The US Food and Drug Administration (FDA) has granted approval for the

An oral SYK inhibitor-fostamatinib disodium hexahydrate.

Trade name Tavalisse

Administered orally as a disodium hexahydrate salt, and is a prodrug of the active compound tamatinib, an inhibitor of the enzyme spleen tyrosine kinase (Syk).

It is an syk inhibitor.

Pregnancy category US: C (Risk not ruled out)

Bioavailability 55% (tamatinib metabolite)

Protein binding 98% (tamatinib metabolite)

Metabolism Gut (ALP to tamatinib)

Liver (tamatinib metabolite by CYP3A4, UGT1A9)

Elimination half-life 15 hours

Excretion fecal (80%), urine (20%)

Syk is a protein tyrosine kinase associated with various inflammatory cells, including macrophages, which are felt to be the cells responsible for ITP platelet clearance.

It is believed to work by interfering with the phagocytosis of antibody coded platelets in the process of ITP.

Syk plays an important role in FcγR-mediated signal transduction and inflammatory propagation.

When FcγRs I, IIA, and IIIA bind to their ligands, the receptor complex becomes activated and triggers the phosphorylation of the immunoreceptor-activating motifs (ITAMs).

Phosphorylation of the immunoreceptor-activating motifs (ITAMs) leads to activated genes which causes a cytoskeletal rearrangement that mediates phagocytosis in cells of the monocyte/macrophage lineage.

Syk plays an important role in FcγR-mediated signal transduction and inflammatory propagation.

Syk inhibition is a therapeutic target for various autoimmune conditions, including rheumatoid arthritis and lymphoma.

Approved for the treatment of thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Has been in clinical trials for rheumatoid arthritis, autoimmune thrombocytopenia, autoimmune hemolytic anemia, IgA nephropathy, and lymphoma.

It has good oral bioavailability, biologic activity, is well tolerated, and does not exhibit collagen or ADP-induced platelet aggregation.

175 mg twice a day achieved persistent responses with platelet counts greater than 50,000 mm3/L on more than 67% of visits.

Toxicity is primarily in GI-related side effects, notable diarrhea, urgency, and vomiting.

Patients with ITP have accelerated clearance of circulating IgG-coated platelets via Fcγ receptor-bearing macrophages in the spleen and liver, leading to different levels of thrombocytopenia and variable degrees of mucocutaneous bleeding.

A significant minority of patients retain persistently low platelet counts despite multiple treatments.

The FDA’s approval of fostamatinib was supported by data from the FIT clinical program.

FIT-1 and FIT-2 included 150 patients with persistent or chronic ITP who had an insufficient response to previous treatment:The patients had a median age of 54, 61% were female, and 93% were white.

Prior ITP treatments included corticosteroids (94%), immunoglobulins (53%), and thrombopoietin receptor agonists (48%), and thirty-five percent of patients had undergone splenectomy.

The patients’ median platelet count at baseline was 16 x 109/L, and 47% were on stable ITP therapy.

In each study, patients were randomized 2:1 to receive fostamatinib or placebo for 24 weeks. In FIT-1, 76 patients were randomized―51 to fostamatinib and 25 to placebo.

In FIT-2, 74 patients were randomized―50 to fostamatinib and 24 to placebo.

All patients initially received fostamatinib at 100 mg twice daily, and most (88%) were escalated to 150 mg twice daily at week 4 or later.

The efficacy based on stable platelet response, defined as a platelet count of at least 50 x 109/L on at least 4 of the 6 visits between weeks 14 to 24.

In FIT-1, 18% of patients in the fostamatinib arm and 0% of those in the placebo arm achieved a stable platelet response.

In FIT-2, 16% of patients in the fostamatinib arm and 4% in the placebo arm achieved a stable platelet response.

For both studies, the incidence of bleeding was 29% in the fostamatinib arm and 37% in the placebo arm.

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