July 2010

UPDATE: FDA Panel Recommends Approval of Oral Fingolimod for Relapsing MS -- If agency follows advice, it would become first oral disease-modifying therapy for MS

A U.S. Food and Drug Administration advisory committee today recommended that the agency approve marketing of fingolimod capsules (formerly called Gilenia, Novartis International AG) for the treatment of relapsing multiple sclerosis. If approved, fingolimod would be the first oral disease-modifying therapy for the treatment of MS. While the FDA is not required to follow the recommendations of its advisory committees, it usually does. According to Novartis, the agency is expected to make a final decision about whether to approve the drug in September 2010.
During an all-day meeting held June 10, 2010, the FDA advisory committee reviewed data about the effectiveness and safety of fingolimod, as well as a proposed plan designed to monitor and mitigate risks – called Risk Evaluation Mitigation Strategies (REMS) that would likely be mandated to monitor safety if the agent is approved. The committee also heard public testimony from individuals and patient advocacy groups, including the National MS Society, which testified to the unmet need for more therapies for people with MS.
Among its discussions, the advisory committee recommended that fingolimod be approved at the dose (0.5 mg once daily) recommended by Novartis and that:
• Fingolimod demonstrated substantial evidence of effectiveness for the treatment of relapsing MS to reduce the frequency of clinical relapses and to delay the accumulation of physical disability;
• the safety data currently known justify the drug’s approval, and the FDA should require a post-marketing study that would proactively gather information about adverse events and longer-term safety, the effects on a broader range of people than were included in the trials, and possible complications of taking other medications including steroids along with fingolimod;
• patients should be monitored during the first dose for possible lowering of heart rate and other potential heart effects, and that some assessments for potential adverse events related to eye (especially macular edema) and lung function be required, to an extent to be determined by the FDA;
• the FDA should consider requiring a study to evaluate whether a lower dose would be as effective as the recommended dose, with fewer adverse events;
• this therapy should be approved as a first-line therapy, meaning that patients would be eligible to take fingolimod without having to try an alternative therapy first.
About the drug: Fingolimod is a new class of therapy in development for treating multiple sclerosis. It binds to a docking site (sphingosine-1-phosphate receptor, or S1P receptor) on immune cells, including T cells and B cells, that have been implicated in causing nervous system damage in MS. The drug appears to induce immune cells to remain in lymph nodes, where they can do little harm, preventing them from migrating into the brain and spinal cord.
Positive results from two large-scale phase III clinical trials have been published showing that fingolimod significantly reduced multiple sclerosis relapse rates. One of the trials also suggested that fingolimod could slow the progression of disability. In December 2009, Novartis applied to the FDA and European regulators for marketing approval of this compound for the treatment of relapsing MS.

What Clinical Trials Found: According to the published results, a large-scale, two-year phase III trial known as FREEDOMS involved 1,272 people with relapsing-remitting MS. Over two years, fingolimod at either of two doses was able to significantly reduce relapse rates (the primary endpoint of the study) and slow disability progression (a secondary endpoint) compared to an inactive placebo. Annual relapse rates were 0.18 for the lower dose, 0.16 with the higher dose, and 0.40 for those on placebo (a reduction of 54% and 60% over placebo, respectively). Disease progression was measured by two standard MS clinical assessment tools known as the EDSS and MSFC, and after 24 months both doses showed slower progression compared to placebo. Secondary measures of disease activity and progression also favored both fingolimod doses, including MR imaging to detect tissue injury and brain atrophy.
The second paper detailed positive results from a one-year clinical trial, called the TRANSFORMS study, comparing two different doses of fingolimod with Avonex® (interferon beta-1a, Biogen Idec). That study involved 1,292 individuals with relapsing-remitting MS. Both doses of fingolimod were able to reduce relapse rates over one year (the primary endpoint of the study), and also reduced disease activity on MR brain imaging. The annualized relapse rate in those taking the lower dose of fingolimod was 0.16, compared to 0.33 in those on Avonex (a comparative reduction of 52%). Those taking the higher dose of fingolimod experienced an annualized relapse rate of 0.20 (a reduction of 38% compared with Avonex). Time to sustained disability progression was no different in the fingolimod and Avonex groups.
At the 2010 meeting of the American Academy of Neurology (Abstract P03.125), investigators reported on an extension of the TRANSFORMS study involving 1027 of the original participants. Those taking fingolimod stayed on the same dose, and those who had been on weekly interferon beta 1a received either 0.5 mg or 1.25 mg of fingolimod for one year. The annualized relapse rate (primary outcome) and inflammatory activity on MRI scans were significantly lower for those taking fingolimod for the entire two-year period compared to those switching to fingolimod at the beginning of the second year.
Safety: In the clinical trials, the lower dose was better tolerated. A few participants experienced a transient reduction in heart rate and blockage of heart conduction (atrioventricular conduction block) which generally normalized after the first dose. There was a slight elevation of blood pressure starting during the second month of therapy. Macular edema (swelling of the center of the retina inside the eye) occurred more frequently with those on the higher dose of fingolimod in both studies.
Elevations in liver enzymes, without accompanying symptoms, were common in those receiving fingolimod. In both studies, a small number of serious herpes infections occurred, including two deaths from herpes infections that occurred in the TRANSFORMS trial in people taking the higher dose of fingolimod.
Other phase III clinical trials of fingolimod, including one involving people with primary progressive MS, are still under way, as are extension studies involving those who’ve completed trials. These and other studies that may be required post-marketing should provide additional data on the safety and efficacy of fingolimod.
Comment: “If the FDA agrees that fingolimod is safe and effective, this would represent significant progress for people with MS – the first oral disease modifying therapy -- and would help address the unmet need for additional therapies,” said National MS Society Chief Medical Advisor Dr. Aaron Miller, Professor of Neurology and Medical Director of the MS Center at Mount Sinai Medical Center in New York City. Dr. Robert Lisak, MD, Chair of Neurology and Professor of Immunology and Microbiology at Wayne State University School of Medicine in Detroit, agreed. “I would welcome having another treatment option for my patients, particularly an oral medication that might make it easier for people to get on and stay on therapy. Taking a disease-modifying therapy is the best way we have of reducing MS disease activity and future deterioration. However, we will need to monitor all new therapies for any long-term safety issues.”
If approved, the decision to take an oral MS therapy should be made by people with MS in collaboration with their MS doctors, taking into account a variety of factors, including the effectiveness of any therapy they are currently using, and weighing potential risks and benefits, costs and lifestyle factors.

FAQ About June 10 FDA Advisory Committee’s Recommendation to
Approve Oral Fingolimod for Relapsing MS

Q. What is fingolimod?
A. Fingolimod is different than current MS therapies on the market and represents a new class of therapy, for one because it is taken orally rather than by injection or infusion, and secondly because of its mode of action. Fingolimod binds to a docking site (sphingosine-1-phosphate receptor, or S1P receptor) on immune cells, including T cells and B cells that have been implicated in causing nervous system damage in MS. The drug appears to force immune cells to remain in lymph nodes where they can do little harm, and prevents them from migrating into the brain and spinal cord. Fingolimod is considered a disease-modifying agent, and if it is approved, it would not be taken along with other disease-modifying therapies.
Q. Does this announcement mean that fingolimod is approved and available for MS?
A. No, this does not mean that fingolimod is approved and available. The FDA will take this committee’s recommendation into account as it completes its review of the clinical trials’ benefit and safety data. The agency is expected to make a decision by September 2010. The FDA is not required to follow the advice of its advisory committees, but it usually does. The Society will have updates as we learn more from FDA announcements.
Q. What is the official brand name of fingolimod?
A. At present fingolimod, or FTY 720, does not have an approved name for marketing. The name proposed by Novartis – Gilenia -- was not accepted by the FDA. The usual reason the agency might reject a proposed name is that it may be too similar to the name of an approved drug, which could cause confusion in prescribing and dispensing the medications.
Q. What types of MS might fingolimod be approved to treat?
A. The application to the FDA requested approval to market fingolimod for the treatment of relapsing forms of MS (http://www.nationalmssociety.org/about-multiple-sclerosis/relapsing-ms/index.aspx). In other words, people who experience periodic MS attacks, such as those who have relapsing-remitting MS or secondary-progressive MS with relapses. However, this agent is also being tested in people with primary-progressive MS (http://www.nationalmssociety.org/about-multiple-sclerosis/progressive-ms/primary-progressive-ms/index.aspx) who experience steady worsening without acute attacks. If the FDA approves fingolimod for relapsing MS, and if it shows significant benefit in primary-progressive trials, it is likely that the sponsor will apply to expand its labeling to include progressive forms of MS.
Q. How is fingolimod taken?
A. Fingolimod comes in capsules. If approved for marketing, it will likely be taken by mouth once a day, which is how it was taken during the clinical trials.
Q. How effective is fingolimod?
A. In a large-scale, two-year phase III trial known as FREEDOMS, involving 1,272 people with relapsing-remitting MS, fingolimod at either of two doses was able to significantly reduce relapse rates (the primary endpoint of the study) and slow disability progression (a secondary endpoint) compared to an inactive placebo. Annual relapse rates were 0.18 for the lower dose (which is the dose the sponsor is asking the FDA to approve) and 0.40 for those on placebo - a reduction of 54% over placebo. Disease progression was measured by two standard MS clinical assessment tools, the EDSS and the MSFC. After 24 months, both doses slowed progression compared to placebo. Secondary measures of disease activity and progression, including MR imaging to detect tissue injury and brain atrophy, also favored both fingolimod doses.
Q. Should I switch from my current therapy to fingolimod?
A. If fingolimod is approved, the decision about whether to take it should be made in collaboration with your MS doctor, taking into account a variety of factors including the effectiveness of any therapy you are currently using, the potential risks and benefits, as well as costs and lifestyle factors.
Q. What are the potential side effects of fingolimod?
A. In clinical trials, some participants experienced a transient reduction in heart rate and blockage of heart conduction (atrioventricular conduction block) which generally normalized after the first dose. There was a slight elevation of blood pressure starting during the second month of therapy. Macular edema (swelling of the center of the retina inside the eye) occurred more frequently with those on the higher dose of fingolimod than the dose being proposed in the sponsor’s application. Elevations in liver enzymes, without accompanying symptoms, were common in those receiving fingolimod. A small number of serious herpes infections occurred, including two deaths from herpes infections that occurred in people taking a higher dose of fingolimod than the dose that the sponsor is proposing to market.
Q. Has fingolimod been proven to be “better” than other disease-modifying therapies?
A. No, fingolimod has not been demonstrated to be “better” than other disease modifying therapies. So far, the only comparison to an existing disease-modifying therapy has been in the one-year, head-to-head “TRANSFORMS” trial against Avonex® (interferon beta-1a, Biogen Idec). This trial suggested short-term superiority of fingolimod, but the trial was too short to be definitive in terms of comparing long-term benefits of the two therapies. In this trial, fingolimod caused more serious side effects than Avonex. Fingolimod has not been compared to other available disease-modifying therapies.
Q. If it is approved, how long would a person take fingolimod?
A. Based on the advisory committee discussions, it is likely that an individual could potentially take fingolimod indefinitely.
Q. If fingolimod is approved, will people taking it have to get any special medical tests or monitoring?
A. The clinical trials showed that there is the potential for significant side effects in some patients even at the lower dose being proposed for marketing. Therefore, it is likely that monitoring would be required if fingolimod is approved for clinical use. Details of a risk management plan (“Risk Evaluation Mitigation Strategies”) that would likely be mandated to monitor safety will be negotiated between the FDA and the sponsor before the agent is approved.
Q. If it is approved, what will fingolimod cost?
A. At this point, there is no information available about what fingolimod may cost – but the actual cost to a person with MS will depend on the provisions of his or her insurance coverage.
Q. If fingolimod is approved, would it be immediately available to everyone who gets a prescription, or would there be a waiting list?
A. According to Novartis representatives, if fingolimod is approved, the company would ensure that there is an adequate supply when the drug becomes available by prescription.
Q. If fingolimod is approved by the FDA, will my health insurance cover it?
A. Coverage will depend on individual insurance plans. It is likely that fingolimod’s sponsor, Novartis, will provide support services to help patients and healthcare professionals access the therapy. Details of support services are likely to be made available by Novartis if and when the agent is approved.
Q. Where can I get additional information about the support that Novartis will provide to help people gain access to fingolimod?
UPDATE: New phone #
A. If and when fingolimod is approved for use, physicians and people with MS can contact Novartis for more information at: 888-NOW-NOVA (888-669-6682)

Q. Are there other oral disease-modifying therapies in development for MS?
A. Yes, there are others in development. Cladribine (sponsored by EMD Serono) has been shown to reduce MS relapses and slow progression in relapsing-remitting MS. It has been submitted to the FDA for marketing approval, but the application has not yet been accepted by the FDA.
Additional oral agents currently in phase III clinical trials are: teriflunomide (sponsored by sanofi-aventis), BG00012 (sponsored by Biogen Idec), and laquinimod (sponsored by Teva Pharmaceutical Industries). They are being tested in relapsing MS and in people at high risk for MS, after earlier trials suggested potential benefits against disease activity.
Q. I’ve been hearing news about other new treatments in development for MS. What are some details?
A. Oral disease-modifying therapies are only one of many exciting treatments moving through the MS pipeline and other promising research avenues that address ways to stop MS progression, restore function and end MS forever. Just a few therapies being tested include the hormone estriol, adult stem cell transplantation, and infused drugs that require infrequent dosing. The National MS Society has established a Rapid Response Fund to pursue new and unexpected research opportunities when they arise, a recent example being our expedited funding of research exploring the potential relationship between CCSVI and the MS disease process. 

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Study Suggests that Smoking and Exposure to Epstein-Barr Virus May Interact as Risk Factors for Developing MS

In a new study, researchers show that two individual factors that were previously identified as increasing the likelihood of developing MS – exposure to Epstein-Barr virus and tobacco smoking – may interact and multiply to substantially increase the risk of developing MS in those with both risk factors. Claire Simon, ScD, Alberto Ascherio (MD, DrPH) (Harvard School of Public Health, Boston) and collaborators in Australia and Sweden report their findings in Neurology. The results warrant confirmation in further studies.
Background: MS is thought to occur when people whose genes make them susceptible encounter something in their environment that triggers this immune-based neurological disease. Although many genes probably contribute to susceptibility, a specific gene that has been shown to confer higher susceptibility to MS is called HLA-DR15, which helps control how the immune system identifies targets for destruction. Although many infectious agents have been investigated at various times as possible triggers of MS, no single virus or bacterium has been proved to cause the disease. However, previous studies have suggested that the risk of MS is increased in persons who have had a history of infectious mononucleosis (caused by the Epstein-Barr virus, or “EBV”) or who have high levels of blood serum antibodies against EBV, which indicate past exposure to the virus. Smoking has been associated with an increased risk of developing MS, as well as the rate of MS progression.
In 2008, the Harvard team found that people who had both the HLA-DR15 gene and high levels of antibodies to the Epstein-Barr virus in the blood serum were nine times more likely to develop MS than those without that gene and with low levels of viral antibodies. (Neurology 2008;70:1113-18) Exploring such interactions between genes and the environment may help us understand what triggers MS and also may point to ways to interfere with the development of the disease.
The Study: For the newly published study, the Harvard team investigated even more complex relationships between MS genes and risk factors. They gathered information on people with MS enrolled in the ongoing Nurses’ Health Studies (a questionnaire-based longitudinal study that track risk factors for chronic diseases in female nurses); the Tasmanian MS Study (a study that identified people with MS in Tasmania); and the Swedish MS Study (in which people with MS were identified in a national health registry). Dr. Simon and colleagues looked at smoking history, presence of EBV antibodies in blood serum, presence the HLA-DR15 gene, and their relationship to MS risk in the combined group of 442 people with MS and 865 controls without the disease.
By pooling results from each of the three studies, the researchers found that each of the factors raised the risk of developing MS at levels consistent with previous studies: those with the HLA-DR15 gene were about three times more likely to develop MS than those without this gene; those with serum EBV antibodies were about two and a half times more likely to develop MS than those without EBV antibodies; and those who ever smoked were about one and a half times more likely to develop MS than those who never smoked.
However, when EBV exposure was taken into account, smoking only increased MS risks among those with high levels of serum EBV antibodies. Current or previous smokers with low levels of EBV antibodies had no increased risk for developing MS, whereas current or previous smokers with the highest levels of EBV antibodies were 70% more likely to develop MS than those with neither risk factor. The presence of the HLA-DR15 gene variation did not appear to modify any of these effects.

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June 2010

Over $2.4 Million Committed to Support 7 Initial CCSVI Grants to Determine the Role of CCSVI (Venous Insufficiency) in MS Disease Process

Over $2.4 million has been committed by the National MS Society (USA) and the MS Society of Canada to support 7 new research projects focusing on the role of CCSVI (chronic cerebrospinal venous insufficiency) in MS.
All research applications underwent a rigorous expedited review process by an international review panel that included experts drawn from all key relevant disciplines including radiology, vascular surgery and neurology. The U.S. National MS Society and the MS Society of Canada worked collaboratively to assemble the reviewers who considered scientific merit, responsiveness to the Request for Applications, experimental design, likelihood of producing definitive data, and the experience of the applicant teams in making their recommendations.
These new studies are necessary because we don’t yet know whether, or if so how, CCSVI contributes to MS disease activity. They will achieve several important goals. First, the new studies will carry out significant steps needed to confirm the phenomenon originally described by Dr. Paolo Zamboni who reported abnormalities in the veins draining the brain and spinal cord in people with MS and resolve the questions raised by him and others as to whether CCSVI is a cause of MS or related to MS in some other manner. Second, these studies will resolve conflicting data from previous research, such as how frequently CCSVI occurs in MS, and how often it occurs in people who do not have MS. Third, if blockages are found, the findings will speed the way to determining whether therapeutic trials to correct them will be helpful in improving or altering MS disease process.
The new projects take a comprehensive look at the structure and function of the veins draining the brain and spinal cord in people representing a spectrum of MS types, severities and durations, and compare them to structure and function of veins in people with other diseases and healthy volunteers. The studies incorporate accepted high standards of experimental blinding and controls designed to provide unbiased results. They also use a variety of imaging technologies including the Doppler ultrasound technology originally used by Dr. Paolo Zamboni and his team.
Together, these studies aim to further understand the role of CCSVI in MS and identify optimal methods for screening for the condition, which would be necessary to determine the next steps required in advancing this CCSVI lead. They will also be of value in designing protocols for possible exploratory therapeutic trials that might be independently undertaken in North America or abroad.
Although there were a number of promising submissions, for this initial round of grants, the international review panel recommended studies they agreed combined the strongest science with the research goals necessary to most quickly determine the scope and meaning of reported abnormalities in blood drainage from the brain and spinal cord in MS. It is hoped these findings will provide clarity regarding the need for next-step therapeutic trials to correct such blockages as Societies around the world pursue. The two-year grants will begin July 1, 2010.
The funded teams, which include an integration of MS and vascular experts, are led by:
• Dr. Brenda Banwell, The Hospital for Sick Children, Toronto, Ontario: studying vein abnormalities in children and teenagers who have MS, and healthy controls of the same age. The team is seeking to determine whether the veins are abnormal at an early age among pediatric MS patients. These findings will add additional depth to studies of CCSVI in adult MS.
• Dr. Fiona Costello, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta: examining a cross-section of people with MS compared to other neurological diseases and healthy volunteers. The team is seeking linkages between vein abnormalities and different aspects of MS activity and tissue damage to gain insight into the significance of differences in vein drainage and their implications for the future treatment of MS.
• Dr. Aaron Field, University of Wisconsin School of Medicine and Public Health, Madison: using magnetic resonance (MRI) scans to generate detailed images of the head and neck veins in people with early and later MS, healthy volunteers, and controls with other neurological conditions. This team is also using the ultrasound techniques originally used by Dr. Zamboni. If they obtain similar results as those published by Dr. Zamboni, it would represent a powerful confirmation of the CCSVI hypothesis and help lead the way toward trials of appropriate treatment.
• Dr. Robert Fox Cleveland Clinic, Cleveland: studying people with MS or who are at risk for MS (CIS) and comparison groups including healthy volunteers and people with brain atrophy (shrinkage) from Alzheimer’s disease. This team is using the ultrasound techniques originally used by Dr. Zamboni, as well as magnetic resonance studies of the veins (MR venography), MRI scans of the brain, and clinical measures to determine MS activity and atrophy. They are also examining neck and spinal cord tissue from MS patients at autopsy to provide a tissue-based evaluation of CCSVI and its possible relationship to MS.
• Dr. Carlos Torres, The Ottawa Hospital, University of Ottawa, Ontario: employing powerful MRI technology to explore vein anatomy and assessing for iron deposits in the brains of people with MS and in age-matched healthy volunteers. These studies work towards mapping out normal variations in brain vein anatomy and providing insight into CCSVI in MS.
• Dr. Anthony Traboulsee, UBC Hospital MS Clinic, UBC Faculty of Medicine and Dr. Katherine Knox, Saskatoon MS Clinic, University of Saskatchewan: studying the prevalence of CCSVI in people with MS and controls without MS, using catheter venography, ultrasound, and magnetic resonance venography. Unique to this study is the inclusion of family members, such as identical twins of MS patients who have not developed MS, in control groups. They also hope to verify the usefulness of techniques that would make it easier to screen for CCSVI.
• Dr. Jerry Wolinsky, University of Texas Health Science Center at Houston: replicating the ultrasound methods used by Dr. Zamboni to investigate the association of CCSVI with major clinical types of MS and in non-MS control groups. The team is also testing whether other imaging methods can confirm the ultrasound findings, while identifying the most reliable technique to screen for CCSVI.
The work of the researchers in these initial studies will not involve the actual treatment of CCSVI, but rather the investigation and determination of its prevalence in different circumstances.
“We don’t know yet whether CCSVI contributes to MS disease activity, and there have been conflicting data as to the frequency of this condition in people with MS,” said National MS Society Chief Medical Advisor Dr. Aaron Miller, Professor of Neurology and Medical Director of the MS Center at Mount Sinai Medical Center in New York City. “The newly funded studies should bring clarity to the debate, and we should know very soon what this phenomenon means in MS and what the next steps should be.”
Recruitment guidelines for participation in each of the funded studies have not yet been released and will differ by project. Funding is expected to flow as of July 1, 2010 and recruitment will begin sometime after this date. The National MS Society plays no role in selecting people to participate in studies but if a there is a broad call for recruitment, the information will be posted on www.nationalmssociety.org/ccsvi when it becomes available.
The studies are two years in length and researchers expect to publish results in peer reviewed scientific journals as outcomes are established. The timing of data analysis, peer review and publication can vary widely and thus it is not possible to predict when results will be available.
As part of our commitment to keeping people with MS and the public informed of progress, researchers will be asked to provide 6-month interim updates to the National MS Society on their grant progress. We will post information as it becomes available.
The U.S. and Canadian MS Societies are also in discussion with the Multiple Sclerosis International Federation to establish an international CCSVI Research Coordinating Committee to consider CCSVI research that is underway around the world.

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Positive Results Published on Clinical Trials of Oral FTY720 (Fingolimod) for Relapsing MS -- Novartis Applies to FDA and European Regulatory Agency for Approval

Positive results from two large-scale phase III clinical trials of oral fingolimod (FTY720) have been published showing it significantly reduced multiple sclerosis relapse rates, and one of the trials also suggested it could slow the progression of disability. The sponsor, Novartis International AG, has announced that it applied for marketing approval in the U.S. and European Union. There are currently no approved oral disease-modifying therapies for MS. The papers were published early online in the New England Journal of Medicine, along with a separate paper that describes results from a clinical trial of another orally administered experimental therapy, cladribine.

About Fingolimod: This is a new class of therapy in development for treating multiple sclerosis. FTY720 binds to a docking site (sphingosine-1-phosphate receptor, or S1P receptor) on immune cells, including T cells and B cells, that have been implicated in causing nervous system damage in MS. The drug appears to induce immune cells to remain in lymph nodes, where they can do little harm, preventing them from migrating into the brain and spinal cord.
First in-depth study results published: One paper, by Ludwig Kappos, MD (University Hospital, Basel, Switzerland) and colleagues, describes results from the large-scale, two-year phase III trial known as FREEDOMS, involving 1,272 people with relapsing-remitting MS. Over two years, fingolimod at either of two doses was able to significantly reduce relapse rates (the primary endpoint of the study) and slow disability progression (a secondary endpoint) compared to those on inactive placebo. Relapse rates were 0.18 for the lower dose, 0.16 with the higher dose, and 0.40 for those on placebo (a reduction of 54% and 60% over placebo, respectively). Disease progression was measured by standard MS clinical rating scales known as the EDSS and MSFC, and after 24 months both doses showed slower progression over those on placebo. Secondary measures of disease activity and progression also favored both FTY720 doses, including MR imaging to detect tissue injury and brain atrophy.

The second paper, by Jeffrey A. Cohen, MD (Cleveland Clinic, Cleveland, Ohio) and colleagues, details positive results from a one-year clinical trial, called the TRANSFORMS study, comparing two different doses of fingolimod with Avonex® (interferon beta-1a, Biogen Idec). That study involved 1,292 individuals with relapsing-remitting MS. Both doses of FTY720 were able to reduce relapse rates over one year (the primary endpoint of the study), and also reduced disease activity on MR brain imaging. The annualized relapse rate in those taking the lower dose of FTY720 was 0.16, compared to 0.33 in those on Avonex (a comparative reduction of 52%). Those taking the higher dose of FTY720 experienced an annualized relapse rate of 0.20 (a reduction of 38% compared with Avonex). Time to sustained disability progression was no different in the FTY720 and Avonex groups.
Safety: In both studies, the lower dose of FTY720 was better tolerated. A few participants experienced a transient reduction in heart rate and blockage of heart conduction (atrioventricular conduction block) which generally normalized after the first dose. There was a slight elevation of blood pressure starting during the second month of therapy. Macular edema (swelling of the center of the retina inside the eye) occurred more frequently with those on the higher dose of FTY720 in both studies. Skin cancers were reported more frequently in those on FTY720 in the one-year TRANSFORMS study, but more malignancies in general were detected in those on placebo in the two-year FREEDOMS study.
Elevations in liver enzymes, without accompanying symptoms, were common in those receiving FTY720. In both studies, a small number of serious herpes infections occurred, including two deaths from herpes infections that occurred in the TRANSFORMS trial in people taking the higher dose of FTY720.

Next Steps: According to the company, these and other data were used to support applications for marketing approval for the lower dose of FTY720, which were submitted in December 2009 to the U.S. Food and Drug Administration and to the European Medicines Agency.
Results from a second large-scale trial called FREEDOMS II have not yet been released. Other phase 3 clinical trials of fingolimod, including one involving people with primary progressive MS, are still under way, as are extension studies involving those who’ve completed trials. These should provide additional data on safety and efficacy.
Comment: “The published results and the company’s application for marketing approval for fingolimod are wonderful news for people with MS,” said John R. Richert, MD, Executive Vice President of Research and Clinical Programs at the National MS Society. “Having oral therapies in the MS pipeline is real progress, and it should increase the number of people who choose to begin therapy earlier and who stay on therapy, which our experts say is the best way to combat future disease activity.”

Gilenia – the Oral Drug for Relapsing MS Formerly Known as FTY720 – Receives Priority Review from FDA – Could take as little as six months for an approval decision

Novartis International AG has been granted a priority review for its oral therapy formerly known as FTY720 or fingolimod, now called Gilenia®, the U.S. Food and Drug Administration. Novartis applied to the FDA and European regulators for marketing approval of this compound for the treatment of relapsing MS in December 2009, using supporting data from two phase 3 trials. There are currently no approved oral disease-modifying therapies for MS.
According to the FDA, a “priority review” designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. A priority review means that the time it takes FDA to review a new drug application is reduced. The goal for completing a priority review is six months from the application date, but the press release suggests that this period could be extended if the FDA requires additional time to evaluate any risk management program that might be proposed for Gilenia.

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May 2010

University at Buffalo Medical Center Issues a Release on Preliminary Findings of its Study of Venous Insufficiency Prevalence in MS

The University at Buffalo Medical Center issued a release reporting on its preliminary findings in its study of venus insufficiency prevalence in MS.
This is the largest study to date looking at the possible relationship between CCSVI and MS disease process. The results reported are based on the first 500 participants in the Combined Transcranial and Extracranial Venus Doppler Evaluation study. 
The preliminary results reported were interesting but somewhat mixed. At least 55 percent of the MS cohort participating in the initial phase of the study showed narrowing of the extracranial veins causing restriction of normal outflow of blood from the brain. This was also true for at least 22 percent of the healthy controls. As interpreted by the investigators, the narrowing of the extracranial veins, at the very least, is an important association in MS and encourages them to continue on the same research course. They advise that they will know more when the MRI and other data collected in the study are available, which for instance, will measure iron deposits in lesions and surrounding areas of the brain.

First Blinded Study of Venous Insufficiency Prevalence in MS Shows Promising Results
BUFFALO, N.Y. -- More than 55 percent of multiple sclerosis patients participating in the initial phase of the first randomized clinical study to determine if persons with MS exhibit narrowing of the extracranial veins, causing restriction of normal outflow of blood from the brain, were found to have the abnormality.
The results were reported today by neurology researchers at the University at Buffalo.
When the 10.2 percent of subjects in which results were border line were excluded, the percentage of affected MS patients rose to 62.5 percent, preliminary results show, compared to 25.9 percent of healthy controls.
These preliminary results are based on the first 500 participants in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study, which began at UB in April 2009. Investigators are planning to examine 500 additional subjects, who will be assessed in the second phase of the study with more advanced diagnostic tools. Complete data on the first 500 will be presented at the American Academy of Neurology meeting in April.

Robert Zivadinov, MD, PhD, UB associate professor of neurology and principal investigator on the study, says he is "cautiously optimistic and excited" about the preliminary data. Zivadinov directs the Buffalo Neuroimaging Analysis Center (BNAC), located in Kaleida Health's Buffalo General Hospital, where the study is being conducted.
"The data encourage us to continue on the same course," he says. "They show that narrowing of the extracranial veins, at the very least, is an important association in multiple sclerosis. We will know more when the MRI and other data collected in the CTEVD study are available." The analyses are being conducted by an independent statistician.
The investigation is the first step in determining if a condition called chronic cerebrospinal venous insufficiency (CCSVI) is a major risk factor for MS. CCSVI is a complex vascular condition discovered and described by Paolo Zamboni, MD, from Italy's University of Ferrara. Zamboni's original investigation in a group of 65 patients and 235 controls showed CCSVI to be associated strongly with MS, increasing the risk of having MS by 43 fold.
Zamboni and Zivadinov hypothesize that this narrowing restricts the normal outflow of blood from the brain, resulting in alterations in the blood flow patterns within the brain that eventually cause injury to brain tissue and degeneration of neurons.
The first 500 patients, both adults and children, were grouped based on their diagnosis: MS, clinically isolated syndrome (CIS) and "other neurologic diseases" (OND), in addition to healthy controls.
All participants in the first phase underwent ultrasound (Doppler) scans of the head and neck in different body postures to view the direction of venous blood flow. MS subjects also underwent MRI scans of the brain to measure iron deposits in lesions and surrounding areas of the brain, using a method called susceptibility-weighted imaging. Iron findings on these images will be related to subjects' disability and neuropsychological symptoms.
Of the total participants, 97.2 percent were adults, with the 280 MS patients comprising the largest disease cohort examined in the study to date. The majority of MS subjects were diagnosed with the relapsing-remitting form of MS. There were 161 healthy controls. Doppler scan results were reported on five specific criteria that affect venous blood flow. Patients who met at least two of the criteria were considered to have CCSVI. More detailed analysis of specific Doppler criteria and their association to disease status is underway.
When the 10.2 percent borderline subjects were included in the "normal" category (no venous insufficiency), the CCSVI prevalence was 56.4 percent in MS subjects and 22.4 percent in healthy controls.
In this large MS cohort, the presence of CCSVI did suggest an association with disease progression, a finding that was not shown in Zamboni's smaller cohort, Zivadinov notes.
The finding that 22.4 percent of healthy controls also met two CCSVI criteria requires continuing investigation, he says.

Bianca Weinstock-Guttman, MD, UB associate professor of neurology in the UB School of Medicine and Biomedical Sciences and a co-principal investigator on the study, notes that the results of the CTEVD research will pose new and provocative questions about the CCSVI theory.
Murali Ramanathan, PhD, associate professor in the Department of Pharmaceutical Sciences, UB School of Pharmacy and Pharmaceutical Sciences, and Ralph Benedict, PhD, UB professor of neurology and psychiatry, also are major contributors to the study.
The University at Buffalo is a premier research-intensive public university, a flagship institution in the State University of New York system and its largest and most comprehensive campus. UB's more than 28,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs. Founded in 1846, the University at Buffalo is a member of the Association of American Universities.

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April 2010

UPDATE: FDA Approves Fampridine SR, Now Called Ampyra,™ to Improve Walking for People with All Types of MS -- Wholesale Price Announced, New Webcast Available from Society

The U.S. Food and Drug Administration has approved the marketing of Ampyra™ (dalfampridine, formerly known as fampridine SR, from Acorda Therapeutics) for its ability to improve walking in people with any type of multiple sclerosis. This is the first therapy specifically approved to treat a symptom of MS, and it represents a big step forward for the many people who may benefit. Update: A new National MS Society Webcast on Ampyra is now available, and additional frequently asked questions are provided below, including newly released cost information.
Comment: “The FDA’s approval of Ampyra is wonderful news for many people with MS who experience problems with walking,” said John R. Richert, MD, Executive Vice President for Research & Clinical Programs at the National MS Society. “This brings a welcome symptomatic therapy that may restore some function and make a real difference in quality of life for a large number of people with different types of MS.” Further study and clinical practice may help determine the extent to which the drug may impact other functions not measured in the clinical trials, and provide hints as to which individuals are most likely to respond.
A new National MS Society video webcast/podcast from MS Learn Online that discusses Ampyra is now available.
Acorda has established a phone line that individuals may call for information:
1-888-881-1918.

FREQUENTLY ASKED QUESTIONS
Q. What is Ampyra? (pronounced amPEERah)
A. Ampyra, formerly known as fampridine SR, is a tablet containing a sustained-release formula of 4-aminopyridine, which 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. The first studies of this potassium-blocking approach in people with MS were supported by the National MS Society.
Q. How is a “symptomatic therapy” different from the approved disease-modifying therapies for MS?
A. A symptomatic therapy is usually a drug that addresses a particular aspect of a disease, but taking it does not change the underlying course of the disease or limit the damage caused by the disease. There are many medications taken by people with MS to manage specific symptoms, such as spasticity, fatigue or depression. While there are FDA-approved disease-modifying therapies that are partially effective against some forms of the disease, as well as rehabilitation and symptomatic treatments for some symptoms, until now there was no pharmacologic treatment available for MS-related difficulty walking.
Q. How common are walking problems among people with MS?
A. A recent survey among more than 1,000 individuals with MS and many of their family members examined the impact of difficulty walking on quality of life among people with MS and their families. Some two-thirds of patients reported difficulty walking and of these, 70% reported that such difficulty was the most challenging part of their MS, and most reported that difficulty walking restricts their daily activities significantly, including their ability to travel.
Q. How Effective is Ampyra?
A. Two phase III clinical trials of the drug were sponsored by Acorda Therapeutics. In the first, involving 301 people with any type of MS, walking speed increased by 25% compared with placebo. Results of this study have been published (February 28, 2009 issue of The Lancet (2009 373;732-738, summarized here. Results from a later, second phase III study involving 240 people with MS, announced in 2008, confirmed the benefits seen in the first, finding that a significantly greater proportion of people on the therapy had a consistent improvement in walking speed compared to those who took placebo. Among those taking Ampyra who improved in walking speed, there was a statistically significant improvement in leg strength.
Q. What are the potential side effects of Ampyra?
A. In the first phase III study, common adverse events (side effects) experienced more often by those on active treatment included back pain, dizziness, insomnia, fatigue, nausea and balance disorder. Two serious adverse events led participants to discontinue taking the drug (one case of anxiety and one seizure in a person who developed sepsis from a urinary tract infection). In the second phase III study, additional common adverse events in those on therapy included urinary tract infection, falls, and headache.
Q. How is Ampyra taken?
A. In clinical trials, participants on active therapy took one tablet of the drug by mouth two times per day. According to a company press release, Ampyra will be taken two times a day, approximately 12 hours apart.
Q. When and how will Ampyra become available for prescription?
A. According to the sponsor, Ampyra is expected to be ready for prescription by March 2010. The drug will be distributed through a network of specialty pharmacies and coordinated by a team providing support services to facilitate access to the drug for patients and healthcare providers.
Q. Who might benefit from taking Ampyra?
A. There is no way of knowing in advance whether any particular individual who has MS might benefit from taking Ampyra. In clinical trials, a proportion of people with all types of MS were found to benefit in terms of walking speed. This proportion ranged from 35% to 43% of those who took the drug in the two phase III clinical trials.
Q. Can anyone with MS take Ampyra?
A. Ampyra was approved for persons with any type of multiple sclerosis. However, the FDA’s approval of Ampyra comes with the warning that the drug should NOT be taken by individuals with a history of seizures, or by those with moderate to severe renal impairment (CrCl 51–80 mL/min).
Q. What is renal impairment, and why is it important that those taking Ampyra have adequate renal function?
A. “Renal” refers to the kidneys, which in essence clean the blood. If a person has adequate kidney function, then Ampyra will be cleared from the blood to a sufficient degree between doses so as to maintain a steady drug level in the blood. If a person has moderate to severe kidney impairment, then there is a danger that the concentration of the drug will increase in the blood beyond the amount considered safe. The result could be increased side effects including seizures, which in clinical trials occurred infrequently. For the same reasons, Ampyra should not be taken in combination with other forms of 4-aminopyridine (4-AP, fampridine), since the active ingredient is the same.
Q. Will taking Ampyra make it possible to stop using my walking aids?
A. There are many different types of walking aids and they address many different types of movement issues, so there is no single answer to this question. It is important that people who try the drug NOT make changes related to walking aids until they determine whether and how the drug affects them. One concern is that in the second clinical trial, a side effect experienced by some participants was increased falling. For that reason, it is important that people taking this medication continue to use caution and discuss any proposed changes in walking aids with their health care provider.
UPDATE: NEW FAQS
Q. How much will Ampyra cost?
A. According to a company press release on February 3, 2010, the wholesale price of Ampyra will be $1,056 per 30-day supply. The actual retail cost to an individual will depend on many factors, such as the cost negotiated by his or her insurer.
Q. Can a person take Ampyra along with other MS medications, such as one of the disease-modifying therapies or symptomatic treatments?
A. According to the prescribing label, yes. The label does not list any medications that might interfere with or interact with this drug. One aspect of the clinical trials of Ampyra was that individuals enrolled continued to take whatever disease-modifying therapies they were using.
Q. Does a person need to be able to walk in order to be prescribed Ampyra?
A. The people who were enrolled in the clinical trials were selected for their ability to walk so that they could be tested for improved walking ability. There is currently insufficient experience using this drug outside of the context of clinical trials to predict at what level of disability or mobility problems the drug would not help. This is a question that individuals should discuss with their health care provider. Further study and clinical practice may help determine the extent to which the drug may impact other functions not measured in the clinical trials, and provide hints as to which individuals are most likely to respond.
Q. Would increasing the recommended daily dosage better help some people?
A. No, in clinical trials there was no benefit seen in doses higher than the recommended prescription dose. There is a possible danger of taking more than is prescribed because of increased chances of adverse events including seizures.
Q. Would a person take Ampyra on an “as needed” basis, or every day?
A. This drug was designed to be taken two times per day at about 12 hours apart so that the amount of drug in the bloodstream is fairly steady. For that reason taking it on an “as needed” basis would probably not be helpful.
Q. How long would a person take Ampyra?
A. The clinical trials were of relatively short duration. Although there is insufficient information on the long-term use of Ampyra to know how long it may be taken, to date no new concerns have emerged in the safety extension studies. The duration of time that someone is on the drug will be determined by each person in consultation with his/her physician, likely based on whether it continues to provide benefit and does not cause unacceptable side effects.
Q. What will happen if an individual stops taking Ampyra – would walking issues get worse?
A. Based on experience from the clinical trials leading to the approval of Ampyra, it appears that walking ability in most individuals returns rapidly to the pre-treatment baseline after an individual stops taking the drug.
Q. Does Ampyra cause MS relapses?
A. Some people in the clinical trials of Ampyra experienced a worsening of their MS symptoms when they stopped taking the medication. It was unclear whether this reflected a return to their pre-trial state or an actual relapse, but the FDA did not make a distinction between the two when listing possible side effects. The FDA did, however, determine that the risk-benefit ratio for Ampyra is satisfactory.
Q. Are there any generic equivalents to Ampyra available?
A. No. Ampyra is a proprietary sustained release formula. For many years some compounding pharmacies have been making the basic chemical in this drug (4-aminopyridine or fampridine) for individual use, but the compounding process increases the risk of inconsistent dosing.
Q. Is Ampyra going to be available to everyone who gets a prescription, or will there be a waiting list?
A. At this point in time there is no reason to believe that there will be a shortage of Ampyra when it is ready for release by Acorda Therapeutics.
Q. Will Ampyra be covered by my health insurance plan?
A. Coverage for Ampyra will depend on individual insurance plans. Acorda has established a team to provide support services to help patients and healthcare professionals access the drug, including working with insurance carriers and providing patient assistance programs, details of which will be available in coming weeks.
Q. Where can I get additional information about the support that Acorda will provide to help people gain access to Ampyra?
A. Acorda has established a phone line that individuals may call for information: 1-888-881-1918. The company has established a team to provide support services to help patients and healthcare professionals access the drug, including working with insurance carriers and providing patient assistance programs such as co-pay mitigation.
Q. Will Ampyra be covered by my health insurance plan?
A. Coverage for Ampyra will depend on individual insurance plans. Acorda has established a team to provide support services to help patients and healthcare professionals access the drug, including working with insurance carriers and providing patient assistance programs, details of which will be available in coming weeks.

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March 2010

Results Published from Phase 3 Study of Oral Cladribine in Relapsing-Remitting MS

Details of positive results from the phase III trial of oral cladribine (EMD Serono), known as the CLARITY study, have now been published, showing that the drug reduced relapse rates significantly more than inactive placebo in a study involving 1,326 people with relapsing-remitting MS. There are currently no approved oral disease-modifying therapies for MS. The results were published early online in the New England Journal of Medicine on January 20, 2010, along with separate papers that describe results from clinical trials of another orally administered experimental therapy, FTY720 (fingolimod).
About Cladribine: Cladribine can interfere with the activity of lymphocytes, a subset of white blood cells that underlie the immune attacks that cause the unpredictable symptoms of MS. Among its other activities in the body, cladribine also reduces the levels of immune messenger chemicals (cytokines) capable of increasing inflammation. Injectable cladribine is used to treat hairy cell leukemia. Positive results from the phase III CLARITY study of oral cladribine were originally announced in a press release in January 2009, and were presented at the American Academy of Neurology’s annual meeting later that year.
In addition to the completed CLARITY study and a two-year extension study of CLARITY, other ongoing studies of oral cladribine funded by EMD Serono include the ONWARD study, an investigation of the safety and effectiveness of adding high or low doses of oral cladribine to interferons in a trial recruiting 260 people with relapsing forms of MS (this study is ongoing, but not recruiting participants); and the ORACLE MS study, designed to evaluate the safety and effectiveness of oral cladribine in people who have experienced a neurological episode that puts them at risk for developing MS (this study is currently recruiting participants). EMD Serono has established a long-term safety registry of people with MS who have participated in cladribine studies.
In November 2009, EMD Serono announced that it had received a “refuse to file” letter from the U.S. Food and Drug Administration for an application requesting approval of cladribine tablets for the treatment of relapsing MS. This usually means that the FDA deems the application incomplete. According to a press release at the time, the sponsor planned to meet with the FDA to determine what would be required for the application to be accepted for review.
This Study: As described in the paper authored by Gavin Giovannoni, MB, BCh, PhD (Queen Mary University London) and colleagues, for the first year of the CLARITY study, 1,326 participants were randomly assigned to receive a low dose of cladribine tablets (two treatment cycles per year, each cycle consisting of one tablet per day for four to five consecutive days), a high dose (four cycles) of cladribine, or inactive placebo. In the second year, both treatment groups received a low dose of cladribine. The primary endpoint was the drug’s effect on relapse rate at two years compared with placebo. Secondary endpoints included effects on disease activity, as detected by MRI scans, the proportion of relapse-free participants, and disability progression.
The relapse rate was reduced significantly compared with placebo in both treatment groups -- by 57.6% in the low-dose group and by 54.5% in the high-dose group. In secondary measures, the proportion of participants who remained relapse-free over 96 weeks was 79.7% in the low dose group, 78.9% in the high-dose group and 60.9% among those on placebo. The risk of a 3-month sustained change in the EDSS scale that measures MS-related disability was reduced by 33% in those on the low dose and by 32% in those on the high dose compared to those on placebo. Cladribine also reduced disease activity as indicated by MRI scans – including fewer active (gadolinium-enhanced) lesions (areas of inflammation).
Safety: One of the most frequent adverse events occurring more frequently in the both groups treated with cladribine was lymphocytopenia (a reduction of a subset of white blood cells), which was mostly mild to moderate. This occurred in 21.6% of those on the low dose, 31.5% of those on the high dose, and 1.8% in those on placebo. Based on the agent’s mode of action, this might be expected, and may require monitoring if the drug becomes an approved therapy. Herpes zoster infection occurred in 20 people (2.3%) treated with cladribine and in none of those on placebo.

There were three cases of cancer in the low-dose group – a melanoma and carcinomas of the pancreas and ovary. One additional case of cancer occurred during a 6-month monitoring period after the trial ended, and one case occurred of a pre-cancerous cervical lesion. The authors comment that given the small number of cases, it is not possible to establish whether a cancer risk is associated with cladribine from this study.

Comment: “These published results are a true step forward in the development of oral therapies for MS,” said John R. Richert, MD, Executive Vice President of Research and Clinical Programs for the National MS Society. “Having oral therapies in the MS pipeline is real progress, and it should increase the number of people who choose to begin therapy earlier and who stay on therapy, which our experts say is the best way to combat future disease activity.”

Positive Results Published on Clinical Trials of Oral FTY720 (Fingolimod) for Relapsing MS -- Novartis Applies to FDA and European Regulatory Agency for Approval

Positive results from two large-scale phase III clinical trials of oral fingolimod (FTY720) have been published showing it significantly reduced multiple sclerosis relapse rates, and one of the trials also suggested it could slow the progression of disability. The sponsor, Novartis International AG, has announced that it applied for marketing approval in the U.S. and European Union in December 2009. There are currently no approved oral disease-modifying therapies for MS. The papers were published early online in the New England Journal of Medicine (links one and two) on January 20, 2010, along with a separate paper that describes results from a clinical trial of another orally administered experimental therapy, cladribine.
About Fingolimod: This is a new class of therapy in development for treating multiple sclerosis. FTY720 binds to a docking site (sphingosine-1-phosphate receptor, or S1P receptor) on immune cells, including T cells and B cells, that have been implicated in causing nervous system damage in MS. The drug appears to induce immune cells to remain in lymph nodes, where they can do little harm, preventing them from migrating into the brain and spinal cord.
First in-depth study results published: One paper, by Ludwig Kappos, MD (University Hospital, Basel, Switzerland) and colleagues, describes results from the large-scale, two-year phase III trial known as FREEDOMS, involving 1,272 people with relapsing-remitting MS. Over two years, fingolimod at either of two doses was able to significantly reduce relapse rates (the primary endpoint of the study) and slow disability progression (a secondary endpoint) compared to those on inactive placebo. Relapse rates were 0.18 for the lower dose, 0.16 with the higher dose, and 0.40 for those on placebo (a reduction of 54% and 60% over placebo, respectively). Disease progression was measured by standard MS clinical rating scales known as the EDSS and MSFC, and after 24 months both doses showed slower progression over those on placebo. Secondary measures of disease activity and progression also favored both FTY720 doses, including MR imaging to detect tissue injury and brain atrophy.
The second paper, by Jeffrey A. Cohen, MD (Cleveland Clinic, Cleveland, Ohio) and colleagues, details positive results from a one-year clinical trial, called the TRANSFORMS study, comparing two different doses of fingolimod with Avonex® (interferon beta-1a, Biogen Idec). That study involved 1,292 individuals with relapsing-remitting MS. Both doses of FTY720 were able to reduce relapse rates over one year (the primary endpoint of the study), and also reduced disease activity on MR brain imaging. The annualized relapse rate in those taking the lower dose of FTY720 was 0.16, compared to 0.33 in those on Avonex (a comparative reduction of 52%). Those taking the higher dose of FTY720 experienced an annualized relapse rate of 0.20 (a reduction of 38% compared with Avonex). Time to sustained disability progression was no different in the FTY720 and Avonex groups.
Safety: In both studies, the lower dose of FTY720 was better tolerated. A few participants experienced a transient reduction in heart rate and blockage of heart conduction (atrioventricular conduction block) which generally normalized after the first dose. There was a slight elevation of blood pressure starting during the second month of therapy. Macular edema (swelling of the center of the retina inside the eye) occurred more frequently with those on the higher dose of FTY720 in both studies. Skin cancers were reported more frequently in those on FTY720 in the one-year TRANSFORMS study, but more malignancies in general were detected in those on placebo in the two-year FREEDOMS study.
Elevations in liver enzymes, without accompanying symptoms, were common in those receiving FTY720. In both studies, a small number of serious herpes infections occurred, including two deaths from herpes infections that occurred in the TRANSFORMS trial in people taking the higher dose of FTY720.
Next Steps: According to the company, these and other data were used to support applications for marketing approval for the lower dose of FTY720, which were submitted in December 2009 to the U.S. Food and Drug Administration and to the European Medicines Agency.
Results from a second large-scale trial called FREEDOMS II have not yet been released. Other phase 3 clinical trials of fingolimod, including one involving people with primary progressive MS, are still under way, as are extension studies involving those who’ve completed trials. These should provide additional data on safety and efficacy.

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February 2010

CCSVI or Blood Flow in the Brain and Venous Insufficiency in MS – Society Leaders Meet with Dr. Zamboni Today. Research Proposals Received from Around the World on February 9th Grant Request Deadline

Summary: Recent preliminary studies indicate that a phenomenon called CCSVI, a reported abnormality in blood drainage from the brain and spinal cord, may contribute to nervous system damage in MS. This hypothesis has been put forth by Dr. Paulo Zamboni from the University of Ferrara in Italy. Based on the results of his initial preliminary findings, Dr. Zamboni states that this pilot study warrants a subsequent larger and better controlled study to definitively evaluate the possible impact of CCSVI on the disease process in MS.
It has been proposed by Dr. Zamboni for further study that CCSVI may be corrected through endovascular surgery, which involves inserting a tiny balloon or stent into blocked veins in order to permit the flow of blood out of the brain and spinal cord, a procedure that has been called “liberation therapy” in some reports.
The National MS Society is pursuing this potential MS lead by undertaking the funding of new research on CCSVI in MS and has invited investigators worldwide to apply for grants on this topic. In response to a January 6 deadline, the National MS Society and the MS Society of Canada received numerous letters of intent from investigators from seven countries. Those letters of intent that met grant guidelines were invited to submit full research proposals, which are due February 9, 2010. The full planned funding timeline is below.
UPDATE: National MS Society leaders met with Dr. Zamboni today in advance of his invited lecture at New York University’s MS Center of Excellence. In meetings and during today’s presentation, Dr. Zamboni suggested that if further evidence supports the link between MS and CCSVI, that its treatment may ultimately add to the arsenal of therapies available for MS. He emphasized the need for more research on his hypothesis, and noted that it is still not proven whether CCSVI is a cause of MS or possibly a product of MS. Dr. Zamboni also noted that people with MS should remain on their immunomodulatory therapies as has his wife after her endovascular surgery.
The Society shares in the public urgency to expeditiously advance any lead that has the potential of stopping, repairing or preventing MS.
CCSVI Research Funding Timeline
January 12, 2010 – Investigators whose letter of intent meet guidelines are invited to submit full research proposals.
February 9, 2010 – Deadline for proposals. 
May 2010 – International panel of experts conducts an expedited review of all applications received through this special request for applications.
June 2010 – Funding decisions announced.
July 1, 2010 – Anticipated start date for funding of any successful research applications.
Taking advantage of the organizations' international scope, the applications will undergo an accelerated review process by an international panel being convened in cooperation with other MS Societies to ensure an expedited, coordinated response. If this hypothesis is confirmed, it could open up new research avenues into the underlying pathology of MS and new approaches to therapy.
Background: In a recent study by Dr. Zamboni and colleagues, the team evaluated abnormalities of blood outflow in major veins draining from the brain and spinal cord to the heart in 65 people with different types of MS, compared with 235 people who were either healthy or who had other neurological disorders. They used sophisticated sonography techniques to detect abnormalities of venous drainage. The investigators reported evidence of slowed and obstructed drainage in the veins draining the brain and spinal cord in many of those with MS. They also reported evidence of the opening of “substitute circles” – where the flow is deviated to smaller vessels to bypass obstructions, and these were often found to have reverse flow (reflux) of blood back into the brain. 
The investigators call this venous obstruction “chronic cerebrospinal venous insufficiency,” or CCSVI. The treatment status of the people with MS (i.e., whether or not they were on an MS disease modifying drug) did not appear to influence whether they showed signs of CCSVI. The authors speculated that the reverse flow of blood back into the brain might set off the inflammation and immune-mediated damage that has been well described in MS. This study was published in June 2009 (J Neurol Neurosurg Psychiatry 2009; 80:392-399).
It is proposed, but not yet proven, that CCSVI may be corrected through endovascular surgery. This surgery is being called “liberation therapy” in some reports. One study getting underway was described at the 2009 ECTRIMS meeting in September. It involves a collaboration between researchers in Italy, Buffalo (NY) and Birmingham (AL) who are attempting to treat venous obstruction in 16 individuals using balloon dilation such as has been used for many years to treat blocked arteries.
In a small, open-label study by Dr. Zamboni and colleagues published in December 2009, the team evaluated the safety and preliminary outcomes of vascular surgery (percutaneous transluminal angioplasty) in 35 individuals with relapsing-remitting MS, 20 with secondary-progressive MS, and 10 with primary-progressive MS. (J Vasc Surg 2009; 50:1348-1358) They reported some positive impacts and suggested that controlled trials were necessary to better determine potential safety and benefits of this procedure.
Next Steps: The National MS Society has prompted communications between MS Societies worldwide and leveraged resources to ensure an open exchange of information and a coordinated and expedited approach to conducting and evaluating additional research on CCSVI. On December 16, 2009, the Society released a worldwide Request for Applications to the scientific community to explore CCSVI, and is collaborating with the MS Society of Canada and possibly other societies to convene an international panel of experts to conduct an accelerated review of proposals. We are also working with our sister MS Societies around the world to assure that our research strategies are coordinated. Through an internationally coordinated and expedited review process, new CCSVI research projects are expected to begin July 1, 2010. (See Research Funding Timeline above for more details.)
According to the Buffalo Neuroimaging Analysis Center, although 500 subjects have already been selected for their initial combined transcranial and extracranial venous doppler evaluation study, they are still seeking participants for a larger-scale clinical study with the aim of evaluating the prevalence of venous obstruction in people with MS. This study does not involve treatment of obstructions. The Buffalo investigators released preliminary findings in a press release and plan to continue the study.
To get the quickest answers and most reliable results about benefits and risks of any surgical procedure that might attempt to address blood flow in or out of the brain, it is crucial that such surgery be performed only as part of controlled trials, especially since there have been anecdotal reports of surgical attempts to treat CCSVI in people with MS resulting in adverse events, including one reported death.
Many questions remain about how and when this phenomenon might play a role in nervous system damage seen in MS, and at the present time there is insufficient evidence to prove that this phenomenon is the cause of MS.
Frequently Asked Questions About CCSVI and MS
Q: What is the National MS Society’s view of CCSVI?
A: In trying to find the cause and more effective treatments for a disease as complex and unpredictable as multiple sclerosis, the Society is steadfast in its commitment to pursue all promising avenues of research that can lead to improved treatments and ultimately, a cure. It is important for researchers to think outside the box and we believe Dr. Zamboni has done this. His hypothesis is a path that must be more fully explored and Dr. Zamboni himself has stated that additional research is essential to evaluate it.
Q: Will the National MS Society fund research into CCSVI in MS?
A: The National MS Society is pursuing follow-up research in how CCSVI might be involved in the MS process and we have invited investigators from around the world whose research is relevant to MS to submit proposals to apply for grants that would explore this lead. These applications will undergo an accelerated review process and an announcement on what grants are to be funded will be made in the late spring.
Q: Do the reports of a possible association between insufficient vein drainage and MS mean that MS is caused by venous insufficiency?
A: Based on results published about these findings to date, there is not enough evidence to say that obstruction of veins causes MS, or to determine when this obstruction may occur in the course of disease. Dr. Zamboni's preliminary research reported that 47% of the people who had the blockage in their internal jugular veins treated surgically had a recurrence of blockage by the end of the initial study. This is one of many reasons why additional research into what all this information might mean to the worldwide effort to arrest MS is so important.
Q: If CCSVI turns out to be important in MS, can it be treated?
A: It is too soon to determine how CCSVI might best be treated. Surgical procedures for CCSVI in MS are still experimental and should be undertaken only as part of formal clinical trials that include all of the standard safeguards that are followed in such trials because of known adverse events and at least one death that occurred as a result of a surgical treatment protocol.
Q: How can I get involved in research on CCSVI in MS?
A: A larger-scale clinical study is getting underway in Buffalo, New York and is now recruiting participants nationwide with the aim of evaluating the prevalence of venous obstruction in people with MS. This study does not involve treatment of venous obstructions.
Q: While research is underway to better understand the possible relationship between CCSVI and the MS disease process, why should I not try this endovascular surgery to prevent my MS from worsening?
A: Though this is a decision that patients with MS need to make with their neurologists, we are not recommending experimental endovascular surgery at this time because of known adverse events and at least one death that occurred as a result of the surgical treatment protocol.
For anyone considering endovascular surgery, the following are some of the possible adverse events that need to be considered:
Complications and even death can occur including the risk of infection at the puncture site, risk for damage to the blood vessel, risk of internal or external bleeding if anti-coagulants are used, and, if a stent is inserted in an attempt to keep the vein from narrowing once more, there is a risk that the stent may become dislodged and go to the heart, which could cause death or the need for emergency heart surgery.
Q: I have MS. Should I be tested for signs of CCSVI?
A: We do not recommend testing for signs of CCSVI unless you are involved in a research study exploring this phenomenon, since at this time there is no proven therapy to resolve any abnormalities that might be observed, and it is still not clear whether relieving venous obstructions would be beneficial or safe.
Q: Does CCSVI make the standard treatments of MS meaningless?
A: No. There is ample evidence proving that the FDA-approved therapies for MS provide benefit for people with most forms of MS.
Q: Should the Society be doing more to support the work of Dr. Zamboni, as some people have suggested?
A: Dr. Zamboni has called for more research to move his preliminary CCSVI research forward and the Society is leading the way in advancing that effort. We have reached out to MS scientists from around the world to fund projects that will explore Dr. Zamboni’s leads, have expedited the grant review process, and brought together international MS organizations and experts to share information and move the research process forward. As in all pilot research, Dr. Zamboni’s work has raised as many questions as it has potentially answered. The Society’s role is to help ensure long term that while we are seeking to stop MS and repair the damage done by the disease, we are also working to ensure that whether someone is diagnosed with MS today or ten years from today that there will be safe and effective treatment options available. It is research such as this that has made MS a treatable disease today.
Q: What are some of the questions raised in Dr. Zamboni’s research that need to be explored?
A: Why has venous obstruction recurred in such a large percentage of patients who underwent the endovascular surgery and what does that mean to the disease process for these individuals? Is there abnormal venous obstruction in all people with MS? How do we determine who might best benefit from endovascular surgery? Can Dr. Zamboni’s results be replicated in larger controlled and blinded studies of MS patients? If so, when does CCSVI occur in the course of the disease – is it a cause or effect of the disease process? How can we address the known risks associated with endovascular surgery? Acknowledging the questions that Dr. Zamboni himself has raised only helps in designing the necessary research to secure the needed answers.
Q: Is it true as some people have suggested that the Society’s dependence on money from the pharmaceutical industry is impeding its support of Dr. Zamboni’s research?
A: No. Less than 4% of the Society’s annual income is received from the pharmaceutical industry. The majority of the funds that the Society uses to support our research and service programs come from special events and the donations of private individuals committed to ending MS. Further, we are fast-tracking our efforts to fund research regarding CCSVI and working in partnerships with MS organizations and experts worldwide to better understand and move forward Dr. Zamboni’s findings.

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January - 2010

$4.5 Million Appropriated to Continue Established MS Research Program

We are pleased to announce that $4.5 million has been appropriated within the FY 2010 Congressionally Directed Medical Research Programs (CDMRP) for multiple sclerosis research. This program is funded through the Defense Department at the direction of Congress and was signed today by the President. This latest appropriation is a continuation of the MS program that was founded in FY 2009.
"This continued opportunity is of great benefit to not only our nation’s 28,000 veterans living with MS, but to everyone and every family touched by the disease," said Joyce Nelson, National MS Society’s President and CEO. "Emerging evidence has shown that combat veterans could be at an increased risk of developing MS. This important ongoing research being conducted under the CDMRP could help us move one step closer to better treatments and a better understanding of the disease."
Congressman Russ Carnahan (MO-3) and Congressman Michael Burgess, M.D. (TX-26) have been strong advocates in this effort and have led a multi-Member letter of support for the appropriations request, garnering the signatures of more than 100 Members of Congress. "We owe it to the brave Gulf War veterans who have proudly served their nation to look into the causes of the higher rate of MS appearing in this population and to research possible cures," said Congressman Russ Carnahan. "By shedding more light on the causes and treatments for MS those with combat service related MS as well as all others with the disease are given hope for a future cure." Congressman Michael Burgess, M.D. continued, "Multiple sclerosis is a cruel disease, and one of the great unsolved mysteries of our day. As a medical doctor and a Member of Congress, I am proud to support work to research and help find cures and treatments for MS and other health care challenges that Americans, including our nation’s veterans, face."
Beginning in 2006, MS activists went door to door and engaged online tools to collect more than 100,000 signatures supporting a research program for MS within the CDMRP. Building on this impetus, Society Chapters with their MS activists and our Federal Advocacy team in Washington, DC participated in hundreds of congressional meetings on the Hill and in home states. They took the case to the media, to town hall forums and testified before Congress. In addition, MS clinicians and people living with MS served on an Integration Panel, which helped to prioritize the MS research areas within the FY 2009 program. The first round of applications for 2010 that will be funded are expected to be announced this spring. "The tireless work of the thousands of MS activists who advocated across the country for these continued appropriations is a vivid example of the power that each of us have in working to create a world free of MS," said David Chatel, National MS Society Executive Vice President, Advocacy.

Other allies who helped petition Congress for this new MS research funding included the American Academy of Neurology, the Paralyzed Veterans of America, United Spinal, AMVETS, the Vietnam Veterans of America, and the Disabled American Veterans.

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2009

A LOOK BACK ON WHERE WE HAVE COME SINCE LAST YEAR

This year saw exciting research progress, with unprecedented opportunities on the horizon and more scientists than ever working on important questions. While the economic environment resulted in an unfortunate slowing of funding creating gaps in planned expenditures to support MS research, it is the hope this impact will be of short duration.

Despite these challenges, the National MS Society continues to propel research forward and move us closer to a world free of MS.

In 2009 the MS Society provided over $33.5 million to support 345 new and ongoing projects in it's research portfolio, plus $1.5 million for Fast Forward, the drug development subsidiary which continues to attract new funding streams. In addition, thanks to the efforts of MS activists, $5 million has been specifically set aside for funding MS research out of the 2009 Department of Defense budget.

The MS Society has nimbly pursued promising opportunities when they arise, such as the recent request for research applications to expeditiously examine the potential impact of the chronic cerebrospinal venous insufficiency (CCSVI) hypothesis on disease process in MS.

Here is just a small sample of the many important, potentially high-impact research results that occurred this year, which support the three research goals set out by our MS Society: stopping MS, reversing the damage and restoring function, and ending MS forever.

STOPPING MS

Several papers published this year provided more evidence that starting on MS therapies early after disease onset, or even before a definite diagnosis, can pay off later by delaying disease progression. In addition, results of clinical trials of oral therapies and therapies with infrequent dosing regimens were presented at medical meetings and in journal articles this year. So far, some appear to have benefit against MS attacks, and safety profiles look acceptable.

Novartis International AG announced that ORAL FTY720 (fingolimod) significantly reduced relapse rates and slowed disability progression over two years on a large-scale, phase 3 trial in relapsing-remitting MS. According to the company, safety data confirmed a positive benefit-risk profile, and the company plans to seek marketing approval at the end of calendar year 2009.

An oral drug was submitted to the FDA for marketing approval in September 2009. In a large-scale clinical trial, cladribine tablets significantly reduced relapse rates and other disease activity in people with relapsing-remitting MS. If the FDA application is successful, it would be the first approved oral disease-modifying therapy for MS.

Positive results were announced by sponsors of a clinical trial of the experimental IV monoclonal antibody ocrelizumab, which significantly reduced disease activity on MRI scans in a study of 220 people with relapsing-remitting MS. Since this was a phase 2 study, additional research will be needed to further determine this drug's safety and benefits.

An international task force convened by the MS Society published a landmark paper in the journal Multiple Sclerosis to guide neurologists through the complex process of distinguishing MS from look-alike disorders ("differential diagnosis"). This paper was the most frequently downloaded paper from the journal's Website this year.

FAST FORWARD made its first investments in promising agents. This effort to speed the delivery of new treatments to people with MS has already attracted over $20 million in new funding.

A small NIH-supported study by Stanford University researchers found that women who breast fed their babies exclusively (without giving supplemental bottles) for at least the first two months postpartum were less likely to have an MS relapse than those who did not breast feed or who did not breast feed exclusively during the first two months.

Multiple previous studies have documented that smoking cigarettes increases the risk of developing MS. Harvard researchers have now tracked hundreds of smokers, ex-smokers and never-smokers, all of whom had MS, for an average of over three years. They reported that disability progressed more quickly in smokers. And in several measures, ex-smokers did not differ substantially from never-smokers, suggesting that quitting may delay MS progression. In two other separate studies, State University of New York, Buffalo researchers reported links between smoking and brain tissue damage observed on MRI scans of people with MS, and Karolinska Institute investigators in Sweden confirmed negative effects of smoking, but found no association between the use of
Swedish snuff and the risk of developing MS. This latter study suggests that a component of cigarettes other than nicotine is responsible for the increased risk of developing MS.

Early, small-scale trials are underway or getting started to test the potential of a special type of adult stem cell found in the bone marrow, called mesenchymal stem cells. Although these cells have the potential for both turning down MS immune attacks and stimulating nervous system repair, it's still too early to know whether this approach will prove safe and beneficial.

To help ensure that stem cell trials are conducted in a scientifically sound way that will move the field forward, the Society convened an international meeting with our counterparts in the U. K., Italy, and France to develop guidelines for stem cell trials, which are expected to be published in 2010.

An international team funded in part by the National MS Society reversed MS in mice by administering lisinopril, a drug commonly used to lower blood pressure. A drug used to treat diabetes (metformin) also improved MS-like disease in mice in a study by Society-funded researchers from Medical University of South Carolina and Mayo Clinic. And researchers from Canada reported that mice recovered from MS-like disease when administered a compound called (GIFT15) formed by fusing two immune proteins.

A European collective of imaging experts known as "MAGNIMS" published new information on imagine and clinical findings that might help explain why some people experience a mild course of MS, also known as "benign" MS. They recommended that cognitive functions, not just physical functions, be taken into account when labeling a person's MS as benign.

The first large-scale clinical ("phase II") trial of the sex hormone estriol in MS, funded by the National MS Society and especially its Southern California chapter, along with the NIH, continued to recruit women with MS to participate, expanding the number of centers to 16 across the US. The two-year trial could lay the groundwork for a larger, definitive trial that could lead to a new treatment option for women with MS.

REVERSING MS DAMAGE & RESTORING FUNCTION

In response to reports that a phenomenon called CCSVI (chronic cerebrospinal venous insufficiency, a dysfunction of the brain blood flow and/or blood drainage) may contribute to nervous system damage in MS, the Society invited investigators to apply for grant funding and created an accelerated review process to explore this lead. If confirmed, this may open up new research avenues into the underlying pathology of MS and new approaches to therapy.

The Society gathered together 70 members of the four international Promise: 2010 Nervous System Repair Teams to share progress and plan next steps to speed clinical trials of therapies to protect and reverse neurological damage. Each team reported impressive progress, with two of the teams about to launch new, small-scale clinical trials of different types of stem cells, with separate funding.

Members of the Society's Nervous System Repair Team led by Professor Charles french-Constant (University of Edinburgh and University of Cambridge, UK) published a paper demonstrating that a complex network of proteins that interact during brain development (called the "Wnt signaling pathway") may also play an important role in the failure of nerve-protecting myelin to repair itself in people with MS. This could provide new clues to reversing myelin damage.

After showing benefits for temporarily improving walking speed in all types of MS in two phase 3 clinical trials, an advisory committee for the FDA recommended marketing approval for Acorda Therapeutics' fampridine (with the proposed new name, Amaya). If approved, this oral drug would be the first approved specifically for managing MS symptoms. The National MS Society funded early stage studies in the development of this drug.

Two groups funded by the Society reported findings on nerve tissue injury and repair that add important information needed to stop MS progression and develop nervous system repair strategies. Mayo researchers found two enzymes that may serve as markers of progressive MS and nerve fiber injury, and investigators at Mount Sinai School of Medicine (New York) reported that a different enzyme is essential for replenishing myelin-making cells that have been depleted by MS.

An oral drug designed to treat uncontrollable laughing and/or crying (also called pseudobulbar affect), a troubling symptom experienced by some people with MS and other neurological disorders, passed another hurdle by showing positive results in a Phase 3 trial. According to company sources, ZenviaTM (Avanir Pharmaceuticals) significantly reduced the rate of laughing and crying episodes and appeared to be safe and well tolerated.

ENDING MS FOREVER

The Society launched a genetics study that should identify most of the common genes that contribute to making people susceptible to developing MS. In the short run this should set us up to discover new disease pathways that can be targeted for therapy. In the longer run, this should provide a map for preventing MS.

Researchers at the University of Buffalo, New York and Italy reported two studies that add to growing findings linking the Epstein-Barr virus (EBV) with multiple sclerosis. One study suggested a link between EBV exposure and the loss of nerve tissue, while the other explored interactions between a person's genes and EBV.

Two studies published in the journal Nature Genetics identified new genes and gene regions that contribute to making people susceptible to developing MS. The findings, by the International Multiple Sclerosis Genetics Consortium and the Australia/New Zealand MS Genetics Consortium, add to a growing list of gene variations linked to MS susceptibility. The National MS Society funded the formation of the International MS Genetics Consortium and studies by the Consortium.

For the first time, researchers in the UK and Canada found evidence of a direct interaction between vitamin D and a common genetic variant, the presence of which increases the risk of developing MS. The research highlights the importance of studying the interaction of genes and the environment to search for the underlying triggers of this complex disease.

The Society convened an international workshop focused on strategies to find the cause of MS, as well as factors that drive progression and ways to estimate MS frequency. One outcome from the workshop is the proposed funding of a two-year pilot project to plan a large study to determine risk factors that drive MS progression and predict prognosis.

The Society also held the first-ever Don Tykeson Fellows Conference to stimulate new research ideas and strengthen the commitment of these bright young people to MS research. Supporting fellows, who are the future of MS research, is a key component of the Society's strategic plan.

These and other leaps forward - accomplished in the midst of the worst economic downturn since the Great Depression - made 2009 a momentous year of progress toward a world free of MS.

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December - 2009

PANEL RECOMMENDS THAT FDA APPROVE FAMPRIDINE-SR (proposed name AMAYA) FOR SYMPTOMATIC TREATMENT OF MS -- FOUND TO IMPROVE WALKING SPEED FOR ALL TYPES OF MS

A U.S. Food and Drug Administration advisory committee today recommended that the agency approve marketing of Fampridine-SR (Acorda Therapeutics, with a proposed name change to AMAYA) for its ability to improve walking speed in people with any type of multiple sclerosis. While the FDA is not required to follow the recommendations of its advisory committees, it usually does. The agency is expected to make a final decision about whether to approve the drug for market on or before the target date of October 22, 2009.

During an all-day meeting held October 14, 2009, the FDA advisory committee considered Acorda Therapeutics' application for approval of Fampridine-SR, reviewing data about the drug's effectiveness and safety. The committee also heard public testimony from individuals and patient advocacy groups, including the National MS Society, which testified to the unmet need for therapies to improve walking for people with MS.

Among its discussions, the advisory committee recommended that the FDA require the sponsor to evaluate the effects of doses lower than originally studied, but that these studies would not be required to be done prior to the drug's marketing approval. In addition, the FDA is likely to require a plan to mitigate potential risks. During its presentation to the committee, Acorda representatives outlined such a plan -- the Risk Evaluation Mitigation Strategies (REMS).

BACKGROUND ON UNMET NEED: Problems with gait (difficulty in walking) are among the most common limitations in MS. While there are six FDA-approved disease-modifying therapies that are at least partially effective against some forms of the disease, as well as rehabilitation and symptomatic treatments for some symptoms, at present there is no pharmacologic treatment specifically available for MS-related difficulty walking. This disability has wide-ranging effects on people's lives, even in its milder manifestations.

A recent survey among more than 1,000 individuals with MS and many of their family members examined the impact of mobility issues, such as difficulty walking, on quality of life among patients with MS and their families. Some two-thirds of patients reported difficulty walking and of these, 70% reported that such difficulty was the most challenging part of their MS, and most reported that difficultly walking restricts their daily activities significantly, including their ability to travel.

ABOUT THE DRUG: Fampridine-SR is a sustained-release formula of 4-aminopyridine, which 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. The first studies of this potassium-blocking approach in people with MS were supported by the National MS Society.

WHAT CLINICAL TRIALS FOUND: Acorda Therapeutics sponsored two phase 3 clinical trials of the drug. In the first, involving 301 people with any type of MS, walking speed increased by 25%. Results of this study have been published (February 28, 2009 issue of the Lancet (2009 373;732-738, summarized here). Results from a later, second phase 3 study involving 240 people with MS confirmed the benefits seen in the first, finding that a significantly greater proportion of people on the therapy had a consistent improvement in walking speed compared to those who took placebo. Among those taking Fampridine-SR who improved in walking speed, there was a statistically significant improvement in leg strength.

In the first study, common adverse events (side effects) experienced more often by those on active treatment included back pain, dizziness, insomnia, fatigue, nausea and balance disorder. Two serious adverse events led participants to discontinue taking the drug (one case of anxiety and one seizure in a person who developed sepsis from a urinary tract infection). In the second study, additional common adverse events in those on therapy included urinary tract infection, falls, and headache.

Further study and clinical practice may help determine the extent to which the drug may impact other functions not measured in the clinical trials, and provide hints as to which patients are most likely to respond.

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WALKING (GAIT), BALANCE, & COORDINATION PROBLEMS

Problems with gait (difficulty in walking) are among the most common mobility limitations in MS. Gait problems are related to several factors.

**  WEAKNESS: Muscle weakness is a common cause of gait, difficulty. Weakness can cause problems such as toe drag, foot drop, "vaulting" (a compensatory technique that involves raising the heel on the stronger leg to make it easier to swing the weaker leg through), compensatory hip hike, trunk lean, or circumduction (swinging leg out to the side). Weakness in both legs is known as para paresis; weakness in only one leg is called mono paresis. Weakness can often be compensated for with the use of appropriate exercises and assisting devices, including braces, canes or walkers.

**  SPASTICITY: Muscle tightness or spasticity can also interfere with gait. Stretching exercises and antispasticity medications such as baclofen or tizanidine are generally effective in treating this symptom.

**  LOSS OF BALANCE: Balance problems typically result in a swaying and "drunken" type of gait known as ataxia. People with severe ataxia generally benefit from the use of an assisting device.

**  SENSORY DEFICIT: Some people with MS have such severe numbness in their feet that they cannot feel the floor or know where their feet are. This is referred to as a sensory ataxia.

**  FATIGUE: Many people will experience increased gait problems when fatigue increases.

Most gait problems can be helped to some extent by physical therapy (including exercises and gait training), the use of appropriate assisting devices and, in some cases, medications. Careful evaluation by a trained health care professional is essential for creating the appropriate therapy program for each individual.

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November - 2009

POSITIVE RESULTS PUBLISHED OF FIRST OF TWO PHASE 3 CLINICAL TRIALS OF FAMPRIDINE-SR

Walking speed improved significantly in a phase 3 clinical trial of 301 people with all types of MS taking oral Fampridine-SR (Acorda Therapeutics, Inc.), a drug designed to provide symptomatic relief by compensating for lost nerve conduction. Fampridine-SR is a sustained-release formula of 4-aminopyridine, which temporarily enhances nerve signaling by blocking tiny pores, or potassium channels, on the surface of nerve fibers. A paper describing the study, by Dr. Andrew Goodman (University of Rochester) and colleagues, is published in the February 28, 2009 issue of The Lancet (2009 373;732-738).

Results from a later, second Phase 3 study, announced in 2008, confirmed Fampridine's benefits reported here. In early February 2009, Acorda announced that it had applied to the FDA for marketing approval of Fampridine for multiple sclerosis.

BACKGROUND: Problems with gait (difficulty in walking) are among the most common mobility limitations experienced by people with MS. Fampridine-SR is a sustained-release formula of 4-aminopyridine, which 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. The first studies of this potassium-blocking approach in people with MS were supported by the National MS Society.

THE STUDY: A total of 301 people with all types of MS participated at 33 sites in the U.S. and Canada. Participants were randomly divided such that 224 were on active treatment and 72 were on inactive placebo over 14 weeks. Participants were permitted to remain on other medications during the trial, establishing the potential of the drug as a symptomatic management strategy that could be used along with their regular medications and disease-modifying therapies.

RESULTS: Thirty-five percent of those on active therapy, versus only eight percent of the placebo group, experienced significant improvements in walking speed. The walking speed for those who responded to therapy improved an average of 25.2% (in the timed 25-foot walk), compared to only 4.7% in the placebo group, and the improvement 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 for individuals; in this study, those who responded to the drug reported feeling less disabled in daily activities requiring mobility.

Other positive outcomes included increased leg strength in those on active treatment, even in some individuals whose walking speed did not improve.

Common adverse events (side effects) experienced more often by those on active treatment included back pain, dizziness, insomnia, fatigue, nausea and balance disorder. Serious adverse events that led to discontinuation of the drug included one case of anxiety and one seizure in a person who developed sepsis from a urinary tract infection. There were no deaths during the treatment phase of the study, but one person died five weeks after the last treatment visit of heart disease, which was deemed by investigators to be unrelated to the therapy.

Results from a later, second phase 3 study, announced in 2008, confirmed the benefits seen in this trial. The company announced that it had applied to the FDA for marketing approval of Fampridine in early February 2009.

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October - 2009

FLU VACCINE AND H1N1 (SWINE FLU) VACCINE INFORMATION FOR 2009-2010

REGULAR FLU SHOT: As in previous years, the National MS Society recommends a regular flu shot as a safe and effective vaccination for people with MS. The flu shot - which is a de-activated or "killed" vaccine - can safely be taken by individuals who are on any of the disease-modifying medications (Avonex, Betaseron, Copaxone, Rebif, Novantrone, or Tysabri), (all are registered trademarks of their respective companies).

FluMist INTRANASAL: In 2003, the FDA approved a flu vaccine nasal spray "for healthy children and adolescents, ages 5-17, and healthy adults, ages 18-49." According to Dr. Aaron Miller, the Society's Chief Medical Officer, FluMist--which is a live, weakened vaccine--is not recommended for use by people with MS, and should specifically  be avoided by any person with MS who is on an immunosuppressive medication such as mitoxantrone (Novantrone), cyclophosphamide (Cytoxan), azathioprine (Imuran), or methotrexate, (all are registered trademarks of their respective companies).

**  Live-virus vaccines are more likely than de-activated-virus vaccines to cause an increase in disease activity in people with MS.

**  A person taking an immunosuppressive medication is more susceptible to developing an infection with the vaccine strain of the virus--an infection that may be particularly severe because the person's immune system is suppressed.

**  The interactions between live vaccines and the disease-modifying medications are not known.

H1N1 (SWINE FLU) VACCINE: The H1N1 (Swine Flu) vaccine is still in production, so its safety and efficiency have not yet been established. It is anticipated that the vaccine will be available in the fall of 2009, probably in October. When it becomes available, the recommendations for its use in people with MS will likely be the same as the recommendations for the regular flu vaccine. If a live, attenuated version of the H1N1 vaccine is also produced, it should be avoided by individuals with MS.

The initial supply of H1N1 vaccine will not be adequate to vaccinate everyone. The CDC has indicated that five groups will initially be targeted for vaccination:

**  Pregnant women

**  Persons who live with or provide care for infants under 6 months of age

**  Healthcare and emergency services personnel

**  Children and young adults aged 6 months to 24 years of age

**  Persons aged 25-64 who have medical conditions that put them at higher risk for influenza-related complications.

It is important to note that people with disabilities (including people with MS) are not necessarily considered part of this high-priority group. However:

**  The flu virus (like any other virus) can precipitate MS exacerbations

**  A person with advanced MS or someone with less severe disease (Kurtzke 6.0) who has reduced pulmonary function or has any difficulty with breathing is considered at risk for complications and a good candidate for the H1N1 vaccine.

We recommend that people talk with their MS doctor to determine if they are a good candidate for the H1N1 vaccine.

IN SUMMARY:

**  People with MS should consult with their physician about obtaining a regular flu shot as soon as the regular flu vaccine is available.

**  They should also discuss with their neurologist whether they should get the H1N1 vaccination because (1) catching the flu would put them at greater risk of an exacerbation, or (2) their MS symptoms are severe enough to put them at risk for flu complications.

**  The FluMist nasal spray vaccine and any live, attenuated version of the H1N1 (of one is produced) are not recommended for people with MS.

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September - 2009

BREASTFEEDING MAY REDUCE LIKELIHOOD OF POSTPARTUM MS ATTACKS

Annette Langer-Gould, MD, PhD (Stanford University) and colleagues followed 32 pregnant women with MS, assessing their disease and breastfeeding status at intervals out to 12 months after giving birth. They found that women who breast fed their babies exclusively (without giving supplemental bottles) for at least the first two months postpartum were less likely to have an MS relapse than those who did not breast feed or who did not breast feed exclusively during the first two months (36% who breast fed exclusively experienced a relapse, as compared to 87% who did not breast feed or who supplemented with formula).

This pilot study, funded largely by the National Institutes of Health, was presented at the 2009 American Academy of Neurology meeting and was published early online in the Archives of Neurology on June 8th, 2009.

While the study is small, it focuses attention on a quandary facing women with MS and their doctors: the crucial time period after giving birth, when there is a higher risk for relapse, and many women are advised to go back on their disease-modifying therapies as soon as possible. Since there is insufficient evidence to support the safety of breastfeeding while using any of these therapies, most babies born to moms with MS are bottle fed, despite known health benefits of breastfeeding for infants. More research is needed to help guide postpartum treatment decisions.

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August - 2009

TWO STUDIES FIND NEW GENES & GENE REGIONS THAT MAKE PEOPLE SUSCEPTIBLE TO MS

Two studies recently published in the journal Mature Genetics report identifying new genes and gene regions that contribute to making people susceptible to developing MS. The findings, by the International Multiple Sclerosis Genetics Consortium and the Australia/New Zealand MS Genetics Consortium, add to a growing list of gene variations linked to MS susceptibility. Identifying all MS genes will likely lead to the development of more effective ways to treat the disease, and open the door to uncovering the cause of MS, which may lead to its prevention.

In an analysis of several genome-wide scans, Philip De Jager, MD, PhD (Brigham & Women's Hospital, Boston) and colleagues in the International Multiple Sclerosis Genetics Consortium (IMSGC, a group of international MS genetic experts created with funding from the National MS Society) report that three genetic variations appear to make people more susceptible to developing MS, including genes that instruct the immune messenger proteins interferon beta and tumor necrosis factor-alpha. (Nature Genetics, Published online: June 14th, 2009) This adds to earlier work by the Consortium and other independent investigators, who have now identified scores of genes that may contribute to MS susceptibility. A small number of these have already been validated and many are currently undergoing validation (confirmatory) studies.

Justin Rubio, PhD (Florey Neuroscience Institute, Melbourne) and colleagues in the Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene, supported by MS Research Australia, among others) published the results of a large-scale gene scan that confirmed the association of several genetic variations previously reported to be linked to MS, and identified two loci (regions on the chromosome where genes are located) on Chromosomes 12 and 20 that have been linked to other autoimmune disorders, but not yet to MS. (Nature Genetics, Published online: June 14th, 2009)

A major effort has been under way for over a decade to search for the genetic underpinnings of MS - the inherited set of genes that make people susceptible to the unknown triggering factor or factors that lead to the disease. If successful, it would give scientists a roadmap to the cause of MS, as well as to concrete targets for new therapies and possibly even ways to prevent the disease. This painstaking search, involving analysis of the genome (all the genes within the body) and the banking of thousands of DNA samples from patients and family members, was jump started when the IMSGC used cutting-edge gene-chip technology to complete the largest replicated whole genome scan for MS yet in 2007. Now, only two years later, the IMSGC and other groups are taking full advantage of these technologies to identify more and more genes that seem to predispose people to MS.

This international group pooled together data from three separate genome-wide studies in people with MS, including 895 people with MS genotyped in its original scan. Genetic material from a total of 2,624 people with MS and 7,220 controls without MS were analyzed, and replicated in a sample of 2,215 people with MS and 2,116 controls without MS. The study confirms that three new genetic variations are associated with MS; these variations exist in the genes for interferon regulatory factor 8, tumor necrosis factor receptor super family member 1A, and CD6 - immune messenger proteins. The data may indicate that these proteins are involved early on in the development of MS, note the authors. With support from the Wellcome Trust, the National MS Society and other sponsors, the IMSGC is conducting a very large scale genetics project to validate their discoveries and identify all remaining genes that exert significant effects on MS susceptibility.

An Australian group compared genetic material from 3,874 people with MS and 5,723 people without MS in search of gene variations that appeared to make people more susceptible to developing the disease. They confirmed several gene variations that had been identified in previous studies, including the immune system-related genes CD58, HLA-DR15, IL2RA, and IL7R. The team also identified two loci on Chromosomes 12 and 20 that have been associated with other autoimmune diseases such as rheumatoid arthritis, but not yet with MS. Further study is necessary to determine the exact nature of the genetic variations at work in MS within these loci, but the authors note one interesting candidate -- CYP27B1 on chromosome 12, a gene that instructs vitamin D. There is growing evidence that vitamin D may help protect against the development of MS.

"The pace of advancing genetics technology must by matched by the willingness of researchers to work together worldwide, and of people with MS to participate in genetics research," says John Richert, MD, Executive Vice President of Research & Clinical Programs at the Society. "These studies demonstrate the highest degree of collaboration among people dedicated to a world free of MS. We are fortunate to be witnessing this exciting era in MS genetics."

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July - 2009

WHY DO SOME PEOPLE HAVE A MILD COURSE OF MS?

MRI experts weigh factors that may help determine when MS is "Benign".

"MS is notoriously unpredictable in its course," commented John R. Richert, MD, a neurologist and head of the Society's research and clinical programs, "and there's no way to reliably predict over the long run whether a person will experience a mild or severe course." Finding a way to predict who will have a mild course of MS would allow doctors to give better advice, and possibly spare some individuals from the expense and inconvenience of taking an MS therapy.

"Right now, the best advice we can give is to get on an MS therapy as soon as possible following a definite diagnosis of MS with active disease, and for many even after experiencing a first attack that puts them at high risk for developing MS," said Dr. Richert. That's because at the time of diagnosis and for years thereafter, it is impossible to know if the disease will be benign or more active, and early treatment is the best defense we have for slowing this disease.

Beyond prognosis, studying benign MS also holds promise for people with all types of MS: If we knew what made some people experience a mild course, that knowledge might be translated into slowing down the disease in people who experience more active MS.

A collaborating group of imaging experts from Europe, called MAGNIMS, recently held a workshop to review major MRI (magnetic resonance imaging) studies that have been done in people who had a benign course of MS (mild MS over 15 or more years), in comparison to those with more typical courses. MRI offers a window to MS activity in the brain that often doesn't show up as obvious symptoms. The workshop results were recently published in the journal Neurology.

The investigators were seeking flags that might distinguish people with mild MS from those with more disabling forms of the disease, and also clues to what factors make a person's MS course mild. While there was no slam-dunk -- no clear-cut MRI findings that were consistently unique to people with a benign course - they uncovered some significant trends.

In general, compared to more active forms of MS, they found that people with a benign course had fewer areas of damage (lesions) and shrinkage (atrophy) in specific areas of the brain critical to movement and other important functions that contribute to disability. These factors, along with the ability of the brain to compensate for damage by moving functions to other regions of the brain (a phenomenon called brain plasticity), may account for the milder course in people with benign MS.

Further research is needed to understand benign MS and to find early predictors that would help doctors advise people in their care. "The group's urging that neurologists take into account individuals' cognitive functions, not just their physical functions, when labeling a person's MS as benign is an important one, and should lead to a refined definition of benign disease," commented Dr. Richert.

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June - 2009

TEAMS FUNDED BY THE MS SOCIETY REPORT ON KEY ENZYMES RELATED TO MS PROGRESSION AND NERVOUS SYSTEM REPAIR

Two teams of researchers funded by the MS Society have reported findings on nerve tissue injury and repair that add important information needed to stop MS progression and develop nervous system repair strategies. Isobel Scarlsbrick, PhD (Mayo Clinic and Foundation, Rochester, MN) and colleagues have found two enzymes that may serve as markers of progressive MS and nerve fiber injury. Patrizia Casaccia, MD, PhD (Mount Sinai School of Medicine, New York) and colleagues reported that another enzyme is essential for replenishing myelin-making cells that have been depleted by MS. Both teams are continuing these lines of research in hopes of identifying targets for the development of new therapies for MS.

Dr. Scarlsbrick reported her team's findings related to MS progression at the annual meeting of the American Neurological Association (Abstract T-99). Dr. Casaccia's report on the enzyme critical for repair appeared in Nature Neuroscience.

PROGRESSIVE MS AND KLK ENZYMES (DR. SCARISBRICK'S TEAM): Understanding the processes that lead to tissue damage in MS is crucial to feed parallel efforts to protect and repair the brain and spinal cord. Dr. Scarisbrick previously found elevated levels of "KLK6" (a newly identified member of the kallikrein enzyme family) in areas of damage found in tissue samples from people with MS. Now, in a follow-up study, the group has studied the levels of KLK6 and other kallikreins in blood samples taken from 35 people with different clinical courses of MS and 62 controls without MS.

The results show that KLK1 and KLK6 were elevated in people with MS, with the highest levels appearing in people with secondary-progressive MS (a course of MS that initially is relapsing-remitting and then becomes progressive, with or without occasional relapses and minor remissions).

The team also exposed nerve cells isolated from mice to KLK1 or KLK6 in the laboratory, and found that the enzymes promoted nerve cell loss. Dr. Scarisbrick is continuing to study the role of these enzymes in nerve fiber injury and hopes to find a way to target them with therapeutic strategies for people with progressive MS.

REPAIR AND HDAC ENZYMES (DR. CASACCIA'S TEAM): MS involves immune attacks against brain and spinal cord tissues, primarily myelin, the insulation that surrounds and protects nerve fibers. Several studies have indicated that, early in the disease, immature myelin-making cells - called, "oligodendrocyte progenitors" - are recruited to generate new myelin. A sufficient number of these cells is needed so that progenitors can migrate to the site of myelin damage and develop into myelin-making cells. Then, genes that instruct the formation of myelin components are activated and myelin is formed. In MS, this process fails. Dr. Casaccia is studying whether some molecules may inhibit the activation of the genes that promote myelin formation.

In this study, Dr. Casaccia's team observed the gene activity during oligodendrocyte development in mice with damaged myelin. They found that enzymes called histone deacetylases (HDACs) were crucial to this process, particularly HDAC1 and HDAC2. Deleting these two enzymes impaired the differentiation of oligodendrocyte progenitors, that is, the process by which these cells develop a more specialized form or function. The team is studying how these findings might be translated into therapeutic strategies.

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May - 2009

REPAIRING DAMAGED TISSUES

Decades of research into nerve physiology, MS tissue damage and the biology of glial cells - the numerous brain cells that support nerve cells - have been laying the groundwork for finding ways to restore normal function in individuals with MS.

Nervous System Repair and Protection teams funded by the MS Society's Promise: 2010 initiative are taking this research to the next level, with a goal of placing nerve tissue-protective treatments in clinical trials by the year 2010.

Other research on this topic focuses on the micro-environment of the brain and conditions conducive to stimulating natural repair, and the potential for cell therapies. Exploring glia, which include cells in the nervous system that make nerve-insulating myelin, is a cornerstone of MS research. Myelin appears to be the main target of the immune attack in MS. The cells that make myelin - oligodendrocytes - also are lost in MS. Researchers study aspects of myelin that make it an immune target, and ways that some brain cells can contribute to the immune attack. They are also looking at factors that are important to the growth and development of oligodendrocytes and myelin, to find ways of promoting myelin repair.

The aim of repairing the nervous system is to achieve an actual reversal of the damage caused by MS and to restore function. When myelin is damaged or destroyed, electrical conduction along the nerve fiber is impaired or stopped. Decades of research on myelin and myelin-making cells make it clear that natural myelin repair occurs, and key molecules and growth factors are being identified that may serve as targets for stimulating myelin repair.

In recognition that during the course of MS the nerve fibers, or axons, are also damaged, a new research focus has emerged: in order to repair the nervous system, we must learn how to regenerate axons as well as myelin. Insights into complex mechanisms involved in nervous system development now make it feasible to aggressively address the task of repairing axons as well as myelin in MS.

Approaches to repairing the nervous system are varied. Some are aimed at inducing the body's own cells to more adequately carry out the repair function. Another approach is to introduce replacement cells from a different source. Research into the potential of stem cell therapy is proceeding rapidly, using cells obtained from a variety of adult and non-adult sources. It is currently not clear which source of stem cells, if any, will be of value in treating people with MS. Similarly, if more than one source proves to be valuable, it is not clear which will be best.

The MS Society and the MS International Federation sponsored a Stem Cell Summit meeting in January 2007 to begin to determine how best to answer these questions. This is a field that is in its earliest stages of development, and the Society is funding research studies that will lead to significant advances in our knowledge on this front.

In conjunction with the efforts to repair axons are new efforts to protect them from degeneration in the first place. For example, it is not clear whether axonal degeneration in MS results from a direct attach on axons by the immune system or, alternatively, if the loss of myelin by itself is enough to cause axonal degeneration (i.e., whether myelin has a protective effect on axons that is lost in the MS disease process). The protection of axons from these and other insults are a new area of intense research efforts in MS.

The Nervous System Repair and Protection Initiative, funded through Promise: 2010 is bringing the dream of protecting and repairing brain tissue and restoring function within our grasp.

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April - 2009

EPIDEMIOLOGIC STUDIES HAVE GIVEN US SOME IMPORTANT CLUES ABOUT WHO DEVELOPS MS

The disease affects more than twice as many women as men.

It is most common among people with a northern European heritage but people of other backgrounds develop the disease also.

MS appears to be more prevalent in temperate regions of the world than in the tropics.

It is diagnosed most often in people between the ages of 20 and 50, although it also can develop quite early or quite late in life.

Some possible risk factors that have been identified for MS include cigarette smoking and Epstein Barr virus.

Some possible protective factors that have been identified for MS include intake of vitamin D and greater exposure to sunlight.

Epidemiological studies ultimately seek to discover the cause of MS, and may also serve as the basis for developing future treatments. Many investigators believe that no single infectious agent or environmental factor is "the" cause of MS. Rather, they are exploring how a susceptible person's immune system reacts to a variety of viral or other infections and environmental exposures, and how immune function is linked to hormonal and other factors.

The National MS Society is currently funding several research projects related to MS epidemiology and infectious triggers. These include:

Anthony J. McMichael, MBBS, PhD (The Australian National University) is conducting "A case control study of past sun exposure and first demyelinating events" to investigate whether vitamin D, through sunlight exposure, reduces the risk of developing MS. Recent research indicates that UVR (or vitamin D synthesized via UVR exposure) can dampen the immune attack. This might provide a biological mechanism for reduced MS where UVR exposure is higher. The team is comparing lifetime sun exposure in two groups - people at risk for developing MS (because they experienced an initial neurological episode) and people without MS -- using advanced imaging technology to examine skin, measuring vitamin D status (produced by UVR), and administering a questionnaire about sun exposure. This study may bring us new insight into non-genetic factors that may make people susceptible to the development of MS, and may suggest new avenues for treatment or prevention.

Researchers at the University of Utah are following up on evidence that colds caused by "picornoviruses" are associated with MS attacks, to detect specific viruses causing the colds that may be linked to MS attacks, and comparing MS attack rates in individuals whose colds are due to picornoviruses compared to other types of virus. This study may provide important clues to the specific viral triggers of some MS attacks, and new leads for preventing or treating those attacks.

Ilya Kister, MD (New York University) is conducting a pilot project on the "Prevalence and significance of migraines and other headaches in MS." Headaches are a common, yet understudied problem among people with MS. Why do headaches seem to be more frequent in MS than among healthy people? Many answers are possible. Dr. Kister's team is carrying out a large-scale study with the aim of characterizing the types of headaches that people with MS experience, estimating how frequently they occur, and comparing symptoms and MRI features in people with MS with and without headaches. The team hopes to better understand headaches in MS and pinpoint effective strategies to help alleviate this troublesome symptom.

Helen Tremlett, PhD (University of British Columbia) is asking, "Do relapses affect disease progression in MS?" by evaluating the long-term relationship between MS attacks and disability in a large group of individuals with MS. The majority of people with MS experience disabling relapses that can last weeks to months before a full or partial recovery occurs. However, the progression to permanent disability is not necessarily associated with a relapse. The team is focusing on patients enrolled in a database that holds data on 6000 people with MS in British Columbia, examining relapse rates in over 2500 people who have not taken disease-modifying drugs and have been followed for up to 23 years. They are investigating the effect of MS relapses occurring at different stages of the disease on disability progression, using measures such as the EDSS, a scale that measures disease activity. This study may provide much-needed information on the progression of MS, and on how to tailor treatments for individuals with this disease.

Lauren Krupp, MD (State University of New York at Stony Brook) has been identifying cases and characteristics of MS in children under 18 in a region of New York, to lay the groundwork for future studies of this rare condition. Her team is attempting to identify as many children with "pediatric MS" who reside in Long Island, New York as possible, and to estimate its prevalence in the general population. They are also determining whether there are any demographic differences, including race, ethnicity and gender, between children with MS and children without MS. This pilot study is an important first step toward furthering our understanding of MS in children.

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March - 2009

NATIONAL MULTIPLE SCLEROSIS SOCIETY AND ALL THOSE BATTLING THIS DISEASE COMMEND PRESIDENT OBAMA'S STEPS IN REMOVING THE BANS ON EMBRYONIC STEM CELL RESEARCH

The National Multiple Sclerosis Society is a driving force in creating a world free of MS. To advance this goal, the Society continues to seek ways to prevent, slow the progression or repair the effects of MS. One channel is by supporting scientifically meritorious medical research, including research using human cells. This is done in accordance with federal, state and local laws and with adherence to the strictest ethical and procedural guidelines. For the past eight years, federal policies have impeded these efforts by severely limiting the number of approved embryonic stem cell lines that could be used in federally funded research and prohibiting the donation of unused embryos for research purposes by people utilizing the services of in vitro fertilization clinics.

President Obama has taken a major step in removing the barriers to a promising path of responsible scientific research and the Society commends him for the new hope and optimism he brings to the millions of people living with chronic and debilitating diseases or disabilities.

GENETICS STUDIES YIELD NEW CLUES TO WHY PEOPLE GET MS

New studies are deciphering the complex picture of genetic characteristics that make people susceptible to MS. Each gives important new clues about why people get MS. Additional large-scale studies, the first stages of which are already underway, promise to uncover the great majority of genes that convey risk for MS, which would pave the way for understanding the basic cause of MS and developing more rational therapies.

CD58 Gene: When it completed the largest replicated whole genome scan (scan of all the genes in the body) for MS to date, the International MS Genetics Consortium (IMSGC) identified and validated variations in two genes that help regulate the immune system as clearly increasing genetic susceptibility to MS, and preliminarily identified several other genes of newly suspected importance in MS. Philip De Jager, MD, PhD (Brigham & Women's Hospital, Boston) and colleagues in the IMSGC now report on one of these other genes, CD58, which instructs the activation of T cells, major players in the immune attack on the brain and spinal cord in MS. They studied this gene in 1530 additional people with MS, and found further evidence of its association with the disease. They pinpointed a specific marker, or segment of DNA, on the gene that is associated with reduced susceptibility to MS. They also showed that the level of CD58 expression (that is, the amount of CD58 protein that is produced from the CD58 gene) is associated with remissions from MS disease activity. Manipulating CD58 is a strategy used to treat other autoimmune diseases, so this study may open up new therapeutic options for people with MS.

KIF1B Gene: Yuri Aulchenko, PhD, Rogier Hintzen, MD, PhD (Erasmus MC University Medical Center, Rotterdam, Netherlands) and colleagues completed a genome-wide study of a unique group - 26 people with MS in the Netherlands who had a common ancestor - a fact unknown to them before the study! They found evidence of heightened risk of developing MS associated with a variant of the gene KIF1B, which is important in the function of nerve cells. The team then sought to confirm these finding in a sample of 2,634 people from the Netherlands, Sweden, and the Canadian Collaborative Project on Genetic Susceptibility to MS, and a group of 2.930 controls without MS. The results strengthened the conclusion that the KIF1B variant is associated with significantly higher risk for developing MS. Since this gene is related to nerve cell function, it may also eventually help to determine why people with MS develop the long-term disability that results from nerve cell damage.

HLA Gene: Stacy J. Caillier, BSc, Jorge Oksenberg, PhD (University of California, San Fransisco) and colleagues have been collecting blood samples from a large number of families affected by MS, funded in part by the National MS Society, focusing on ethnic groups with lower MS susceptibility (e.g., African-Americans) and higher susceptibility (e.g., individuals of Northern European descent), and searching for commonalities and differences that may help pinpoint genes of importance in MS. Here they report an important new finding on HLA genes, which are involved in immune function and have long been associated with MS. The team tackled the problem of how to discern the roles of two different closely related HLA genes - HLA-DRB1 and HLA-DRB5 - by studying a data set of 1635 African-Americans, including 769 people with MS. They found that HLA-DRB1 is associated with MS susceptibility even in the absence of HLA-DRB5, indicating that the former is the primary gene relating to susceptibility. People without HLA-DRB5 were at increased risk of developing secondary-progressive MS, however, this gene may protect against disease progression.

GPC5 Gene: This same team completed a genome-wide study of genetic variations in 978 people with MS and 883 controls without MS. One of their most compelling findings is a link between the GPC5 gene with MS risk. This gene is implicated in nerve fiber regeneration, and previous work by this team suggested that variations in the gene may also help determine a person's response to interferon beta therapy. The team also found that genes relating to MS susceptibility were separate from those linked to disease course.

"Each of these studies give us important new clues to why people get MS and even why it may progress," said John Richert, MD, Executive Vice President of Research and Clinical Programs for the National MS Society. "Of the genes identified so far, some function within the immune system and some are related to nervous system function. There is increased excitement and opportunity to study the many genes related to susceptibility and severity of MS", he added. "In fact, we're currently raising funds for a new international, large-scale study, the first stages of which are underway, that promises to uncover most of the remaining genes that convey risk for MS. This would pave the way for understanding its root causes and for developing more rational therapies and even prevention."

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February - 2009

INTRIGUING LEADS ON THE HORIZON

Decades of basic and applied research into MS and the basic workings of the immune and nervous systems have built a critical platform of knowledge that is serving as a springboard for progress. At the same time, new technologies, such as gene chip technology and new MRI-based imaging techniques, are allowing scientists to revisit age-old questions about MS, and may lead to insights into what causes this disease and what can be done to stop it and reverse its damage.

Researchers are tracking down exciting leads and making headway in virtually every field related to MS. Here are some examples:

**** THE FARTHER ONE LIVES FROM THE EQUATOR, THE HIGHER ONE'S RISK OF MS. Society researchers are exploring whether sunlight exposure is a protective factor, and are looking at many other risk or protective factors for clues to the cause of MS.

**** CAN ROBOTICS RETRAIN THE BRAIN TO IMPROVE WALKING ABILITY? Based on the idea that repetition can help restore strength, balance, and recognition of sensory cues that make walking possible, improving walking ability.

**** MS IS UNPREDICTABLE. Any individual's disease progression, severity, specific symptoms and response to therapies cannot be easily foreseen. But an international team of researchers is taking clues from patterns of MS damage seen in the brain to try to predict the best treatment for any individual.

**** WOMEN ARE MORE PRONE TO DEVELOPING MS, but when men get the disease, it can be more severe.

**** OUR BRAINS HAVE STORES OF CELLS CAPABLE OF REPLACING MYELIN. Can scientists find a way to stimulate these cells to repair MS damage, or do cell transplants hold more promise? Society researchers are on the cutting edge of these important questions.

**** RESEARCHERS BELIEVE THAT A PERSON'S GENES DETERMINE WHETHER THEY ARE SUSCEPTIBLE TO DEVELOPING MS, yet even identical twins have different risks for the disease, depending on their experiences.

**** MS COSTS THE U.S. ECONOMY ABOUT $28 BILLION PER YEAR. Our health care delivery and policy researchers are investigating this and other important issues, such as job discrimination, insurance experiences, and optimal health care settings.

**** DEEPER UNDERSTANDING OF DESTRUCTIVE AND PROTECTIVE IMMUNE FACTORS IN MS, is opening up new opportunities for turning off the attack or to protect brain tissues. Experimental therapies in the pipeline include some in pill form. YEH!

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January - 2009

TREATING MS SYMPTOMS WITH STEM CELLS

Dr. Richard Burt and colleagues at Northwestern University report on the safety and benefits from an early phase study of experimental transplantation of individuals' own blood stem cells to turn off the immune attacks in MS. Unlike some of the previous studies of this procedure, this one involved 21 people with relapsing-remitting disease, rather than people with later stage, progressive disease. (The study results were reported early online on January 30, 2009 in Lancet Neurology.)

In this uncontrolled trial, they found that the procedure was relatively safe, and after an average of 37 months, none had progressed and a significant portion experienced a reversal of at least 1 point on their disability (EDSS) scores, and 76% remained free from relapses. As pointed out by the investigators, it will take larger-scale, controlled trials to determine whether this expensive, potentially risky procedure is superior to other approved treatment options. Controlled trials of this procedure are now recruiting participants.

Autologous hematopoietic stem cell transplantation is similar to bone marrow transplantation to treat cancer, except that it uses the patients' own blood or bone marrow stem cells. In treating MS, the procedure generally involves removing, from the blood stream, a person's cells that are capable of regenerating into new immune cells. These "stem cells" are stored, and the rest of his or her immune cells are destroyed by various chemotherapy or other regimens. Then the stored stem cells are reintroduced by injection. Eventually they grow and repopulate the body with immune cells. The hope is that the new immune cells will no longer attack myelin or other brain tissue, so that the person has perhaps a completely new immune system. However not with out risk. This procedure is strictly investigational, and it carries the risk of death because the body is nearly helpless against infection during the several weeks it takes for the immune system to be restored. There is no proof yet that it can cure a person with MS.

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December - 2008

YOUNG RESEARCHERS SHINE

The MS - Society's 2008 National Conference brought together nearly a hundred young research fellows to add their voices and talents to solving the puzzle of MS. History shows that scientific breakthroughs often come from new thinking, fresh ideas, and young people. The conference is encouraging young scientists ready to embark on careers in biomedical research to focus on the final path of finding the way to stop MS in it's tracks.

The conference aimed to promote the sharing of research information among research fellows and faculty grant recipients, develop a sense of community among investigators, stimulate new research ideas, and strengthen commitment to MS research.

"I'm new to the field of MS, and I'm gratified to see how collaborative everyone is," said Daniel C. Tanner, PhD, a fellow at the University of Rochester.

Twenty-one fellows presented their work on strategies to stop immune attacks against myelin and other central nervous system tissues in MS, including:

>< Yueting Zhang, PhD (Mount Sinai School of Medicine) presented findings from a team led by her mentor Gareth John, VetMB, PhD, on immune messenger protein interleukin-11. The team found that this protein promotes the survival and maturation of myelin-making cells, leading to increases in myelin formation in tissue samples from people with MS.

>< Philip L. Jager, MD, PhD (Brignam & Women's Hospital) reported on his team's finding that CD58, a possible location for one of many MS susceptibility genes, appears to contain genetic variations relevant to inflammation as well as nerve degeneration, but that these may be genetically distinct processes.

>< Ellen Mowry, MD (University of California, San Francisco), a Sylvia Lawry Physician Fellow training to conduct MS clinical trials, presented her team's findings that someone whose initial MS event is resolving the unpredictability of MS.

"You can read about MS in medical papers," said fellow Jennifer, PhD, of Harvard University. "But what you learn from talking to someone with the disease is so much more real." Dr. Kanter, whose father had MS, encouraged her colleagues to participate in Walk MS and Bike MS. She participates in the 50-mile Challenge Walk with her mother and sister. "If you want to feel the happiness that you get when an experiment goes well, go to a National MS Society event -- you'll feel it every time!" she said.

A second Fellows Conference is planned for 2010, "It was great to meet so many people who have a common passion," said Astrid Cardona, PhD a Career Transition Fellow at the Cleveland Clinic Foundation. "How could we fail with all those great people behind us!"

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November - 2008

LEUKEMIA DRUG CAN HALT, REVERSE MS

LONDON (AFP) - Researchers at the University of Cambridge said Thursday they have found that a drug originally developed to treat leukemia can halt and even reverse the debilitating effects of Multiple Sclerosis (MS).

In trials, alemtuzumab reduced the number of attacks in sufferers and also helped them recover lost functions, apparently allowing damaged brain tissue to repair so that individuals were less disabled than at the start of the study. "The ability of an MS drug to promote brain repair is unprecedented," said Dr. Alasdair Coles, a lecturer at Cambridge University's department of clinical neuroscience's, who coordinated many aspects of the study. "We are witnessing a drug which, if given early enough, might effectively stop the advancement of the disease and also restore lost function by promoting repair of the damaged brain tissue."

The MS Society, Britain's largest support charity for those affected by the condition, said it was "delighted" at the trial's results, which must be followed up with more research before the drug can be licensed. "This is the first drug that has shown the potential to halt and even reverse the debilitating effects of MS and this news will rightly bring hope to people living with the condition day in and day out," said head of research Lee Dunster.

MS is an auto-immune disease that affects millions of people worldwide, including almost 100,000 in Britain and 400,000 in the United States. It is caused by the body's immune system attacking nerve fibres in the central nervous system, and can lead to loss of sight and mobility, depression, fatigue and cognitive problems. There is NO cure, and few effective treatments.

In the trial, 334 patients diagnosed with early-stage relapsing-remitting MS who had not previously been treated were given alemtuzumab or interferon beta-1a, one of the most effective licensed therapies for similar MS cases. After three years, alemtuzumab was found to reduce the number of attacks the patients suffered by 74% over the other treatment, and reduce the risk of sustained accumulation of disability by 71% over interferon beta-1a. Many individuals who took alemtuzumab also recovered some of their lost functions, becoming less disabled by the end, while the disabilities of the other patients worsened, the study in the New England Journal of Medicine said.

Alastair Compston, professor of neurology and head of the clinical neuroscience's department at Cambridge, said alemtuzumab was the "most promising" experimental drug for the treatment of MS. He expressed hope that further trials "will confirm that it can both stabilize and allow some recovery of what had previously been assumed to be irreversible disabilities."

Alemtuzumab was developed in Cambridge and has been licensed for the treatment of chronic lymphocytic leukemia.

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June, 2008

FAMPRIDINE-SR INPROVES WALKING SPEED IN ALL TYPES OF MS IN SECOND PHASE 3 STUDY

Walking speed improved significantly in a clinical trial of 240 people with all types of MS taking Fampridine-SR (MS-F204, Acorda Therapeutics, Inc.) compared with those taking inactive placebo. Fampridine-SR is a sustained-release formula of 4-aminopyridine, which temporarily enhances nerve signaling. These phase 3 study results were reported by Acorda in a press release dated June2, 2008. The company is planning to file for approval of this drug to treat mobility issues in MS in 2009.

Problems with gait (difficulty in walking) are among the most common mobility limitations in MS. Fampridine-SR is a sustained-release formula of 4-aminopyridine, which 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. The first studies of this potassium-blocking approach in people with MS were supported by the National MS Society.

In an earlier phase 3 study of 283 people with all types of MS, walking speed increased by 25% compared with placebo. Two serious adverse events led patients to discontinue Fampridine - one case of anxiety and one seizure in a person who developed sepsis from a urinary tract infection. (Abstract #S32.003, AAN 2007)

LAQUINIMOD RESULTS PUBLISHED: ORAL DRUG REDUCES DISEASE ACTIVITY IN PHASE 2 STUDY

Treatment with oral laquinimod (Teva Pharmaceutical Industries) reduced disease activity by 40.4% compared with inactive placebo in a phase 2 study of 306 people with relapsing-remitting MS. Laquinimod is believed to affect the immune attack on the brain and spinal cord that occurs in MS. Giancarlo Comi, MD (Scientific Institute San Raffaele, Milan) and colleagues, who originally reported the results at the Annual Meeting of the American Academy of Neurology in 2007, now publish these results in the Lancet (2008; 371: 2085-92). A phase 3 study of laquinimod is underway on 1000 people with relapsing-remitting MS.

Multiple sclerosis involves immune-system attacks against the central nervous system. Currently approved therapies for MS involve injections or infusions. Having an effective therapy on pill form would be a big step forward for people with MS. Laquinimod is an oral therapy that is thought to shift the balance of immune cells away from inflammation. The drug is related in structure to linomide, which showed early promise but in phase 3 clinical trials caused significant adverse events including cardiac toxicity.

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April, 2008

DISAPPOINTING RESULTS FROM TRIAL OF RITUXIMAB IN PRIMARY-PROGRESSIVE MS

Drug did not achieve primary goal of slowing progression, sponsors still analyzing other outcomes.

A study of intravenous rituximab (Rituxan, Genentech and Biogen Idec) in 439 people with primary-progressive MS has shown that the drug did not slow disease progression when compared with inactive placebo, the primary endpoint of the study. These results have been announced in a press release from Genentech and Biogen Idec dated April 14, 2008. The companies say that they will continue to analyze the data and will present the results at an upcoming medical meeting.

"News" articles are derived from research releases made by the National MS Society