Interferon Could Be A Key To Preventing Or Treating Multiple Sclerosis

31 Oct 2008

Multiple sclerosis (MS) results when the body's own defense system attacks nerve fibers in the brain and spinal cord. Now scientists led by John Russell, Ph.D., at Washington University School of Medicine in St. Louis have shown that interferon-gamma plays a deciding role in whether immune cells attack and injure the central nervous system (brain and spinal cord) in mice.

Interferon-gamma is an immune system protein that helps the body defend itself from invaders. In their latest research, which appeared in the October issue of the Journal of Experimental Medicine, the researchers show that interferon-gamma determined whether activated immune cells previously primed to go after nerve cells would actually cause nerve damage in experimental mice.

The researchers found that in the cerebellums and brainstems of the mice, interferon-gamma was protective. However, in the spinal cord, interferon-gamma had the opposite effect, permitting nerve cell damage.

"Some studies show that the most serious cases of MS in people occur when the immune system specifically targets the cerebellum, a part of the brain responsible for sensory perception, coordination and movement control," says Russell, professor of developmental biology. "Our study suggests that researchers need to look at the amount of interferon-gamma produced in the cerebellum and other brain regions in people with MS."

The researchers studied mice genetically engineered to be physiologically "blind" to interferon-gamma the mice had none of the usual receptors on their cells that recognize and respond to interferon-gamma. So in these mice it was as though interferon-gamma didn't exist.

In the interferon-insensitive mice, immune cells primed to attack nerves and then injected into the mice's veins were able to get into the cerebellum and brain stem and initiate nerve cell damage leading to MS-like disease.

In comparison, in mice with normal interferon-gamma recognition, immune cells were prevented from entering the brain and causing problems. The exact mechanism to account for this is still under study.

"Down the road, we would like to investigate whether we can prevent disease in the cerebellum in mice if we promote interferon production in that brain region," Russell says. "One way to do that would be to use gene therapy to insert a gene that would increase interferon in the mice's brains. Then we would test the mice to see if they gained protection against MS-like disease."

In contrast to its protective role in the brain, in the spinal cord interferon-gamma helped instigate nerve damage. In mice with intact interferon-gamma recognition, activated and injected immune cells were able to enter the spinal cord and cause injury. In mice without interferon recognition, the immune cells were unable to initiate spinal cord inflammation, and no damage occurred.

"Our research shows that certain characteristics inherent in different regions of the brain and spinal cord can provoke immune attacks on nerve cells," Russell says. "An understanding of the mechanisms involved in immune system invasion of the nervous system may allow development of better models for determining prognosis and treating many neurological diseases such as multiple sclerosis."

This latest research bolsters Russell's central hypothesis about MS and related disorders, which goes against some widely held assumptions. He holds that in physiological circumstances that ultimately lead to MS, the central nervous system itself allows or even aids immune system attacks.

"A scientifically popular view of how MS occurs is that the immune system somehow gets armed against normal brain antigens and attacks neurons," Russell says. "In that view, brain cells have a passive role. But in this and previous research, we've shown that there's a 'conversation' between the immune system and the central nervous system and that molecular signals passed between them are involved in the development of MS-like disease in mice."

Lees JR, Golumbek PT, Sim J, Dorsey D, Russell JH. Regional CNS responses to IFN-γ determine lesion localization patterns during EAE pathogenesis. Journal of Experimental Medicine. 2008 Oct 27;205(11):2633-2642.

Funding from the National Multiple Sclerosis Society and the National Institutes of Health supported this research.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Washington University in St. Louis
1 Brookings Dr., Campus Box 1070
St. Louis
MO 63130
United States
http://www.wustl.edu

Biogen, Elan shares fall as third Tysabri patient suffers brain infection

30 October 2008

Biogen Idec and partner Elan Corp have suffered a slide in their respective share prices after a new case of progressive multifocal leukoencephalopathy in a multiple sclerosis patient being treated with Tysabri, was disclosed.

In a filing to the US Securities and Exchange Commission, Biogen said that the relevant regulatory agencies had been notified of a confirmed case of PML, a potentially deadly brain infection, in a patient suffering from MS in the USA who had been on Tysabri (natalizumab). The disclosure comes after Biogen and Elan reported in July that two cases of PML had emerged in Europe.

In the latest case, the filing reveals that the patient received 14 injections of Tysabri. The patient has a history of prior disease-modifying therapies including beta-interferons and Texa’s Copaxone (glatiramer acetate) and he/she had also been treated with methotrexate for a rheumatology condition. The individual is now under the care of their treating physician, Biogen said.

PML has played a major part in the history of Tysabri. These recent cases are the first to be recorded since the reintroduction of natalizumab in the USA and approval in Europe two years ago. Biogen and Elan had voluntarily withdrawn the drug a year earlier after three patients developed the brain infection.

Since reintroduction, sales of Tysabri have soared – by the end of September there were 35,500 patients using the drug worldwide and in the third quarter of this year, 3,700 new patients were added. It has also now available in the USA as a treatment for Crohn's disease and Biogen and Elan expect that 100,000 MS patients will be taking the drug by 2010.
.
Biogen and Elan have a strict monitoring programme in place for the therapy and the reintroduction of Tysabri was based in part on the number of PML cases not exceeding the level acceptable to the US Food and Drug Administration (one in every 1,000). As only three cases have been reported, the treatment is well within that limit but the news has certainly spooked investors.

In after-hours trading last night, Biogen shares had fallen by as much as 15%, while this morning Elan stock has been hit. At 9.40 UK time, the Irish firm’s shares were down 18% to 4.80 euros.

Ian Hunter, an analyst at Goodbodys in Dublin, has issued a research note this morning saying “we believe that this new case should do little to projected numbers of patients on Tysabri, given that the considerable pull back in momentum after the first two cases…will have accounted for the majority of those patients and physicians wary enough of the PML risk” to consider not taking or prescribing the drug. However, the fact that this patient was on the drug for 13 months and the other two were on it for 14 and 17 months “may suggest that there is a timing issue and that it takes over a year on Tysabri for the interaction between drug and patient to lead to the development of PML”.

By Kevin Grogan

Novel Oral Agent for MS May Reduce Brain Lesions

By Crystal Phend, Staff Writer, MedPage Today
Published: October 23, 2008
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

Patients given oral fumarate at the highest dose had 69% fewer new inflammatory lesions enhanced by gadolinium on brain MRI scans at 12 to 24 weeks of treatment compared with placebo (P<0.0001), reported Ludwig Kappos, M.D., of University Hospital Basel, and colleagues in the Oct. 25 issue of The Lancet.

In the phase IIb dose-ranging trial, the experimental drug also reduced the annualized relapse rate by 32% compared with placebo, although the difference was not significant (P=0.272).

Fumarate, also known as BG00012, may have dual neuroprotective and anti-inflammatory effects by activating a pathway that defends against neuronal death from oxidative stress, protects the blood-brain barrier, and supports myelin integrity in the central nervous system, the researchers said.

If the longer-term phase III studies now underway show the agent to be as effective as the currently available injection- or infusion-only drugs, fumarate may have an advantage as initial treatment based on convenience alone, Dr. Kappos' group said.

"BG00012 could also be an alternative for patients who cannot tolerate or choose not to initiate injectable therapies because of injection-related effects or anxiety," they said.

However, fumarate will have to compete with a number of other oral agents being developed, commented Per Soelberg Sorensen, M.D., and Finn Sellebjerg, M.D., Ph.D., both of Rigshospitalet in Copenhagen, in an accompanying commentary.

Phase III studies of at least four other oral agents -- cladribine (Leustatin), fingolimod, teriflunomide, and laquinimod -- are in progress for relapsing-remitting multiple sclerosis.

"Within the next four to five years neurologists may be able to choose between up to five new oral drugs for relapsing-remitting multiple sclerosis," Drs. Sorensen and Sellebjerg wrote.

The decisive factor in which drug wins out will be the balance between efficacy, safety, and convenience, they said.

But the findings of this study suggest fumarate may have a better benefit-to-risk profile than these oral competitors or approved first-line injectable drugs, they suggested.

The trial included 257 patients ages 18 to 55 with relapsing-remitting multiple sclerosis treated at 43 centers across Europe and Russia.

Participants were randomized to receive double-blind treatment for 24 weeks with oral fumarate at a dose of 120 mg once daily, 120 mg three times daily, or 240 mg three times daily, or to placebo.

The highest dose group had significantly fewer total new gadolinium-enhancing lesions on MRI at weeks 12, 16, 20, and 24 combined -- the primary endpoint -- compared with the placebo group (1.4 versus 4.5, P<0.0001).

This type of lesion indicates blood-brain barrier breakdown and continued inflammatory activity within the central nervous system, the researchers noted.

Gadolinium-enhancing lesions have been linked to acute clinical relapses and cerebral atrophy, although the short follow-up precluded atrophy as an outcome in the study, they said.

The highest-dose group also had a 48% reduction in the mean number of new or enlarging T2-hyperintense lesions over 24 weeks (P=0.0006) and a 53% reduction in new T1-hypointense lesions compared with placebo (P=0.014).

Lower doses of the experimental agent were also associated with fewer total new enhancing lesions, although there were no significant differences compared with placebo (3.3 with 120 mg once daily and 3.1 with three times daily versus 4.5).

Although the study was not powered for relapse endpoints, annualized relapse rates were reduced by 32% with the highest dose of fumarate over the first 24 weeks (0.44 versus 0.65 with placebo, P=0.272).

In an extension period of 24 weeks for safety assessment, during which patients continued on their assigned dose and the placebo group switched to the highest fumarate dose, relapse rates dropped further.

The reductions compared with the first 24 weeks were 43% for the lowest dose group, 40% for the intermediate dose group, and 64% for the highest dose group, and 60% for those who switched to fumarate after placebo.

"This result could indicate a delayed and increasing effect of BG00012 over time," Dr. Kappos' group suggested.

The researchers said the experimental drug was safe and generally well tolerated.

The most common adverse events included flushing, multiple sclerosis relapse, and headache. Abdominal pain was also significantly more common with the highest dose than with placebo.

The editorialists noted, however, that it was worrying that 25% of patients on the highest dose of fumarate withdrew from the study, with 13% of patients in this group discontinuing because of adverse events.

The study was funded by Biogen Idec.

Dr. Kappos reported participating as principal investigator, member, or chair of planning and steering committees or advisory boards in multiple sclerosis clinical trials sponsored by Allozyne, Amgen, Bayer HealthCare Pharmaceuticals, Bayer-Schering Pharma, Bayhill, Biogen Idec Inc, Eisai, Elan Pharmaceuticals Inc, Genmab, Genzyme, Merck-Serono, Medicinova, Novartis, sanofi-aventis, Shire, Roche, Teva, UCB, and Wyeth.

He also reported giving lectures on the diagnosis and management of multiple sclerosis sponsored by non-restricted educational grants from one of the sponsors and receiving research and clinical operations funding at his center supported by non-restricted grants from one or more of the sponsors and by grants from the Swiss MS Society, the Swiss National Research Foundation, the European Union, and the Gianni Rubatto Foundation.

Co-authors reported conflicts of interest for Biogen Idec, GlaxoSmithKline, Schering AG, Novartis, Bayer Schering, and the US National Institutes of Health, Serono, Teva, Octapharma, sanofi-aventis, Teva, Antisense Pharmaceuticals, Janssen Cilag, Johnson & Johnson, Orion, UCB, AstraZeneca, and Roche.

Dr. Sorensen reported receiving honoraria for lecturing and advisory councils, trial steering committees, travel expenses for attending meetings, or research grants from Biogen Idec, Bayer Schering, Merck Serono, TEVA, Biopartners, sanofi-aventis, and Genmab. Dr. Sellebjerg has received honoraria for lecturing and advisory councils, travel expenses for attending meetings, or research grants from Biogen Idec, Bayer Schering, Merck Serono, and TEVA.

Primary source: Lancet
Source reference:
Kappos L, et al "Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study" Lancet 2008; 372: 1463-72.

Additional source: Lancet
Source reference:
Sorensen PS, Sellebjerg F "Oral fumarate for relapsing-remitting multiple sclerosis" Lancet 2008; 372: 1447-48.

Opexa Provides Additional Promising Data Including Statistically Significant Reduction in Disability With Tovaxin® for the Treatment of Multiple Scle

Tovaxin Also Demonstrates Reduction in Relapse Risk and Myelin T-cell Reactivity in Patients With More Active Disease

THE WOODLANDS, Texas--(BUSINESS WIRE)--Opexa Therapeutics, Inc. (NASDAQ:OPXA), a company dedicated to the development of patient-specific cellular therapies for the treatment of autoimmune diseases such as multiple sclerosis (MS) and diabetes, today announced additional positive data from the company’s Phase IIb TERMS clinical trial (Tovaxin® for Early Relapsing Multiple Sclerosis). The latest analysis focused on a prospective group of patients (n=50) with an annualized relapse rate (ARR) of greater than 1 at study entry which is comparable to ARR baselines of patients in previous Tovaxin studies. These findings demonstrate a statistically significant improvement in disability as measured by the Expanded Disability Status Scale (EDSS) (p=0.045) for patients treated with Tovaxin as compared to those receiving placebo. In this group, 28.1 percent of patients treated with Tovaxin showed an improvement in EDSS as compared to only 5.6 percent in the placebo group. Additionally, there was an 88 percent reduction in the level of brain atrophy and a more than 20 percent reduction in the number of gadolinium (Gd) lesions progressing to black holes in the Tovaxin group, which may suggest a beneficial neuroprotective effect. Overall, the analysis shows that patients treated with Tovaxin demonstrated a benefit across all clinical and magnetic resonance imaging (MRI) endpoints (primary, secondary and tertiary) in this patient population. Immunology data also appears to support Tovaxin’s mechanism of action, indicating that patients with less myelin T-cell reactivity have a lower risk of relapse. Additional quality of life measurements, such as the Timed 25 foot Walk, also showed a benefit for Tovaxin over placebo (0.14 vs. -0.02, as measured by respective Z scores).

The data shows that these patients when treated with Tovaxin demonstrate an ARR of 0.28 which represents a 55 percent reduction compared to those patients on placebo. This relapse rate is on par with the lowest relapse rates observed with currently available MS treatments which range from 0.2 to 0.9. Study findings also show Tovaxin possesses an impressive safety and tolerability profile. Opexa expects to conduct a Phase II close-out meeting with the United States Food and Drug Administration during the first half of 2009 to discuss next steps for the further clinical development of Tovaxin. Opexa is actively engaged in discussions with potential strategic partners for the Tovaxin program.

The TERMS study provided Opexa the opportunity to create a comprehensive database of clinical immunology and epitope data in MS patients that may significantly advance the understanding and treatment of the disease. This type of information is particularly important for Opexa as Tovaxin’s dual mechanism of action involves the depletion of myelin-reactive T-cells in the peripheral blood and the regulation of anti-inflammatory T-cells to rebalance an MS patient’s immune system. Previous studies show that if the myelin-peptide reactivity in a patient’s peripheral blood is reduced, the clinical symptoms associated with MS will also be reduced. The initial analysis of the study’s immunology and epitope database has shown that patients treated with Tovaxin appeared to have less myelin-peptide reactivity over the course of the study than those on placebo. This was measured using Opexa’s proprietary Epitope Analysis Assay (EAA) which assessed reactivity across all three key myelin proteins at several time points throughout the 52-week study. Additionally, over the full course of treatment, more patients on Tovaxin remained in the lower quartile of peptide reactivity (56 percent) than those on placebo (39 percent). This epitope data appears to correlate with the study’s MRI and clinical endpoints which, among other findings, showed that following the full course of treatment (weeks 28-52), the ARR in the Tovaxin group dropped to 0.065 (0.749 for placebo).

The pattern emerging from the analysis of the immunology and epitope database suggests that those patients exhibiting a higher T-cell reactivity often demonstrated a worsening of at least one MRI endpoint (Gd lesion, Gd volume, new T2 count or progression to black holes) and one clinical endpoint (either relapse or EDSS). The converse also appears true with less T-cell reactivity implying less or no worsening of certain MRI and clinical endpoints.

Additionally, the immunology data shows that reactivity to all three of the key myelin proteins (MOG, PLP and MBP) was broadly present in study patients, which may be an important finding for the future treatment of MS. Opexa is also assessing which specific peptides from each of the proteins may provide the most relevant targets for the company to enhance its manufacturing process and further strengthen its intellectual property portfolio.

“Tovaxin seems to be demonstrating a benefit to these patients as indicated by immunology, MRI and clinical parameters,” stated Dr. Clyde Markowitz, associate professor of neurology and director of the MS center at the University of Pennsylvania School of Medicine. “This is interesting data and additional trials are certainly warranted to further explore the potential of this novel treatment.”

Previously reported top-line results from the TERMS study demonstrated that Tovaxin was safe and well tolerated with no serious adverse events related to treatment. The most common adverse event related to Tovaxin was mild injection site reaction. Continued analysis of safety and tolerability data has confirmed these top-line results with no serious adverse events observed in any Tovaxin-treated patients during the entire study.

“This landmark first-in-class study has yielded impressive results for Tovaxin in MS patients with high disease burden, including a marked reduction in disability, relapse risk and levels of T-cell reactivity. These findings are very encouraging and we are eager to continue the clinical development of this novel therapeutic,” commented Neil K. Warma, president and chief executive officer of Opexa Therapeutics. “There remains a tremendous unmet medical need for MS patients, and we believe a safe and effective patient-specific treatment may generate considerable interest among regulatory authorities, patients, physicians and potential strategic partners. With this in mind, we remain committed to aggressively pursuing our two primary objectives: the continued development of Tovaxin towards a pivotal Phase III trial and a high-value partnership for the Tovaxin program. With the MS market exceeding $6 billion and growing, we believe Tovaxin is very competitively positioned from a safety, efficacy and patient compliance perspective.”

About Tovaxin

Tovaxin is an individualized T-cell therapeutic vaccine that consists of attenuated patient-specific myelin-reactive T-cells (MRTCs) against peptides of proteins from Myelin basic protein (MBP), Myelin oligodendrocyte glycoprotein (MOG) and Proteolipid protein (PLP) or combinations thereof. Tovaxin’s dual mechanism of action combats the demyelination of the nerve fibers in the central nervous system, the underlying cause of MS. Clinical results have demonstrated that Tovaxin produces the following therapeutic effects:

* Anti-idiotypic effect – Induces an immune response that depletes and regulates the circulating pathogenic myelin-reactive T-cells that attack the myelin sheath of nerve fibers.
* Anti-ergotypic effect – Rebalances the overall immune system by causing a shift from pathogenic inflammatory T-cells to anti-inflammatory T-cells.

Tovaxin is manufactured in Opexa’s in-house cGMP facility.

About the TERMS Study

The TERMS study was a Phase IIb multi-center, randomized, double blind, placebo-controlled trial in 150 patients with Relapsing-Remitting Multiple Sclerosis or high risk Clinically Isolated Syndrome (CIS). The study involved 2:1 randomization with 100 patients receiving Tovaxin and 50 receiving placebo. According to the study protocol, patients received a total of five subcutaneous injections at weeks 0, 4, 8, 12 and 24. The primary efficacy endpoint of the TERMS trial was the cumulative number of gadolinium-enhanced brain lesions (CELs) using MRI scans summed over weeks 28, 36, 44 and 52. The trial’s secondary efficacy endpoints included annualized relapse rate (ARR), new CELs at weeks 28 through 52 and T2-weighted lesion volume compared to baseline.


About Opexa

Opexa Therapeutics develops and commercializes cell therapies to treat autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and diabetes. The Company is focused on autologous cellular therapy applications of its proprietary T-cell and stem cell therapies. The Company's lead product is Tovaxin, a T-cell therapy for multiple sclerosis is in Phase IIb trials. The Company holds the exclusive worldwide license for adult multipotent stem cells derived from mononuclear cells of peripheral blood. The technology allows large quantities of monocyte-derived stem cells to be produced efficiently for use in autologous therapy, thus circumventing the threat of rejection. The Company is in preclinical development for diabetes mellitus. For more information visit the Opexa Therapeutics website at www.opexatherapeutics.com.

Cautionary Statement Relating to Forward - Looking Information for the Purpose of "Safe Harbor" Provisions of the Private Securities Litigation Reform Act of 1995

This press release contains forward-looking statements which are made pursuant to the safe harbor provisions of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. The forward-looking statements in this release do not constitute guarantees of future performance. Investors are cautioned that statements in this press release which are not strictly historical statements, including, without limitation, statements regarding current or future financial performance and position, management's strategy, plans and objectives for future operations, plans and objectives for product development, plans and objectives for present and future clinical trials and results of such trials, plans and objectives for regulatory approval, litigation, intellectual property, product development, manufacturing plans and performance, constitute forward-looking statements. Such forward-looking statements are subject to a number of risks and uncertainties that could cause actual results to differ materially from those anticipated, including, without limitation, risks associated with: the success of collaborative relationships, our ability to compete with larger, better financed pharmaceutical and biotechnology companies, new approaches to the treatment of our targeted diseases, our expectation of incurring continued losses, our uncertainty of developing a marketable product, our ability to raise additional capital to continue our treatment development programs, the success of our clinical trials, our ability to develop and commercialize products, our ability to obtain required regulatory approvals, our compliance with all Food and Drug Administration regulations, our ability to obtain, maintain and protect intellectual property rights for our products, the risk of litigation regarding our intellectual property rights, our limited manufacturing capabilities, our dependence on third-party manufacturers and value added resellers, our ability to hire and retain skilled personnel, our volatile stock price, and other risks detailed in our filings with the Securities and Exchange Commission. We assume no obligation to update any forward-looking information contained in this press release or with respect to the announcements described herein.

Permalink: http://www.businesswire.com/news/opexa/20081023005419/en

Study Results: Multiple Sclerosis Patients Have Significant and Sustained Reduction in Disability and Risk Of Relapse On Alemtuzumab Versus Approved T

Date: October 22, 2008

Final Phase 2 Data Published in New England Journal of Medicine
International Phase 3 Alemtuzumab Studies Enrolling

Genzyme Corporation (Nasdaq: GENZ) and Bayer HealthCare Pharmaceuticals Inc. today announced study results showing that patients with early relapsing-remitting multiple sclerosis (RRMS) taking once-yearly cycles of alemtuzumab reduced their risk of relapse by 74 percent and the risk of sustained accumulation of disability by 71 percent compared to patients treated with the active comparator Rebif® (high-dose interferon beta-1a). Importantly, the mean disability of patients on alemtuzumab improved from baseline, whereas the mean disability of those on Rebif worsened. The treatment benefits of alemtuzumab were sustained for at least three years, even though the majority of alemtuzumab-treated patients were last dosed two years earlier. These results come from the final three-year analysis of a Phase 2 clinical study (CAMMS223) reported in the Oct. 23 issue of the New England Journal of Medicine. The study involved 334 patients who had not previously been treated for their disease.

“The alemtuzumab trial data continue to suggest a potentially new and exciting treatment for patients with early, active multiple sclerosis,” says Alastair Compston, Professor of Neurology and the head of the Department of Clinical Neurosciences at the University of Cambridge, United Kingdom, and the study’s principal investigator. “This randomized study confirms findings from prior studies demonstrating that treatment with alemtuzumab can have a profound and durable impact on patients with relapsing-remitting multiple sclerosis, including restoring some lost function in many patients.”

“Symptoms of multiple sclerosis result from an immune system attack on the protective insulation surrounding nerve fibers of the central nervous system. We believe alemtuzumab shuts down this immune system attack, treating the disease at its root cause,” says Alasdair Coles, Senior Lecturer, Department of Clinical Neurosciences, University of Cambridge and a lead investigator in the study.

Common non-serious adverse events in the trial included infusion-associated reactions in the alemtuzumab patients and flu-like symptoms in patients using Rebif. Alemtuzumab-treated patients were more likely than Rebif patients to experience infections, which were predominantly mild to moderate in severity, as well as autoimmune thyroid disease. Three percent of alemtuzumab-treated patients developed the potentially serious autoimmune adverse event immune thrombocytopenic purpura (ITP), a disorder characterized by a low platelet count and corresponding increased risk of uncontrolled bleeding. Additional study and trial safety information is below.

“The trial was larger and follow-up was longer than the typical Phase 2 trial in multiple sclerosis. It is important to note that we compared the investigative drug directly against a widely used therapy rather than against placebo. The trial did not show an increased risk of life-threatening or opportunistic infections, but a proportion of alemtuzumab patients experienced new autoimmune disease. We have been able to create a robust patient monitoring program that allows us to proceed into our two international Phase 3 trials with greater assurance on safety associated with patient management,” says Dr. Richard Moscicki, chief medical officer for Genzyme.

According to the National Multiple Sclerosis Society, approximately 400,000 Americans acknowledge having MS, and every week about 200 people are diagnosed. Worldwide, multiple sclerosis may affect 2.5 million individuals. The disease causes a wide range of symptoms including difficulty with walking, numbness, fatigue and impairment of vision, and progresses to permanent, severe disability in the majority of patients. Relapsing-remitting MS is the most common presenting form of the disease.

“We are pleased to see potential new treatment options move positively through the MS pipeline,” says Dr. John Richert, executive vice president for research and clinical programs at the National Multiple Sclerosis Society, “and as alemtuzumab is moved into Phase 3 studies, we hope that individuals with MS will consult with their physicians to assess whether they are appropriate patients and if so will consider the pros and cons of participating in these important clinical trials.”

Additional New Top-Line Data

New and previously unreported top-line data from secondary analyses of the CAMMS223 Phase 2 clinical trial, presented last month at the World Congress on Treatment and Research in Multiple Sclerosis (WCTRIMS), revealed that the proportion of clinically disease-free patients was significantly higher in the alemtuzumab group than in the Rebif group at year one (86 percent vs. 63 percent), year two (81 percent vs. 48 percent), and year three (71 percent vs. 39 percent, p-values <0.0001). “Clinically disease-free” was defined as the absence of both relapses and sustained accumulation of disability during the time-period assessed.

The top-line data from WCTRIMS also showed that the proportion of patients free of sustained accumulation of disability over a six-month period was also significantly greater in the alemtuzumab group than in the Rebif group at year one (97.2 percent vs. 87.0 percent), year two (94.3 percent vs. 82.4 percent), and year three (91.0 percent vs. 73.8 percent, p-values <0.005).

Further, the proportion of relapse-free patients over time was significantly greater in the alemtuzumab group than in the Rebif group at year one (91.1 percent vs. 69.3 percent), year two (88.2 percent vs. 58.5), and year three (80.2 percent vs. 51.6 percent, p-values <0.0001).

Phase 2 Extension Trial

Genzyme with Bayer support has launched an extension of the CAMMS223 trial to examine safety and efficacy outcomes beyond three years, and to compare two distinct retreatment strategies. The results should provide an understanding of the long-term effects of prior alemtuzumab treatment as well as the safety and sustained efficacy of additional alemtuzumab retreatment delivered in fixed annual cycles or as needed for resumed MS disease activity. In the fixed arm, patients will receive two annual cycles of alemtuzumab (12 mg/day for three consecutive days/cycle). In the as-needed arm, retreatment is deferred until a patient relapses or develops two or more new/active brain lesions on MRI.

Phase 3 Trials

Genzyme with Bayer support is sponsoring two Phase 3 trials in which patients are now enrolling. The CARE-MS I Phase 3 study (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis), is a randomized, rater-blinded study that will again compare alemtuzumab to Rebif in patients with relapsing-remitting MS who have not been previously treated for their disease. The CARE-MS II trial is studying patients who have continued to relapse while using approved MS therapies.

Physicians or patients in the United States seeking additional information about the CARE-MS Phase 3 trials should go to www.care-ms.com or call Genzyme Medical Information at 800-745-4447.

About Study CAMMS223

In the Phase 2 trial, 334 patients with active relapsing-remitting multiple sclerosis were enrolled at 49 medical centers in Europe and the United States. Patients in the trial were randomized to treatment with alemtuzumab at one of two dose levels (12 or 24 mg per day intravenously) for five days during the first cycle and three days 12 months later during the second cycle of therapy, or Rebif (44 mcg administered by subcutaneous injection three times per week, as indicated in its product label). A third cycle of alemtuzumab therapy was received by 46 patients at month 24.

The trial compared the efficacy of alemtuzumab with Rebif using two primary outcome measures: the Relapse Rate and the time to Sustained Accumulation of Disability as evidenced by an increase in the Expanded Disability Status Scale (EDSS) score for six consecutive months. Efficacy assessments were made by independent neurologists blinded to patients’ treatment assignments. The EDSS is a 10-point scale in which every 0.5-point step marks a notable deterioration in neurological capabilities.

The mean disability score of patients after alemtuzumab actually improved (by 0.39 EDSS points) indicating a recovery of neurologic functions. The median disability score improved to a similar extent after alemtuzumab. In contrast, mean disability worsened in the Rebif group (by 0.38 EDSS points) resulting in a difference of nearly a full EDSS point (0.77 difference, p<0.0001) at three years.

Safety Data

A total of six alemtuzumab-treated patients, and one Rebif-treated patient, in this study developed a serious adverse event, immune thrombocytopenic purpura (ITP). ITP is a disorder characterized by a low platelet count and corresponding increased risk of uncontrolled bleeding. The Rebif patient with ITP was asymptomatic but ITP persisted at the time of study completion. In the previously reported alemtuzumab-related fatal case, symptoms of ITP were experienced but were not recognized in time, thus delaying medical attention. Of the remaining alemtuzumab cases, four patients were diagnosed promptly, responded well to medical treatment, and have been stable without a need for ongoing treatment. The other alemtuzumab-treated case experienced spontaneous remission of ITP. A patient monitoring program was instituted in the trial, and there have been no new cases of ITP reported in CAMMS223 in approximately two years.

Common non-serious adverse events in the trial included infusion-associated reactions in the alemtuzumab patients and flu-like symptoms in patients using Rebif. Alemtuzumab-treated patients were more likely than Rebif patients to experience infections, particularly of the upper respiratory tract; infections were predominantly mild to moderate in severity and there were no life-threatening or fatal infections. Though alemtuzumab transiently lowers white blood cell counts, the trial did not show an increased risk of opportunistic infections. Serious infections were infrequent in the alemtuzumab-treated patients. Approximately 23 percent of alemtuzumab-treated patients developed autoimmune thyroid-related adverse events, including Graves’ disease, and were managed using conventional therapies.

Alemtuzumab is an investigational drug for the treatment of MS and must not be used in MS patients outside of a formal, regulated clinical trial setting in which appropriate patient monitoring measures are in place.

About Alemtuzumab

Alemtuzumab is licensed in the United States as a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), and outside of the U.S. for the treatment of B-CLL in patients who have been treated with alkylating agents and for whom fludarabine combination therapy is not appropriate. The product was launched in its oncology indication in 2001 in the US, where it is marketed by Bayer HealthCare Pharmaceuticals Inc. as Campath®, and in Europe, where it is named MabCampath®.

Alemtuzumab is a humanized monoclonal antibody that binds to a specific target, CD52, on cell surfaces and directs the body’s immune system to destroy those cells. It is the first and only monoclonal antibody approved by the FDA for the treatment of patients with B-CLL.

Genzyme and Bayer are co-developing alemtuzumab in oncology and multiple sclerosis. Bayer holds exclusive worldwide marketing and distribution rights to alemtuzumab.

Campath for B-CLL has a boxed warning that includes information on cytopenias, infusion reactions, and infections. The most commonly reported adverse reactions in patients with B-CLL were infusion reactions (fever, chills, hypotension, urticaria, nausea, rash, tachycardia, dyspnea), cytopenias (neutropenia, lymphopenia, thrombocytopenia, anemia), and infections (CMV viremia, CMV infection, other infections). Other commonly reported adverse reactions include vomiting, abdominal pain, insomnia and anxiety. The most commonly reported serious adverse reactions are cytopenias, infusion reactions, and immunosuppression/infections.

About Genzyme

One of the world's leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 10,000 employees in locations spanning the globe and 2007 revenues of $3.8 billion. In 2007, Genzyme was chosen to receive the National Medal of Technology, the highest honor awarded by the President of the United States for technological innovation.

With many established products and services helping patients in nearly 90 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company's products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune disease, and diagnostic testing. Genzyme's commitment to innovation continues today with a substantial development program focused on these fields, as well as cardiovascular disease, neurodegenerative diseases, and other areas of unmet medical need.

About Bayer HealthCare Pharmaceuticals Inc.

Bayer HealthCare Pharmaceuticals Inc. is the U.S.-based pharmaceuticals business of Bayer HealthCare LLC, a subsidiary of Bayer AG. Bayer HealthCare is one of the world's leading, innovative companies in the healthcare and medical products industry, and combines the activities of the Animal Health, Consumer Care, Diabetes Care, and Pharmaceuticals divisions. Bayer HealthCare Pharmaceuticals comprises the following business units: Women's Healthcare, Diagnostic Imaging, General Medicine, which includes Cardiology and Primary Care and Specialty Medicine, which includes Hematology, Oncology and Multiple Sclerosis. The company's aim is to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases.

This press release contains forward-looking statements regarding Genzyme’s future plans and business strategies, including: its expectations for the success of alemtuzumab to treat MS, and its expectations regarding the information to be gained from the phase 2 extension trial. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these forward-looking statements, including: that the phase 3 trials are not successful; that the phase 2 extension trial fails to produce the anticipated results regarding longer-term effects; and the risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission under the Securities Exchange Act of 1934, as amended, including without limitation the information under the heading "Risk Factors" in Genzyme’s Quarterly Report on Form 10-Q for the quarter ending June 30, 2008. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release, and Genzyme undertakes no obligation to update or revise these statements.

This news release contains forward-looking statements based on current assumptions and forecasts made by Bayer Group management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in our public reports filed with the Frankfurt Stock Exchange and with the U.S. Securities and Exchange Commission (including Form 20-F). The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

Genzyme®, Campath®, and MabCampath® are registered trademarks of Genzyme Corporation. All rights reserved. Rebif® is a registered trademark of EMD Serono, Inc.

Genzyme’s press releases and other company information are available at www.genzyme.com and by calling Genzyme’s investor information line at 1-800-905-4369 within the United States or 1-678-999-4572 outside the United States.

Bayer HealthCare Pharmaceuticals Inc. press releases and other information are available at www.bayerus.com.

Editor’s Note: This study appears in the October 23, 2008 issue of the New England Journal of Medicine. The citation is N Engl J Med 2008;359:1786-1801.

Terms and Conditions of Use | Privacy Policy | © 2002-2008 Genzyme Corporation. All rights reserved.

Avigen Announces AV650 Did Not Meet Efficacy Endpoints in Phase 2b Clinical Trial for Spasticity in Patients With Multiple Sclerosis

ALAMEDA, Calif., Oct 21, 2008 (GlobeNewswire via COMTEX News Network) -- Avigen, Inc. (Nasdaq:AVGN), a biopharmaceutical company innovating therapeutics for neurological care, today announced that the top-line data from its Phase 2b study of AV650 (tolperisone HCl) for the treatment of spasticity associated with multiple sclerosis (MS) did not achieve statistical significance on its primary endpoint of a reduction from baseline of patients' Ashworth scores as compared to placebo. The reduction of muscle spasm, a secondary endpoint, also failed to achieve statistical significance. There were no safety issues. The trial was adequately powered, and all statistical parameters were in line with expectations.

"We are disappointed with the result of this trial," said Kenneth Chahine, Ph.D., J.D., Avigen's President and Chief Executive Officer. "We had hoped AV650 would become an important new treatment option for people in the United States who currently suffer from spasticity. While we will continue to review the additional data from the trial and consider further options, we are confident in the trial design and the quality of the top-line results.

"We will now shift our focus and resources toward the clinical development of our AV411 program. At the end of 2008, we will have approximately $50 million of cash and securities. This represents approximately 2 years of cash and provides a strong foundation for advancing the development of AV411 for neuropathic pain and opioid addiction and withdrawal."

About the Trial

This double-blind, randomized clinical trial was conducted in 27 MS centers in Germany and other European countries to evaluate safety, tolerability, pharmacokinetics and efficacy in up to 150 MS patients suffering from spasticity. This trial was being conducted to Good Clinical Practice standards by a leading international clinical research organization. Following a five-week double blind assessment, patients were offered the opportunity to continue for up to twelve months in an open-label safety phase. The primary efficacy endpoint was the Ashworth scale, a standard tool used in the clinic to measure increased resistance to passive limb movement. Secondary endpoints included Brief Pain Index (BPI), painful spasm diaries, and clinical impression of change.

Avigen is a biopharmaceutical company focused on developing and commercializing small molecule therapeutics to treat serious neurological disorders, including neuropathic pain and opioid addiction and withdrawal. Avigen's strategy is to complete the requirements of clinical development for each of the candidates in its product pipeline, and continue to look for opportunities to expand its pipeline through a combination of internal research, acquisitions, and in-licensing, with the goal of becoming a fully integrated commercial biopharmaceutical company that remains committed to its neurology products. Avigen is currently developing AV411 for neuropathic pain, as well as opioid withdrawal and addiction in collaboration with the National Institute on Drug Abuse. Additionally, the company is advancing AV513, a novel therapy for the treatment of multiple bleeding disorders, including hemophilia A and B, toward clinical trials. For more information about Avigen, consult the company's website at www.avigen.com.

The Avigen, Inc. logo is available at http://www.globenewswire.com/newsroom/prs/?pkgid=2981

Statement under the Private Securities Litigation Reform Act

The statements in this press release relating to Avigen's expectations regarding the quality of the top-line results from the AV650 Phase 2b spasticity trial and its consideration of further options based on a review of additional data from the trial, its expectation regarding the level of its financial resources at December 31, 2008 and how long its financial resources will last, its expectation regarding shifting resources toward the clinical development of AV411, and its goal of becoming a fully integrated commercial biopharmaceutical company remaining committed to its neurology products, are forward-looking statements. These risks and uncertainties include, among others, the fact that development of small molecule therapeutics and other therapeutic discovery and development is a time- and resource-intensive process, which may result in the expenditure of a significant amount of time and resources with no progress towards clinical trials or marketable product resulting from the effort; the risk that Avigen will not be able to obtain regulatory approvals for its drug products, which is required prior to marketing drug products; and the risk that early positive preclinical and clinical results will not guarantee that the potential products will ultimately be effective in treating the indications for which they are developed, or exhibit the unique properties they appear to possess. In addition, there are many other risks and uncertainties inherent in the development of drug products. Other risks and uncertainties relating to Avigen are detailed in reports filed by Avigen with the Securities and Exchange Commission, including Avigen's Quarterly Report on Form 10-Q for the period ended June 30, 2008, under the caption "Risks Related to Our Business" in Item 2 of Part I of that report, which was filed with the SEC on August 11, 2008.

This news release was distributed by GlobeNewswire, www.globenewswire.com

SOURCE: Avigen, Inc.

Avigen, Inc.
Michael Coffee, Chief Business Officer
510-748-7372
IR@avigen.com

Bugs In The Gut Trigger Production Of Important Immune Cells, Study Finds

ScienceDaily (Oct. 17, 2008) — A new study reveals that specific types of bacteria in the intestine trigger the generation of pro-inflammatory immune cells, a finding that could eventually lead to novel treatments for inflammatory bowel disease and other diseases.

The study by NYU Langone Medical Center researchers is published in the October 16 issue of the journal Cell Host and Microbe. The new finding adds to the growing body of research showing that the kinds of bacteria in our intestine, and in our stomach, have an impact on our health.

"There is more and more evidence that gut flora have a tremendously important influence on human health," says Yasmine Belkaid, Ph.D., chief of the mucosal immunology unit in the laboratory of parasitic diseases at the National Institutes of Health "If some set of microbes induces a specific immune response, this points to a way to manipulate the immune system," says Dr. Belkaid. "This new study is the first report that has associated a defined set of gut flora with the induction of specific immune cells."

The new research is from the laboratory of Dan Littman, M.D., Ph.D., the Helen L. and Martin S. Kimmel Professor of Molecular Immunology at NYU School of Medicine and a Howard Hughes Medical Institute Investigator. "It's not the amount of microbial flora but the kind of microbial flora that seems to count," says Dr. Littman.

The new study found that cytophaga-flavobacter-bacteroidetes (CFB) bacteria were associated with the creation of Th17 cells in mice. Typically, in both mice and humans, most of the bacteria found in the gut fall into the CFB phylum or another phylum called Firmicutes. These bacteria play many roles, such as aiding in digestion and protecting against pathogens by outcompeting harmful bacteria.

Inflammatory bowel disease (IBD) affects as many as 700,000 people each year and is one of the most prevalent gastrointestinal diseases in the United States. Treatment with antibiotics has had limited success. But pinpointing the specific species of bacteria that influence the balance of inflammatory cells, says Dr. Littman, could lead to more sophisticated treatments that fine-tune bacteria in the intestine and, in turn, dampen the production of inflammatory cells.

The Yin and Yang of Immunity

A healthy immune system is a balancing act between two opposing yet intimately connected forces, one calming, the other inflammatory. Sometimes called the yin and yang of adaptive immunity, pro-inflammatory cells (the "yang") dominate when the body needs protection, and regulatory cells (the "yin") soothe the immune system when it doesn't.

When this balance is disrupted and there is an overload of fiery yang cells, inflammatory disease results. In recent years, scientists have linked a striking number of autoimmune disorders to excess pro-inflammatory cells, including psoriasis, inflammatory bowel disease, and multiple sclerosis. "The number of inflammatory diseases known to involve T helper 17 (Th17) cells," – the fiery yang cells – "seems to be growing every week," says Dr. Littman.

For this reason, Dr. Littman has been studying the molecular pathways that stimulate the production of these cells. Recently, his team reported on a promising potential therapeutic target that may help ameliorate diseases associated with overproduction of Th17 cells.

In the new study, Dr. Littman's team observed that newborn mice that remain isolated from bacteria never generate any of these cells. Normally, newborn mice are born without any bacteria or Th17 cells in their intestines. They begin to generate the cells only after they begin to eat food and ingest bacteria. These observations suggested that the introduction of bacteria in the gut is associated with the creation of Th17 cells.

To determine if the bacteria actually cause the generation of Th17 cells, the team gave normal, bacteria-filled mice antibiotics that selectively killed some of the bacteria in their small intestine. Some of these antibiotics also depleted their Th17 cells, indicating for the first time a causal link between specific bacteria and the generation of inflammatory cells.

Littman's team then found a colony of mice that have intestinal bacteria but do not have Th17 cells. This colony, it turned out, had different bacteria in their guts than other colonies. "The same way people from different countries have different bacteria in their guts, mice from different colonies will have different bacteria," explains Dr. Ivaylo Ivanov, an author of the study and a post-doctoral fellow in Dr. Littman's laboratory. In this case, "one colony has the bacterial species associated with Th17 cells and the other doesn't."

By comparing the intestinal bacteria in mice, the team discovered that cytophaga-flavobacter-bacteroidetes (CFB) bacteria were associated with the creation of Th17 cells. Dr. Littman's team is now working to determine the specific bacteria that induce pro-inflammatory immune cells in mice. They will use this information to help determine the bacterial species in the intestines of humans that trigger the overproduction of these cells.

Dr. Littman also is interested in identifying the signals emitted by bacteria that influence the innate immune system, which responds to immediate threats from foreign pathogens and produces substances that spur naive or unspecialized T cells to develop into Th17 cells. Manipulation of the bacteria or their products, says Dr. Littman, could then be used to shift the balance of pro-inflammatory and regulatory immune cells.

Adapted from materials provided by NYU Langone Medical Center / New York University School of Medicine.

Improving Therapeutic Options for Multiple Sclerosis

Improving Therapeutic Options for Multiple Sclerosis: An Interview With Edward Fox, MD, PhD

Elizabeth Samander, PhD

Medscape Neurology & Neurosurgery. 2008; ©2008 Medscape
Posted 10/16/2008

Editor's Note

New data from key trials in multiple sclerosis (MS) regarding novel therapeutic approaches were presented at the World Congress on Treatment and Research in Multiple Sclerosis held from September 17-20, 2008, in Montreal, Canada. Medscape Scientific Director Elizabeth Samander, PhD, interviewed Edward Fox, MD, PhD, about the results of these trials and what implications these results may have on clinical practice and the future management of patients with MS.

Medscape: Dr. Fox, in your opinion, what were the most compelling research findings presented at the World Congress on Treatment and Research in Multiple Sclerosis (WCTRIMS) meeting this year?

Dr. Fox: The overall message from the meeting this year was that a number of medications are currently being investigated that hold great promise for the treatment of multiple sclerosis (MS). Research was presented from numerous trials involving novel therapies, including monoclonal antibody and oral products. There was a substantial amount of evidence presented on both of those categories, including further data from completed phase 2 trials and descriptions of ongoing phase 3 trials. The number of medications that we have under current investigation is really quite large, so it is difficult to see the timeline for these medicines actually being brought to market. We had hoped that these studies would fully enroll quickly, so that we would have finalized data coming within the next few years. However, it is likely that there will be some delays because of the large number of competing trials with slower-than-expected enrollment.

Monoclonal antibody agents discussed at the meeting included alemtuzumab, rituximab, and daclizumab.[1-6] Those antibodies have certainly been well-tested in phase 2 trials, and plans are ongoing for phase 3 trials in relapsing-remitting MS. There was also a phase 3 trial regarding rituximab[1,5,7] for the treatment of primary progressive MS. The primary endpoint of time to confirmed disease progression did not show a statistically significant difference between rituximab and placebo. However, subcohort analysis suggested a benefit for those patients with active magnetic resonance imaging (MRI) at entry into the study. I think that the overall feeling about B-cell depletion in the treatment of MS is very positive. We are looking forward to other studies, including ones on ocrelizumab,[8] another monoclonal antibody, which can selectively deplete B cells and thereby reduce MS disease activity.

The data presented on the alemtuzumab trial was further information from the phase 2 trial, which showed a highly significant decrease in the number of relapses seen in patients on alemtuzumab compared with patients receiving interferon beta-1a subcutaneously 3 times weekly.[4] The data presented were on a 3 year follow-up trial designed to evaluate the percentage of patients who were clinically disease-free. These were patients who did not have relapses and did not have a progression of disability during the course of the trial. The superiority of alemtuzumab compared with beta-interferon was sustained throughout the 3 years on study. Within the third year it was found that 71% of the patients who were on alemtuzumab were clinically disease-free compared with 38% of those who were receiving interferon beta-1a. These findings have led to the development of 2 phase 3 trials currently enrolling patients.

Medscape: What other novel therapeutic approaches are undergoing clinical trials?

Dr. Fox: The oral medications discussed at this meeting included cladribine,[9-11] fingolimod,[12-14] BG-00012,[15,16] teriflunomide,[1,13,17] and laquinimod.[18] All of these oral agents, as well as several others, are showing promise for the treatment of MS. It may be that any or all of these products will have success in the treatment of MS, but at this time we're still in the discovery phase for the safety as well as for the efficacy of these medications.

The phase 2 trials that have been performed have primarily been based on looking for a reduction in new MRI activity in patients with multiple sclerosis. They all have shown various degrees of benefit in reducing gadolinium-enhancing lesions on MRIs during the course of the phase 2 trials. However, these trials were rather short and generally were not powered to show significant clinical outcomes. An exception was the phase 2 trial on fingolimod, which did show a substantial reduction in relapse rate as well.

The phase 3 trials are going to be looking not only at reduction in MRI activity, but will also be looking at the important clinical measures that will be required for these medications to be licensed. Those include a reduction in relapse rate and prevention of sustained accumulation of disability compared with placebo. These clinical outcome measures may or may not be found despite the MRI evidence that has been seen in the past, because there has been a disconnect between MRI activity and clinical activity seen in several previous agents tested for MS.

Medscape: There is evidence that disease-modifying treatments, although partially effective, are associated with injection-related side effects and suboptimal patient adherence. These findings may suggest that novel therapeutic strategies, including oral therapies, monoclonal antibodies, symptomatic treatments, and combination regimens, are warranted. What is the role of these novel agents in the therapeutic armamentarium with respect to first-line use, add-on treatment for failed first-line therapy, or as an effective induction agent?

Dr. Fox: Certainly our hope is that there's going to be an increased number of agents available for the treatment of MS, but it's going to be necessary to determine at what stage of disease we would use these medications.[19] The strategy of phase 3 trials is typically in first-line treatment of relapsing-remitting MS, in a placebo-controlled trial evaluating medication over a period of 2 years. This certainly gives us an idea as to what its overall effectiveness can be, and the newer treatments will be evaluated for the ability to reduce relapses and accumulation of disability. Phase 3 trials will also have to show an acceptable safety profile and risk management plan. The first-line agents that we currently have on the market, glatiramer acetate and the beta interferons, will likely continue to have a role in first-line therapy when we look at long-term efficacy and safety measures of the newer medicines. It will likely take a number of years to determine the true safety of the monoclonal and oral agents, and their overall use as first-line therapies will depend on these data.

The concern that we have about using any of the new agents as an add-on treatment for failed first-line therapy is again, a safety issue. If it's being used in a combination with other immunomodulatory or immunosuppressive therapy, we cannot currently define the safety of such an approach. This has been a major concern lately with the findings of opportunistic infections such as progressive multifocal leukoencephalopathy in patients who are immunosuppressed. Switching from ineffective first-line therapy to a new therapy is going to be the most likely use in clinical practice soon after these agents reach the market.

Using any of these agents as an effective induction agent is going to require more data from trials where this has been specifically tried. Older medications such as mitoxantrone have been tested as induction therapies with some very favorable results, but the novel agents that are being investigated right now have not been similarly tested.[20-24] Therefore, I believe that the novel agents are likely to be used as first-line or second-line agents rather than initially as induction agents.

Medscape: What is the evidence for agents optimized for neuroprotection and neurorepair?

Dr. Fox: Ideally, any medication that we use as a preventive medicine for MS would have neuroprotective and neurorepair abilities. Research has shown a frequent association of better clinical outcomes if there's prevention of atrophy. The concept of neuroprotection is that we are preventing axonal loss and neuronal loss during the early stages of MS prior to the onset of disability. All of the trials that are looking at atrophy measures are addressing this issue to some degree, but we would like to have advanced imaging metrics to look more directly at the preservation of axonal and neuronal function.

The World Congress and Treatment for Research of Multiple Sclerosis Meeting had a substantial amount of data that were presented regarding these advanced imaging metrics, including magnetic resonance spectroscopy (MRS) and magnetization transfer imaging (MTR). Measurement of neuronal loss by optical coherence tomography (OCT) is also a very promising method of evaluating the degree of atrophy seen in MS.[25] It is likely that the novel therapies currently being investigated will also be tested in a similar manner. It is reassuring to know that we are seeing some positive data on neuroprotection. Improving repair mechanisms may require a new type of medication that would stimulate the production of new myelin growth rather than working as an immunosuppressant medication.

Medscape: What are the limitations and benefits of these novel therapeutic agents, with respect to safety and efficacy, compared with long-approved therapies such as interferon beta and glatiramer acetate?

Dr. Fox: The-first line therapies that we are currently using for the treatment of MS have been on the market for a number of years. The users of these medicines have a certain comfort level with these medications now and the understanding that the long-term data have indicated a relatively good safety profile.

Immunomodulating therapies do not appear to cause the degree of risk that the immunosuppressant therapies may cause. We understand the risk-benefit ratios of the medicines that have been on the market for a number of years, but the novel therapies that are currently under investigation will undoubtedly have a higher degree of uncertainty as to their safety for many years to come. It is quite possible that the novel therapies are going to have immunosuppressant activity that could lead to increased risk for opportunistic infections, limiting their use as first-line therapies.

The efficacy measures, on the other hand, may show direct or indirect evidence of superiority to the first-line therapies. If indeed the therapeutic abilities of these novel therapies are great enough, then we may accept a higher risk potential with these medications and use them as first-line therapy. However, I don't think that the true measure of a medication's safety will be known at the time it enters the market.

Medscape: Does the increase of potential therapeutic agents complicate how to choose first-line therapy?

Dr. Fox: I think with the advent of more choices, we're going to have a greater divide among practicing neurologists as to how they approach the disease. Right now there's fairly good uniformity among neurologists in terms of how to treat early MS. There are differences in opinion about the optimal medication strategies for people with aggressive or chronic disease. But early active disease is currently treated by a limited number of agents that have relatively similar outcome measures in terms of their ability to control the disease. If we have new medicines available to us over the next several years that have a much different risk-benefit ratio with greater promise of disease control but increased risk, I feel that there's likely to be a group of neurologists who will use these medications first line. But there will be a number of other neurologists who are much more conservative in their acceptance of the new medications and will limit the new medicines only to those patients who have failed existing therapies.

Medscape: The fields of genetics and proteomics are beginning to play a large part in the discovery of novel therapeutic targets. How do these newly identified targets impact the development of individualized therapeutic strategies?

Dr. Fox: As we understand the pathology of MS better, we may find that certain medications are tailored for some patients more than others. For example, the biomarkers that may eventually be used for MS would determine whether we would want to use therapies that were depleters of B cells, T cells, monocytes, or a wide-spectrum immunosuppressant.[26,27] Critical to this line of thinking is the understanding of the mechanism of action of our current medications, which remains somewhat murky to this day, because MS is a highly variable and unpredictable disease with different pathologies among different patients. If we understood the pharmacogenomics of MS better, we might be able to tailor appropriate therapies much more accurately.

Medscape: What are some of the outstanding challenges in the treatment of MS that need to be addressed in the future?

Dr. Fox: Balancing the risks and benefits of medications in the treatment of MS has become increasingly important in the last few years. The major challenge in understanding the nature of this disease is elucidating the prognostic factors for an individual patient, so that we may prevent the development of permanent disability that at this point cannot be alleviated. If we can determine which patients have early, aggressive MS before the development of axonal loss and atrophy, we stand a much greater chance of being able to appropriately determine who might require stronger immunosuppressant. Our challenge going forward is to address both the inflammatory and the degenerative nature of MS with medications that effectively control the disease. Data presented at the World Congress on Treatment and Research in Multiple Sclerosis suggests we are now closer to that goal.

Medscape: Thank you Dr. Fox for sharing this information and your insights with us today.

This activity is supported by an independent educational grant from Teva.
References

1. Linker RA, Kieseier BC, Gold R. Identification and development of new therapeutics for multiple sclerosis. Trends Pharmacol Sci. 2008 Sep 17. [Epub ahead of print].
2. Gasperini C, Cefaro LA, Borriello G, et al. Emerging oral drugs for multiple sclerosis. Expert Opin Emerg Drugs. 2008;13:465-477. Abstract
3. Burton JM, O'Connor P. Novel oral agents for multiple sclerosis. Curr Neurol Neurosci Rep. 2007;7:223-230. Abstract
4. Brinar V for the CAMMS223 Study Group. Alemtuzumab Phase 2 Extension Study Design (CAMMS223): assessing long-term outcomes and potential benefits of additional alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P17.
5. Naismith R, Trinkaus K, Fairbairn M, Lauber J, Piccio L, Cross A. Rituximab as add-on therapy for breakthrough disease: clinical effects over 24 weeks. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P476.
6. Neyer L, Singer R, Wang H, Caras I. Daclizumab exhibits efficacy in multiple sclerosis subjects positive for interferon-beta neutralizing antibodies. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P479.
7. Hawker K. Efficacy and safety of rituximab in patients with primary progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, multicenter trial. Parallel Session 10 of Late Breaking News of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Scientific Program S78.
8. Dörner T, Burmester GR. New approaches of B-cell-directed therapy beyond rituximab. Curr Opin Rheumatol. 2008;20:263-268. Abstract
9. Guarnaccia J, Rinder H, Smith B. Preferential effects of cladribine on lymphocyte subpopulations. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P55.
10. Laugel B, Challier J, Siegfried C, Chvatchko Y, Weissert R, Galibert L. Cladribine exerts a modulatory effect on T-cell activation. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P80.
11. Rieckmann P, Giovannoni G, Cook S, et al, for the CLARITY Study Group. Cladribine tablets in relapsing-remitting multiple sclerosis: study design of the 2-year, phase III b CLA RITY (CLA dRibine tablets Treating multiple sclerosis orallY) extension study. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P453.
12. Kappos L, Radue E, O'Connor P, et al., for the FREEDOMS Study Group. Oral fingolimod (FTY 720) in patients with relapsing multiple sclerosis: 3-year results from a phase II study extension. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P72.
13. Kappos L, Polman C, Radue E, et al. Oral fingolimod (FTY 720) in relapsing-remitting multiple sclerosis: baseline patient demographics and disease characteristics from a 2-year phase III trial (FREEDOMS). Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P73.
14. Montalban X, Comi G, Anel J, et al. Oral fingolimod (FTY 720) in relapsing multiple sclerosis: impact on health-related quality of life in a phase II study Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P400.
15. MacManus D, Miller D, Kappos L, R. Gold, et al. The effect of BG00012 on conversion of gadolinium-enhancing lesions to T1-hypointense lesions. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P459.
16. Gold R, Kappos L, Miller D, et al. Safety profile of BG00012, an oral formulation of dimethyl fumarate for patients with relapsing MS. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P50.
17. Tallantyre E, Evangelou N, Constantinescu CS. Spotlight on terfilunomide. Int MS J. 2008;15:62-68. Abstract
18. Comi G, Abramsky O, Arbizu T, et al., for the LAQ/5062 Clinical Advisory Board and Study Group. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 9-month double-blind active extension of the multi-center, randomized, double-blind, parallel-group placebo-controlled study. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P31.
19. Gold R. Combination therapies in multiple sclerosis. Neurology. 2008;255 Suppl 1:51-60.
20. Vollmer T, Panitch H, Bar-Or A, et al. Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis. Mult Scler. 2008;14:663-670. Abstract
21. Le Page E, Leray E, Taurin G, et al. Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: treatment response factors in a 5 year follow-up observational study of 100 consecutive patients. J Neurol Neurosurg Psychiatry. 2008;79:52-56. Abstract
22. Filippi M, Le Page E, Leray E, Edan G, Comi G. Magnetic resonance imaging results of a 3-year randomized trial comparing two therapeutic strategies in aggressive relapsing-remitting multiple sclerosis: mitoxantrone as induction for 6 months followed by interferon-b-1b versus interferon-b-1b. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P254.
23. Perumal J, Hreha S, Caon C, et al. Intense immunosuppression as the initial disease-modifying therapy in clinically active relapsing multiple sclerosis. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P490.
24. Ramathal J, Boggild M. Glatiramer acetate following mitoxantrone induction in relapsing-remitting multiple sclerosis: extended experience. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P498.
25. Balcer L. OCT: window on multiple sclerosis. Parallel Session 5 of Advances in Imaging Techniques of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Scientific Program S43.
26. Garcia-Montojo M, Alvarez-Lafuente R, Dominguez-Mozo M, De las Hera V, Bartolome F, Arroyo R. MxA and MMP-9/TI MP-1 ratio as biomarkers of treatment efficacy and disease activity in multiple sclerosis patients. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster 452.
27. Melnikov A, Scholtens D, Reder A, Balabanov R, Stefoski D, Levenson V. Composite methylation profiles of blood DNA as biomarkers for multiple sclerosis. Disease-modifying therapy-part 2. Program and abstracts of the World Congress on Treatment and Research in Multiple Sclerosis; September 17-20, 2008; Montreal, Quebec, Canada. Poster P869.


Interviewer: Elizabeth Samander, PhD, Scientific Director, Medscape LLC

Interviewee: Edward J. Fox, MD, PhD, Clinical Assistant Professor, University of Texas Medical Branch, Round Rock, Texas

Disclosure for Interviewer: Elizabeth Samander, PhD, is a member of the professional editorial group at Medscape and has reported no relevant financial relationships.

Disclosure for Interviewee: Edward J. Fox, MD, PhD, has disclosed that he has received grants for clinical research from Biogen-Idec, BioMS, EMD-Serono, Genzyme, Opexa Therapeutics, Sanofi-Aventis, and Teva Neuroscience. Dr. Fox has also disclosed that he has received grants for educational activities from Bayer, Biogen-Idec, EMD-Serono, Pfizer, and Teva Neuroscience. Dr. Fox has also disclosed that he has served as an advisor or consultant to Bayer, Biogen-Idec, EMD-Serono, Genzyme, Opexa Therapeutics, and Teva Neuroscience.

Pipex Pharmaceuticals, Inc. Completes Corporate Name Change to Adeona Pharmaceuticals

ANN ARBOR, Mich., Oct 16, 2008 (GlobeNewswire via COMTEX) -- Pipex Pharmaceuticals, Inc. (the "Company" or "Pipex"), a pharmaceutical company developing innovative late-stage oral drug candidates for the treatment of autoimmune and central nervous system diseases, announced today that it has completed a corporate name change from Pipex Pharmaceuticals, Inc. to Adeona Pharmaceuticals, Inc.

As a result of the name change, the American Stock Exchange (AMEX) will begin to trade the Company's shares of common stock as of today, under the new ticker symbol 'AEN.'
Nicholas Stergis, Chief Executive Officer of Adeona, commented, "As previously announced, we are pleased to have completed our corporate name and ticker symbol change. Our primary focus is toward the continued development of new disease-modifying treatments for autoimmune and central nervous system diseases. This strategy and direction is evident by our recent in-licensing of oral dnaJP1 for the treatment of rheumatoid arthritis (RA) which has completed a 160-patient, double-blind, placebo-controlled phase II clinical trial in RA patients. Oral dnaJP1 complements our existing immunology pipeline which includes, TRIMESTA, an oral treatment for multiple sclerosis (MS) which is currently in a 150-patient double-blind, placebo-controlled phase IIb clinical trial is being funded by a $5 million grant."

About Adeona
Adeona Pharmaceuticals, Inc. ("Adeona") is a specialty pharmaceutical company that is developing proprietary, late-stage drug candidates for the treatment of central nervous system and autoimmune diseases. Adeona's strategy is to exclusively in-license clinical-stage drug candidates for the treatment of unmet medical diseases. Adeona is focused on developing products to treat, rheumatoid arthritis, multiple sclerosis, dry age-related macular degeneration (AMD), and fibromyalgia.

This press release contains forward-looking statements, within the meaning of Section 21E of the Securities Exchange Act of 1934, that reflect Adeona Pharmaceuticals, Inc.'s current expectations about its future results, performance, prospects and opportunities, including statements regarding our late stage pipeline of products and its focus on development of new disease modifying treatments for autoimmune diseases. Where possible, the Company has tried to identify these forward-looking statements by using words such as "anticipates," "believes," "intends," or similar expressions. These statements are subject to a number of risks, uncertainties and other factors that could cause actual events or results in future periods to differ materially from what is expressed in, or implied by, these statements including the risks set forth in our recent Form 10-Q and other filings with the Securities and Exchange Commission. We cannot assure you that we will be able to successfully develop or commercialize products based on our technologies, including, dnaJP1, TRIMESTA, Zinthionein, oral flupirtine, SOLOVAX, oral TTM, or CD4 inhibitors, particularly in light of the significant uncertainty inherent in developing, manufacturing and conducting preclinical and clinical trials of new pharmaceuticals, and obtaining regulatory approvals, that our technologies will prove to be safe and effective, that our cash expenditures will not exceed projected levels, that we will be able to obtain future financing or funds when needed, that product development and commercialization efforts will not be reduced or discontinued due to difficulties or delays in clinical trials or due to lack of progress or positive results from research and development efforts, that we will be able to successfully obtain any further grants and awards, maintain our existing grants which are subject to performance, that we will be able to patent, register or protect our technology from challenge and products from competition or maintain or expand our license agreements with our current licensors, or that our business strategy will be successful. All forward-looking statements made in this press release are made as of the date hereof, and the Company assumes no obligation to update the forward-looking statements included in this news release whether as a result of new information, future events, or otherwise.

This news release was distributed by GlobeNewswire, www.globenewswire.com
SOURCE: Adeona Pharmaceuticals, Inc.

Adeona Pharmaceuticals, Inc.
Nicholas Stergis, Chief Executive Officer
(734) 332-7800

Redington, Inc.
Investor Relations
Thomas Redington
(203) 222-7399


(C) Copyright 2008 GlobeNewswire, Inc. All rights reserved. End of Story

Former Immune Response Corp. files for liquidation

By BRADLEY J. FIKES - Staff Writer | Wednesday, October 15, 2008 8:07 PM PDT ∞

CARLSBAD ---- The battered biotech company formerly known as The Immune Response Corp. finally has thrown in the towel.

Orchestra Therapeutics filed for Chapter 7 bankruptcy Monday in U.S. Bankruptcy Court for the Southern District of California. The company listed assets of $1.64 million and liabilities of $32.61 million.

Co-founded by the late Jonas Salk in 1986 to develop a vaccine to treat AIDS called Remune, Immune Response was one of North County's most famous biotech companies.

In the early '90s, as its vaccine showed signs of activity against HIV, the virus that causes AIDS, Immune Response became a Wall Street darling.

But the company failed in repeated attempts to prove Remune actually helped those infected with HIV. While its stock plummeted and investors lost interest, Immune Response kept searching for other products.

In April 2007, the company changed its name to Orchestra Therapeutics. The company's main hope was to develop a vaccine for multiple sclerosis, which it called NeuroVax.

But failing to make a profit through Remune, NeuroVax or any of its other drug candidates, Orchestra barely kept going, raising a few hundred thousand dollars at a time from various investors.

In its filing, Orchestra included a long list of creditor claims, including the city of Carlsbad, seeking $335; Delaware's Division of Corporations, seeking $288,000; Gazzard-St. Stephen's Research Ltd. in the U.K., seeking $195,000; Levit Zacks Accounting, seeking $59,000; the Nasdaq stock market, seeking $31,000; and Shred It in Vista, seeking an amount described as "unknown."

Contact staff writer Bradley J. Fikes at (760) 739-6641 or bfikes@nctimes.com.

Link Between Vaccine and MS Unproven

TUESDAY, Sept. 30 (HealthDay News) -- Children vaccinated against hepatitis B probably are not at an increased risk of developing multiple sclerosis (MS) unless they were inoculated with a particular brand of the vaccine, according to a new study.

The French study found that children with MS were almost twice as likely to have received the vaccine called Engerix B three or more years before the disease's onset. Further studies will need to be done to determine whether the vaccine is a direct cause of the development of MS.

The study, which involved 349 children with MS and 2,941 children without the disease, is to be published in the Oct. 8 online issue of Neurology.

The U.S. Centers for Disease Control and Prevention has more about vaccinations.

SOURCE: American Academy of Neurology, news release, September 2008

Tysabri PML Cases Cause European Regulators to Recommend Stronger Warnings

September 29th, 2008

The European Medicines Agency, an advisory body for drug regulators in Europe, recommended last week that the warning label for the multiple-sclerosis drug Tyasabri be updated following new reports of users developing a rare brain disease known as PML, or progressive multifocal leukoencephalopathy.

Tysabri (natalizumab) is an intravenous injection given every 28 days to treat Crohn’s Disease or multiple sclerosis (MS). It has been shown to prevent relapse, cognitive decline and vision loss which could be associated with multiple sclerosis.

Shortly after Tysabri was introduced in 2004, it was associated with side effects that could lead to PML, which is a potentially fatal brain infection. After three cases of PML resulted in two deaths, a Tysabri recall was issued in 2005, and the drug was re-introduced the next year with stricter guidelines for usage and more prominent warnings about the possible Tysabri PML side effects.

European and American drug regulators have been re-examing the risk of progressive multifocal leukoencephalopathy in recent months, after new reports of PML among Tysabri users surfaced in July 2008. According to filings with the SEC, the drugs makers, Biogen Idec and Elan Corporation, identified two PML cases in Europe, which were the first new diagnosed Tysabria PML cases since 2006.

On September 25, 2008, the European Medicines Agency’s Committee for Medical Products for Human Use (CHMP) called for drug regulators to strengthen the Tysabri progressive multifocal leukoencephalopathy warnings in Europe. They recommended that the drug’s prescription information be updated and strengthened to highlight the potential Tysabri side effects for patients with relapsing-remitting multiple sclerosis (MS).

The European regulatory committee did not call for a Tysabri recall, as they indicated that the benefits of the drug still do outweigh the risks. However, in light of these new PML cases, they felt that the current warnings in Europe need to be strengthened to raise awareness about the risk of the brain disease from Tysabri.

In August 2008, the FDA issued a MedWatch Alert regarding the new reports of PML associate with Tysabri. They indicated that the prescribing information in the United States would be revised to include information for prescribers and patients about the cases of PML that occurred among patients taking Tysabri as a monotherapy. The U.S. drug regulators also recommended that doctors should monitor their patients for signs and symptoms of PML.

that they are investigating the reports to determine what, if any, regulatory actions are necessary regarding the Tysabri side effects.

Progressive multifocal leukoencephalopathy is a rare viral infection which causes inflammation at multiple locations in the brain, leading to progressive brain damage. Symptoms could include loss of vision, impaired speech, paralysis, cognitive decline and weakness. There is no known cure for PML, but the disease can sometimes be slowed or stopped by reducing immunosuppression. In many cases the brain infection is fatal.

MS Patients Have Higher Spinal Fluid Levels Of Suspicious Immune Molecule

ScienceDaily (Sep. 30, 2008) — A protein that helps keep immune cells quiet is more abundant in the spinal fluid of patients with multiple sclerosis (MS), further boosting suspicion that the protein, TREM-2, may be an important contributor to the disease.

More of an immune-control protein might seem like a boon to MS sufferers, whose symptoms are caused by misdirected immune attacks on the protective lining that coats nerve cell branches. But researchers at Washington University School of Medicine in St. Louis found the extra TREM-2 was not in the right place to reduce aggression in immune cells, a revelation that could eventually lead scientists to new pharmaceutical targets for MS prevention.

"Previously, TREM-2 had only been seen on the surface of immune cells; in the new study, we found it floating freely in spinal fluid," says lead author Laura Piccio, M.D., Ph.D., postdoctoral fellow. "This is only speculation for now, but these 'free agent' copies of TREM-2 could be making it harder for the TREM-2 that is attached to immune cells to keep the cells' aggressiveness under control."

Piccio explains that TREM-2 is a receptor protein, which means that another molecule activates it. Scientists don't currently know what that other molecule is, but the "free agent" TREM-2 in the spinal fluid could be binding to the molecule, reducing the chances that it will bind to and activate TREM-2 attached to immune cells. If Piccio and her colleagues can confirm their theory, the TREM-2 in the spinal fluid or its unknown partner could become targets for new MS treatments. The findings appear in the journal Brain.

Epidemiologists estimate that 400,000 people in the United States have MS. Symptoms, which often strike in episodic bursts, include bladder and bowel dysfunction, memory problems, fatigue, dizziness, depression, difficulty walking, numbness, pain and vision problems. The disease is more common among Caucasians than any other group and affects two to three times as many women as men.

TREM-2 first came to MS researchers' attention because of Nasu-Hakola disease, a rare genetic disorder that involves a mutation in the gene for TREM-2. Among other symptoms, Nasu-Hakola causes loss of the same protective sheath around nerve cell branches that is damaged by MS.

One place where the TREM-2 protein commonly appears is the macrophage, an immune cell that performs a variety of functions, including cleaning up debris and emitting inflammatory signals that escalate immune attacks. Macrophages come in two classes: one that promotes inflammation and one that suppresses it. TREM-2 is present only on the anti-inflammatory macrophages.

Prior experiments had shown that activation of the TREM-2 receptor can help reduce immune inflammation and promote phagocytosis, a process that lets cells consume things. In the context of the central nervous system, researchers think this allows macrophages to consume dying nerve cells and to perform "housekeeping functions," such as shutting down inflammatory processes.

"The main thing we knew about MS and the function of TREM-2 before this study was that blocking TREM-2 in a mouse model of MS made their conditions worse," says senior author Anne Cross, M.D., professor of neurology and head of the neuroimmunology section.

After Piccio identified TREM-2 in the spinal fluid, she compared that form of the protein in patients with various types of MS, patients with other inflammatory diseases of the central nervous system, and patients with non-inflammatory central nervous system diseases. To ensure that the soluble TREM-2 wasn't seeping into the patients' spinal fluid from the bloodstream, they also analyzed TREM-2 levels in blood.

While there were no differences in blood levels, the soluble form of TREM-2 was significantly higher in the spinal fluid of MS patients.

Scientists are trying to develop a mouse line where the TREM-2 gene has been disabled to learn more about the protein's contributions to the immune system.

Journal reference:

1. Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Rinker II J, Naismith RT, Panina-Bordignon P, Passini N, Fenoglio C, Galimberti D, Scarpini E, Colonna M, Cross AH. Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain, 2008; DOI: 10.1093/brain/awn217

Adapted from materials provided by Washington University School of Medicine.