new info? or not

A board to discuss the anticipated multiple sclerosis treatment Rituxan.

new info? or not

Postby Lars » Thu Mar 19, 2009 6:59 pm

I didn't see this posted so.... here it is. Question, how does Rituximab differ from the other monoclonal antibodies such as Campath and Tysabri?
Thanks Lars

Rituximab
Breaking News from Dr. Vollmer

In the development of new therapies for multiple sclerosis, there are occasions in which the results of a study surprise investigators and challenge their long-held beliefs about MS. A recent example is the evolving story concerning the development of a drug called rituximab as a treatment for MS, specifically primary progressive MS.
Rituximab, also known as Rituxan, was approved by the FDA in 1997 for use in the treatment of certain lymphomas and rheumatoid arthritis. Since then, more than 900,000 patients with various diseases have been treated with rituxiumab; as such a great deal is known about the safety profile of the therapy. Several small studies reported positive findings in MS patients treated with this medication, which led to two large studies on MS: one a preliminary study of 104 people with relapsing MS, and the second, a larger trial involving over 439 with primary progressive MS. The results of the relapsing remitting trial were published in the New England Journal of Medicine last year. According to Dr. Vollmer, those receiving rituximab experienced substantially fewer relapses and developed 92% fewer enhancing MRI lesions during the 48 weeks of the trial than those receiving placebo.
More recently, the results of the study in primary progressive MS were presented in preliminary form at an international meeting on MS held in Montreal. After 96 weeks, fewer people in the rituximab group (30.2%) experienced disability progression than in the placebo group (38.5%), but this was within a range that might have occurred by chance. Preplanned subgroup analysis, however, did detect a clear benefit for younger people and people with inflammatory MRI lesions. The hope is that the results will soon be published in more detail in the medical literature because they raise several important issues for the medical and MS communities.
First, it raises important research questions. Rituximab is a monoclonal antibody that targets B lymphocytes only. It does not directly affect T lymphocytes, which have been thought to be the key driver of the attack on the central nervous system in MS with B lymphocytes playing only a peripheral role. The rituximab trials show that B lymphocytes play a much more central role in MS than previously thought. Indeed, such results have led to a dramatic increase in therapies aimed at B lymphocytes in development for MS.
Second, it raises practical treatment issues. Despite some evidence of effectiveness, it appears Genetech, the company that markets rituximab in the United States, will not pursue the development of rituximab as a therapy for people with MS. This is apparently because the drug will lose patent protection in the near future, meaning it might become available in a less expensive generic form. Newer molecules with longer future patent protection are being developed by several companies as treatments for MS, but these newer agents will not be available for several years at best, whereas ritiximab is available in pharmacies today.
Thus, as has been the case in other areas of medicine, the situation challenges physicians and families dealing with MS to consider if, based on the data available to date, rituximab is appropriate for some patients with MS – particularly those with primary progressive MS who share characteristics with the responders in the phase III trial and for whom there are no approved or demonstrably effective other therapies currently available. Should rituximab be used as an "off-label" treatment, without specific FDA approval?
Additionally, another question arises: should the MS community itself take on the responsibility of developing the agent further by funding additional clinical trials so rituximab can possibly receive FDA approval as an MS treatment? These are difficult but important questions. Meanwhile, complex treatment decisions will need to be made on the basis of imperfect evidence and against an unclear regulatory environment.
It also challenges health insurers for obvious reasons. There are many medications used to treat MS patients that are not specifically approved by the FDA for use in MS, and there are other medications already approved for other diseases that are being developed for MS. As has been the case in the past, the business interest of the pharmaceutical industry does not appear to be in alignment with the medical interests of patients with MS.
In the interest of disclosure of possible conflicts of interests, Dr. Vollmer would like to note that although he does not have a financial interest or own stock in pharmaceutical companies, he has received research grants related to rituximab from Genentech and has received honoraria for consultation from Genentech, Biogen, Teva, Serono and other pharmaceutical companies manufacturing drugs for MS patients. As such, he feels it is important that patients and physicians review these studies themselves and independently come to a decision on the potential role of rituximab in the treatment of MS.
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Postby patientx » Fri Mar 20, 2009 7:44 am

Question, how does Rituximab differ from the other monoclonal antibodies such as Campath and Tysabri?


Lars,

The answer to your question is buried in the article:

Rituximab is a monoclonal antibody that targets B lymphocytes only. It does not directly affect T lymphocytes, which have been thought to be the key driver of the attack on the central nervous system in MS with B lymphocytes playing only a peripheral role. The rituximab trials show that B lymphocytes play a much more central role in MS than previously thought. Indeed, such results have led to a dramatic increase in therapies aimed at B lymphocytes in development for MS.


Each of these monoclonal antibodies has one specific target (hence the "mono"). For Rituximab, it is the CD-20 protein found in B-cells. For Campath, the target is the CD-52 protein that is found on both T-cells and B-cells. With Tysabri (and I may be getting this slightly wrong), the target is a receptor on blood vessel walls that binds with T-cells. By targeting this receptor, T-cells are prevented from penetrating the blood-brain barrier.

Thanks for posting this article. It starts to address a question that I've had for a while now. If researchers believe MS is a T-cell mediated disease, the why do therapies like Rituxan, which target B-cells, seem to work well for MS? Another B-cell MAB, Ocrelizumab, is in the works for clinical trials.
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Re: new info? or not

Postby NHE » Fri Mar 20, 2009 4:17 pm

patientx wrote:Each of these monoclonal antibodies has one specific target (hence the "mono").


That's close but not quite 100% accurate. Monoclonal antibodies do indeed have a specific target. However, the term monclonal comes from the fact that these antibodies are produced from a single clone of plasma cells which all originated from a single B cell.

Brittanica wrote:When activated by an antigen, a circulating B cell multiplies to form a clone of plasma cells, each secreting identical immunoglobulin molecules. It is such immunoglobulins—derived from the descendants of a single B cell—that are called monoclonal antibodies.


Each clone of plasma cells produce an antibody which targets a specific region of a protein. This region is usually identified by its amino acid sequence. In contrast, polyclonal antiobodies are produced from multiple clones of plasma cells. Each of these clones produce an antibody which recognizes a different amino acid sequence. A polyclonal antibody will thus contain a mixture of antibodies all which could target the same antigen but target different parts, i.e., different amino acid sequences, of that protein. A monoclonal antibody is thought to be more specific since it will only target one region (or amino acid sequence) of an antigen.

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Postby patientx » Sat Mar 21, 2009 5:49 pm

Right. Thanks for the correction.
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