Psoriasis - R-115866
One of the factors that regulates the growth and differentiation of mammalian epithelial tissues is all-trans-retinoic acid. This naturally occurring retinoid binds to the retinoic acid receptors, which are transcription regulatory factors.
One of the factors that regulates the growth and differentiation of mammalian epithelial tissues is all-trans-retinoic acid. This naturally occurring retinoid binds to the retinoic acid receptors, which are transcription regulatory factors.
If the body's metabolism of retinoic acid is not working properly, then it can result in retinoid deficiency, and diseases that are characterised by hyperkeratinisation and desquamation, including psoriasis and acne.
This promising target has already been investigated as a treatment. While the first drug designed to hit it, the retinoic acid metabolism blocking agent liarozole, showed promise, the absence of CYP isozyme specificity leaves it wide open to side-effects. Another drug in this class, R-115866, or Rambazole, has been developed by Barrier Therapeutics, which was recently acquired by Stiefel. It is a specific inhibitor of human CYP26 so should produce the desired effects in psoriasis and acne, without the expected side-effects of the older compound.1
Several trials have been carried out. In an open label Phase IIa trial, 19 patients with moderate to severe plaque psoriasis were given 1mg of the drug once a day for eight weeks, and then a two-week follow up period.2 After a week, the median psoriasis area severity index score had reduced by 7.8%; at the end of the follow-up, the reduction was 49%. A quarter of patients had a reduction of at least 50%.
A Phase IIb dose finding study has also been carried out, again in patients with moderate to severe psoriasis. This time, 176 patients were given 0.5, 1 or 2mg of the drug or placebo once a day for 12 weeks. After 20 weeks, nearly half of the patients given the highest dose were cleared or almost cleared of their psoriasis, compared with 20% of the placebo group.
The drug is also being investigated as a potential treatment for acne.3 A total of 17 patients with moderate to severe facial acne vulgaris were given 1mg oral doses once a day for 12 weeks, and at the end of the study there was a mean reduction in inflammatory lesions of more than three quarters, and the incidence of all lesions bar closed comedones was significantly reduced after the first four weeks. A topical gel formulation is also being tested.If the body's metabolism of retinoic acid is not working properly, then it can result in retinoid deficiency, and diseases that are characterised by hyperkeratinisation and desquamation, including psoriasis and acne.