Sunday, 21 July 2013

Cladribine kills T and B cells

Mitosek-Szewczyk K, Tabarkiewicz J, Wilczynska B, Lobejko K, Berbecki J, Nastaj M, Dworzanska E, Kolodziejczyk B, Stelmasiak Z, Rolinski J. Impact of cladribine therapy on changes in circulating dendritic cell subsets, T cells and B cells in patients with multiple sclerosis. J Neurol Sci. 2013 Jul 5. doi:pii: S0022-510X(13)00263-3.


BACKGROUND:Cladribine causes sustained reduction in peripheral T and B cell populations while sparing other immune cells. We determined two populations of dendritic cells (DCs): namely CD1c+/CD19- (myeloid DCs) and CD303+/CD123+ (plasmacytoid DCs), CD19+ B lymphocytes, CD3+ T lymphocytes and CD4+ or CD8+ subpopulations in patients with multiple sclerosis after cladribine therapy.
METHODS:We examined 50 patients with secondary progressive multiple sclerosis (SP MS) according to McDonalds et al.'s criteria, 2001. Blood samples were collected before the initiation of cladribine therapy and after 1st, 2nd, 3th, 4th and 5th courses of treatment. DC subsets, T and B cells were analyzed by flow cytometry.
RESULTS: During cladribine treatment the myeloid DCs CD1c+/CD19- did not change (p=0.73175), and the plasmacytoid DCs CD303+/CD123+significantly increased (p=0.00034) which resulted in significant changes in the ratio of myeloid DCs to plasmacytoid DCs (p=0.00273). During therapy, B lymphocyte CD19+ significantly decreased (p=0.00005) and significant changes in CD4+ cells (p=0.00191), changes in CD8+ cells (p=0.05760) and significant changes in CD3+ (p=0.01822) were found.
CONCLUSIONS:We noticed significant trend to increase the CD303+ circulating the dendritic cells. This population produces large amounts of IFN-alfa. We found significant and rapid decrease in B cells and CD4+ Th cells. Our results suggest two possible ways of beneficial cladribine influence on immune system in MS. Induction of IFN-alfa producing cells and their predominance over BDCA-1+ DCs, which are associated with cytotoxic response. Additionally, cladribine could influence two populations of lymphocytes: B cells and Th lymphocytes responsible for induction of immune response against myelin antigens.
There is no evidence that cladribine is good for SPMS and in fact data that is does not work. It is good for RRMS.

Whilst we are talking about costs generic cladribine would cost less than £1,000 a year..and is an induction treatment that could be £1-2,000 a lifetime, when talking about cost of drugs it is appealing if only was considered safe and effective. 

Rather than do the necessary studies for the FDA and EMA, maybe this was a reason that oral cladribine (movectro) was dropped and pulled from market. Maybe it would be a drug that killed the golden goosen as the generic drug would have surfaced.

What about Fumaderm verses BG-12?

In an era of Idea from Government and the Wellcome Trust of drug re-purposing these would be low-hanging fruit, but how to you deal with the regulators?

It is all well and dandy funding clinical trials...this is what Academic Neurologists do....but then what?....who takes that through to licencing and who carries that cost?. 

Without this bit of joined-up thinking there should be no point starting in the first place because phase II, then phase III and then "oh hell what do we do now" is a waste of money, waste of time and a waste of hope.

If there is no alternative then that is easier, but what if there is an alternative but it is just too expensive to use e.g. Lucentis and Avastin..same drug different price. Use one off label and be sued by the manufacturer. So you need a licencing strategy. Who will hold that licence at thousands of pounds a year...NHS Ltd. I wonder.


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