Inflammatory bowel disease - RDP-58
The incidence of inflammatory bowel disease is estimated to have increased six-fold in 25 years.
The incidence of inflammatory bowel disease is estimated to have increased six-fold in 25 years.
Both Crohn's disease and ulcerative colitis are caused by abnormal immune responses. Tumour necrosis factor a is thought to be a key mediator in the development of the inflammation, and antibodies against TNF-a, such as infliximab, can reduce inflammation and promote healing of the damaged mucosa. However, their administration is not without its problems.
An alternative would be peptides derived from the heavy chain of HLA class I molecules, and such a peptide, RDP-58, is being developed by Genzyme, first discovered by SangStat Medical Corporation. The 10 residue peptide is essentially made up of unnatural D-isomer amino acids, which are resistant to breakdown by the body's enzymes. This removes one of the usual problems found with peptide drugs - that they are too unstable in the presence of protease enzymes in the digestive tract, and hence are rarely orally available.
A Phase I trial was carried out in 24 healthy male volunteers to establish its safety.1 The subjects were given 25, 100 or 300mg of the peptide once a day for 28 days. There was no significant alteration in the subjects' haematology or biochemistry, and only mild side-effects were reported.
As a result, a multi-centre parallel prospective randomised blinded placebo-controlled Phase II trial was carried out:2 127 patients with mild to moderate ulcerative colitis were given 100, 200 or 300mg RDP-58 or placebo a day for 28 days. Similar side-effect profiles were seen in those given active and placebo. At the end of the month, patients given the two highest doses experienced significantly higher response rates.
A further Phase II trial has been carried out in 104 patients with Crohn's disease. Again, they were given 100, 200 or 300mg active or placebo once a day for 28 days, but insufficiently significant differences were seen between the treatment groups. Further trials are being carried out in both indications, and it is also being investigated as a possible therapy for other conditions, including multiple sclerosis and psoriasis.