June 29 (Bloomberg)—Injections of embryonic stem cells, versatile building blocks that can take on many functions, can reconstitute aging immune systems, according to a study of cows appearing today in the journal Cloning and Stem Cells.

Stem-cell injections replaced the immune systems of two older cows that lived 400 days afterwards without complications, said study leader Robert Lanza, medical director of ACT Holdings Inc., a Worcester, Massachusetts, biotechnology company.

Using a technique similar to one South Korean researchers have experimented with in humans, Lanza cloned cow embryos by putting DNA from a cow’s skin cell in the animal’s egg cell to grow an embryo. It will probably be at least five years before such therapies are suitable for use in people, Lanza added.

“Think of an elderly person who’s susceptible to pneumonia,” he said. “With a simple injection, you could give them new, useful cells.”

The study demonstrates how tissues genetically matched to a DNA donor might be used to treat patients with immune disorders, said Piero Anversa, a stem-cell researcher and director of the Cardiovascular Research Institute at New York Medical College.

“This is a very impressive study,” Anversa said in an interview. “There is no precedent to what has been done in this paper.”

Replacement Cells

Stem cells are genetically programmed to grow new tissues and replace damaged cells. Researchers consider embryonic stem cells the most powerful type because they can create the widest variety of cells.

People with injured immune systems, such as those with HIV, the virus that causes AIDS, are at high risk of infection with bacteria and viruses. Lanza designed the study to see whether he could replace the immune system in older, weaker cows without eliminating their existing immune cells.

“We thought the cells might be competitive enough to make room in the immune system on their own,” he said in a telephone interview. “If you were doing this in people, you wouldn’t want to kill off all the immune cells in an AIDS patient if you didn’t have to.”

http://www.advancedcell.com/recent-news-item/stem-cells-might-replace-ailing-immune-system-cow-study-finds

By Kristen Philipkoski | Also by this reporter

02:00 AM Jun. 30, 2005 PT

Scientists have shown that stem cells can bring renewed youthful vigor to aged cows, and they hope the same will be true in humans.

Stem cells were injected into elderly cows -- animals whose age was equivalent to an 80-year-old human. Tests showed boosted immune systems and rejuvenated blood vessels more than a year after an injection of a tablespoonful of stem cells taken from cloned bovine fetuses.

Scientists invigorated the immune systems of these three cows by injecting them with bovine fetal stem cells. Researchers hope a similar technique could do the same for humans.
Photo: Courtesy of Advanced Cell Technology

The technique is not ready for use with humans, because the cells were taken from fetuses that developed for up to 120 days, which would clearly raise ethical questions if practiced in humans. But, the scientists who performed the study believe embryonic stem cells taken from days-old embryos in a petri dish, perhaps some leftover post-in-vitro fertilization, could impart the same benefits.

"The cells are so competitive and youthful that they just take over," said Robert Lanza, vice president of medical and scientific development at Advanced Cell Technology in Worcester, Massachusetts. Researchers from the Memorial Sloan-Kettering Cancer Center in New York City, University of Pennsylvania and the Mayo Clinic also worked on the project.

Scientists already know that bone marrow transplants can cure diseases like leukemia. The paper, published in the June 2005 issue of Cloning and Stem Cells, shows that the fetal stem cells repopulated one cow's bloodstream without using the harsh immunosuppressive drugs or tissue-matching necessary for bone marrow transplants today. The method also eliminates the risk of graft-versus-host disease. To compare results, they administered the drugs to the other two cows at different doses.

"This is a brilliant paper that breaks new ground in developing a large-animal model to understand crucial aspects of therapeutic cloning," said Gerald Schatten, professor of obstetrics, gynecology and reproductive sciences and cell biology and physiology at the University of Pittsburgh School of Medicine.

The technique seems to "reboot" the immune system, Lanza said, which could help patients with autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, juvenile diabetes, lupus and inflammatory bowel disease, among others.

"Cloned cells taken from the animals formed gigantic white-blood-cell colonies that are only seen with very, very young cells," he said.

The scientists created clones of three cows and implanted them inside other cows' uteruses. When the embryos had developed for up to 120 days, they removed the fetuses and isolated stem cells from clones' livers and injected them in to the older cows. (Cow fetuses don't produce the desired stem cells until they've developed for more than 100 days, Lanza said.)

The researchers attached a genetic marker to the stem cells so they could follow where the stem cells traveled in the adult cows' body. They found the markers in rejuvenated blood vessels as well as in new white blood cells circulating in the cows' bloodstreams.

"Implanting the embryo would obviously be unethical in humans," Lanza said. It's also unnecessary, he said, because the stem cells can be obtained from very early embryos in a petri dish without implantation.

Nigel Cameron, a senior fellow and international advisory board member of the Center for Bioethics and Human Dignity, said it was "very disturbing" that the cells were taken from three-month old fetuses.

"Prima facie it looks very implausible that they could be moving from (cows to humans)," Cameron said. "And what is so interesting is that we have one state, New Jersey, in which the law has been designed specifically to protect this kind of ghoulish fetal harvesting." (The New Jersey law (.pdf) allows cloning for research but outlaws reproductive cloning.)

In any case, it's still not 100 percent clear that the technique will have the same results in humans, Schatten said.

"There's lots of good news in this paper, and it certainly brings us a step closer to clinical reality," he said. "But because of some technical problems in growing embryonic stem cells from cattle embryos, the full cycle of therapeutic cloning has not yet been totally tested."

Several countries, including Canada, Australia and Germany, and some U.S. states, have outlawed human therapeutic cloning.

"This study underscores that laws against SCNT (somatic cell nuclear transfer, or therapeutic cloning) might very well destroy the best hope of millions of patients for cures," said Bernard Siegel, director of the Genetics Policy Institute in Wellington, Florida.

http://www.wired.com/news/medtech/0,1286,68044,00.html

by John C. Martin
Article Date: 07-29-05

A new, international study suggests that stem cells, the primitive cells that give rise to cells found in the brain, could be the key to treating multiple sclerosis.1 In the study using a group of mice, researchers at the San Raffaele Hospital in Milan, Italy found that immature nerve cells known as neural stem cells injected into the animals' bloodstreams resulted in suppression of immune attacks that is believed to lie at the heart of multiple sclerosis.

Stem Cells: Myelin Protectors
The unexpected findings, if confirmed in future research, suggest that these stem cells may not only serve as replacement cells for tissue repair, but may also protect the brain from inflammation. "In central nervous system inflammation, neural multipotent precursor [stem] cells are able to promote neuroprotection by maintaining undifferentiated features and exerting unexpected immune-like functions," wrote Stefan Pluchino, MD, and his colleagues in the Neuroimmunology Unit at San Raffaele Hospital in Milan, Italy.

Stem cells are designed to differentiate into a wide variety of cell types in the body. They can also divide indefinitely to replenish other cells. When stem cells divide, they can remain a stem cell or evolve into another type of cell with a specialized function, such as a muscle cell.2

A New Focus
In recent years, medical experts have been experimenting with ways to repair the damage in the central nervous system that results after MS strikes. While some studies have suggested that the body successfully repairs some of the damage,3 it isn't enough. However, experts have found that the adult brain contains stem cells that might serve as replacements for the damaged tissue. Thus, at the center of the latest research have been efforts to either induce stem cells to repair damaged myelin (a fatty substance surrounding nerve cells in the brain that is a key target of the attacking immune system in people with MS) or other cells, or a possible stem cell transplant.4

While stem cell transplantation has been successful in other animal studies,5 scientists have found that repair of damaged tissue has only occurred in isolated areas of the brain, whereas MS involves lesions scattered throughout the brain and spinal cord. Thus, finding a way to introduce potential replacement cells that can migrate throughout the central nervous system and home in on damaged areas has been a significant challenge in recent years.

Relapse Reductions Noted
Most recently, Pluchino and his team have been investigating the transplantation of neural stem cells, which then differentiate into various other cells, then migrating to distant sites of injury in the central nervous system.6 In their latest research, they were attempting to define how the stem cells migrated into the brain and sites of injury.

In their study, the investigators injected neural stem cells taken from the brains of adult mice into the blood of mice with a disease similar to relapsing-remitting MS. Some mice were injected at the onset of disease and others were injected at the first sign of a flare-up.

The mice that were injected at disease onset started to recover in between 30 and 60 days, and experienced a significant reduction in the number of relapses compared to untreated mice. Mice injected at the first relapse recovered later, but showed a threefold reduction in the number of relapses between 60 and 90 days compared with mice that weren't treated.

The team also found that that a protein on the surfaces of the stem cells allows them to cross from the blood into the brain, and facilitated their movement in the brain. A wide range of immune proteins were also found on the surfaces of these stem cells that serve as "docking sites" to receive signals from immune cells involved in the attacks in the central nervous system.

A portion of the transplanted cells remain in an immature state, as well, collecting around blood vessels where immune cells enter the brain during MS. These stem cells showed signs that they were able to turn off activated immune cells and reduce inflammation, protecting brain tissues from immune-mediated damage.

"These results indicate that undifferentiated adult neural precursor cells have relevant therapeutic potential in chronic inflammatory central nervous system disorders because they display immune-like functions that promote long-lasting neuroprotection," Pluchino and his team wrote.

The findings, while optimistic, should be confirmed in larger studies, they pointed out.

1. Pluchino S, Zanotti L, Rossi B et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 2005 Jul 14;436(7048):266-71.
2. National Institutes of Health. Stem Cell Basics. Available at: http://stemcells.nih.gov/info/basics/. Accessed July 25, 2005.
3. Nait-Oumesmar B, Lachapelle F, Decker L, Baron-Van Evercooren A. Do central nervous sytem axons remyelinate? Pathol Biol (Paris) 2000 Feb;48(1):70-9.
4. Jefferson S, Jacques T, Kerinan BW, Scott-Drew S, Milner R, ffrench-Constant C. Inhibition of oligodendrocyte precursor motility by oligodendrocyte processes: implications for transplantation-based approaches to multiple sclerosis. Mult Scler 1997 Apr;3(2):162-7.
5. Oka S, Honmou O, Akiyama Y et al. Autologous transplantation of expanded neural precursor cells into the demyelinated monkey spinal cord. Brain Res 2004 Dec 24;1030(1):94-102.
6. Pluchino S, Quattrini A, Brambilla E et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 2003 Apr 17;422(6933):688-94.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.

http://www.msneighborhood.com/content/in_the_news/archive_2256.aspx

http://www.thisisms.com/

Campath-1H is a experimental treatment for MS currently in clinical trials. While this new report touches upon the promising efficacy of the treatment, its main focus is on the difference between the effectiveness of therapeutic intervention at the relapsing-remitting stage of Multiple Sclerosis versus the secondary progressive stage. The ultimate conclusion is that early and potent treatment can significantly improve the patient's health, whereas attempting to do the same when the disease has already progressed lacks impact. In a very important point, this is even true when the MRI scans show no further disease progression-- reiterating what we have learned about secondary progressive MS not being an inflammatory condition, but rather one of neuronal/axonal loss and/or degradation. Now this study does not mean that people who are secondary progressive are beyond therapeutic hope-- what it implies is that secondary progressive patients will not benefit from this specific type of treatment targeting the reduction of inflammatory cells (e.g., likewise with Tysabri), presumably because the disease is no longer an inflammatory condition by that point. This is a positive finding, as it helps narrow the scope of treatment rather than blindly trying various poweful therapies in the hopes one will work. As bystanders to the research, it becomes quite clear that treating MS effectively will require tailored therapies-- if not to the individual then to the individual's disease stage. While we already see this in the current therapies, reinforcement breeds familiarity. "From 1991-2002, we treated 58 patients with multiple sclerosis (MS) using the humanised monoclonal antibody, Campath- 1H, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed. In both the relapsing- remitting (RR) and secondary progressive (SP) stages of the illness, Campath-1H reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of patients with SP disease, treated with Campath-1H 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differently affected depending on the phase of the disease." Click "read more" for the full abstract...

Posted by Administrator on Friday, July 29 @ 14:34:44 EDT (34 reads)
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http://www.thisisms.com/

In yesterday's investor conference call, BiogenIdec (co-sponsor of Tysabri along with Elan, who has a similar call scheduled for Thursday), provided a brief but positive update on the status of Tysabri. - The safety review of the trial patients is still on track to be completed by the "end of the summer." Happily, they finally defined what "end of summer" meant to them: September 21st! - After conclusion of the safety review, they will commence discussions with the regulatory bodies on how to bring Tysabri back to the market in terms of label changes, additional testing, etc. - During the previous quarter, Biogen spent $20M USD to cover the cost of Tysabri production (!) and to develop a high-titre production process (essentially, a more efficient process for producing Tysabri) - In a new development, Biogen/Elan are taking initial steps to begin re-dosing patients who had previously been on Tysabri clinical trials, as well as beginning additional trials as had been previously planned prior to the discover of PML. - Biogen does not feel that these trials will be required for bringing Tysabri back to the commercial market (Very important!). Part of the reason for this is that, prior to suspension, there were already post-marketing trial commitments in place, not all of which Biogen had been able to commence. - Previous studies (Phase II) showed that patients who were taken off of Tysabri treatment had relapses begin recurring after about 6 months-- though there was no rebound above the level seen in the placebo patients. Therefore, the FDA will theoretically be aware that MS patients in the Tysabri trials before the marketing suspension are reaching the point where they should begin relapsing. As such, there is a sliver of hope that re-dosing of former Tysabri clinical trial patients could begin by early September 2005. To be clear-- This is SPECULATION. However, note that it is easier to restart clinical trials then it is to re-introduce the drug to the general market. Click "read more" for a link to a recording of the call...

Posted by Administrator on Wednesday, July 27 @ 12:22:53 EDT (84 reads) (Read More... | 2529 bytes more | comments? | Score: 4)

Wed Jul 27, 1:09 PM ET

STOCKHOLM (AFP) - Swedish researchers have created new functioning brain cells from stem cells drawn from the brains of living adults, sparking hope that effective treatments for devastating illnesses like Parkinson's and Alzheimer's could be at hand, media reported.

Neurosurgeons withdrew the stem cells from the brains of adults during routine surgery for hydrocephalus, or water on the brain, a researcher at the Stockholm Karolinska Institute told the Swedish daily Svenska Dagbladet.

As long as an agent was present to induce cell division, the extracted stem cells created new and working brain cells.

"So far we have managed to produce several millions of new cells from the original stem cells. About 25 percent of them are (active) neurons," Ulf Westerlund, who presented his doctoral thesis on the subject last week, told the paper.

When the researchers added glutamate, a salt that functions as a neurotransmitter in the central nervous system, the new cells communicated in a network, according to Westerlund.

"This means we had working synapse connections that are needed for nerve cells to work," he said.

Stem cells are nascent cells which can develop into replacement cells for damaged organs or body parts.

Researchers have long attempted to find ways of replacing dead brain cells with healthy ones in order to reverse the tragic effects of such diseases as Alzheimer's, Parkinson's and multiple sclerosis, in which the brain slowly dies.

In cooperation with the University of California at Los Angeles, Westerlund and other Swedish researchers have inserted the extracted human stem cells into the spinal marrow of rats, revealing that also there the cells continued to divide and create new cell neurons.

The injection of stem cells into the rats also appeared to lead to quicker recovery for allodynia, or pain that results from a non-injurious stimulus to the skin, according to Westerlund.

"The mere potential of these cells has had a significant impact of how we today evaluate the regenerative capacity of the central nervous system and, importantly, on the possible means for science to provide insights in neural repair," he wrote in his thesis.

http://news.yahoo.com/photo/050727/photos_hl_afp/050727170941_7syxhzhr_photo0;_ylt=AqKrXLdGh_NBbuTynSsOAi.KOrgF;_ylu=X3oDMTA3bGk2OHYzBHNlYwN0bXA-

http://news.yahoo.com/news?tmpl=story&u=/afp/20050727/hl_afp/swedenhealthstemcells_050727170941

Time is GMT + 8 hours Posted: 27 July 2005 1219 hrs NUS scientists unlock 'schizo' protein By Vinita Ramani, TODAY Multiple sclerosis attacks the nerve fibres responsible for transmitting communication signals and affects every sufferer differently

Scientists from the National University of Singapore (NUS) have discovered a novel protein that can provide fundamental clues to better understanding of neurological disorders such as schizophrenia and multiple sclerosis.

The team of scientists from the Department of Anatomy at the Yong Loon Lin School of Medicine at the NUS said that the protein controls the development of specialised brain cells which, in turn, provide insulation to the nerve signalling network.

If these brain cells develop abnormally, the shield that protects nerve fibres can dysfunction or get destroyed. And once this shield is no longer protecting the fibres, nerve pathways are affected and neurological disorders occur.

"It is basically like a short circuit. If a signal comes from the eyes and another comes from the hand, the two can 'crosstalk' and cause hallucinations, for example," said the Department of Anatomy's Dr Liang Fengyi.

These range from symptoms such as muscular weakness and loss of coordination, as in the case of multiple sclerosis, or illogical patterns of thinking and delusions, which characterise schizophrenia. Led by the head of the department Professor Ling Eng Ang and Dr Liang, the nine-member research team believes that its discovery is "fundamental and exciting".

The scientists have named the novel protein "juxtanodin" and feel it is fundamental to understanding the "myelin sheath" that shields the nerve fibres.

"Without this, we cannot talk about therapeutic intervention," said Prof Ling. So does the discovery spell hope for sufferers of neurological diseases?

"That is the million dollar question right now. The discovery has been critical in better understanding the structural components of the central nervous system and major disorders.

"We hope to continue the research and eventually work with hospitals," Prof Ling said. The research was supported by the faculty's Academy Research Fund, A*Star's Biomedical Research Community and DBS.

The findings have been published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), which is disseminated to more than 25,000 institutions and individuals worldwide.

"We are proud that work of this quality is becoming a regular feature at NUS. Publishing original work from Singapore in PNAS is a major achievement," said Dr John Wong, dean of the Yong Loon Lin School of Medicine. - TODAY/sh


http://www.channelnewsasia.com/stories/health/view/160049/1/.html

Two-thirds of animals with severed spines regained use of hind limbs

Updated: 7:39 a.m. ET July 27, 2005

WASHINGTON - Genetically engineered stem cells can help rats’ severed spinal cords grow back together, according to a study published Tuesday.

Rats given the treatment, using stem cells taken from rat embryos, could move their legs again after their spines were severed in the lab, said the researchers’ report in the Journal of Neuroscience.

The scientists hope the approach, which generated a new fatty cover for the spinal cord cells called the myelin sheath, also could be shown to work in people.

The key is using the right stem cells and then stimulating them correctly, said the researchers, who were led by Scott Whittemore of the University of Louisville School of Medicine in Kentucky.

“These findings suggest the possibility that transplantation therapy using a subset of neural stem cells and neurotrophic factors might improve functional recovery in human spinal cord injury,” said Dr. Michael Selzer, a professor of neurology at the University of Pennsylvania Medical Center in Philadelphia.

Spinal cord injuries can be caused by accidents or infections and affect 250,000 people a year in the United States alone, costing $4 billion annually, according to the National Institute of Neurological Disorders.

Whittemore’s team took specific cells from rat embryos called glial restricted precursor cells — a kind of stem cell or master cell that gives rise to nerve cells.

They genetically engineered these cells to do a little extra work by producing a compound called a growth factor — in this case, a new one called multineurotrophin. It was designed to coax immature neural stem cells to mature and become specialized cells called oligodendrocytes.

Oligodendrocytes help myelin grow onto nerve fibers, which cannot grow or function without this fatty protective coating.

Two-thirds of the rats in the study regained some hind limb movement, the researchers said.

http://www.msnbc.msn.com/id/8717240/

26 Jul 2005

Biogen Idec and Elan Corporation, plc 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.

Other efficacy data from SENTINEL at two years, including MRI measures and immunogenicity, were similar to previously reported one-year results.

Common adverse events included headache, nasopharyngitis, limb pain, depression, flu-like symptoms, diarrhea, insomnia, sinusitis, influenza, nausea, muscle pain, anxiety and cough. The rate of infection was 1.6 per patient-year in both AVONEX plus TYSABRI-treated patients and AVONEX plus placebo-treated patients. Serious infections occurred in 2.9 percent of AVONEX plus placebo-treated patients and 2.7 percent of AVONEX plus TYSABRI-treated patients. TYSABRI has been associated with hypersensitivity reactions, including serious systemic reactions which occurred at an incidence of less than 1 percent of patients.

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. Two of the patients with confirmed PML had received AVONEX plus TYSABRI for over two years as part of the SENTINEL trial. Biogen Idec and Elan's comprehensive safety evaluation concerning TYSABRI and any possible link to PML is ongoing. The results of this safety evaluation will be discussed with regulatory agencies to determine the appropriate path forward for TYSABRI.

"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. As always, our primary commitment is to improving the lives of people with MS."

"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."

SENTINEL is a two-year, randomized, multi-center, placebo-controlled, double-blind study of 1,171 AVONEX-treated patients in 123 clinical trial sites worldwide. In the trial, AVONEX-treated patients who continued to experience disease activity were randomized to add TYSABRI (n=589) or placebo (n=582) to their standard regimen.

The companies anticipate that two-year data from SENTINEL will be presented at the 21st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Thessaloniki, Greece, which begins September 28, 2005.

About TYSABRI

Biogen Idec and Elan are collaborating equally on the development of TYSABRI in MS, Crohn's disease, and rheumatoid arthritis. On February 28, 2005, Biogen Idec and Elan announced that they voluntarily suspended TYSABRI from the U.S. market and all ongoing clinical trials. Worldwide regulatory agencies are being kept informed of developments related to TYSABRI.

Information about TYSABRI, including the voluntary suspension of marketing and US prescribing information, is available at 1-800-456-2255 and http://www.TYSABRI.com.

About Multiple Sclerosis

MS is a chronic disease of the central nervous system that affects approximately 400,000 people in North America and more than one million people worldwide. It is a disease that affects more women than men, with onset typically occurring between 20 and 40 years of age. Symptoms of MS may include vision problems, loss of balance, numbness, difficulty walking and paralysis.

About Biogen Idec

Biogen Idec creates new standards of care in oncology, neurology and immunology. As a global leader in the development, manufacturing, and commercialization of novel therapies, Biogen Idec transforms scientific discoveries into advances in human healthcare. For product labeling, press releases and additional information about the company, please visit http://www.biogenidec.com. About Elan Elan Corporation, plc is a neuroscience-based biotechnology company. We are committed to making a difference in the lives of patients and their families by dedicating ourselves to bringing innovations in science to fill significant unmet medical needs that continue to exist around the world. Elan shares trade on the New York, London and Dublin Stock Exchanges. For additional information about the company, please visit http://www.elan.com.

Safe Harbor/Forward Looking Statements

This press release contains forward-looking statements regarding the potential for TYSABRI and the timing of the presentation of the two-year data from SENTINEL. These statements are based on the companies' current beliefs and expectations, and are subject to risks and uncertainties that could cause actual results to differ materially. There is no assurance, for example, that TYSABRI is not linked to PML, that there are not or will not be more PML cases or other serious adverse events associated with TYSABRI or that we will be able to gain sufficient information to fully understand the risks associated with TYSABRI. There is also no assurance that the companies will be able to resume marketing and sales of TYSABRI in any indication. There is also no assurance that all experiences with TYSABRI will be the same or that the potential for TYSABRI will not be affected by unexpected new data or technical issues. For more detailed information on the risks and uncertainties associated with TYSABRI and the companies' drug development and other activities, see the periodic and other reports of Biogen Idec Inc. and Elan Corporation, plc filed with the Securities and Exchange Commission. The companies assume no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

http://www.biogen.com

http://www.medicalnewstoday.com/medicalnews.php?newsid=27999

"Stephen Meyer"
Subject: Comments on BIOMARK Article

Steve - You have a newspaper article about a woman with MS - Jan
Wilkes in England. I searched the web for her and it looks like she
went to BioMark, which uses umbilical cord stem cells. I
investigated this place with our neurologist, the web, and
inquiries, re my husband's stroke - when I actaully had a one-on-one
phone interview,BioMark's "Doctor" of many degrees of which she
won't tell me of what, could NOT answer my questions.

In fact, here is the response to my neurologist after she reviewed
the "Scientific" documentation BioMark sent me:

"My thoughts: The Duke study has used cord blood to form cells that
differentiated into brain or heart cells, which hopefully will be
shown capable of producing enzymes/proteins that were missing in the
recipient. For example, the Duke studies showed that a particular
missing chemical could be produced by the cord cells- in a test
tube. This has not yet been done in a human, as per this report.
While very amazing and a huge step- I think this is many steps
removed from the transplanted cells replacing the full function of
missing brain cells (like in stroke). The Biomark company suggests
cord blood may treat neurodegenerative conditions- which usually
involve missing chemicals. I do not consider stroke a
neurodegenerative condition (in contrast to the biomark profile,
which lists many non-degenerative conditions in their list). Stroke
involves the complete (but static, not progressive) destruction of
many many cell types- all of which need "replacement" in an ideal
ther! apy. The evidence here provides not even a suggestion of this
kind of effect.

I would not advise a cord transplant in the absence of some studies
suggesting efficacy in stroke. However- participation in such
studies may be very reasonable.

Sorry for my skepticism- I cannot mislead you with false hope."

This is from some googling about Jan WIlks and her miracle cure that
I found googling - and believe me, if I thought this were true -
Michael and I would be on the Concord to England and Holland.

From:
http://www.bnn-online.co.uk/comments_display.asp?
HeadlineID=1213&Year=2005
"Stem cell therapy by biotechnology company Biomark is Mrs Wilks's
only hope."

Linda M. Roberts
linduhland@yahoo.com
www.wistemcellnow.org


>From your Sunday, July 24th email list:

Subject: Stem cell therapy helps MS sufferer--THE ADVERTISER

Stem cell therapy helps MS sufferer
By ADAM POWELL in London
THE ADVERTISER
23jul05

A MOTHER crippled by multiple sclerosis is walking again after
controversial treatment at a clinic in Holland.

Jan Wilks relied on a wheelchair after being diagnosed five years
ago with the wasting disease which destroys the nervous system.

But after raising $31,000 for experimental treatment involving
injections of stem cells she was able to stand up, then take a few
steps.

"The best moment was when my little boy! looked at me, burst into
tears, and said `Mummy, you can walk'," said Mrs Wilks, 45, at home
in Liverpool yesterday.

The improvement has continued and she is now beginning to lead a
normal life with husband Paul, 40, and sons Daniel, 12, and four-
year-old Reece.

July 19, 2005 18:00

Shares in pharmaceutical company Elan surged in Dublin today after it released figures showing that its suspended Tysabri drug improved the effectiveness of Biogen's Avonex in the treatment of multiple sclerosis.

'The addition of Tysabri to Avonex resulted in a 24% reduction in the risk of disability progression compared to the effect provided by Avonex alone,' the two companies said. There was also a 56% relative reduction in the rate of clinical relapses.

The companies halted sales of and trials of Tysabri in late February after it was discovered that some patients taking the drug in combination with another treatment had contracted a rare brain disease called PML.

The two firms are currently conducting a safety review before a decision can be made on a possible return of Tysabri to the market. Elan reports its second quarter results on July 28, and may give an update on the progress of the review then.

Shares in Elan closed 56 cent higher at €6.57 in Dublin this evening.

by John C. Martin
Article Date: 07-22-05

A 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."MS remains a significant area of unmet medical need, and we are hopeful that the novel mechanism of action of MLN1102 could provide patients with a new treatment option," said Nancy Simonian, MD, senior vice-president of Clinical, Regulatory, and Medical Affairs at Millennium.

Chemokine Receptors: Holding Them Back
The drug specifically targets certain chemokine receptors on the surfaces of a group of white blood cells known as macrophages and monocytes, blocking their action. Several preclinical studies have suggested that chemokine receptors, which are normally designed to direct certain cells of the immune system toward a disease-causing organism or infectious agents in the body, may play a key role in the inflammatory response.1,2

During the acute phase of multiple sclerosis, the activity of chemokine receptors moves into high gear, as seen in both studies of humans and animals.3,4 Apparently, these compounds direct T-cells and other white blood cells into the central nervous system, where damage to neurons and myelin occur. As such, chemokine receptors have been the target of research investigating new medicines for multiple sclerosis.

How MS Begins
MS is a disease characterized by areas of inflammation and scarring in the central nervous system. Damage occurs mostly to nerve fibers and myelin, a fatty sheath that covers and protects these nerve fibers. As a result, nerve "communication" is disrupted, and neurological impairment results.

Medical experts theorize that MS is an autoimmune disease in which, for an unknown reason, the body's immune system goes haywire, attacking normal body tissue rather than disease-causing invaders like bacteria or viruses. While MS is not an inherited disease, research has shown that it may strike people who have an increased susceptibility to autoimmune disease. It's estimated that between 350,000 and a half million people in the United States have been diagnosed with MS. The illness is more common in women and Caucasians. The large majority of patients are diagnosed between the ages of 16 and 60, though it's not uncommon for the disease to strike in early childhood or after age 60.5

Can a Drug Block Chemokine Receptor Activity?
In the phase 2, proof-of-concept study of MLN1202, about 40 patients are being enrolled. Both safety and tolerability of the drug will be scrutinized, as well as its effect on MS activity. Researchers will be conducting magnetic resonance imaging (MRI) exams to determine that. "MLN1202 is designed to specifically target the [chemokine] receptors found primarily on monocytes and macrophages, versus all leukocytes, which may be beneficial in lowering the risk of systemic immune suppression," Simonian explained.

This is potentially beneficial because a drug that would suppress the entire immune system would leave a person with MS susceptible to infections from viruses, bacteria, and the like. MLN1202, by contrast, suppresses only a small group of immune cells.

The drug is currently being evaluated in two unrelated clinical trials—one, involving patients with another autoimmune disease, rheumatoid arthritis. Additional studies to test the effectiveness of the drug in atherosclerosis and a tissue disease known as scleroderma are also being planned, Millennium stated.

1. Glabinsk AR, Ransohoff RM. Targeting the chemokine system for multiple sclerosis treatment. Curr Opin Investig Drugs 2001 Dec;2(12):1712-9.
2. Zhang GX, Baker CM, Kolson DL, Rostami AM. Chemokines and chemokine receptors in the pathogenesis of multiple sclerosis. Mult Scler 2000 Feb;6(1):3-13.
3. Muller DM, Pender MP, Greer JM. Chemokines and chemokine receptors: potential therapeutic targets in multiple sclerosis. Curr Drug Targets Inflamm Allergy 2004 Sep;3(3):279-90.
4. Kivisakk P, Mahad DJ, Callahan MK et al. Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann Neurol 2004 May;55(5):627-38.
5. Multiple Sclerosis Foundation. MS Info. Available at: http://www.msfacts.org/info/info_faq.html. Accessed July 14, 2005.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.

http://www.msneighborhood.com/content/in_the_news/archive_2253.aspx

Efficacy of the epidural blood patch for the treatment of post lumbar puncture headache BLOPP: A randomised, observer-blind, controlled clinical trial [ISRCTN 71598245]
R Oedit^{* 1} , F van Kooten^{* 1} , SLM Bakker^{* 2} and DWJ Dippel^{* 1
1}Erasmus Medical Centre, Rotterdam, The Netherlands
²Amphia General Hospital, Breda/Oosterhout, The Netherlands

BMC Neurology 2005, 5:12 doi:10.1186/1471-2377-5-12

Published

5 July 2005

Abstract

Background

Post dural punction headache (PDPH) occurs in 10% to 40% of the patients who had a lumbar puncture. Its symptoms can be severe and incapacitating. The epidural blood patch is widely accepted as the treatment of choice for postdural puncture headache. Uncontrolled studies report rapid recovery after patching in 90% to 100% of treated patients. However, sufficient evidence from randomised, controlled clinical trials is lacking.

Methods

BLOPP (blood patch for post dural puncture headache) is a randomised, single centre, observer-blind clinical trial. Patients with PDPH for at least 24 hours and at most 7 days after lumbar puncture will be randomised to treatment with an epidural blood patch (EDBP) or to conventional treatment, i.e. 24 hours bed rest and ample fluid intake. PDPH 24 hours after treatment, classified on a 4-point scale (no, mild, moderate, severe) is the primary outcome. The secondary outcome is the presence of PDPH 7 days after treatment. We estimated that a sample size of 2 × 20 patients would provide us with a power of 80% to detect a relative reduction in number of patients with persisting PDPH after 24 hours of 50% at the usual significance level α = 5%, taking into account that in approximately 10% of the patients the PDPH will have resolved spontaneously after one day.

Discussion

The EDBP is accepted as the treatment of choice for PDPH although randomised, controlled data is scarce. Our randomised, observer-blind clinical trial enables us to compare the efficacy of two clinically practiced methods of PDPH treatment; EDBP versus conventional treatment, as they are applied in clinical practise.
http://www.biomedcentral.com/1471-2377/5/12/abstract

http://tinyurl.com/8a5s9

LIVERPOOL DAILY POST

My son wept as he saw me walk again Jul 19 2005

By Mary Murtagh, Liverpool Echo


AS Reece Wilks watched his mother walk towards him he burst into
tears of joy.

The four-year-old knew his mother Jan had multiple sclerosis and was
used to seeing her in a wheelchair.

The mother-of-two's condition had been getting worse when locals
raised £13,000 for revolutionary stem cell treatment in Holland.

Within hours of the treatment Mrs Wilks was out of her wheelchair
and walking unaided for the first time in years.

"It is like a miracle," said the 45-year-old from Stockbridge Lane,
Page Moss. "I feel fantastic and I have no pain. It is like the
start of a whole new life for me. I can put my wheelchair up in the
loft now."

Mrs Wilks's youngest son Reece burst into tears when he saw her back
on her feet again saying: "Mum, you can walk."

Mrs Wilks's 40-year-old husband Paul and eldest son Daniel, 12,
watch in amazement as she regains basic skills she thought were lost
forever - taking a shower, tucking her children up in bed and making
a family meal.

Now Mrs Wilks is looking forward to going back to work at Asda and
seeing colleagues who helped pay for the treatment.

She said: "The girls at work won't believe their eyes."

Mr Wilks was made redundant from his job as security manager at Asda
a few days before the family flew out to Holland.

But his wife's amazing recovery has eased his worry about losing his
livelihood.

He said: "The difference is fantastic. She looks a lot better; her
eyes and complexion are clearer, and she isn't exhausted all the
time.

"She has so much more energy. She is just going from strength to
strength. I can hardly believe it."



STEM cells are the building blocks for every tissue and organ in the
body.

They can be used to treat a range of conditions such as Parkinson's
and Alzheimer's diseases and several forms of cancer.

Stem cells have the ability to grow outside the body and can be
transplanted to produce tissue regrowth in patients with tissue
degenerating diseases.

The cells can be taken from a variety of sources, including unborn
foetuses - but this makes stem cell therapy controversial because it
raises medical ethics issues.

Stem cells used to treat Jan Wilks came from umbilical cords which
would have otherwise been destroyed.

Her treatment - which took just a few hours in a private Dutch
clinic - saw cells put into her body via a drip, and an injection
into the spine to repair damage.

Helen Yates, managing executive of the charity MS Resource Centre,
said: "Stem cells are an exciting new avenue to explore in the
treatment of MS but there are no guarantees with it. It is very much
an experimental treatment.

"Jan is not the only person I have heard of who has had stem cell
treatment and reported improvements in their condition.

"There should be some words of caution though; people need to be
looked after properly after the treatment and need careful
observation. The treatment is also irreversible - once you have stem
cells in your system that is it.

"We are very hopeful and positive about stem cell therapy."

Anyone wanting information on stem cell therapy can contact MSRC on
0800 783 0518.

Mrs Wilks was diagnosed with the disease in 2000. Her condition had
no treatment or cure and would have eventually crippled then killed
her.

She was in constant pain, could not walk far and relied on walking
sticks and a wheelchair.

She said: "I used to be in agony when I got up in the morning. I was
exhausted by the time I got downstairs.

"But now I can make the bed, walk downstairs and I feel normal
again. I am walking straighter, my eyes are brighter and I haven't
needed to use my stick."

Mr Wilks spent hours on the internet searching for alternative
treatments and discovered stem cell therapy was being used elsewhere
in the world to help slow the progress of diseases such as
Parkinson's, cancer and MS.

But the procedure is not yet available in the UK and is very
expensive.

Mrs Wilks's family was preparing to sell their home to pay for
treatment in Holland when colleagues at the Asda store in Huyton
stepped in to help, raising more than £13,000 in just three months.

A sponsored bike ride, donations and collection buckets at city Asda
stores all boosted the coffers.

Pam Barham, one of the Asda fundraisers, greeted Jan when she popped
into the store yesterday.

She said: "It was lovely to see Jan. You could see straight away
that she was much better. Her feet weren't swollen, her eyes were
clear and she was walking.

"Everyone was over the moon to find her better. The money we raised
could not have gone to a better person.

"This is a credit to everyone who raised money for Jan. We had
donations from the Round Table, the Masons and even a cheque from a
Canadian couple."

Mrs Wilks is due to see her consultant next month, and is hoping to
amaze him with her recovery.

marymurtagh@liverpoolecho.co.uk

http://icliverpool.icnetwork.co.uk/0100news/0100regionalnews/tm_objectid=15753993%26method=full%26siteid=50061-name_page.html

Wrongful death case alleges negligence in Tysabri clinical trial

By Jeffrey Krasner, Globe Staff | July 21, 2005

The widower of a woman who died from a rare brain disease after participating in a clinical trial of Biogen Idec's multiple sclerosis drug Tysabri yesterday sued the Cambridge company and its partner, Elan Pharmaceuticals of Ireland.

The wrongful death suit, filed in Middlesex Superior Court by Walter Smith of Colorado Springs, Colo., charges the companies with negligence, fraud, and violation of state consumer laws in the Feb. 24 death of Anita Louise Smith, 46.

''My wife didn't have to die," Smith said in a statement released by his lawyer. ''If we had all the information we should have had, she'd be with us today."

The suit asks for compensation for Anita Smith's pain and suffering, and also for punitive damages, but doesn't specify a dollar amount.

The complaint centers on the allegation that the companies knew or should have known that Tysabri and Avonex, Biogen Idec's other MS drug, suppress the immune system when taken together, reducing the ability of the body to defend itself against infection. The suit alleges the companies knew of the potential danger, yet recklessly proceeded with tests in clinical trials.

In addition, the complaint alleges, the dangers and risks weren't disclosed to Smith, so she could not have provided true informed consent to participate in the trial.

''When a pharmaceutical company fraudulently conceals a known danger of a drug, a person cannot properly consent to using that pharmaceutical," said Jerrold S. Parker of Parker & Waichman LLP of Great Neck, N.Y., who is representing the Smith family. ''They had knowledge of these issues before Anita Smith took this combination cocktail, yet they never told Anita Smith and they never told Walter Smith."

Biogen Idec spokesman Jose Juves said the company hadn't yet seen a copy of the complaint, filed late yesterday afternoon. ''Our thoughts and sympathies go out to the Smith family during this difficult time," he added. ''This unforeseen event occurred during a clinical trial designed to determine the safety and efficacy of Tysabri. At the first signal of a potential problem, Biogen Idec quickly and decisively halted dosing in the trials and began an extensive ongoing safety evaluation."

Davia Temin, a spokeswoman for Elan, said the company does not comment on litigation. ''However, we do believe we've taken and are taking all appropriate actions to ensure patient safety," she said.

Tysabri was initially developed by a firm that was later acquired by Elan, Ireland's biggest drug company. In 2000, Elan agreed to develop Tysabri with Biogen Corp., which had already developed a multiple sclerosis drug, Avonex.

Pivotal trials for Tysabri alone and Tysabri taken with Avonex yielded such positive results that the firms sought marketing approval from the Food and Drug Administration just one year into a planned two-year trial. The agency gave the drug accelerated review and it was approved for sale last November.

But the drug was sold for only three months before the companies voluntarily suspended sales and clinical trials in February, saying one person had died of a rare disease and a second was suspected of having it. Since then, the companies have attributed a second death to the disease, progressive multifocal leukoencephalopathy, but have declined to comment on additional suspected cases until it completes a full safety review this summer.

The suspension of the drug is a disappointment to patients, who had long-awaited a drug more effective than existing MS treatments. Tysabri proved itself superior in preventing debilitating relapses of the disease. But some doctors now believe the combination of Tysabri and Avonex weakened the immune system and made it possible for opportunistic infections like PML to take hold.

The story of Anita Smith puts a human face on what has so far been discussed in the context of clinical trials, adverse events and arcane medical data.

Smith, a mother of two, received her first dose of Tysabri in April 2002 as part of a trial of Tysabri and Avonex together. In November 2004, she began experiencing problems with speech, mental perception, and hand-eye coordination, according to the complaint, and an MRI scan showed a ''dramatic abnormality" in the left side of her brain.

In early February, she spent nine days in a local health center before being transferred to a Denver hospital, where she was diagnosed with PML. She died at a hospice on Feb. 24 ''after enduring intractable pain and suffering," according to the complaint. Four days later, Biogen Idec and Elan pulled the drug off the market.

A native of Glenwood Springs, Col., Smith moved to Colorado Springs and in 1982 married her husband. They worked together in his towing business. She loved animals and had three Dalmatians. Her interests included gardening, stained glass, interior decorating, crosswords, cooking, the Denver Broncos, ''and driving her red, really fast Jeep," according to an obituary published in The Gazette of Colorado Springs.

''As alleged in the complaint, this is a tragic death resulting from pharmaceutical products whose use was unreasonably dangerous and which never should have been given to Mrs. Smith," said Jason Mark, another lawyer with Parker & Waichman, who also represents the Smith family.

Cases such as the one filed yesterday have proliferated in recent years, said Andrew Finkelstein, managing partner of Finkelstein & Partners LLP, a Newburgh, N.Y., law firm that specializes in product liability.

''Over the last 10 to 12 years, there's been a significant increase in the amount of litigation against pharmaceutical companies that is directly correlated with the FDA's fast-track system of approving drugs with fewer clinical trials," Finkelstein said. ''The net result is there are more adverse events beyond the scope of what was reasonably expected."

Jeffrey Krasner can be reached at krasner@globe.com.

http://www.boston.com/business/globe/articles/2005/07/21/colorado_widower_sues_elan_and_biogen?mode=PF

BERLIN, Germany, July 20 /PRNewswire-FirstCall/ -- Schering AG, Germany (FSE: SCH, NYSE: SHR) announced today that over 2100 patients with relapsing-remitting multiple sclerosis (RRMS) have been enrolled into the BEYOND (Betaferon(R) Efficacy Yielding Outcomes of a New Dose) study. BEYOND is the largest-ever, randomized, blinded, clinical MS study and is being conducted in more than 200 centers in 26 countries.

With more than 16 years of clinical trial and real world experience, Betaferon(R) 250 mcg is a proven effective and well-tolerated therapy for relapsing forms of MS. The BEYOND study evaluates if patients with RRMS derive even greater benefit from a Betaferon(R) 500 mcg dose (BEYOND Dose) that is twice the approved dose (Betaferon(R) 250 mcg) and is higher than that of any currently available interferon.

Additionally, the BEYOND study compares the efficacy of Betaferon(R) with glatiramer acetate (a non-interferon) in patients with RRMS. This will be the first head to head comparison of Betaferon(R) with glatiramer acetate.

"The BEYOND study is expected to show that the BEYOND Dose of Betaferon(R) is more efficacious than any currently available interferon", said Dr Joachim-Friedrich Kapp, Head of Specialized Therapeutics of the Schering Group. "Our goal is to noticeably improve the outcome and prognosis for MS patients".

Results from the first phase of the BEYOND program, published in September 2003, showed that the BEYOND Dose of Betaferon(R) was safe and well tolerated. The final results of the study program are expected in 2007.

The BEYOND trial is part of Schering's comprehensive study program with Betaferon(R) in Multiple Sclerosis. Besides BEYOND it encompasses the BENEFIT trial investigating the impact of early treatment as well as the 16-Year LTF (long term follow up) study for the evaluation of the long-term safety and effectiveness of Betaferon(R) treatment over 16 years.

   Additional information   About Betaferon(R):  

Betaferon(R) has the broadest experience of any MS medication. In the U.S., Europe and Japan, Betaferon(R) has been approved for all relapsing forms of MS. It is able to reduce the number of MS episodes by one third, and it reduces the frequency of moderate to severe episodes by as much as 50%.

Schering AG is a research-based pharmaceutical company. Its activities are focused on four business areas: Gynecology&Andrology, Oncology, Diagnostic Imaging as well as Specialized Therapeutics for disabling diseases. As a global player with innovative products Schering AG aims for leading positions in specialized markets worldwide. With in-house R&D and supported by an excellent global network of external partners, Schering AG is securing a promising product pipeline. Using new ideas, Schering AG aims to make a recognized contribution to medical progress and strives to improve the quality of life: making medicine work

This press release has been published by Corporate Communication of Schering AG, Berlin, Germany.

Your contacts at Corporate Communication:

Media Relations: Oliver Renner , T: +49-30-468-124-31, oliver.renner@schering.de

Investor Relations: Peter Vogt, T: +49-30-468-128-38, peter.vogt@schering.de

Pharma Communication: Dr Claudia Schmitt, T: +49-30-468-158-05, claudia.schmitt@schering.de

   Your contacts in the U.S.:   Media Relations: Marcy Funk, T:+1-973-487-2095, marcy_funk@berlex.com  

Investor Relations: Joanne Marion, T: +1-973-487-2164, joanne_marion@berlex.com

Find additional information at: www.schering.de/eng

Certain statements in this press release that are neither reported financial results nor other historical information are forward-looking statements, including but not limited to, statements that are predictions of or indicate future events, trends, plans or objectives. Undue reliance should not be placed on such statements because, by their nature, they are subject to known and unknown risks and uncertainties and can be affected by other factors that could cause actual results and Schering AG's plans and objectives to differ materially from those expressed or implied in the forward-looking statements. Certain factors that may cause such differences are discussed in our Form 20-F and Form 6-K reports filed with the U.S. Securities and Exchange Commission. Schering AG undertakes no obligation to update publicly or revise any of these forward-looking statements, whether to reflect new information or future events or circumstances or otherwise.

Schering AG

CONTACT: Your contacts at Corporate Communication: Media Relations:Oliver Renner , T: +49-30-468-124-31,oliver.renner@schering.de, Investor Relations: Peter Vogt, T:+49-30-468-128-38, peter.vogt@schering.de, PharmaCommunication: Dr Claudia Schmitt, T: +49-30-468-158-05,claudia.schmitt@schering.de, Your contacts in the U.S.: MediaRelations: Marcy Funk, T:+1-973-487-2095,marcy_funk@berlex.com, Investor Relations: Joanne Marion, T:+1-973-487-2164, joanne_marion@berlex.com

http://www.rednova.com/news/display/?id=180782&source=r_health

Source: PRNewswire-FirstCall

Author: Barry A. Singer, MD

Complete author affiliations and disclosures are at the end of this activity.
http://www.medscape.com/viewprogram/4281_pnt

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Release Date: June 30, 2005; Valid for credit through June 30, 2006

Target Audience

This activity is intended for general neurologists, primary care practitioners, nurse practitioners, physician assistants, and nurses.

Goal

The goals of this activity are to improve the diagnosis of multiple sclerosis and its treatment, focusing on relapsing-remitting disease. Specific topics discussed are the following: (1) the use of MRI in diagnosis and monitoring disease activity, (2) assessing treatment failure, (3) switching primary therapy, (4) add-on therapy, and (5) new treatments in development.

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Differentiate between the types of MS.
2. Review the use of MRI in initial diagnosis and in monitoring disease activity.
3. Assess treatment failure.
4. Evaluate options for switching primary therapy.
5. Examine add-on therapies and new products currently in development.

Credits Available

Physicians - up to 1.0 AMA PRA Category 1 continuing physician education credits ;
Nurses - up to 1.2 ANCC continuing nurse education contact hours

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Contents of This CME/CE Activity

1. Advances in MS: A Case-Based Approach to Management
   Introduction
   Case Presentation
   Classification of the Patient's Clinical Course
   Factors Associated With an Increased Likelihood of Disease Progression
   Assessment of Treatment Failure
   Factors to Consider When Assessing Treatment Failure
   Evidence-Based Data for Switching to Another Interferon Medication
   Evidence-Based Data for Switching to Glatiramer Acetate
   Evidence-Based Data for Switching to Mitoxantrone
   Evidence for Preventing Progression of Disability Over the Long Term With Treatment
   Add-on Therapies to US Food and Drug Administration-Approved Immunomodulatory Agents for Relapsing-Remitting Disease
   Potential New Treatment Options for This Patient on the Horizon
   Conclusion
   References
   
   

Advances in MS: A Case-Based Approach to Management

Introduction

Multiple sclerosis (MS) is an autoimmune disease that targets the myelin of the brain, spinal cord, and optic nerves. This immune attack results in demyelination and, potentially, axonal injury. The inciting trigger that activates this immune response is unknown. Potential causes may be a combination of genetics and environmental exposures to pathogens, such as viruses.

The disease affects young adults with the mean age of onset at about 30 years. Two thirds of people with MS are women. Eighty-five percent of patients initially have a relapsing-remitting course in which acute exacerbations are generally followed by neurologic improvements.^[1] Over time, disability accrues from residual neurologic impairment from relapses and/or a progressive course of worsening function. Physical disability, such as loss of ambulation or vision, can severely restrict the lives of individuals with MS. Cognitive disabilities, such as short-term memory loss and impairment in multitasking, can result in loss of employment with marked psychological and socioeconomic consequences. Natural history studies have demonstrated that 90% of patients have developed progressive disease after 25 years without treatment.^[2]

The introduction of immunomodulatory treatment options has begun to alter the clinical course for people living with relapsing-remitting MS. Beta-interferon and glatiramer acetate injections have been shown to reduce relapse rates and reduce disability progression.^[3-6] Hospitalizations and absences from work due to relapses can significantly disrupt an individual's life. Furthermore, some relapses can lead to residual disability.^[7] Interferon beta-1a and mitoxantrone have also been shown to reduce the probability of disease progression to a statistically significant degree in relapsing-remitting MS patients.^[4,5,8]

1. Survey - What is the most important barrier to the optimal management of MS? Breakthrough relapses that lead to residual disability Immunomodulatory treatment risks Long-term effects of steroids Limited data on add-on agents when treatment fails 2. Survey - How confident are you that you are up-to-date in the diagnosis and management of MS? Not at all confident Somewhat confident Confident Very confident

Case Presentation

A 29-year-old, right-handed man presents for evaluation of worsening balance. Three years ago, he developed intermittent right face numbness for 2 months. Two years ago, he developed right leg tingling for approximately 3 months. He also noted that his balance was intermittently impaired at that time. A magnetic resonance imaging (MRI) scan of the brain, obtained 2 years ago, demonstrated 22 enhancing lesions and 29 T2-hyperintense lesions (Figure 1).

Figure 1. Contrast-enhancing T1 lesions prior to treatment initiation.

No lumbar puncture was performed. At that time, interferon beta-1a 30 mcg intramuscularly (IM) was started on a weekly basis.

One and a half years ago, he developed double vision that lasted for 2 weeks; the images appeared horizontally displaced. Currently, his balance is poor. He must hold onto walls and falls as many as 10 times per month. His legs feel strong, but are stiff. Both his feet tingle. He describes a sense of urinary urgency with a frequency of once an hour. At times, his bladder does not seem to empty completely. He also reports that ejaculation is delayed. He developed depression that has now resolved with fluoxetine. Fatigue had disrupted work and home life, but has now significantly diminished on modafinil. He denies experiencing vertigo, tinnitus, hearing loss, or constipation. His short-term memory has been only minimally impaired, and multitasking ability has been excellent.

His medical history is otherwise unremarkable. He has had no previous surgeries. He is currently taking IM interferon beta-1a 30 mcg weekly, fluoxetine 40 mg daily, and modafinil 200 mg daily, and he denies having medication allergies. He is a nonsmoker and he occasionally drinks alcohol. His parents are both healthy with no significant family history of neurologic illness.

On neurologic examination, he is alert and fully oriented. His speech is fluent without dysarthria. Past presidents are intact to Reagan. "World" spelled backward is correct. Serial 7's are intact to 86. Immediate object recall is 3 out of 3, but only 1 out of 3 in 5 minutes with and without cues. His visual fields are full and his visual acuity is 20/20 bilaterally without correction. Pupils are equal, round, and reactive to light. He has no papilledema or pallor. Extraocular movements are full. His face is symmetric with normal sensation. His hearing is intact and his palate is upgoing bilaterally. Sternocleidomastoid and trapezius strength are intact. His tongue is midline.

His motor exam is notable for moderate spasticity bilaterally in the legs. Strength resistance testing is 5 of 5 in all extremities without a pronator drift. Light touch, pinprick, and proprioception are normal. Reduced vibratory sensation is noted in the left leg and distal to the midshin on the right. Reflexes are normal in the upper extremities, but sustained clonus is present at the knees and ankles bilaterally. Bilateral Babinski's are present. There is no finger-to-nose dysmetria. Heel-to-shin dysmetria is moderate on the right and mild on the left. His gait is severely spastic. Romberg testing is negative and he is able to tandem walk.

A follow-up MRI scan of the brain with gadolinium demonstrates only 1 enhancing lesion in the left occipital lobe. An interval increase in T2 lesions from 29 to 40 occurred. Fluid-attenuated inversion-recovery (FLAIR) axial and sagittal images 2 years after treatment are shown in Figures 2 and 3, respectively.

Figure 2. Fluid-attenuated inversion-recovery axial images 2 years after treatment with intramuscular interferon beta-1a 30 mcg weekly.

Figure 3. Fluid-attenuated inversion-recovery sagittal images 2 years after treatment with intramuscular interferon beta-1a 30 mcg weekly. Presence of callosal lesions noted.

3. Survey - How would you classify this patient's clinical course? Relapsing-remitting (Relapsing-remitting disease is the best description for his clinical course. People with this type of MS experience attacks of the disease with subsequent full or partial recovery of neurologic deficits. Some patients have a stepwise increase in neurologic disability.) Secondary progressive (This is not the best description for his clinical course. People with this type of MS start with relapses, but develop progressive disability that increases over time. Most patients slowly get worse with or without superimposed relapses.) Primary progressive (This is not the best description for his clinical course. People with this type of MS experience a slow and steady progression of a chronic neurologic deficit without relapses.)

Classification of the Patient's Clinical Course

Relapsing-remitting disease is the best description for this patient's clinical course. Eighty-five percent of patients initially have this type of MS.^[1] Relapsing-remitting disease is characterized by clearly defined relapses and followed by partial or complete recovery periods free of disease progression. Relapses experienced by patients can clearly result in residual disability. In one study by Lublin and colleagues,^[7] worsening disability 3 months after relapses was observed in pooled placebo patients from pivotal clinical trials. Thirty percent of placebo patients progressed 1 point and 41% progressed 0.5 points in the Expanded Disability Status Scale (EDSS) 3 months after a relapse.

A secondary progressive course generally implies a steady progressive decline in function. Early in the secondary progressive stage, patients can still have superimposed relapses in addition to the continuous downward slope of increasing disability. Although this patient is at high risk for secondary progressive disease with time, his clinical course is more consistent with relapses with residual disability after each attack.

Fifteen percent of patients have primary progressive MS. In this clinical course, symptoms, such as leg weakness, gradually worsen over years without the presence of relapses.^[1]

4. Survey - What aspects of the patient's history and examination suggest an increased likelihood of disease progression? Horizontal diplopia and ataxia (This aspect suggests an increased likelihood of disease progression, but the best answer is all of the above.) Bilateral leg spasticity and vibratory loss (This aspect suggests an increased likelihood of disease progression, but the best answer is all of the above.) Male gender (This aspect suggests an increased likelihood of disease progression, but the best answer is all of the above.) Frequent relapses (This aspect suggests an increased likelihood of disease progression, but the best answer is all of the above.) All of the above (This is the best answer because all aspects suggest an increased likelihood of disease progression.)

Factors Associated With an Increased Likelihood of Disease Progression

Brainstem and spinal cord demyelination are unfavorable predictors of disease course. Horizontal diplopia and ataxia suggest pontine involvement. Bilateral leg stiffness, bilateral foot tingling, bladder dysfunction, and sexual dysfunction may be indicative of myelopathy. The patient's examination supports spinal cord involvement with bilateral leg spasticity, vibratory loss, dysmetria, sustained clonus, and Babinski signs.

Together, these observations suggest an increased likelihood of disease progression. An important consideration is that men tend to fare worse in terms of disease progression. This patient is also at higher risk because he experienced 3 relapses in his first 2 years.^[9]

5. Survey - Do you believe that this patient has experienced treatment failure? Definitely yes Possibly Definitely no Unsure

Assessment of Treatment Failure

Clinically, this patient experienced marked worsening of his disability despite being on interferon beta-1a 30 mcg weekly. In 2 years, he developed ataxia, spasticity, foot paresthesias, bladder dysfunction, fatigue, and depression. Therefore, his response to this immunomodulatory regimen could be considered a treatment failure. He has had a marked decrease in enhancing T1 brain lesions, but continues to accumulate T2 burden on MRI.

6. Survey - Which of the following factors should be considered when assessing treatment failure in this patient? Progression of disability (This factor should be considered, but the best answer is all of the above.) Relapse rate (This factor should be considered, but the best answer is all of the above.) MRI activity (This factor should be considered, but the best answer is all of the above.) All of the above (This is the best answer because all of these factors should be considered when assessing treatment failure.)

Factors to Consider When Assessing Treatment Failure

There are no definitive guidelines for the assessment of treatment failure, so a number of factors should be considered. Significant progression of disability while undergoing therapy is one parameter used to define treatment failure. Because current therapies are only partially effective in slowing the progression of disease, the acceptable amount of disability progression for a specific treatment can be difficult for the neurologist to determine. Progression on the EDSS of 1 or more points is concerning. This patient, for example, had substantial worsening of disability, including development of spasticity, ataxia and bladder dysfunction, fatigue, and depression.

Relapse rate can also help determine treatment failure. If the relapse rate increases to 2 or more episodes a year, the current treatment regimen should be reevaluated. A neurologist may opt not to change therapy for 2 mild attacks in a year, but a change should be considered for 2 or more attacks requiring methylprednisolone intravenously. This patient describes an episode of diplopia 6 months after treatment initiation consistent with a relapse. Because he failed to describe other discrete attacks, he did not fail treatment with relapse rate as a parameter.

MRI is another way to monitor disease activity in MS. Important MRI measures to assess disease activity are the following: (1) T2 lesion number, (2) T2 lesion volume, and (3) gadolinium-enhancing T1 lesions. As described previously, a follow-up MRI scan of this patient's brain with gadolinium showed only 1 enhancing lesion in the left occipital lobe. This radiographic change likely reflects a strong effect of interferon beta-1a on inflammatory change at the blood-brain barrier. In contrast, a significant interval increase in the number of T2-hyperintense lesions from 29 to approximately 40 was seen on FLAIR imaging. His marked increase in T2-hyperintense brain lesions indicates ongoing demyelination over the past 2 years regardless of just 1 enhancing lesion on the follow-up scan.

Therefore, his response to IM interferon beta-1a 30 mcg weekly would be considered a treatment failure because ongoing progression of disability and accumulating T2 MRI disease burden are evident.

7. Survey - Would you switch this patient to a different treatment regimen? Definitely yes Possibly Definitely no Unsure 8. Survey - What treatment option would you choose for this patient? No change; continue interferon beta-1a 30 mcg IM weekly Switch to interferon beta-1a 44 mcg subcutaneously 3 times weekly Switch to interferon beta-1b Switch to glatiramer acetate Switch to mitoxantrone

Evidence-Based Data for Switching to Another Interferon Medication

A switch to another interferon medication would seem reasonable for this patient because he has been progressing clinically.

Two randomized trials have compared the efficacy of IM interferon-beta-1a 30 mcg weekly with other interferon formulations. The EVIDENCE Trial illustrated the superiority of interferon beta-1a 44 mcg subcutaneous 3 times weekly compared with 30 mcg IM weekly at least in the short term for relapses and MRI lesions.^[10,11] The patients were not blinded to the treatment arm, but the evaluating neurologist was blinded. The proportion of patients who were relapse-free at 24 weeks, the primary outcome measure, was 75% with 44 mcg subcutaneously 3 times weekly and 63% with 30 mcg IM weekly (P = .0005). At the end of 48 weeks, 62% of patients on 44 mcg subcutaneously and 52% of patients on 30 mcg IM remained relapse-free (P = .009). The difference between the medications was more pronounced on MRI imaging. Over 48 weeks of the trial, the 44-mcg regimen yielded a 36% decrease in the mean number of T2 lesions per patient per scan, a 38% decrease in the proportion of T2-active scans per patient, and a 32% increase in T2-inactive patients compared with the 30-mcg regimen (all P < .001). There was a trend toward a reduction of disability progression risk, but this trend was not statistically significant. During the 34-week crossover period of the EVIDENCE Trial, patients had 50% fewer relapses (P < .001), and there was a 22% decrease in the mean number of T2-active lesions per patient per scan (P < .02) when patients were switched from 30 mcg IM weekly to 44 mcg subcutaneously 3 times weekly.

The Independent Comparison of Interferon (INCOMIN) trial, performed in Italy, compared interferon beta-1a 30 mcg IM weekly with interferon beta-1b 250 mcg every other day.^[12] The trial was randomized, but only the MRI component of the trial was blinded. The percentage of patients who were relapse-free over 2 years was 36% in the interferon beta-1a group and 51% in the interferon beta-1b group (P = .03). Confirmed progression of disability occurred in 30% of the interferon beta-1a patients and in 13% of the interferon beta-1b patients (P = .005). The percentages of patients who were free of new T2 lesions were 26% and 55% in the interferon beta-1a and beta-1b groups, respectively. The percentages of patients who were free of enhancing lesions were 49% on interferon beta-1a and 76% on interferon beta-1b.

Therefore, randomized, clinical trial data have demonstrated advantages of interferon beta-1a 44 mcg 3 times weekly subcutaneously and interferon beta-1b compared with interferon beta-1a 30 mcg weekly IM. The differences in clinical efficacy are more apparent on relapses and MRI activity because the only significant difference on disability progression was nonblinded in the INCOMIN trial.

Evidence-Based Data for Switching to Glatiramer Acetate

A switch to glatiramer acetate is another option to consider for this patient. Because no randomized trial data comparing interferon beta-1a with glatiramer acetate are available, neurologists must rely on the pivotal monotherapy trial data to evaluate the effectiveness of this treatment. A 29% reduction in relapse rate was observed with glatiramer acetate compared with placebo (P = .007) in this trial.^[3] In comparison, a 32% reduction in relapse rate was observed with interferon beta-1a compared with placebo (P = .002) in the 172 of 301 patients who finished the 2-year trial. The intention-to-treat analysis of all the interferon beta-1a trial patients demonstrated an 18% reduction in relapse rate over placebo (P = .04).^[4] Although direct comparisons across trials can be misleading, glatiramer acetate may be equivalent, if not superior, to interferon beta-1a 30 mcg weekly for relapse reduction.

Although relapse reduction is a goal for this patient, slowing the progression of disability is more critical. Interferon beta-1a demonstrated a 37% reduction in the probability of disease progression over 2 years.^[4] In contrast, trial data on reducing the progression of disability with glatiramer acetate are lacking. In the 2-year pivotal trial, 78.4% of patients in the glatiramer acetate group and 75.4% of patients in the placebo group were progression-free (sustained for 90 days). Therefore, in this trial, glatiramer acetate did not significantly slow the progression of disease. On the other hand, a positive effect of glatiramer acetate was seen on nonsustained disability, which was defined as worsening of EDSS ascertained from one exam at one time point in the study.^[3] Transient worsening may simply reflect a relapse rather than a true fixed change in disability. Of importance, all the interferon studies relied on confirmed progression that stipulated that worsened disability was still present in a follow-up neurologic exam 3 or 6 months later.

Evidence-Based Data for Switching to Mitoxantrone

Mitoxantrone is another treatment choice for a patient with worsening relapsing-remitting or secondary progressive disease. Administered every 3 months intravenously, mitoxantrone can be a potent agent to reduce relapses, progression of disability, and MRI activity. In a 2-year clinical trial, confirmed progression of disability occurred in 8% of mitoxantrone-treated patients and in 22% of patients in the placebo group. This 62% benefit of treatment was statistically significant (P = .036). The annual exacerbation rate with mitoxantrone was 68% lower than with placebo (P = .001). In addition, the mean number of new T2 MRI lesions was 85% lower than with mitoxantrone (P = .03).^[8]

Toxicity risks should be carefully considered before switching this patient to mitoxantrone. Cardiotoxicity can result in a reduced ejection fraction, so new guidelines recommend obtaining echocardiograms or MUltiple Gated Acquisition (MUGA) scans prior to each infusion. The maximum duration of therapy is 2 years, based on cumulative dose. Leukopenia, infection, and rare leukemia can occur. In women, permanent amenorrhea has been reported. Because of the potential risks, trying another immunomodulatory agent first would be reasonable for this patient. If this approach is ineffective, mitoxantrone remains a very effective option.

9. Survey - Does research suggest that long-term treatment of this patient's MS will prevent progression of disability? Definitely yes Possibly Definitely no Unsure

Evidence for Preventing Progression of Disability Over the Long Term With Treatment

Because a cure for MS has remained elusive, long-term treatment will be important to control this patient's disease. Evidence for reducing the risk of disability progression is an important clinical outcome measure as well as a critical treatment goal for patients.

Interferon Beta-1a 30 mcg and 60 mcg

Interferon beta-1a administered in 30-mcg and 60-mcg weekly IM injections resulted in no difference in disability progression over 4 years.^[13] However, no placebo arm was present, so the long-term effect of these regimens on disability is unknown. In the pivotal interferon beta-1a 30-mcg IM weekly trial, the reduction in progression of disability was 37% over 2 years.^[4] This result is based on the 172 patients who finished the trial. These 172 patients seem to have responded better to interferon beta-1a because they experienced a 32% reduction in relapse rate, whereas the intention-to-treat analysis of all 301 patients yielded an 18% reduction in relapse rate.

Interferon Beta-1a 44 mcg

Interferon beta-1a 44 mcg given 3 times weekly subcutaneously showed a statistically significant 30% benefit in reducing the risk of disability progression of relapsing-remitting disease at 2 years (P = .014).^[5,14] An 8-year follow-up of 382 out of the 560 originally randomized patients examined median time to progression of 1 EDSS point. The median time to progression was 4 years for patients who received placebo for 2 years and then received 44 mcg or 22 mcg of interferon beta-1a for 6 years. In contrast, it took 7.2 years for half the patients to progress in the cohort of patients randomized to the 44-mcg arm for the full 8 years.^[15]

Interferon Beta-1b

Interferon beta-1b demonstrated a trend in reduction of disability progression over 5 years in a randomized, double-blind study.^[16] The reduction in the probability of disease progression with interferon beta-1b was 23.4%, but this was not statistically significant (P = .096). Although 372 patients entered this trial, only 166 patients were followed in the double-blind cohort to 5 years. Over the first 3 years of the trial, interferon beta-1b also had no significant effect on confirmed progression of disability in relapsing-remitting patients (P = .161).^[6] Results from the European secondary progressive trial showed a reduction in the probability of disability progression with interferon beta-1b, whereas results from the North American trial showed no disability benefit with interferon beta-1b.^[17]

Glatiramer Acetate

Glatiramer acetate did not demonstrate a significant benefit on disability progression over 10 years with an intent-to-treat analysis.^[18] The 59 patients who received glatiramer acetate subcutaneously daily over 10 years experienced a mean increase in EDSS of .9. The 63 patients initially treated with placebo for 36 months and then switched to glatiramer acetate in the open-label phase experienced an increase in EDSS of 1.02. No statistically significant difference was found in this intention-to-treat analysis. Patients who dropped out of the open-label phase of this study had greater disability than the patients remaining on glatiramer acetate over 10 years. Of those patients who dropped out, 29% switched or combined therapies with glatiramer acetate, and 26% perceived their disease as worsening.^[19] Therefore, as many as 55% of patients who dropped out were not responding well to glatiramer acetate, which may account for their greater long-term disability.

Slowing the progression of disability over the long term is a major objective for this young man with a lifelong illness. Based on the long-term clinical trial results, initiation of interferon beta-1a 44 mcg subcutaneously 3 times weekly would meet this objective for this patient. Interferon beta-1b might decrease his disability over time, but the trial data for 2 and 5 years were not statistically significant for reduction in disability progression. No long-term evidence on disability progression is available to confirm the use of interferon beta-1a 30 mcg IM weekly and glatiramer acetate subcutaneously weekly.

10. Survey - Would you consider an add-on therapy to this patient's existing therapy? Definitely yes Possibly Definitely no Unsure

Add-on Therapies to US Food and Drug Administration-Approved Immunomodulatory Agents for Relapsing-Remitting Disease

Various add-on therapies to US Food and Drug Administration (FDA)-approved immunomodulatory agents are available for relapsing-remitting disease. Because this patient has had increased disability and MRI T2 activity, an add-on medication may be an option to attain better disease control. Add-on therapies may help reduce relapses, disability progression, and MRI activity. However, it should be noted that trial results for many of these agents are limited due to small study sizes.

Methylprednisolone

Zivadinov and colleagues^[20] randomized 81 patients with relapsing-remitting disease to receive either 5 days of methylprednisolone with a prednisone taper every 4-6 months, or to receive the same steroid regimen for relapses only. The group that received regular pulse steroid infusions had a 32% reduction in the probability of disability progression compared with the group that received treatment only for relapses (P [21] The risk of developing MS at 2 years was 16.7% with placebo, 14.7% with oral prednisone, and only 7.5% with intravenous methylprednisolone for the treatment of optic neuritis. Adverse effects of steroids are hyperglycemia, avascular necrosis, psychosis, osteoporosis, cataracts, glaucoma, and gastritis.

Methotrexate

There are limited efficacy data for oral weekly methotrexate in the treatment of MS. In a study by Goodkin and colleagues^[22] with 60 patients, a significant reduction in disability progression of the upper extremities was observed with 7.5 mg of methotrexate weekly vs placebo over 2 years. In another study by Calabresi and colleagues^[23] with 15 patients, methotrexate 20 mg weekly added to interferon beta-1a 30 mcg weekly resulted in a 44% reduction in enhancing lesions over baseline MRI activity compared with interferon beta-1a alone. Risks to consider with methotrexate use are leukopenia, infection, hepatic injury, pulmonary fibrosis, retroperitoneal fibrosis, and secondary malignancies.

Azathioprine

Azathioprine is another oral immunosuppressant therapy with some data to support efficacy in MS. When azathioprine was added to interferon beta-1b in an open-label study at the National Institutes of Health, contrast-enhancing lesions decreased by 69% (P = .002).^[24] In addition, a meta-analysis of data from 7 studies revealed better odds for reductions in relapse and EDSS scores with azathioprine therapy.^[25] Risks to be considered with adding on azathioprine are leukopenia, infection, hepatic injury, and secondary malignancies.

This patient may benefit from the addition of an add-on medication, such as pulsed intravenous methylprednisolone, oral methotrexate, or oral azathioprine. However, a switch to a higher dose interferon may be a better initial option for him. Risks of these add-on agents must be weighed against the limited efficacy data.

11. Survey - Would you consider adding a monoclonal antibody to this patient's regimen in the future if available? Definitely yes Possibly Definitely no Unsure

Potential New Treatment Options for This Patient on the Horizon

All of the current FDA-approved medications for this patient have been proven to be only partially effective in the treatment of relapsing-remitting MS. New treatment options are needed so patients like this man can have the best chance of minimizing long-term disability. The 2 main types of new treatments currently being studied in clinical trials are monoclonal antibodies and oral immunomodulatory medications.

Monoclonal Antibodies

Natalizumab. The monoclonal antibody natalizumab was FDA-approved for the treatment of relapsing-remitting MS in November 2004. This antibody binds to an integren on the surface of activated lymphocytes and prevents the lymphocyte from adhering to the vascular cell-adhesion molecule on the endothelial cell. As a result, transendothelial migration that is needed to cause inflammatory activity in the central nervous system cannot occur. In the 2-year trial, natalizumab reduced relapses by 68% (P < .001) and reduced the probability of disability progression (P = .002) compared with placebo.^[26] Treatment with natalizumab was associated with an 83% reduction in new or enlarged T2 MRI lesions (P < .0001), a 92% reduction in gadolinium-enhancing lesions (P < .0001), and 76% fewer new black holes.^[27]

Biogen voluntarily withdrew natalizumab from the marketplace in February 2005 after 2 cases of progressive multifocal leukoencephalopathy developed in MS patients receiving therapy in combination with interferon beta-1a 30 mcg IM weekly. A subsequent case was retrospectively discovered in a Crohn's patient who died while receiving treatment with natalizumab.

Monoclonal antibodies in development. Daclizumab is a promising monoclonal antibody therapy directed against the interleukin (IL)-2 receptor. Anti-CTLA4 antibodies, which disrupt T cells from interacting with antigen-presenting cells, are also being investigated in preliminary studies.^[28] Monoclonal antibodies that are directed against the proinflammatory cytokines IL-12 and IL-23 and the B-cell surface marker CD20 are also being studied.

Oral Immunomodulatory Medications

Oral agents with preliminary encouraging results in phase 1 or phase 2 clinical trials are cladribine, fumarate, laquinimod, and statins. These agents have immunosuppressive or immunodulatory properties that may potentially influence the disease course in MS.

Conclusion

This young man with MS has several treatment options to change the natural history of his disease. Ideally, the treatment selected will reduce his relapses, slow the progression of his disability, and decrease his MRI activity. Because current therapies are only partially effective, knowing when to change treatments is sometimes difficult. Neurologists must rely on pivotal monotherapy trials, randomized comparison trials, and limited add-on agent studies to choose the next treatment plan when current treatment fails. New options, such as monoclonal antibodies and oral immunomodulatory medications, will likely continue to advance the treatment of MS.

References

1. Paty DW, Ebers GC. Multiple Sclerosis. Philadelphia, Pa: FA Davis; 1998.
2. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989;112:133-146. Abstract
3. Johnson KP, Brooks BR, Cohen JA. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology. 1995;45:1268-1276. Abstract
4. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996;39:285-294. Abstract
5. PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352:1498-1504. Abstract
6. IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43:655-661. Abstract
7. Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003;61:1528-1532. Abstract
8. Hartung HP, Gonsette R, Konig K, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomized, multicentre trial. Lancet. 2002;360:2018-2025. Abstract
9. Scott TF, Schramke CJ, Novero J, et al. Short-term prognosis in early relapsing-remitting multiple sclerosis. Neurology. 2000;55:689-693. Abstract
10. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology. 2002;59:1496-1506. Abstract
11. Coyle P, Goodin D, O'Connor P, et al. The EVIDENCE study crossover. Program and abstracts of the 13th Meeting of the European Neurological Society; June 14-18, 2003; Istanbul, Turkey.
12. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomized multicentre study (INCOMIN). Lancet. 2002;359:1453-1460. Abstract
13. Clanet M, Radue EW, Kappos L, et al. A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS. Neurology. 2002;59:1507-1517. Abstract
14. Gooden DS, Frohman EM, Garmany GP, et al. Disease modifying therapies in multiple sclerosis. Neurology. 2002;58:169-178. Abstract
15. Paty D, Kappos L, Moraga MS, et al. Long-term observation efficacy and safety follow-up of the PRISMS cohort. Program and abstracts of the European Committee for Treatment and Research in Multiple Sclerosis; September 17-20, 2003; Milan, Italy.
16. IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology. 1995;45:1277-1285. Abstract
17. European Study Group on Interferon beta-1b in Secondary Progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet. 1998;352:1491-1497. Abstract
18. Ford C, Johnson K, Brooks B, et al. Sustained efficacy and tolerability of glatiramer acetate in relapsing-remitting multiple sclerosis patients for over 10 years. Program and abstracts of the European Committee for Treatment and Research in Multiple Sclerosis; September 17-20, 2003; Milan, Italy.
19. Johnson KP, Panitch HS, Ford CC, Lisak RP; Copaxone Study Group. Longterm slowing of disability progression in patients receiving continuous glatiramer acetate compared with those withdrawing from therapy: 10 year results from an ongoing trial. Program and abstracts of the American Academy of Neurology Meeting; April 24-May 1, 2004; San Francisco, California. Abstract S20.004.
20. Zivadinov R, Rudick RA, De Masi R, et al. Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology. 2001;57:1239-1247. Abstract
21. Beck RW, Cleary PA, Trobe JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group. N Engl J Med. 1993;329:1764-1769. Abstract
22. Goodkin DE, Rudick RA, VanderBrug Medendorp S, et al. Low-dose oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol. 1995;37:30-40. Abstract
23. Calabresi PA, Wilterdink JL, Rogg JM, et al. An open-label trial of combination therapy with interferon beta-1a and oral methotrexate in MS. Neurology. 2002;58:314-317. Abstract
24. Markovic-Plese S, Bielekova B, Kadom N, et al. Longitudinal MRI study: the effects of azathioprine in MS patients refractory to interferon beta-1b. Neurology. 2003;60:1849-1851. Abstract
25. Yudkin PL, Ellison GW, Ghezzi A, et al. Overview of azathioprine treatment in multiple sclerosis. Lancet. 1991;338:1051-1055. Abstract
26. Polman C, O'Connor P, Havrdova E, et al. Clinical results from AFFIRM: a randomized, double-blind, placebo-controlled, multicenter trial to determine the efficacy and safety of natalizumab in patients with relapsing multiple sclerosis. Program and abstracts of the American Academy of Neurology 57th Annual Meeting; April 9-16, 2005; Miami Beach, Florida. Abstract S16.003.
27. Miller D, O'Connor P, Havrdova E, et al. The efficacy of natalizumab on MRI measures in patients with relapsing multiple sclerosis: results from the AFFIRM trial. Program and abstracts of the American Academy of Neurology 57th Annual Meeting; April 9-16, 2005; Miami Beach, Florida. Abstract S16.005.
28. Khoury J, Viglietta V, Buckle G, et al. A phase I trial of CTLA41g treatment in MS. Program and abstracts of the American Academy of Neurology 57th Annual Meeting; April 9-16, 2005; Miami Beach, Florida.

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Author

Barry A. Singer, MD

Assistant Professor of Clinical Neurology, Washington University School of Medicine, St. Louis, Missouri Disclosure: Barry A. Singer, MD, has disclosed that he has received grants for clinical research from Serono and Pfizer and grants for educational activities from Biogen. Dr. Singer has also disclosed that he has served as an advisor or consultant to Serono, Pfizer, Berlex, Biogen, and Teva Neuroscience.

Editor

Marni Kelman, MSc

Program Director, Medscape Neurology & Neurosurgery Disclosure: Marni Kelman has disclosed no relevant financial relationships.

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