Diacerein for the treatment of epidermolysis bullosa simplex

Epidermolysis bullosa simplex type Dowling-Meara (EBS-DM) is a rare condition of the skin and mucous membranes, affecting 1 in about 50.000 people. Up to date, no causal therapy is available and treatment is restricted to the amelioration of symptoms like pruritus and pain. Dominant mutations in keratins of basal keratinocytes lead to a conformational change of these intermediate filament (IF) components, their aggregation in the cytoplasm upon minor mechanical trauma and subsequently to a collapse of the IF network and the cytolysis of basal keratinocytes. For K14 based EBS-DM we found, that the inflammatory cytokine interleukin 1 beta (IL-1ß) is constitutively activated in patient keratinocytes. In a positive feedback loop, it leads to the activation of the c-jun N-terminal kinase pathway and the overexpression of K14 and IL-1ß itself. However, when treating patient keratinocytes with IL- 1ß antibody or the small molecule diacerein, expression approximated wildtype levels and keratinocytes were less susceptible to stress. These results led to a pilot study, in which five EBS-DM patients were treated with a 1% diacerein cream. The study consisted of an open phase, during which all patients received 1% diacerein cream to apply underneath both armpits, and a placebo-controlled phase, where armpits were randomized and patients received 1% diacerein cream for one armpit and placebo for the other. The outcome of this study was a statistically significant reduction of blisters during the open phase. During the double-blinded controlled phase, only one time interval showed a significant difference between placebo and diacerein. Overall, data analysis was challenging because only three out of five patients finished the controlled phase per protocol. However, the promising results during the open phase are very much encouraging the present application. Here, we suggest a placebo-controlled, randomized, double-blinded trial, including 15 EBS-DM patients (aged 6-19 years). The study design comprises a placebo and an intervention group of patients and consists of a 4-weeks part for efficiency analysis with the primary endpoint being a reduction of blister numbers by 40%, and a follow-up, with the secondary endpoint being the time until the achievement of the initial blister number. Patients will be monitored at their local centers by a study nurse. This procedure will be done in two subsequent years, with a cross-over of patient groups. This allows the exclusion of temperature effects, which are known to influence blistering, and differences in blister numbers between patients are excluded to influence the result.

For the first time, a specific treatment was successfully tested to be effective in butterfly children. In a specific subtype of this condition a significant reduction of blister number was achieved. For patients, this means an important increase in the quality of life. Therefore, this product will now be further developed in order to make it available for all compatible patients. Butterfly children are persons suffering from the rare skin disease epidermolysis bullosa (EB. Characteristic for this condition, which is triggered by mutations in either one of 18 genes, are blisters and wounds on the skin and mucous membranes (like the mouth or esophagus). Patients suffer from pain and itch. In some cases, there are recurring infections of the wounds and sometimes patients are prone to developing particularly aggressive tumours. Currently there is no effective therapy available for EB and the treatment is constricted to pain management and wound care. First gene therapeutic approaches are currently under investigation in selected patients, however, these are not applicable for all types of EB. Aim of this research project was the development of a therapy applicable for patients suffering from the simplex type of EB (EBS), which is triggered by gene mutations within either the keratin 5 or the keratin 14 gene. Of particular interest is that these two genes will still be translated into proteins, but these cannot fulfill their function the mechanical stabilization of the cell as they clump within the cell. These clumps then trigger an inflammatory reaction, which makes the patients skin even more sensitive and blisters arise even more easily. In this project, we tested the small molecule diacerein, an active component isolated from the rhubarb root, in a clinical trial on 17 patients. Children from 4 to 18 were included and blister numbers were reduced on average by 87%. Also, no side effects that were assumed to be related to the ointment were observed. The positive results of this trial facilitated the uptake of this project by Castle Creek Pharmaceuticals, aiming to perform a pivotal clinical trial in order to obtain market approval for this product.