Therapy Analysis - Sickle cell anaemia
Treatment
There is currently no cure for sickle-cell anaemia. With such a large proportion of the world's population affected by the disease, there is a vital need for companies to actively focus on developing treatments for this life-threatening disease. Currently there are 16 products in active development for the disease, and only two of these are available for use (graph 1).
A major milestone was reached in 2006, when Xechem launched its four-plant cocktail, Nicosan (niprisan) in Nigeria, with European and US filings as Hemoxin to follow. Reaching out to the African country, it has given hope to tens of thousands of Nigerians in the fight against sickle-cell disease. Clinical Phase III trials in 82 patients in Nigeria have proven the effectiveness of this drug, showing complete remission of the disease in 73% and a substantial reduction in crisis after 6 months of treatment in the rest of the group. Though launched for indications such as Alzheimer's disease, alcoholism, vertigo and specific learning difficulties such as dyslexia, UCB's Nootropil (piracetam), an acetylcholine agonist, has been found to be useful in the treatment of VOC in sickle-cell. It is approved in the treatment of sickle-cell in Singapore. Nootropil is thought to reduce erythrocyte adhesion to vascular endothelium, hinder vasospasm, and facilitate microcirculation.
There is no common pharmacological action for drugs in development for battling sickle-cell (graph 2). Mechanisms of action range from acetylcholine agonists to tumour necrosis factor antagonists, and selectin inhibitors. GlycoMimetics is developing selectin antagonists, which include E-selectin inhibitors and GMI-1070, a pan-selectin inhibitor, both in preclinical development. Selectins play a role in neutrophil recruitment in an early stage of the inflammatory cascade. In a murine model of VOC in sickle cell disease, a mixture of antibodies against E and P selectins improved blood flow, and GMI-1070 increased blood flow by 3 times compared to control in mice.
Icagen is developing senicapoc, currently in Phase III, a first-in-class small-molecule erythrocyte potassium channel blocker. By blocking the Gardos ion channel, it prevents the loss of salt and water, thus preventing increases in HbS concentration and resulting polymerization. A registration filing was expected in 2009; however, this drug has been met with a negative opinion in the US from the Data Monitoring Committee stating that the Phase III ASSERT trial will yield a low probability in achieving a reduction in VOC rate. Data from the trial indicated the expected increases in haemoglobin and haematocrit and decreases in reticulocytes as well as LDH and bilirubin occurred; however, there was no significant difference in safety between the test drug and placebo. A decision on the future development of senicapoc for this indication will be made following final data analysis.
SuperGen has developed Dacogen (decitabine) for myelodysplastic syndrome, with multiple cancer indications to follow, but is in Phase II trials for sicklecell, for which it has US orphan drug status. This antimetabolite analogue of 2'-deoxycytidine, administered intravenously, inhibits DNA methyltransferase and induces expression of cancer-testis antigens (CTAs) on the surface of cancer cells. Expression of CTAs is thought to precipitate removal of cancer cells by the immune system. The bone marrow can then continue to produce RBCs. In 2 Phase I/II trials in 8 patients with sickle-cell anaemia, 100% responded to decitabine. In a 36wk Phase I/II trial in 6 sickle-cell anaemia patients, foetal haemoglobin levels increased from 3 to 14% and average haemoglobin levels increased by 22%. There were no sickle-cell episodes during treatment and side-effects were minimal. A Phase II study in sickle-cell anaemia patients with subcutaneous dosing confirmed intravenous data.
