A 1% diacerein ointment could be a safe and well-tolerated way to treat generalized severe epidermolysis bullosa simplex (EBS), according to a study involving two boys treated for four weeks.
In vitro data suggested that the diacerein ointment was retained in the skin for a prolonged period of time.
The study, “Basal pharmacokinetic parameters of topically applied diacerein in pediatric patients with generalized severe epidermolysis bullosa simplex,” was published in the Orphanet Journal of Rare Diseases.
Patients with generalized severe EBS experience skin blistering and wounding upon minor mechanical trauma. Though it has shown promising results in dystrophic and junctional subtypes of EB, ex vivo gene therapy – in which genetic manipulation of cells is done outside the body and then returned to the patient – is not yet available for EBS.
Diacerein is a slow-acting, small molecule that is converted to rhein in the body, and suppresses inflammation by blocking the inflammatory mediators interleukin-1B and caspase-1.
Data from clinical trials showed that topically applied diacerein reduced blister numbers. A pilot study, in particular, showed a stable decrease in blister numbers in patients with generalized severe EBS, and a Phase 2/3 trial in 17 patients revealed that a 1% diacerein cream reduced blister numbers in 87% of participants within three months.
Despite these findings, pharmacokinetic data — the study of a compound’s absorption, distribution, metabolism, and excretion — on topically applied diacerein is still lacking.
A team from Paracelsus Medical University in Austria has now analyzed the metabolism of a 1% diacerein ointment, in vitro and in vivo, to verify the skin activation of diacerein and to better understand the beneficial effects of rhein.
The study (DRKS00005412) is an extension of a Phase 2/3 trial that provided the basis for a worldwide Phase 3 clinical trial (NCT03154333) testing CCP-020 (1% diacerein ointment), developed by Castle Creek Pharmaceuticals. It included experiments in five samples of pig skin using a method called Franz diffusion cell, a way to study compound administration across the skin.
The 1% diacerein ointment was applied every 24 hours for three days. Samples were collected at six, 24, 48, and 72 hours to evaluate the ability of diacerein/rhein to cross the pig skin’s outer layer, called the epidermis. Skin biopsies were collected at the end of the experiment to measure rhein levels.
Rhein was detected in three of the five samples after six hours. Continued diacerein application further increased rhein levels, with maximum concentration at 72 hours (6.39 micrograms/mL). Biopsy data further showed that, assuming a 100% conversion of diacerein to rhein, 37.4% (average of 368 micrograms) of rhein was retained within the skin after 72 hours.
Results in pig skin samples showed that “diacerein is rapidly metabolized within the skin into its active form rhein, relevant for the therapeutic strategy in treating [generalized severe] EBS patients,” the team wrote.
Investigators then assessed rhein levels in two generalized severe EBS patients, who applied the 1% ointment over a period of four weeks onto 3% of their body surface. Both patients had blisters at the start of the treatment. The average daily dose of rhein — also assuming that all diacerein is converted to rhein — was 34 mg for the first patient, an 8-year-old boy, and 19 mg for the second patient, a 7-year-old boy.
Blood and urine samples were collected at treatment start, and after 14 and 28 days. Rhein was detected in all samples. Its levels remained stable, but differed significantly between the two patients after four weeks of treatment. According to the team, this may be due to different renal clearance, which will have to be accounted for in future studies.
In agreement with findings from prior clinical trials also in patients with generalized severe EBS, no diacerein ointment-related side effects or complications were reported.
Compared with results at 24 hours after single-dose oral intake of diacerein, the results showed nearly 150 times lower systemic rhein levels over four weeks of treatment with topical diacerein.
Oral administration of diacerein has been associated with major side effects affecting the gastro-intestinal tract, which led to the European Medicines Agency’s decision to no longer recommend it for patients ages 65 and older.
In contrast, “topical administration of diacerein renders the probability of such side effects highly unlikely,” the researchers wrote.
They believe that “1% diacerein ointment is a safe and well-tolerated targeted therapy for the treatment of epidermolysis bullosa.”
Having in vivo data from only two patients is a major limitation of the study, the researchers said, nothing the need for further studies to better understand the effects and pharmacokinetic profile of topical diacerein.