Update on clinical trials in sickle cell disease

MST-188 Otherwise known as Purified Poloxamer 188, is a designated orphan drug by the US Food and Drug Administration (FDA) for trial in sickle cell disease. It is a synthetic co-polymer of polyoxyethylene (POE) and polyoxypropylene (POP) and is thought to have beneficial effects on blood flow, as well as having anti-inflammatory and anti-thrombotic  effects. In addition to sickle cell disease, it is also actively under investigation to see whether it is helpful in heart attack victims (myocardial infarction) and in patients who have reduced blood flow in their arms or legs from narrowing of the arteries. The compound is thought to work by the POP binding to hydrophobic (water hating) elements on the surface of the lining of the blood vessels (vascular endothelium) leaving the hydrophilic (water loving) element, PEP to interact with the blood. In this way it is thought that it restores a non-adhesive surface to the vascular endothelium promoting more efficient blood flow. The technical term for agents acting in this way is a surfactant, or as someone said “WD-40 for the blood”. In the context of sickle cell disease therefore it is hoped that MST-188 will reduce the pain and duration of a painful crisis by restoring blood flow more quickly.

MST-188 is currently promoted by the pharmaceutical company Mast Therapeutics Inc., based in San Diego, California. The drug has a relatively long history and was originally trialled under a different name, RheothRx. The first report of its use in sickle cell disease was in 1997, in the medical journal Blood, when a group from The University of North Carolina, Chapel Hill reported on treating 50 patients with sickle cell disease in crisis and showed significant reductions in crisis duration (16-45%), length of hospital stay (1-2 days) and a reduction in analgesia use (by x3-5). No side effects were reported. It subsequently became clear, however, that patients treated with RheothRx after a myocardial infarction were at risk of a sudden deterioration in kidney function. This inhibited further researchers from using the drug in sickle cell disease.

This risk of kidney damage was found to be reduced by purifying the drug and removing low molecular weight components which seemed to be responsible for the side effects. The purified polymer was then used in a second sickle cell trial, by the same group from Chapel Hill, this time involving 255 patients with sickle cell disease in crisis. As is often the way when a larger group of patients were involved, the results were much less exciting. Overall the duration of crisis was only reduced by one hour in the treated group compared to those given a placebo. However, some of the smaller groups within the overall patient group appeared to have a much better response, so for example, in children the duration of the crisis was reduced by 21 hours and this effect reached statistical significance.

On the basis of these results a third trial is currently underway co-ordinated by Mast Therapeutic’s, Study Director Dr Santosh Vetticaden. This is known as the EPIC trial (Evaluation of Purified poloxamer In children in Crisis) and aims to recruit 300+ children. The trial opened in May 2013 and it is not thought that it will close until December 2015. Currently patients are being recruited at 43 centres, all in the USA. The study aims to determine whether MST-188 reduces the duration of a painful crisis, whether it reduces the frequency of recurrent crises and re-admission to hospital, and whether it reduces the frequency of the acute chest syndrome. MST-188 is a given intravenously at a dose of 100mg/kg over one hour on admission to hospital and the infusion is then continued at a lower dose of 30mg/kg/hr for the next 48 hours.

MP4CO This drug also promotes blood flow and oxygen delivery. It is a form of modified normal, human haemoglobin which has been conjugated with polyethylene glycol and saturated with carbon monoxide, and is being developed by Sangart. It is given by intravenous infusion and is thought to promote oxygen delivery to the tissues by a variety of mechanisms, including reducing inflammation and inhibiting sickling. Initial safety studies in stable patients with sickle cell disease (not in crisis)  were reported at ASH (American Society of Haematology) conference in 2013 by Dr J Howard, from Guys and St Thomas’s Hospital, London. No significant side effects were noted at escalating doses and it is hoped to proceed to phase two studies to assess the drugs ability to reduce crisis duration and severity.

Aes-103 This is another “orphan drug” currently under clinical trial in sickle cell disease. It is being developed by AesRx, a drug company named after Aesculapius, the God of Healing in ancient Greek mythology. Aes-103 is a small molecule (chemical name: 5-hydroxymethly-2-furfural or 5HMF) which is a potent anti-sickling agent. This was initially demonstrated in transgenic mice, in other words, mice who had been given sickle cell disease by the “injection” of sickle cell genes, by a group of scientists from Pennsylvania and published in the British Journal of Haematology in 2005. The compound is present naturally in many foods, such as coffee, honey, dried fruits and fruit juices, especially prune juice. It is absorbed orally, meaning that it can be taken by mouth, a big advantage. It binds to the amino terminal of the alpha chain of haemoglobin and stabilises the haemoglobin in the high oxygen affinity state or R-state. The relevance of this is that sickle haemoglobin will not polymerise, or form tactoids, when it is in the R-state. Aes-103 also seems to stabilise red cell membranes, protecting the red cells against the shear stress induced by passage through small blood vessels.

Results of safety studies in patients with sickle cell disease were reported in December 2013 at the ASH conference by a group led by Dr Gregory Kato from the National Institute of Health, Bethesda, Maryland, USA. They showed that the drug was well tolerated at varying doses levels (300-4000mg taken as a single dose, or every 6 hours) and there were trends showing, (1) a reduction in pain, proportional to the concentration of the drug inside the patients’ red cells, (2) a slight fall in bilirubin and LDH (lactate dehydrogenase) levels suggesting a diminution of haemolysis and (3) an increase in oxygen saturation.

Aes-103 is currently being used in a phase 2 trial in a collaboration between the company, AesRx, and the National Institute of Health in Bethesda, co-ordinated by Stephen Seiler the CEO of the company. The trial started in September 2013 and aims to treat stable patients with sickle cell disease for 28 days, to assess safety and tolerability, as well as the drug’s effects on various features of their sickle cell disease. Aes-103 has not shown any evidence of side effects as yet but, because it will have to interact and inhibit sickling in 30-50% of all sickle haemoglobin molecules, it is likely that large doses will be required, and the issue of side effects and possible interactions with other proteins in the body remains a real concern.

Modifiers of Hb F A variety of new drugs are under study, which may increase the production of foetal haemoglobin (Hb F) . Hydroxycarbamide has been available for many years but some patients do not respond or are unable to tolerate this drug.

Decitabine is a drug which promotes Hb F by inhibiting DNA methyltransferase, and so reduces the methylation of DNA. It is used in the treatment of malignant blood conditions such as myelodysplasia and leukaemia and is related to the drug azacytidine. Azacytidine has been trialled in sickle cell disease but was found to be too toxic and abandoned. Whether decitabine will be any safer remains to be seen. A trial, co-ordinated by the National Institute of Health opened in June 2011 and is due to close in December 2016.

Vorinostat and panobinostat are two similar drugs which promote the formation of Hb F in a different way, by reducing the de-acetylation of histones, they are known as histone deacetylase inhibitors or HDAC inhibitors. Histones are proteins, which are wind around our DNA and are able to affect its function in various ways. Both of these drugs are used as anti-cancer therapies and safety issues in sickle cell disease remain an issue. A trial assessing the safety of vorinostat in sickle cell disease is due to close in October 2014.


About rogerjamos

I am a consultant haematologist who has worked in Hackney, London, UK with patients who have sickle cell disease for many years. Knowledge is power; the hope is that this blog will empower patients by putting them in touch with contemporary research into sickle cell disease and facilitating informed discussion on the issues raised. Dr Roger Amos MA, MD, FRCPath
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