Autoimmune diseases – fostamatinib

Spleen tyrosine kinase, or SYK, has potential as a target in various autoimmune conditions, such as rheumatoid arthritis

fostamatinib

Spleen tyrosine kinase, or SYK, has many biological functions, one of which is as part of the intracellular signalling cascade for surface immunoglobulin receptors on B lymphocytes, and also the Fc receptor that is expressed on several immune effector cells. It therefore has potential as a target in various autoimmune conditions, such as rheumatoid arthritis (RA). Fostamatinib is an orally available prodrug that is designed to inhibit SYK, discovered by Rigel Pharmaceuticals and being developed by AstraZeneca for a number of different autoimmune conditions.

It is furthest advanced in rheumatoid arthritis. Two studies have reported positive results. In one double-blind, placebo-controlled trial, 189 patients receiving methotrexate treatment whose RA was still active despite the treatment were given ascending doses of fostamatinib or placebo.1 After 12 weeks, 72% given 150mg daily doses achieved 20% improvement on the American College of Rheumatology’s criteria, and 65% of the 100mg group, compared with 32% given 50mg and 38% on placebo. Improvements were seen within a week of the trial starting.

In a larger trial, 457 RA patients with a similar profile were given 100mg, 150mg or placebo.2 Rapid positive responses were seen in 57% and 67% of those given the active, compared with 35% of the placebo group. However, less promising results emerged from a third study, in 229 patients, published earlier this year.3 No difference was seen in the ACR20 rate between the active group, given 100mg doses, and those on placebo. However, there was a difference in some of the secondary endpoints, and several Phase III trials are under way.

A Phase I/II trial has also been carried out in non-Hodgkin lymphoma and chronic lymphocytic leukaemia.4 In the Phase I part of the trial, dose limiting toxicities of neutropoenia, diarrhoea and thrombocytopoenia were observed at higher doses, and 200mg doses twice a day were selected for the Phase II part. Here, 68 patients with various forms of recurrent B-NHL were enrolled, and the best objective response rates were 55% in small lymphocytic leukaemia and chronic lymphocytic leukaemia. The median progression-free survival was 4.2 months. Trials continue.

references

1. M.E. Weinblatt et al. Arthritis Rheum. 2008, 58, 3309

2. M.E. Weinblatt et al. N. Engl. J. Med. 2010, 363, 1303

3. M.C. Genovese et al. Arthritis Rheum. 2011, 63, 337

4. J.W. Friedberg et al. Blood, 2010, 115, 2578

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