other positive outcomes included increased leg strength in those on active treatment. Two serious adverse events that led to the discontinuation of dosing were anxiety in one participant and a seizure during a serious infection in another. (Abstract #S32.003)

·A previously reported six-month, phase 2 controlled study of oral fingolimod (FTY720, Novartis Pharma AG) showed possible benefits in relapse rate and MRI-detected disease activity in relapsing MS, and the drug is now being tested in a larger, phase 3 trial. During the phase 2 study, investigators also measured depression at the beginning of the study and also at 3 months and 6 months into the trial in 239 participants.

Dr. Ludwig Kappos (University Hospital, Basel, Switzerland) and colleagues reported that those on either of two doses of fingolimod showed significant improvement in their depression scores versus those on inactive placebo. After the study, all participants were invited to continue or begin taking the active therapy. During 18 months of this extension study, the improvement in depression scores was sustained and extended to those who had switched from placebo to fingolimod. (Abstract #P06.085)


Experimental infusions:

·Two groups reported on studies of rituximab (Rituxan®, Genentechand Biogen Idec), a drug thatdepletes immune B cells, which may play a role in the immune attack on brain and spinal cord tissues in MS. Dr. Amit Bar-Or (Montreal Neurological Institute) and collaborators administered two intravenous infusions of rituximab two weeks apart, and then another dose six months later, to 26 people with relapsing-remitting MS (RR MS, a course of MS characterized by clearly defined flare-ups followed by partial or complete recovery periods). Patients were followed for one year.

The primary goal of the study was to determine the safety and tolerability of the drug, and secondary goals were to assess its effects on relapse rate and disease activity observed on MRI scans. Adverse events consisted of mild to moderate infusion-related reactions. Thenumber of active (gadolinium-enhancing) MRI-detected brain lesions was significantly reduced from week 4 through week 48. Relapses were also reduced significantly. (Abstract #S02.001)

Dr. Stephen Hauser (University of California at San Francisco) and colleagues administered two infusions of rituximab two weeks apart to 69 people with RR MS and inactive placebo to 35 people. The primary goal of the study was to determine the drug’s effect on active brain lesions, and other goals included the proportion of patients relapsing by week 24. The number of active lesions was reduced by 91% in the group taking rituximab versus those on placebo, and significantly fewer people in the treatment group had relapses. More infusion-related reactions occurred in the group taking rituximab. (Abstract #S12.003)

Rituximab is approved for use with certain types of lymphoma and a form of arthritis. The drug has been associated with severe adverse effects including fatal infusion reactions and progressive multifocal leukoencephalopathy; these have not occurred in the MS studies. A clinical trial of rituximab is ongoing in 435 people with primary-progressive MS (a course of MS characterized by a slow but nearly continuous worsening of disease from the onset).

·Dr. Alasdair J. Coles (Adenbrooke’s Hospital, University of Cambridge, UK) reported 24-month results from a phase 2 clinical trial comparing high and low doses of the immune-suppressing monoclonal antibody Campath® (alemtuzumab, Genzyme) with Rebif® (interferon beta-1a, EMD Serono, Inc. and Pfizer, Inc.) in people with relapsing-remitting MS who had never taken any other disease-modifying therapies.

Those taking either dose of Campath experienced significant reductions in the risk of MS relapse compared with those on Rebif (at least 75% reduction) and at least 65% reductions in the risk for progression of disability over 2 years, compared with Rebif. Serious adverse events have led the company to suspend this study, however: there were a significantly greater proportion of patients with thyroid problems after two years of Campath treatment, and six persons on either dose of Campath developed severe idiopathic thrombocytopenic purpura (ITP, a condition in which low blood platelet counts can lead to abnormal bleeding). One patient died, and five were treated and now have normal platelet counts. Participants continue to be monitored for ITP. According to a Genzyme press release, the company is in active discussions with regulatory authorities regarding the Campath program, and is planning two larger-scale phase 3 clinical trials. (Abstract #S12.004)


Combination Therapies:


·Dr. Jeffrey Cohen (Cleveland Clinic Foundation) and colleagues presented results from the Avonex Combination Trial the ACT study in which the drug was combined with oral methotrexate, intravenous methylpredisolone or both in people with RR MS who were experiencing disease activity while taking Avonex. Results so far suggest trends that favor the combination of all three, but no differences have reached statistical significance. Further data analysis is ongoing. (Abstract #S02.005)

·Investigators continued to report data from a 15-month study exploring the effectiveness of a brief (3 monthly infusions), low dose of mitoxantrone (such as Novantrone®, EMD Serono) followed by initiating therapy with Copaxone® (glatiramer acetate, Teva Neuroscience) in 40 patients with relapsing-remitting MS.This regimen has been previously reported as safe and well-tolerated, and to have reduced active MRI-detected lesions by 70% after 15 months compared to those taking Copaxone alone.

Dr. Douglas L. Arnold (Montreal Neurological Institute) and colleagues presented the effects of the combination therapy on specific MRI (magnetic resonance imaging) measures, and found significant additional benefits for those on combination therapy, including reductions in active MRI lesions and volume of lesions, and reduction of the proportion of active lesions that evolved into chronic “black holes” indicative of chronic tissue damage. (Abstract #P06.104)

In related work, Dr. Timothy Vollmer (Barrow Neurological Institute, Phoenix) and colleagues reported on MRI outcomes in an extension of the study after an additional 9 months of Copaxone in 30 patients who participated. The investigators found that MRI-detected benefits were achieved early on and were sustained through the 24-months compared to MRI scans before treatment. (Abstract #06.096)

·Dr. Luanne Metz (University of Calgary, Alberta) and colleagues studied the effects of adding on oral minocycline an antibiotic to Copaxone versus treatment with Copaxone and placebo in 40 people with RR MS. Minocycline has been shown to inhibit proteins that contribute to the immune attack in MS. The primary outcome measured was a reduction in active brain lesions. The results show a trend to improvement in this outcome, as well as in relapse risk but the results did not reach statistical significance. Treatment was safe and well tolerated.The authors note that further study of minocycline is warranted because it is safe and inexpensive. (Abstract #S02.003)


Followup studies of approved therapies:

·Dr. Mark Freedman (University of Ottawa, Ontario, Canada) and colleagues reported on a follow-up to the BENEFIT study, in which treatment with Betaseron® (interferon beta-1b, Bayer HealthCare Pharmaceuticals) was shown to delay the onset of clinically definite MS in people at high-risk for the disease compared with people who did not receive treatment. In the follow-up study, both groups are now receiving Betaseron, and the study is assessing the impact of early treatment versus delayed treatment on the progression of MS. Of the original study group of 468 people, 418 are enrolled in the follow-up study, with 261 in the early treatment group, and 157 in the delayed treatment group. The results after one year show that early treatment with Betaseron reduced the risk for disease progression as determined by the EDSS scale of disease activity by 40%. This is the first immune-modulating drug shown to slow the rate of disability progression in this population.The study is continuing for two more years. (Abstract #S02.004)

·A new formulation of Rebif® (interferon beta-1a, EMD Serono, Inc. and Pfizer, Inc.) is proving to be more tolerable than the original formulation, according to data from an ongoing two-year study presented by Dr. James Simsarian (Neurology Center of Fairfax) and colleagues. The new formulation is designed to reduce the development of neutralizing antibodies (Nabs), which are immune system proteins that may reduce effectiveness of interferon treatments. In this study, 260 people with relapsing forms of MS took 44 mcg of reformulated Rebif three times weekly, and the results were compared with historical data from the EVIDENCE study (in which the original Rebif was compared to Avonex.

At 48 weeks, 13.9% of patients treated with the new formulation were Nab positive, compared with 24.4% of patients in the EVIDENCE study at 48 weeks. The proportion of patients who spontaneously reverted to being Nab negative was double that from the EVIDENCE study, and the concentration, or titers, of Nabs were generally lower, with half as many showing titers over 1000 NU/mL. Injection-site reactions were lower compared to the EVIDENCE study, and the investigators found no unexpected safety issues or adverse events. (Abstract #P06.077)

·Among reports related to Tysabri® (natalizumab, Biogen Idec and Elan Pharmaceuticals), Dr. C. Bozic and colleagues (Biogen Idec, Inc., Cambridge, MA) reported on its safety for relapsing MS. No additional patients are known to have developed PML (progressive multifocal leukoencephalopathy, a rare and frequently fatal disease of the central nervous system) in some 18,000 people worldwide who have been exposed to Tysabri at some point during or after clinical trials. (During clinical trials, two patients with MS who were taking Tysabri in combination with interferon beta-1a developed PML; one of those cases was fatal. A third case of PML, also fatal, was uncovered in another person who had taken Tysabri during a clinical trial for Crohn’s disease.)

Thus far over 5,700 patients have received infusions of Tysabri in the U.S. through the mandatory TOUCH™ prescribing program. These patients have received an average of 3.4 infusions (ranging from 1 to 8). The overall reporting rate of serious hypersensitivity reactions (allergic reactions) to infusions has been 0.8%; the majority occurred at the second infusion. Most of those experiencing serious hypersensitivity to infusion, includinganaphylaxis(a severe, whole-body allergic reaction), had received treatment before market suspension, and experienced anaphylactic reactions after being re-dosed after an extended period without treatment. (Abstract #P06.0895)

Results of an open-label extension study of the two-year AFFIRM clinical trial that compared Tysabri against inactive placebo were presented by Dr. Paul W. O’Connor (St. Michael’s Hospital, Toronto) and colleagues. The data suggest that the drug’s benefits continued beyond two years. In the original study, 627 patients with relapsing MS were on active treatment, against 315 patients on placebo. Significant benefit was seen in both relapse rates and progression of disability.

In the extension study, 531 patients continued on Tysabri and 259 of those on placebo were switched to Tysabri; the plan was for both groups to be followed for an additional 2 years. Before the extension study was stopped early because of the above-mentioned incidents of PML, many of the participants had received additional doses of Tysabri. The median duration of Tysabri treatment experienced by those originally in the AFFIRM treatment group was 2.72 years, and for AFFIRM placebo patients 0.60 years.

Evaluating data available from the extension study, the investigators reported that Tysabri continued to decrease the risk of disability progression at 3 years, with the cumulative probability of disability progression in those continuing on therapy at 13%, compared to 23% in placebo patients at the end of the 2-year AFFIRM study. The rate of relapse also decreased in those switched from placebo and continued to decrease in those continuing on therapy. (Abstract #P06.082)


Other Important Studies



Do sleep disturbances contribute to fatigue?

·Fatigue is a frequent and troubling symptom of MS. Dr. Mark Gudesblatt and colleagues (South Shore Neurologic Associates, Bay Shore, NY) investigated the frequency of sleep disorders in 27 individuals with relapsing-remitting and secondary-progressive MS. Using “polysomnography,” a technique that measures brain activity, airflow and other phenomena during sleep, the investigators found that all of the patients had sleep abnormalities that could contribute to fatigue. These abnormalities included obstructive sleep apnea, delayed REM onset and impaired sleep efficiency. The investigators concluded that patients complaining of fatigue in MS should have sleep studies done to evaluate the possibility that unrecognized sleep disorders that might be responsive to non-medication therapy. This study adds to a growing body of literature related to sleep disturbances in MS. (Abstract #P04.083)


Looking for ways to predict MS:

Finding a way to predict whether a person with a single neurological episode will go on to develop MS would open up the possibility for earlier, possibly preventive, treatment.

·Grantee Dr. Jeffrey L. Bennett (University of Colorado Health Science Center), the National MS Society’s 2006Stephen Reingold Research Awardwinner, and colleagues have been searching for a way to predict whether a person with an early possible symptom of MS (a condition called CIS) will go on to develop definite MS. Comparing blood and spinal fluid from people with definite MS versus those with CIS, the team found that the presence of immune antibodies with a particular molecular component (called heavy chain variable domain VH4/VH2) could reliably predict that an individual with CIS would develop definite MS within 6 months. Further research is needed to firm up this potentially important finding as a reliable biomarker that can facilitate early diagnosis. (Abstract #S26.004)

·Dr. Leonora Fisniku and the well established MS investigation group at the Institute of Neurology (Queen Square, London) presented results of 20 years of follow-up of 85 patients who originally presented with CIS suggestive of MS and who had MRI scans at the outset. After 20 years, 63% developed definite MS. Those who showed abnormal signs on their original MRI were more likely to develop MS (50 out of 57 individuals), and those whose original MRI scans were normal were less likely to develop definite MS (5 out of 28).The investigators also found that those who still had a relapsing-remitting course after 20 years had lower brain lesion volumes than those whose disease evolved into secondary-progressive MS. (Abstract #S42.004)


Tools to Measure Disease Activity:

·Society grantees Drs. Bianca Weinstock-Guttmann, Murali Ramanathan (State University of New York at Buffalo) and colleagues tracked immune changes in the blood of 52 people with MS, and used MRI and neurological tests to monitor the disease state clinically. The team reports that BDNF (brain derived neurotrophic factor), a protein produced in the brain and immune cells, increased in response to disease activity and seemed to play a protective role. This study shows that BDNF may help to mediate “crosstalk” between the attacking immune system and the nervous system in MS, and may thus be useful in developing neuroprotective strategies. (Abstract #P01.057)

·The eyes may be the “windows to the soul,” but recent research also suggests they may be a window to monitoring MS disease activity. Several investigative teams, including the National MS Society’s Nervous System Repair team led by Dr. Peter Calabresi (Johns Hopkins University, Baltimore) reported on the use of a new technique called OCT (optical coherence tomography), which measures the thickness of the nerve layer at the back of the eye and may prove to be a simple tool to detect disease progression.

In one study presented by Dr. Eliza Gordon-Lipkin, the team found that the thinning of the nerve layer (retina) at the back of the eye echoes evidence of brain shrinkage or atrophy, measured by MRI scans in MS.  They conclude that OCT may therefore provide global information regarding disease progression in the brains of MS patients. (Abstract #P02.044)

In another study presented by Dr. Mathew Pulicken, the team examined visual function and the thickness of the retina in people with MS and people without MS. They found that all those with MS had thinner nerve layers than those without the disease. They also found that people with relapsing-remitting MS had comparatively thicker layers than those with primary-progressive MS and secondary-progressive MS. Taken together with other studies, the team concluded that OCT can detect sub-clinical changes in retinal layer, and may be useful as an outcome measure in clinical trials of neuroprotective or neuroreparative therapies. (Abstract #S52.005)

·Dr. Scott Davis, Society grantee Craig Crandall (University of Texas Southwestern Medical Center, Dallas) and colleagues studied whether infrared oculography, a method for measuring an eye movement abnormality (internuclear opthalmoparesis, INO) that occurs in MS, may help to measure symptoms and how treatments affect them. The team used infrared oculography to determine if eye movement slowed during heating, indicating fatigue, and improved after cooling. (Many people with MS experience a temporary worsening of symptoms when the weather is very hot or humid.)

In people with INO and heat sensitivity, eye movement abnormalities occurred in response to whole body heating. These abnormalities decreased to baseline levels with whole body cooling. No such abnormalities occurred in people with MS without INO, or in people without MS. This study presents a noninvasive strategy for determining the success of therapeutic strategies by measuring their effects on INO. (Abstract #P03.037)

·Dr. Annika M. Berger, Society grantee Dr. Charles Guttmann (Brigham and Women’s Hospital, Boston) and colleagues explored whether MRI imaging of the brainstem (the lower portion of the brain adjacent to the spinal cord) would help to estimate MS damage to the spinal cord. Spinal imaging is not performed as often as brain imaging, due to extra time and expense. The team reviewed brain and spinal imaging scans which had been administered to 50 people with MS, and found that brainstem images did correlate with those from the spinal cord. These findings indicate that brainstem images may help doctors to estimate spinal cord damage in people with MS. (Abstract #P02.045)


Update from a Pediatric MS Center of Excellence:

·Drs. Dorothee Chabas, Emanuelle Waubant and colleagues reported on the experiences of the Pediatric MS Center of Excellence at the University of California at San Francisco, one of six such centers funded through the National MS Society’s Promise:2010 campaign. The center has seen 67 pediatric patients younger than 18 since January 2006. Among 41 of these patients who have been diagnosed with MS or CIS (a single, isolated neurologic event suggesting loss of nerve-insulating myelin), 55% were not white, which is in contrast to the university’s adult MS population, who are 75% white. Seventy-eight percent of the children are taking one of the disease-modifying drugs that were approved for adults with MS. The authors note the challenges in diagnosing MS in children, leading to the large number of as-yet-undiagnosed patients. (Abstract #P04.064)


I


nvestigating MS genes:

·Investigators at the University of California, San Francisco have been banking genetic material from MS families and individuals for more than a decade. That painstaking work, funded by the National MS Society, the NIH and others, is paying off and permitting the identification of genes that make people susceptible or less susceptible to MS. Beyond susceptibility, the UCSF researchers have also been searching for clues to genes that might help determine the course of the disease in any individual.

Dr. Darin T. Okuda presented the UCSF group’s study of a gene that helps determine a person’s immune responses. The group had previously shown that people who have a gene on chromosome 6, called HLA DRB1*1501, were more likely to have more MS brain lesions than those without the gene. This study involved about 480 individuals with MS, half of whom had the DRB1*1501 gene. Testing for disease changes over one year using a series of clinical measures called the MSFC (MS functional composite), they found a decline in the measure of cognitive function, and no difference for walking and other measures. This is the first study to suggest that patients carrying this particular gene may be at greater risk for cognitive problems over time. This early finding is not likely to cause any changes in clinical practice. (Abstract #S22.001).

·Dr. Bruce Cree (UCSF) and colleagues presented results of another gene study suggesting that this same gene (DRB1*15) and related ones may be associated with an earlier average age at disease onset in African Americans and a typical course of MS (as opposed to opticospinalMS, for example,where the disease is restricted to the optic nerve and spinal cord and has been found to occur more often in African Americans than in whites). Ongoing studies by this group and others involved in the International MS Genetics Consortium should continue to tease out genetic influences at play in MS. (Abstract #P07.085)

-- Research and Clinical Programs

The National MS Society is proud to be a source of information about MS. Our comments are based on professional advice, published experience and expert opinion, but do not represent individual therapeutic recommendation or prescription. For specific information and advice, consult your personal physician.

Actos is a registered trademark of Takeda Pharmaceuticals

Avonex is a registered trademark of Biogen Idec

Betaseron is a registered trademark of Bayer HealthCare Pharmaceuticals

Campath is a registered trademark of Genzyme

Copaxone is a registered trademark of Teva Pharmaceutical Industries Ltd

Novantrone is a registered trademark of EMD Serono, Inc.

Rebif is a registered trademark of EMD Serono, Inc.

Rituxan is a registered trademark of Genentech and Biogen Idec

TOUCH is a trademark of Elan Pharmaceuticals, Inc.

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