counts in cerebrospinal fluid and blood following firategrast treatment
in subjects with relapsing forms of multiple sclerosis.Grove RA,
Shackelford S, Sopper S, Pirruccello S, Horrigan J, Havrdova E, Gold M,
Graff O. Eur J Neurol. 2013 Feb 18. doi: 10.1111/ene.12097. [Epub ahead
is an orally bioavailable alpha4 beta1/alpha4 beta7
integrin antagonist designed to reduce trafficking of lymphocytes into
the central nervous system (CNS). This could decrease multiple sclerosis
(MS) activity, but may compromise CNS immune surveillance. We aimed to
quantitate the effect of firategrast treatment on cerebrospinal fluid
(CSF) lymphocyte count and the extent/speed of recovery after its
METHODS:Forty-six subjects with relapsing forms of
MS were treated for up to 24 weeks with open-label firategrast, 900
(females) or 1200 (males) mg twice daily. CSF and blood cell counts, and
lymphocyte composition were determined using flow cytometry.
(n, range) CSF lymphocyte counts (cells/µl) at weeks 0, 24, 28 and 36
were: 5.3 (44, 0.3-70.2), 3.3 (31, 0.0-99.0), 3.0 (32, 0.0-58.2) and 3.5
(29, 0.0-274.8). CD4+, CD8+ T- and CD19+ B-lymphocyte counts followed a
similar pattern. Minimal changes were observed for CD3-CD16+CD56+
natural killer cells. Median CD4 : CD8 ratios were: 2.9 (41, 1.1-10.9),
2.2 (29, 0.6-5.9), 3.8 (28, 1.6-9.0) and 3.8 (21, 2.1-9.4). Blood
lymphocyte counts were elevated at weeks 4 and 24, consistent with the
mechanism of firategrast, and returned to baseline when firategrast was
discontinued. There were minimal changes in CD4 : CD8 ratios.
treatment was associated with modest decreases in median CSF total,
CD4, CD8 and CD19 lymphocyte counts. The generally small magnitude of
decreases suggests that sufficient numbers of lymphocytes can access the
subarachnoid space, preserving CNS immune surveillance.
Since Tysabri was developed there was a hope that we could find a chemical pill that works just like tysabri ad blocks white cells getting into the brain. In many animal studies they have not looked as good as using antibodies, but here we have firatrgrast. It has been tested in MS and is indeed not as effective as Tysabri in relation to the reduction in gadolinium enhancing lesions as reported last year.
In this study they looked in the cerebrospinal fluid and found that the number of white blood cells dropped but they were not absent. They suggest that this leaves enough immune survellence so that may be good in stopping the development of PML. However it also probably means it will be less effective at dealing with MS, which is sort of supported by previous MRI studies. The cell number in the blood increased because they were stuck there as they could not escape. Is this going to be a safer alternative to tysabri? we will have to wait for phase III studies.
Labels: Firategrast, Tysabri