Entrez PubMed CLICK FOR FULL ARTICLE
CONCLUSION: Lesion evolution on MRI appears to be a patient-specific phenomenon, although the outcome seems to vary according to the phase and severity of the disease.

CLICK HERE

NEJM -- linkLetter from Biogen Idec

NEWSWEEK LINK

Biogen Idec - link for news releaseCambridge, MA and Dublin, Ireland - July 18, 2005 - Biogen Idec (NASDAQ: BIIB) and Elan Corporation, plc (NYSE: ELN) announced today that SENTINEL, the Phase III TYSABRI (natalizumab) add-on trial with AVONEX(Interferon beta-1a), achieved the two-year primary endpoint of slowing the progression of disability in patients with relapsing forms of multiple sclerosis (MS). The addition of TYSABRI to AVONEX resulted in a 24 percent reduction in the risk of disability progression compared to the effect provided by AVONEX alone. Data from SENTINEL also demonstrated that the addition of TYSABRI to AVONEX led to a 56 percent relative reduction in the rate of clinical relapses compared to that provided by AVONEX alone. The reduction in relapse rate was statistically significant and sustained over the entire two-year study period.On February 28, 2005, Biogen Idec and Elan announced that they voluntarily suspended TYSABRI from the U.S. market and all ongoing clinical trials based on reports of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal, demyelinating disease of the central nervous system. The companies have previously reported three confirmed cases of PML, two of which were fatal. "These data demonstrate the effect of TYSABRI on disability progression and clinical relapses. We continue to believe in the therapeutic benefit of TYSABRI in MS, a disease with significant unmet medical need," said Burt Adelman, MD, executive vice president, Development, Biogen Idec. "Our extensive safety evaluation, in collaboration with leading experts and regulatory agencies, is on track and we hope to have findings by the end of the summer.TYSABRI continues to show benefit in the treatment of immune-mediated diseases," said Lars Ekman, MD, PhD, executive vice president and president, Research and Development, Elan.

"Patient safety is our top priority. We remain strongly committed to defining TYSABRI's benefit-risk profile and determining the appropriate path forward."

link...source: Biogen Idec Inc.Neutralizing Antibodies can significantly decrease the effectiveness of IFN-b in the treatment of MS

Wired News: LINKCongress seemed ready to pass an embryonic stem cell bill able to withstand a threatened veto by President Bush, but opponents appear to be stalling for time

LINK TO FULL ARTICLESwiss drug maker Novartis AG's FTY720 pill to treat multiple sclerosis offers much promise but but trials will not begin until the fourth quarter. Studies so far have shown a reduction of more than 50 percent in relapses and a reduction of as much as 80 percent relative to a placebo in terms of brain lesions seen in scans

Switzerland-based Serono SA also is working on a pill to treat MS. Meanwhile, Britain's GlaxoSmithKline PLC plans to file for regulatory approval of a competing drug in 2008.

LINKThe family of a woman who died in February after participating in a clinical trial of multiple-sclerosis medications has filed a lawsuit against the manufacturers of the drugs.

MS Neighborhood : LINKA drug that targets compounds that direct the movement of damage-causing immune cells in the central nervous system is about to be scrutinized in a new clinical trial. The study will test the drug, known by its code name, MLN1102, manufactured by Millennium Pharmaceuticals, as a possible treatment for multiple sclerosis.

LINK..Pharmaceutical Business ReviewSchering AG has completed the enrollment of 2,100 patients for a study of Betaferon, one of its top drugs, which treats the relapsing-remitting form of multiple sclerosis. The study will examine the effects of a high dosage of the drug.

Science Blog
CLICK HERE FOR LINK TO COMPLETE ARTICLEScientists have pinpointed a chemical messenger, IL12, that frees some white blood cells from the body's normal constraints, allowing the cells to act like renegades that could damage nerves in the central nervous system. The work, to be published in the July 15 issue of the Journal of Immunology and just published on-line, helps explain one of the fundamental mysteries of multiple sclerosis

CLICK HERE FOR LINK TO COMPLETE ARTICLEA case study about a young man with MS. It describes his clinical status and discusses various treatment options that he and his medical caregiver could consider. This case study highlights how the choice of treatment is not very clear-cut in MS, particularly when someone continues to have relapses or progression while on a disease-modifying drug.

CLICK HERE FOR LINK TO COMPLETE ARTICLEElan Corporation, plc and Biogen Idec announced today that ENCORE, the second Phase III induction trial of TYSABRI(R) (natalizumab) for the treatment of moderately to severely active Crohn's disease (CD) in patients with evidence of active inflammation, met the primary endpoint of clinical response as defined by a 70 point decrease in baseline Crohn's Disease Activity Index (CDAI) score at both weeks 8 and 12.On February 28, 2005, Elan Corporation, plc and Biogen Idec announced that they voluntarily suspended TYSABRI from the U.S. market and all ongoing clinical trials. This decision was based on reports of progressive multifocal leukoencephalopathy (PML), a rare and potentially fatal, demyelinating disease of the central nervous system. Elan and Biogen Idec's comprehensive safety evaluation concerning TYSABRI and any possible link to PML is ongoing. At the time of the dosing suspension, all ENCORE study patients had completed dosing based on the study protocol and collection and analysis of data followed.

CLICK HERE FOR LINK TO COMPLETE ARTICLEThis report summaries the effects of stem cell therapy, used for three people with very rapidly progressing MS.

The course of MS is highly variable with some people having minimal symptoms for many years and others having more progressive disease from onset. A very small percentage of people with multiple sclerosis (MS) have an extremely "aggressive" form of MS, characterised by very rapid accumulation of disability from diagnosis and in some case frequent and highly disabling relapses.

NEJM -LINK TO AUDIOJohn Gearhart is a stem-cell biologist at the Institute for Cell Engineering, Johns Hopkins School of Medicine.

CLICK FOR FULL STORYFirst Lady of Massachusetts, Ann Romney, gives an insightful look at how her will to ride dressage horses helped her cope with the debilitating disease Multiple Sclerosis.you would never guess that on an October morning in 1998 she woke up and was physically unable to get out of bed. She soon was diagnosed with Multiple Sclerosis (MS), a chronic neurological disease that affects the central nervous system in unpredictable ways.

linkResearchers at the San Raffaele Hospital (Milan, Italy) published unexpected results of studies in which immature nerve cells (adult mouse neural stem cells) injected into the blood of mice with MS-like disease were able to suppress the immune attacks that damage the brain and spinal cord tissues. The study, funded in part by the National MS Society, is being reported by Drs. Stefano Pluchino, Gianvito Martino and colleagues in the July 14, 2005 issue of Nature. These surprising findings, if confirmed, suggest that neural stem cells that reside in the adult brain may not only serve as replacement cells for tissue repair, but in some circumstances may also protect the brain from inflammation. Further research is needed to confirm these results and to address multiple issues involved in translating such experiments into finding ways to fight the immune attack and protect and repair brain tissues in people with MS.

Conclusion: These exciting and unexpected findings from a respected group of investigators, if confirmed, suggest that transplanted neural stem cells may serve not only as replacement cells for tissue repair, but in some circumstances may also protect the brain from inflammation. Further research is needed to confirm these results and to address multiple issues involved in translating such experiments into finding ways to fight the immune attack and protect and repair brain tissues in people with MS.

Effects of dose titrationMultiple sclerosis (MS) treatment with interferon beta is associated with well-known, easily managed adverse events, including influenza-like symptoms and injection-site reactions that decline over time. Initial dose titration has been shown to be one way of limiting these adverse events. Hence, a placebo-controlled, multicentre study of 98 patients was set up to explore whether a slower, four-stage, 4-week titration to a final dose of 250 microg subcutaneous interferon beta-1b might improve tolerability over a more rapid two-stage, 2-week titration in patients with relapsing-remitting MS. Frequency of adverse events was found to be similar between the two regimens: notably, no difference in the incidence of injection-site reactions, with a trend towards fewer influenza-like symptoms in the slow-titration group. Relative to placebo, significantly fewer patients receiving interferon beta-1b relapsed. This was more pronounced in the rapid-titration group than in the slow-titration group, showing that rapid and significant improvements in relapse rates were achieved within 90 days of starting interferon beta-1b. Although a rapid-titration regimen results in a quicker onset of clinical benefit, slow titration showed a non-significant trend towards reduced influenza-like symptoms.

Ginkgo Findings by scientists in the Oregon Health & Science University School of Medicine's Department of Neurology and the OHSU MS Center of Oregon appear to back up that claim. A study presented this month at the American Academy of Neurology's 57th Annual Meeting in Miami Beach, Fla., suggests that ginkgo may be effective in improving attention in MS patients with cognitive impairment. Side effects also were minimal.

The study's lead author, Jesus Lovera, M.D., a research fellow and instructor in neurology, OHSU School of Medicine, said those receiving ginkgo "performed better on a test that measures a person's ability to pay attention and to sort conflicting information."

Entrez PubMed
In January 2002 the New York City Chapter of the National Multiple Sclerosis Society convened a panel of experts to review the issue of depressive affective disorders associated with multiple sclerosis (MS). This Consensus Conference was supported by a grant from the Goldman family of New York City. RESULTS: The panel reviewed summaries of current epidemiologic, neurobiologic, and therapeutic studies having to do with depressive disorders among MS patient populations. Depressive disorders occur at high rates among patients with MS, and there is reason to believe that the immunopathology of the disease is involved in the clinical expression of affective disorders. The depressive syndromes of MS have a major, negative impact on quality of life for MS sufferers, but are treatable. At the present time, most MS patients with depression do not receive adequate recognition and treatment. CONCLUSIONS: The Goldman Consensus Conference Study Group provides recommendations for improved screening, diagnosis, and clinical management for depressive affective disorders among patients suffering from MS.

National MS Society | Research BulletinResearchers at the San Raffaele Hospital (Milan, Italy) published unexpected results of studies in which immature nerve cells (adult mouse neural stem cells) injected into the blood of mice with MS-like disease were able to suppress the immune attacks that damage the brain and spinal cord tissues. The study, funded in part by the National MS Society, is being reported by Drs. Stefano Pluchino, Gianvito Martino and colleagues in the July 14, 2005 issue of Nature. These surprising findings, if confirmed, suggest that neural stem cells that reside in the adult brain may not only serve as replacement cells for tissue repair, but in some circumstances may also protect the brain from inflammation. Further research is needed to confirm these results and to address multiple issues involved in translating such experiments into finding ways to fight the immune attack and protect and repair brain tissues in people with MS.

Background: In recent years, scientists have been exploring ways to repair the damage of brain and spinal cord tissues during the course of the immune attack in MS. Evidence suggests that the body successfully repairs some myelin damaged in MS, but not enough to keep up with its loss. Research has shown that adult brains contain stem cells – also known as precursors or progenitors – that might serve as replacement cells. It has been hoped that, given the right signals, these may be stimulated to grow into viable new tissue. The search for these signals is an active area of research. Another possibility being explored is cell transplantation.

Studies involving transplantation of immature myelin-making cells (oligodendrocyte precursors) have been to some degrees successful in rodent models, triggering recovery of function and restoring nerve conduction. However, such repair has only been successful in isolated areas of the brain, whereas MS and MS-like diseases in animal models involve lesions scattered throughout the brain and spinal cord. Finding a way to introduce potential replacement cells that can migrate throughout the central nervous system and home in on damaged areas has presented a significant hurdle in this field.

The San Raffaele Hospital team and others have been investigating transplantation of neural stem cells, which have the potential to develop into various types of brain cells – including nerve cells and myelin-making cells – and which appear capable of expanding their numbers extensively, and moving to distant sites of injury within the brain. In 2003, they reported that neural stem cells transplanted into mice with an MS-like disease were able to migrate to multiple areas of myelin and nerve fiber damage in mice with an MS-like disease, repair this damage, and restore clinical function. (Nature 2003;422:688-694). In the current study, the team attempted to define the mechanisms responsible for the migration of these cells into the brain and to sites of injury. This study was funded in part by the National MS Society (USA), the Myelin Project, the Italian MS Foundation and the Italian Minister of Health.

The Study: Dr. Pluchino and colleagues injected neural stem cells, taken from the brains of adult mice, into the blood of mice with a relapsing-remitting form of EAE, an MS-like disease. Relapsing-remitting disease involves clearly defined flare-ups followed by partial or complete remissions. Some mice were injected at the onset of disease, and others at the onset of the first relapse.

Mice in which neural stem cells were injected at disease onset started to recover between 30 and 60 days, and experienced a twofold reduction in relapses compared with untreated mice. Mice injected at the first relapse started to recover later, but showed a threefold reduction of the relapse rate between 60 and 90 days, compared with untreated mice. Both groups showed a significant reduction in the extent of myelin damage and nerve fiber loss compared to untreated mice.

The team then explored the mechanism by which the neural stem cells entered the brain from the bloodstream. They reported that a protein on their surface called VLA-4, which is also found on immune cells and allows them to cross from the blood into the brain, facilitated their movement into the brain. In addition, the investigators reported finding a wide range of immune proteins to be active on the transplanted neural stem cells; these proteins serve as “docking sites” to receive signals from immune cells active in the attack. Furthermore, they reported that a portion of the transplanted cells remained in an immature state and accumulated in the brain around blood vessels (perivascular areas) where immune cells enter the brain during active disease. These transplanted cells showed signs of being able to turn off activated immune cells and reduce inflammation, thus protecting brain tissues from immune-mediated damage.

Conclusion: These exciting and unexpected findings from a respected group of investigators, if confirmed, suggest that transplanted neural stem cells may serve not only as replacement cells for tissue repair, but in some circumstances may also protect the brain from inflammation. Further research is needed to confirm these results and to address multiple issues involved in translating such experiments into finding ways to fight the immune attack and protect and repair brain tissues in people with MS.

LinkResearchers have found a chemical messenger that frees some white blood cells from the body's normal constraints, allowing the cells to act like renegades that could damage nerves in the central nervous system.

The work, published in the Journal of Immunology, helps explain one of the fundamental mysteries of multiple sclerosis ( MS ).

It was discovered that a chemical messenger, found at high levels in MS patients, allows some immune cells known as T-effector cells to evade normal regulation.
Instead, the cells bypass their usual gatekeepers and could become active in the body's tissues, including the brain and spinal cord.

Researchers believe that during multiple sclerosis, renegade T-effector cells damage the myelin coating that covers nerve cells, causing the disease's symptoms. While another subset of white blood cells called T-regulatory cells normally control the activation of T-effector cells, investigators found that the chemical messenger interleukin-12 ( IL12 ) allows some cells to sidestep that regulation and run amok.

LINK - The Boston Globe Elan Corp. and Biogen Idec Inc.'s multiple sclerosis drug Tysabri may have killed patients because interaction with another Biogen product, Avonex, led to a buildup and overdose of the medicine, an NCB Stockbrokers analyst said.

An interaction of Tysabri, recalled Feb. 28, and Avonex, an older MS drug sold by Biogen ''essentially leads to almost double the intended Tysabri concentration after only 20 weeks," NCB analyst Orla Hartford said yesterday in a note to investors. ''Patients on Tysabri alone did not accumulate the drug."
The effect Avonex has on Tysabri will likely ''form a central part of the case made to the FDA for Tysabri's relaunch," she said. Hartford, who analyzed data submitted to the US Food and Drug Administration during the approval process, expects the treatment to be reintroduced in 2006.
''Elan's continuing with the review, which is on track, and will comment when it has been completed," said Elizabeth Headon, a spokeswoman for Elan at Murray Consultants.
Tysabri was withdrawn after being linked to progressive multifocal leukoencephalopathy, a rare neurological disease, in two patients, both of whom were taking a combination of the two drugs. Elan and Biogen Idec are reviewing medical records of patients who have taken the drug. The companies will meet with the FDA to determine whether the drug can be sold again.
''The efficacy of Tysabri in treating multiple sclerosis is undeniable and we continue to believe that Tysabri will return to the market as a significant therapy," Hartford said.
Shares of Biogen rose 56 cents yesterday to close at $34.65 on the Nasdaq Stock Market.
Tysabri is the cornerstone of Elan chief executive Kelly Martin's plan to reach profitability and repay debt due in 2008 and 2011. He said in May he's confident the drug will return to the market.
Hartford said that over a sustained period of time, Tysabri accumulated in the system partially because the body is less able to process it, which leads to an ''overdosing," she said.
The Tysabri accumulation may have led to a suppressed local immune system in the brain and may have been a key predisposing factor in the two cases of PML seen in combination therapy, Hartford said.
A third patient, identified in March, wasn't taking Avonex, but was on azathioprine, another immunosuppressive drug. Other possible cases have been reported to the FDA, but they haven't been confirmed.

Multiple Sclerosis Society of London Website - linkMitoxantrone is a potent immunosuppressant used in the treatment of some forms of cancer. It is licensed in the US for the treatment of worsening relapsing remitting MS and relapsing progressive MS. This study investigated the effectiveness of mitoxantrone as a "rescue therapy" for people taking beta interferon who continued to experience disabling relapses or significant disability progression.
Ten people who experienced more than three relapses a month and had rapid disability progression took part in the study. Neurological assessments, MRI scans and blood tests, both to monitor ongoing inflammation, were completed initially, every three months and within three days of a relapse. After six months receiving just beta interferon participants received three infusions of mitoxantrone into the vein, in combination with steroids, shown to shorten the recovery time after a relapse, once monthly. After an additional six months of just beta interferon therapy people who did not show a benefit from the first combination therapy again received intravenous infusions of mitoxantrone, in addition to beta interferon therapy, at the rate of once every three months. All participants were monitored for the following 15-18 months.

During the first three months of mitoxantrone treatment none of the participants experienced any relapses and disability levels stabilised. The amount of inflammation present also significantly decreased compared to levels present during beta interferon therapy alone. During the following six months of just beta interferon treatment the relapse rate remained significantly reduced and inflammation levels remained low. Disability levels for seven of the 10 participants remained stable after the initial mitoxantrone treatment. The remaining three participants received additional mitoxantrone, as described. During further mitoxantrone treatment these participants experienced no new relapses and their disability stabilised. Overall, mitoxantrone was well tolerated with a low number of adverse events reported.

In conclusion, mitoxantrone administered concurrently with beta interferon was effective in significantly reducing both the relapse rate and levels of inflammation in people with MS. It also effectively stabilised disability progression in people with rapidly progressive disease. Positive effects were still detectable after 15 months. The authors highlight that further studies of agents for rapidly progressing MS are warranted.

MS Neighborhood : LINKPeople with multiple sclerosis may have significant differences in certain genes that make them more susceptible to the disease. A new study has found that MS patients have less activity in the so-called FOXP3 gene located in a small group of T-cells.1

A Possible MS Target
This abnormal, quiescent activity in the gene may reflect the suppressed ability of the body to block immune system cells' attack against myelin and the nerve fibers in the central nervous system it protects, say scientists at Oregon Health & Science University in Portland.

"This is an important marker," said lead researcher Arthur Vandenbark, PhD, a professor of Neurology and Molecular Microbiology and Immunology. "This is the first publication that links FOXP3 with reduced suppression in MS."

- CME Teaching Brief - MedPage Today- LINKThe multiple sclerosis drug Tysabri (natalizumab), withdrawn from the market following reports linking it to two cases of a rare fatal opportunistic infection, appears to work with other drugs to allow reactivation of an otherwise innocuous latent virus.

That's the consensus of investigators in a special early release of information scheduled for publication in the July 28 New England Journal of Medicine. The drug, launched with great promise for MS patients, was withdrawn on Feb. 28.

That NEJM issue will contain details of three separate case reports of patients who developed progressive multifocal leukoencephalopathy, or PML, during treatment with Tysabri. Two patients were treated for MS and one for Crohn's disease.

One of the patients with MS and the patient with Crohn's died from PML. The other MS patient became quadriplegic and lost the ability to speak. This patient improved after discontinuation of Tysabri, followed by further therapy with Ara-C (cytarabine), which has been shown to be effective in the laboratory against the suspected viral infection.

Last week, the Boston Globe reported that Tysabri's maker, Biogen Idec, had informed the FDA of a possible fourth case of PML, in a woman with MS who had taken it along with the company's other MS drug, Avonex (interferon beta-1a). Her case was not reported in the journal, and her condition could not be ascertained immediately. However, the NEJM said it was the Globe report that triggered the early release of its data.

Although PML was diagnosed in only three (now possibly four) of the 3,000 or so patients who took Tysabri in clinical trials, drug safety monitors were alarmed because the infection is almost always seen only in severely immunocompromised patients. These include AIDS patients or organ transplant recipients who are taking immunosuppressants. Until these case reports, there were no known cases of PML in patients with MS.

PML is caused by reactivation of a clinically latent infection with the JC polyomavirus. These often-fatal opportunistic infections of the central nervous system destroy oligodendrocytes in the brain, resulting in demyelination of multifocal areas and deterioration of various neurologic functions.

The JC virus is acquired by most people during childhood and antibodies against the virus are present in 50% to 86% of adults. The virus remains dormant in the bone marrow, kidney, and spleen, and infection is usually asymptomatic unless the person is immunocompromised.

Tysabri is a humanized monoclonal antibody against α4-integrins, receptor proteins involved in cellular binding and response to extracellular matrix. When used in conjunction or in sequence with other drugs that affect immune function, Tysabri appears to interrupt normal lymphocyte function, allowing the JC virus to grow unchecked, said Igor J. Kralnick, M.D., of Harvard Medical School in an interview.

"In the patients who received natalizumab and also had other medications such as Avonex, it's likely that the prevention of normal migration of the lymphocytes in the tissue allows the virus to replicate without being contained, and finds its way to the brain and causes the disease," said Dr. Kralnick, who co-authored an editorial accompanying the NEJM case reports.

"It is also not entirely ruled out that some people have the virus latent in the brain and in certain circumstances need to have the trafficking of the lymphocytes to prevent the virus from reactivating within the brain."


One patient, a 46-year-old woman who had received 37 monthly doses of Tysabri, plus weekly Avonex injections for relapsing-remitting MS, died about three years after starting on Tysabri. At autopsy, she was found to have multiple large and small PML lesions in tissue sections taken from most areas of both cerebral hemispheres, according to a NEJM report by B.K. Kleinschmidt-DeMasters, M.D., and colleagues at the University of Colorado Health Sciences Center.

The second fatal PML case reported in the NEJM occurred in a 60-year-old Belgian man who had received five doses of Tysabri for Crohn's disease as part of a clinical trial, wrote Paul Rutgeerts, M.D., Ph.D., and colleagues at the University of Leuven Hospitals in Leuven, Belgium.


The patient died five months after reporting to the emergency room with severe confusion and disorientation. Although he was originally thought to have died from an astrocytoma, the investigators took another look at the serum samples and brain lesion tissues taken at biopsy after hearing about two other cases of PML in patients on Tysabri.

The investigators found evidence of the JC polyomavirus in blood samples taken three months after the patient had started on an open-label trial of Tysabri, but before he had exhibited symptoms. The patient had previously taken the immunosuppressant Imuran (azathioprine), but had discontinued it eight months before admission to the hospital.

In the third case reported in the NEJM, researchers reported on a 23-year-old man who had received 28 infusions of Tysabri, in addition to weekly injections of Avonex. He developed a rapidly progressive case of PML that did not respond to treatment with corticosteroids, Vistide (cidofovir) and IV immune globulin. The infection left the patient "quadriplegic, globally aphasic, and minimally responsive."

Three months after stopping Tysabri, his physicians detected widespread inflammation of the CNS, which they attributed to immune-reconstitution inflammatory syndrome. Following a course of Ara-C, the patient had improvement of symptoms, including return of speech and ability to walk, although he still had cognitive and neurologic impairment. The authors reported that the reasons for improvement were unclear as Ara-C has been shown to be effective in vitro, but it failed to show efficacy in a randomized control trial in HIV patients with PML.


"Our case report suggests that some degree of recovery from natalizumab-associated PML is possible," wrote Annette Langer-Gould, M.D., of Stanford and colleagues there and at the University of California San Francisco.

Biogen Idec, the drug-maker, noting the recovery, commented in a letter to the NEJM that accompanied the research papers, “It is possible that testing for the appearance of JC virus in plasma, along with a high degree of clinical suspicion, will permit early diagnosis and discontinuation of natalizumab therapy and allow patients to recover. Similar findings have been reported for BK virus, a related polyomavirus that infects transplant recipients.”

"Earlier this year, Biogen Idec (nasdaq: BIIB - news - people ) and Elan (nyse: ELN - news - people ) pulled their multiple sclerosis drug, Tysabri, after the drug was linked to a disorder called progressive multifocal leukoencephalopathy (PML). Three of the 3,000 patients who took Tysabri in clinical trials developed PML, which is caused by the JC virus, which is often dormant in many patients. Today, the New England Journal of Medicine published case reports on all three of those patients. Alongside the reports, which provide a great deal of detail on how PML developed, the journal also published an editorial by Joseph Berger and Igor Koralnik, two of the world's top experts in PML who have worked as consultants for Biogen Idec and Elan. The two write that the linkage between the drug and PML, though unexpected seems clear. But they also provide a bit of light to investors, writing that it may be possible to detect the proliferation of JC virus before much of the damage is done and then stop Tysabri treatment. It remains an open question whether the Food and Drug Administration will require a new clinical trial to prove that is the case. Biogen Idec says it hopes to finish its safety review by the end of the summer. Shares of Biogen Idec and Elan were both up 4% ahead of the announcement" FORBES MAGAZINE

Wiley InterScience: Journal: Abstract....LINK"Deficient eye and hand movements are present in patients with multiple sclerosis. In the present study, eye and hand movements were simultaneously measured during visually guided wrist step-tracking tasks in 16 patients with intention tremor and 15 healthy controls. The coupling between eye and hand movements was analyzed during simultaneous eye-hand tracking, and interactions were studied by comparing the coordinated eye-hand condition with isolated eye- or hand-tracking conditions. Despite movement abnormalities, the onset of eye and hand movements was highly correlated and an invariant coupling between the saccadic completion time and hand peak velocity was found, suggesting that the temporal coupling was very much preserved. The differences between the experimental tracking conditions suggest that, in MS patients with intention tremor, the ocular system influenced the hand movements. Intention tremor amplitude was reduced when there was no preceding saccadic eye movement, whereas conversely, eye movements were not affected by different hand tremor severity."

The Lancet Neurology...LINK TO ARTICLEInterferon beta was the first therapy to be approved for the treatment of relapsing-remitting multiple sclerosis (MS) more than 10 years ago. Interferon beta reduces relapse rates and disease burden and activity, and it may have beneficial effects on the progression of long-term disease disability. The occurrence of neutralising interferon-beta antibodies has been postulated as a possible cause of the failure of interferon beta in some patients with MS. Here we discuss the basic mechanisms that may account for the generation of an interferon-beta antibody response and its biological implications. We review the evidence for neutralising antibodies as a consequence of interferon-beta treatment, and discuss the implications for the treatment of MS. Strategies to assess and manage the long-term impact of neutralising antibodies will be outlined.

Dr Raj Kapoor from The National Hospital for Neurology and Neurosurgery, London....linkUntil recently, it was thought that disability in MS was caused mainly by the gradual loss of the fatty insulating layer of myelin which surrounds nerve fibres (axons), and which allows them to conduct electrical signals. However, we now know that most of the permanent disability in MS occurs because the axons themselves degenerate.

Experience suggests that the current strategy of modifying the immune system may not be able by itself to prevent this axonal degeneration and consequent disability, and that we will need to develop a second strategy, termed neuroprotection, to achieve this goal. In order to do so, we will need to identify and to inhibilt the mechanisms by which axons are damaged.

Research work has already identified several such mechanisms.

LINK PubMed
"These data showed that the combination of CTX plus IFN beta halted the progression of disease in active and deteriorating MS patients suggesting the necessity of RCTs to test the efficacy of this combination therapy in active RRMS patients or in patients who experienced treatment failure in response to disease modifying drugs (DMDs)."

PubMed...LINK
"Malignant forms of multiple sclerosis (MS) represent a limited group of very aggressive demyelinating diseases, which rapidly progress to severe disability leading often to life-threatening conditions. On these clinical entities, currently available therapies for MS are not very effective. Recently, it has been demonstrated that intense immunosuppression followed by autologous stem cell transplantation (ASCT) can affect the clinical course of individuals with severe MS and completely abrogate the inflammatory activity detected by magnetic resonance imaging (MRI). We report on the treatment with intense immune ablation followed by ASCT of three patients with malignant MS whose clinical course indicated a dramatically poor prognosis. This procedure succeeded in halting the rapidly worsening course of disease. The effect was long lasting, as demonstrated by a sustained efficacy over a two-year period in two subjects and 12 months in the third case. In addition, a striking effect on inflammation-related MRI findings was obtained. These results support a role for intense immunosuppression followed by ASCT as treatment in rapidly evolving malignant MS cases unresponsive to conventional therapies."

CLICK HERE FOR FREE VIDEO OR A COMPLETE TRANSCRIPTWilliams a proponent of medicinal use of drug

Case Western Reserve University-LINKCritical first step in understanding myelin repair and its role in treatments: A collaboration of five of the world's leading neuroscientists has identified three new "switches," or signals, operating in the brain and spinal column that appear to turn on and off the nerve cell's ability to repair myelin. Myelin is the protective coating surrounding nerve cells that is damaged by multiple sclerosis (MS). The scientists' findings are a critical first step in understanding myelin repair and its role in treatments for MS and other demyelinating diseases. "We believe there are a number of mechanisms at work in MS which prevent immature brain cells from developing into myelinating cells, or cause the death of myelinating cells," said Rusty Bromley, COO of the Saratoga, Calif.-based Myelin Repair Foundation (MRF), which funds the scientists' research.

MRF President Scott Johnson, a former Silicon Valley entrepreneur who suffers from MS, founded MRF in 2002 with a single purpose: to identify drug targets that would lead to treatments for MS within five years. To date, he has raised $6 million to support the research, including an initial $1 million donation from Intuit co-founder Scott Cook and a $250,000 award from Boston biopharmaceutical company Biogen Idec.

Phase II data presented today at the 15th European Neurological Society (ENS) meeting in Vienna showed that FTY720, a novel oral medication for the treatment of multiple sclerosis (MS), reduced the rate of clinical relapses by more than 50% and inflammatory disease activity as measured by magnetic resonance imaging (MRI) by up to 80% over six months compared to placebo.

Benefits of FTY720 therapy were seen as soon as after two months of treatment and continued to increase over the six month treatment period compared to placebo. Over 90% of patients completed the study.

Oregon Health & Science University researchers have measured genetic changes reflecting a drop in the body's ability to suppress inflammatory cells that attack nerve fibers and promote progression of multiple sclerosis. In a study published in the July issue of the Journal of Neuroscience Research, OHSU scientists, in collaboration with The Immune Response Corp. of Carlsbad, Calif., found that MS patients have lower expression of the FOXP3 gene found in a subset of T-cells that may regulate defense against MS and other autoimmune diseases, such as diabetes and arthritis. They say that when FOXP3 is reduced due to abnormalities in its expression, the suppressive activity of regulatory T-cells, or T-regs, also plummets.

Teva Pharmaceutical Industries Ltd. (NASDAQ: TEVA) and Active Biotech AB (Stockholm: ACTI.ST) announced today the submission of an investigational new drug application (IND) to the U.S. Food and Drug Administration (FDA) to initiate a clinical trial in the U.S. with laquinimod to assess drug-drug interaction. Based on the results of this study and of the ongoing phase IIb study in Europe (see below), the phase III clinical program to confirm the efficacy and safety of laquinimod in relapsing forms of MS, is planned to start in 2006. Laquinimod is a novel orally administered immunomodulatory substance, developed by Active Biotech and recently licensed to Teva.

Bloomberg.com:Top WorldwideNovartis will present data at the European Neurological Society meeting in Vienna on a study of the medicine, called FTY720, in 281 patients with relapsing forms of the debilitating illness. Existing medicines including Rebif, Avonex and Betaseron all have to be injected. Oral treatments may capture as much as 40 percent of the market, Serono Deputy Chief Executive Jacques Theurillat said April 12.....The Novartis drug has a number of hurdles to overcome. The data being presented is only from the second of the three stages of testing generally required before approval. Regulators are also likely to be cautious following the early approval and then recall of Biogen Idec and Elan Corp.'s Tysabri, Lombard Odier analyst Karl Heinz Koch said......Preliminary data released earlier this month showed that FTY720 cut the rate of MS relapses by about 55 percent compared with placebo. Seventy percent of the patients on placebo were relapse-free, compared with 86 percent of the patients in both groups taking the drug, the study, led by Ludwig Kappos at the University Hospital in Basel, Switzerland, Novartis' hometown, showed.

In a different study, Tysabri cut the rate of MS relapses by 66 percent compared with a placebo in a trial of 942 patients. Data from clinical trials show that interferons like Avonex and Rebif reduce relapses by about 30 to 40 percent.

LINK"Multiple Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and neurodegenerative pathophysiological characteristics. Due to similarities in the clinical presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency and MS may be difficult. Additionally, low or decreased levels of vitamin B12 have been demonstrated in MS patients. Moreover, recent studies suggest that vitamin B12, in addition to its known role as a co-factor in myelin formation, has important immunomodulatory and neurotrophic effects. These observations raise the questions of possible causal relationship between the two disorders, and suggest further studies of the need to close monitoring of vitamin B12 levels as well as the potential requirement for supplementation of vitamin B12 alone or in combination with the immunotherapies for MS patients."

LINKOver the past two decades, numerous clinical trials have been conducted on drugs for treating MS-related fatigue. Of these agents, amantadine has been studied for the longest period, and has shown efficacy in about one third of patients with MS-related fatigue on several commonly used scales. Two randomized -trials of the central nervous system stimulant pemoline have yielded unimpressive results; efficacy was seen at higher doses but coupled with an unacceptable risk of adverse events. The wake-promoting agent modafinil is the only agent to show efficacy compared with placebo on the Fatigue Severity Scale, a measure that is highly resistant to "impulse answering" and is thus viewed as one of the most difficult scales on which to show -benefit. This article reviews fatigue in MS and proposes a rational strategy for evaluation and management of this most common MS symptom.

LINK: PubMed
New criteria for the diagnosis of multiple sclerosis (MS) were published as the result of an internationally formed committee. To increase the specificity of diagnosis and to minimize the number of false diagnoses, the committee recommended the use of both clinical and paraclinical criteria, the latter involving information obtained from magnetic resonance imaging, evoked potentials, and cerebrospinal fluid (CSF) analysis

PubMed....LINK
The strong correlation found between a composite DT-MRI score and disability suggests that a full and accurate assessment of cervical cord damage in MS provides information that usefully contributes to an explanation of the clinical manifestations of the disease.

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