New drugs in development
Open Door - August 2007 pages 6-7
In the previous issues of Open Door we have reviewed research for treatments for primary progressive MS (read article) and new oral drugs in development for relapsing remitting MS (read article). In this article we look at some of the other new treatments, which are currently in development.
Monoclonal antibodies
What is a monoclonal antibody?
B-cells are a type of lymphocyte or white blood cell, and form part of the immune system. B-cells produce antibodies in response to antigens, markers on the surface of substances that are foreign to the body, such as bacteria, viruses, pollen and other materials. Each B-cell produces just one antibody, and that antibody binds to one specific antigen. Once the antibody has bound to the antigen, it sets in motion an immune response to eliminate the antigen.
A B-cell producing a particular antibody can be isolated and grown in cell culture to produce large amounts of a highly specific, purified antibody - this is known as a monoclonal antibody.
In the laboratory, B-cells can be stimulated to see markers on the body's own cells as antigens and produce antibodies against them. For example, antibodies can be generated that bind to antigens on specific lymphocytes, resulting in an immunological response to these cells. This approach offers the potential for a highly selective targeting of lymphocytes involved in the immunological processes that occur in multiple sclerosis without compromising the remainder of the immune system.
While similar techniques have been used to produce the monoclonal antibodies described here, each one targets a different part of the immune system and works in a very different way.
Alemtuzumab (Campath)
This monoclonal antibody is currently licensed to treat a type of leukaemia. Campath binds to an antigen called CD52 which is found on the surface of certain T-cells, a type of lymphocyte involved in the MS immune response.
A phase II clinical trial is due to finish in August 2007. This is comparing two doses of Campath with the beta interferon drug Rebif for treating early, active relapsing remitting MS. Analysis of data from the first two years of the trial shows that, compared to Rebif, the Campath groups had a 75% reduction in the risk of relapse and a 65% reduction in the risk of becoming more disabled.
Two significant side effects have occurred during Campath treatment:
- idiopathic thrombocytopenic purpura (ITP), a disorder that prevents blood from clotting
- overactive thyroid gland (Graves disease)
Additional safety measures have been added to the trial to allow early diagnosis and treatment of these side effects.
Natalizumab (Tysabri)
Tysabri has recently been approved by NICE for rapidly evolving, severe relapsing remitting MS (see news item). It binds to a specific adhesion molecule on the immune cell surface known as alpha-4 integrin and is thought to act by preventing the cells that can damage nerves from passing into the central nervous system via the blood-brain barrier.
Daclizumab (Zenapax)
Daclizumab is licensed for prevention of kidney transplant rejection. It was designed to block the activity of interleukin 2, a chemical messenger in the immune system, and interfere with the growth of lymphocytes. Recent studies have shown that it increases the activity of natural killer cells, another immune system cell.
A retrospective analysis of 55 people with relapsing remitting and secondary progressive MS who had received daclizumab reported that disability scores improved or stabilised in 60% and worsened in 40%. In other studies, daclizumab showed promise in treating people who had failed to respond to beta interferon or glatiramer acetate.
A phase II trial of daclizumab in relapsing remitting MS is due to start in October 2007.
Rituximab (Rituxan)
Rituximab is licensed to treat leukaemia and non-Hodgkins lymphoma. It reduces the numbers of B-cells in the immune system. Most of the existing treatments interact with or deplete T-cells, so rituximab provides the means for investigating the role of B-cells in the immunological changes occurring in MS. In two separate studies reported at the American Academy of Neurology Annual Meeting in Boston earlier this year, positive effects on both MRI lesions and relapse rates were found.
Phase II and III trials are underway in relapsing remitting and primary progressive MS.
Rituximab has been associated with a number of severe side effects including progressive multifocal leukoencephalopathy (PML) and fatal infusion reactions, although these have not been reported in MS trials.
Other drugs in development
MBP8298
Myelin basic protein (MBP) is believed to be important in the process of myelination of nerves in the brain and spinal cord. MBP8298 is a copy of part of MBP and is thought to act by causing or restoring tolerance to immune attack at this section of MBP.
In a phase II clinical trial, 32 people with progressive MS received an infusion of MBP8298 every six months for 24 months. A statistically significant delay in clinical progression was found in people with a particular genetic makeup (65-75% of all people with MS). In this subgroup, MBP8298 treatment resulted in a delay in progression of MS (78 months for MBP8298 vs 18 months for placebo).
Phase III clinical trials of MBP8298 in secondary progressive and phase II in relapsing remitting MS are currently underway.
Tovaxin
Tovaxin is an autologous T-cell vaccine, which means it is prepared from a sample of the patient's own cells. Myelin-reactive T-cells are extracted from the blood and irradiated to produce a vaccine. When the vaccine is injected, the body sees these modified T-cells as being foreign and attacks them, priming the immune system to attack non-irradiated, myelin-reactive T-cells as well.
In a small preliminary study, Tovaxin showed promise, reducing relapses by 90%.
A phase II study is now underway.
NeuroVax
NeuroVax contains a combination of three protein fragments (peptides), which appear on the surface of T-cells involved in the immune response in MS. Recent studies have suggested that treatment with NeuroVax stimulates production of certain regulatory T-cells, which in turn decrease the levels of other T-cells which attack myelin.
A phase II trial has just started in Central and Eastern Europe.
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