The results of a major, new trial in sickle cell disease (SUSTAIN) have just been published in the New England Journal of Medicine and presented at the American Society of Haematology meeting in San Diego. The trial involved the novel drug crizanlizumab (SEG101 or SelG1), a humanised monoclonal antibody. The drug was developed by Selexys Pharmaceuticals who were bought out by Novartis in 2016, on the back of this successful trial, for a reputed sum of $665 million. Crizanlizumab binds to P-selectin. a chemical located on the inner lining of blood vessels, or endothelium, and thereby prevents the adhesion of red cells, neutrophils and monocytes. It is administered by a 30 minute intravenous infusion usually given every month.
A painful vaso-occlusive crisis is initiated by the formation of sickled red cells and the adhesion of these sickled red cells, together with white cells, to the inner lining of blood vessels. Adhesion is a vital process, accelerating the blockage of small blood vessels by clumps of red cell and white cells, which restricts blood flow and the supply of oxygen and leads to the development of pain. In patients with sickle cell disease both the red cells and the endothelium are “stickier” than normal due to the activation or up-regulation of a variety of chemicals promoting cellular adhesion. One of these key chemicals is P-selectin, which is stored inside endothelial cells and re-located to the cell surface when the endothelial cells are activated. It is therefore a key molecule to target if the aim is to prevent cell adhesion.
Crizanlizumab was tested in a Phase II randomised control trial led by Professor Kenneth Atago from Chapel Hill, North Carolina, USA. 60 centres participated in the study, the majority in the USA with others in Brazil and Jamaica. 198 patients, aged 16-65 years, with different types of sickle cell disease, participated in the study; they all had between 2 and 10 painful crises during the previous 12 months and a significant number were taking hydroxycarbamide as well. They were randomised to three groups; high (67) and low (66) dose crizanlizumab and placebo (65). Neither the patients nor the doctors looking after them knew which group they had been allocated to. Each patient received a monthly IV infusion of crizanlizumab or placebo for 52 weeks, depending on which group they had been allocated to, after which the results were analysed.
The headline result was that high dose crizanlizumab significantly reduced the frequency of all sickle cell crises by 45% compared with the placebo group and doubled the proportion of patients who experienced no pain at all during the year long study (from 17% in the placebo group to 36% in the high dose group). Beneficial effects on pain reduction were seen in all types of sickle cell and irrespective of whether or not patients were taking hydroxycarbamide. In addition, the time from starting treatment to first crisis was prolonged from 1.4 months in the placebo group to 4.1 months in the high dose group and the number of days spent in hospital during the year were reduced by 42% (from 6.9 days in the placebo group to 4.0 days in the high dose group). Disappointingly, given the major reduction in the frequency of crises, the researchers were unable to demonstrate any improvement in the patient’s quality of life, although this may just reflect the limitations of the questionnaires that were used.
In terms of side effects, these seemed to be minimal and to consist mainly of influenza-like symptoms, such as fever and muscular-skeletal aching, together with diarrhoea, itching, vomiting and chest pain, which affected a minority of patients . Five patients died during the study, but these occurred equally in all groups and were due to sickle cell related problems like the acute chest syndrome. 55 serious adverse events were recorded but again these were equally distributed between the three groups and cannot therefore be attributed to the effects of crizanlizumab.
This is a very important trial for all those with sickle cell disease. It is the first time in the last 20 years, since the publication, also in the New England Journal of Medicine, of the results of the hydroxycarbamide trial in 1995, that a drug has been shown to reduce the frequency of painful crises in a well controlled clinical trial. Remarkably, the effectiveness of crizanlizumab is very similar to hydroxycarbamide; the latter reduced the frequency of painful crises by 44%, compared to 45% for crizanlizumab. The next step, of course, will be to make sure these positive results can be replicated in a second study and to try and work out which patients with sickle cell disease are likely to benefit the most from this innovative treatment.
There is potentially a major problem though. Monoclonal antibodies, such as crizanlizumab are eye wateringley expensive; in 2012 the average cost of a years treatment with this class of drug in the USA was approximately $200,000 (=£164,000). This compares with less than £200 for a years treatment with hydroxycarbamide. Clearly, at these sorts of prices it will never be possible to use crizanlizumab in the developing world, where most people with sickle cell actually live. It’s use in the UK, for the estimated 12,500 patients with sickle cell here, would increase the drug budget of the NHS by an astronomical amount. What crizanlizumab will actually cost is unclear at the moment and it remains to be seen whether Novartis, who have just paid out $665 million for the rights to the drug, will market it at a price health care services can afford.
Listen to Dr Kenneth Ataga discuss the crizanlizumab trial at the American Society of Haematology meeting in San Diego last December.