Potential Treatment For Multiple Sclerosis Begins Clinical Trials

13 Apr 2008

A potential treatment for multiple sclerosis (MS), developed by University of Greenwich in association with Kings College, London, has begun clinical trials.

The life sciences company BTG plc, which has licensed the research, is running the trials on a new compound, known as BGC20-0134.

Dr Laurence Harbige and Dr Mike Leach, from the Biomedical & Drug Discovery Research Group in the University of Greenwich School of Science, developed the new treatment following many years of research.

Dr Laurence Harbige explains: "Although the cause of multiple sclerosis is unknown, there is strong evidence that it involves the regulation of the immune system through molecules in our bodies called cytokines. In MS, the balance of these cytokines is altered, leading to inflammation in the brain which can result in serious disability."

Dr Mike Leach adds: "This new treatment should encourage the immune system to rebalance itself, by inhibiting the production of inflammatory cytokines while promoting the production of helpful anti-inflammatory ones."

These initial trials, in volunteers, will look at how the new treatment works in the body and whether it leads to an increase in the helpful cytokines. A pilot study of a prototype treatment developed by the University of Greenwich team, which is related to this compound, has already shown promising results. It demonstrated clinical benefits in patients with a common form of multiple sclerosis, called relapsing-remitting. It led to decreases in relapse rates, disability and pain, along with improvements in quality of life. Preclinical research on the new compound, BGC20-0134, indicates that it may be three times as potent as this prototype.

Professor Tom Barnes, Pro Vice-Chancellor for Research & Enterprise at the University of Greenwich, congratulates the team behind the discovery: "It is very good news that this research is now in clinical trials. Our university aims to carry out work which is useful to society and this discovery is a classic example of that. It highlights the excellence of the research staff at Greenwich and also the business orientation of the university, through this partnership with BTG plc. Drs Harbige and Leach are to be congratulated on this important milestone."

Louise Makin, BTG's Chief Executive Officer, comments: "The effective treatment of multiple sclerosis remains a significant unmet need. We are pleased to have started clinical development of BGC20-0134, which has the potential to address different forms of the disease and has the advantage of being an oral product."

GREENWICH UNIVERSITY
Old Royal Naval College
Park Row, Greenwich
London
SE10 9LS
http://www.gre.ac.uk

DNA Vaccine Against Multiple Sclerosis Appears Safe, Potentially Beneficial

CHICAGO, IL -- August 13, 2007 -- A newly developed DNA vaccine appears safe and may produce beneficial changes in the brains and immune systems of individuals with multiple sclerosis, according to an article posted online today that will appear in the October 2007 print issue of Archives of Neurology, one of the JAMA/Archives journals.

In patients with multiple sclerosis (MS), the immune system attacks the myelin sheaths that protect nerve cells in the brain and spinal cord, according to background information in the article. The nerve cell's axon, which transmits messages to other neurons, is eventually destroyed.

The cause of MS is unknown, but evidence points to the involvement of immune cells and antibodies that recognize and attack specific substances in the myelin, such as myelin basic protein. Certain cytokines, small proteins produced by cells that trigger inflammation, also may play a role.

Amit Bar-Or, MD, of the Montreal Neurological Institute and colleagues tested a DNA vaccine, BHT-3009, that encodes a full-length human myelin basic protein. Between 2004 and 2006, the researchers administered the vaccine to 30 patients with relapsing-remitting MS [characterized by symptomatic periods and periods of remission] or secondary progressive MS [when symptoms progressively worsen, but there still may be periods of remission].

After 1, 3, 5 and 9 weeks, participants received intramuscular injections of placebo or BHT-3009 (in doses of.5 mg, 1.5 mg or 3 mg), with or without 80-mg pills of atorvastatin calcium, a lipid-lowering drug previously shown to be effective in autoimmune conditions. After 13 weeks, participants who initially received placebo received four injections of BHT-3009.

Magnetic resonance imaging (MRI) and other safety evaluations were performed at the beginning of the study, and again after 5, 9, 13, 26, 38 and 50 weeks.

"BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI and produced beneficial antigen-specific immune changes," the authors write. These changes included a reduction in the number of cytokine-producing CD4+ T cells (a type of white blood cell) specifically targeting myelin proteins. This reduction was found in the blood as well as in the cerebrospinal fluid of three patients who voluntarily underwent lumbar puncture after completing the course of BHT-3009. Atorvastatin did not appear to provide additional benefit.

"There were no increases in clinical relapses, disability, drug-associated laboratory abnormalities, adverse events or the number and volume of contrast-enhancing [visible on MRI] lesions on brain MRI with BHT-3009 treatment compared with placebo," the authors write. "In fact, there was a trend toward a decrease in the number and volume of contrast-enhancing lesions in the brain in patients treated with BHT-3009 compared with placebo."

Based on these results, a phase 2b trial -- a randomized clinical trial in approximately 290 patients -- of BHT-3009 is already under way. "If successful in MS, antigen-specific DNA vaccines can be developed for prevention or treatment of related diseases, such as type 1 diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis and myasthenia gravis," the authors conclude.

The work described in this article was funded by Bayhill Therapeutics, Inc.


ArchNeurol. 2007;64(10):(doi:10.1001/archneur.64.10.nct70002).


SOURCE: American Medical Association

Childhood Sun Exposure May Lower Multiple Sclerosis Risk

By Judith Groch, Senior Writer, MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
July 24, 2007

LOS ANGELES, July 24 -- Exposure to the sun may be a risk factor for skin cancer, but it seems to have a protective effect against multiple sclerosis, according to a twin study.

Action Points
Explain to patients who ask that in this study of genetically identical twins, the twin who spent more time in the sun as a child, had a lower risk of developing multiple sclerosis.

Explain to patients that the cause of multiple sclerosis is unknown, but that this study may provide insight into potential avenues for future research.

In a study of 79 pairs of monozygotic twins, the twin who spent more hours outdoors as a child had a 25% to 57% reduced risk of developing MS, Thomas M. Mack, M.D., M.P.H., of the University of Southern California, and colleagues, reported in the July 24 issue of Neurology.

Despite a strong genetic component, with an approximately 20% concordance among identical twins, environmental effects have been suggested by the role of latitude and of migration within genetically uniform groups, the researchers said.

To eliminate genetic confounding, the researchers sought twins, at least one of whom had MS, by yearly newspaper advertisements throughout North America from 1980 through 1992. Diagnosis was verified by updated medical documentation through 2005.

The analysis was limited to monozygotic twin pairs in which only one of the pair had MS and their childhood exposure to the sun differed. The twins had ranked themselves before 1993 in relation to each of nine childhood sun-exposure activities.

The diagnoses of the twin cases occurred between the ages of 15 and 50, with roughly two-thirds diagnosed from age 20 to 40.

Sun exposure included nine activities, those in the four major seasons, on hot and cold days, and time spent sun tanning, at the beach, or playing team sports. A sun exposure index was calculated as the sum of those exposures for which one twin ranked higher than his or her co-twin.

The odds ratio (OR) for MS ranged from 0.25 to 0.57, depending on the activity and the time of year.

For example, the risk of MS was substantially lower (OR 0.40, 95% CI 0.19 to 0.83, P=0.06) for the twin who spent more time sun tanning than for his or her sibling. For twins who spent more time playing team sports, the OR was 0.44 (CI, 0.19-1.02, P=0.06).

For each unit increase in the sun index, the relative risk of MS decreased by 25%, independent of birthplace and age at diagnosis, the researchers said.

The protective influence was seen among female twins only, they noted, but added that this novel finding must be viewed with caution because only 13 male pairs were involved in the study.

Exposure to sunlight might induce protection against an autoimmune disease by any of several immunosuppressive mechanisms, the researchers said. Ultraviolet radiation may exert its effect directly by producing cytokines, and reducing natural killer cell activity, thus affecting innate immunity.

Ultraviolet radiation can also act indirectly by producing vitamin D and suppressing melatonin secretion, with the resultant effects on Th1-Th2 balance, they speculated.

This effect is probably achieved by activated vitamin D suppressing production of cytokines associated with MS activity, such as IL-2, and tumor necrosis factor alpha, and stimulating opposing cytokines, the researchers said.

Because the researchers used relative exposure within pairs and were unable to directly quantify exposure, they could not estimate the level of exposure that might confer protection, and such estimates would be inaccurate under any circumstances, they said.

Furthermore, estimates of "time spent in the sun" or "in outdoor activities" involve substantial recall bias, given the long interval between sun exposure and diagnosis, the researchers said.

This study, Dr. Mack and his colleagues wrote, reports the importance of sun exposure among individuals with identical genetic risks. "Studies of the pathway by which sun exposure reduces MS risk should receive high priority if we are to unravel the mystery of MS etiology," they concluded.

The authors reported no conflicts of interest. The study was supported by grants from the National Multiple Sclerosis Society, the National Institute of Neurological Disorders and Stroke, the National Cancer Institute, and the National Institute of Environmental Health Sciences.

Additional Multiple Sclerosis Coverage

Primary source: Neurology
Source reference:
Islam T et al "Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins" Neurology 2007; 69: 381-388