GSK's Revolade works, but why?
disorder has shown good results in trials so far, but while experts
remain mystified as to why it works, a true cure will remain
elusive.
Revolade (eltrombopag) is a small molecule drug designed to treat idiopathic thrombocytopenic purpura (ITP), a disorder characterised by low platelet counts in the blood. It is caused either by an autoimmune reaction where the body produces antibodies that destroy a person's platelets or, in around 40 per cent of patients, where the body simply doesn't produce enough platelets in the first place. The autoantibodies also kill platelet-producing cells called megakaryocytes. The overall effect is that the patient suffers from spontaneous bruising and bleeding. There are between 50,000 and 100,000 individuals diagnosed with chronic ITP in the US and in severe cases, intracranial bleeding can be life threatening. In fact 75 per cent of the deaths from the disease are caused by such events, according to Professor Adrian Newland, head of haematology at Bart's Hospital, London and one of those involved in the clinical trials for Revolade. Revolade was discovered as the results of a research collaboration between GSK and Ligand Pharmaceuticals. The companies do know how the drug works; it activates the thrombopoietin receptor on cells in the bone marrow. This in turn stimulates the proliferation and differentiation of megakaryocytes, and thus increases platelet count. The obvious problem would seem to be that surely the immune system will simply destroy these new platelets as well, leaving the patient back at square one. However, Professor Newland explained to DrugResearcher.com that this isn't the case; the new platelets are left untouched by the autoantibodies and the experts who ran the clinical trial are at a loss to explain why. "It doesn't seem to enhance platelet destruction. We would have expected it to and we were quite surprised when it didn't," Prof. Newland told DrugResearcher.com during an interview. The drug is currently in Phase III clinical trials and Prof Newland recently outlined encouraging data at the European Hematology Association Congress in Vienna Austria. Given once a day, 59 per cent of patients in the study achieved target platelet counts, compared with 16 per cent on placebo. This is important because this figure is above the proportion of patients who suffer from ITP because their body doesn't produce enough platelets. This suggests that Revolade can also treat those whose platelets are destroyed by their own immune system. He went on to explain that overall figures for bleeding events were placed at 36 per cent of patients on placebo, compared with 16 per cent of patients on Revolade. However, if only those who responded to therapy were taken into account, spontaneous bleeding was eradicated completely. Currently, patients with ITP are first given steroids. If that doesn't work well, then the patient can be given intravenous immunoglobulin (IVIG); a product containing antibodies extracted and pooled from the plasma of over a thousand blood donors). As a last resort, chemotherapy can be used to suppress the immune system and removing the spleen - where the platelets ore often actually destroyed once marked by the autoantibodies. GSK is hoping to gain approval for Revolade sometime in 2008. How doctors will use the drug is, as yet unclear, but Prof. Newland said he thought the first line of attack would still be steroids as they are "simple, cheap and effective in a fair proportion [of patients]". Instead, he suspects that the drug could begin to take over from the use of antibodies and removing the spleen. "Taking a tablet once a day is a significant improvement on major surgery or an infusion of blood products on a regular basis," he said. It is the most advanced oral therapy for ITP in development, with Amgen's peptide drug administered subcutaneously and Rigel's oral drug still in Phase II trials. This latter drug, R788, inhibits the Syk kinase protein, which blocks autoantibody receptor signalling in macrophages and B-cells. If drug developers can work out exactly why there isn't an autoimmune reaction to eltrombopag-produced platelets, then it could serve as the starting point for an even better therapy. One thing is for sure though; if GSK know, they're not letting on just yet.
