New potential strategies for treating thrombocytopoenia include a non-peptide agonist being developed by Eisai
If the blood contains a subnormal number of platelets, thrombocytopoenia ensues and clotting is inhibited, increasing the risk of bleeding. There are numerous causes, ranging from bone marrow failure to the body destroying platelets or the spleen storing too many. The underlying cause may be a disease (leukaemia or chronic liver disease), a hereditary condition, or other possibilities such as vitamin deficiency.
A potential strategy for treatment is to agonise the thrombopoietin receptor. The first attempts at this involved biologics – a recombinant human thrombopoietin and a truncated, non-glycosylated form. Both failed in trials after some healthy subjects developed an antibody that neutralised endogenous thrombopoietin.
Newer potential treatments do not have sequence homology with the natural hormone, and include the non-peptide agonist avatrombopag, being developed by Eisai.1 In a randomised, double blind, placebo-controlled, dose finding Phase II trial in patients with chronic immune thrombocytopoenia, 64 patients who had had at least one form of treatment were given the drug in doses of 2.5, 5.0, 10 or 20mg/day or placebo.2
There was a dose-dependent response by the end of the trial, with no responders in the placebo group, and responders in the treatment arms ranging from 2 out of 15 in the 2.5mg group to 12 out of 15 in the highest dosage group. It was generally well tolerated.
In a six month extension study3 on 53 subjects who completed the trial, the original blinded dose was given if they had responded and, if they had not, they were started on open label 10mg doses, increased by 10mg every two weeks depending on response, to a maximum of 40mg in non-responders and 20mg in responders. A total of 53% of subjects achieved a durable platelet response, at a rate of 36% in previous non-responders and 72% in the responder group. About two thirds of subjects experienced bleeding. Phase III trials are underway.
1. M. Fukushima-Shintani et al. Exp. Hematol. 2008, 36, 1337
2. J. Bussel et al. Haematologica 2011, 96 (Suppl. 2), Abst 525
3. J. Bussel et al. Haematologica 2011, 96 (Suppl. 2), Abst 221