Pipeline topical reduces epidermolysis bullosa blistering

Dr. PallerCastle Creek Pharmaceuticals announced in June 2017 that the first patient had enrolled in its phase 2/3 study assessing the safety and efficacy of its pipeline diacerein 1% ointment to treat epidermolysis bullosa simplex.

"Currently there are no treatment options that target the underlying cause of [epidermolysis bullosa simplex], the most common form of a family of rare conditions leading to extremely fragile skin," Amy Paller, M.D., director of the Northwestern University Skin Disease Research Center and lead trial investigator, said in a company press release. "The topical formulation of diacerein 1% that we are investigating is potentially disease-modifying, which would represent an important advance in treatment for patients."

The investigational topical works to block a key inflammatory signaling pathway associated with epidermolysis bullosa simplex, potentially strengthening epidermal tissue and supporting healing. In a phase 2 study of 17 patients with the skin condition, diacerein 1% ointment use resulted in an average 60% reduction in blistering after four weeks.

The international phase 2/3 randomized, double-blind, parallel group study is designed to enroll about 80 patients with epidermolysis bullosa simplex. It will compare the safety and efficacy of diacerein 1% ointment applied once daily for eight weeks to the same regimen with a control ointment. Researchers will be monitoring patient-reported pruritus, pain and mobility, according to company news.

Alain Hovnanian, M.D., Ph.D., professor of genetics at Necker Hospital for Sick Children and director of a skin

Dr. Hovnanianresearch laboratory at the National Institute for Health and Medical Research (INSERM) and Imagine Institute for genetic diseases, Paris, France, has devoted his career to treating and researching genetic dermatological conditions - most of which are epidermolysis bullosa types.

Dr. Hovnanian tells Dermatology Times, if diacerein 1% ointment pans out in studies, this could be a breakthrough treatment in an area where patients have few options.

“EB simplex can be severe in infancy and early childhood. Children are covered with blisters. In this specific form, which we call generalized severe, they also develop thickening of the palms and soles, or palmoplantar keratoderma, which is very painful,” Dr. Hovnanian says. “The condition results in severely impaired quality of life due to pain and itching.”

The vast majority of EB simplex conditions are caused by mutations of the keratin 5 or keratin 14 gene, according to Dr. Hovnanian.

“Diacerein is a small molecule, which is a component of the rhubarb root. It is a prodrug of rhein, which blocks the release of interleukin-1 beta (IL-1ß) from the plasma membrane by inhibiting the plasma membrane-bound IL-1 converting enzyme. The principle of this new treatment is, therefore, to inhibit IL-1ß signaling pathway,” he says.

The idea for the drug came from research by Wally et al that showed increased expression and activity of IL-1β, increased expression of keratin 14 and increased activation of the c-jun N-terminal-kinase (JNK) stress pathway in keratinocytes from patients with the most severe generalized form of epidermolysis bullosa simplex. They also found activation of IL-1β signaling in keratinocytes due to keratin 14 mutation was reversed using anti IL-1ß neutralizing antibodies, which block IL-1ß activity¹, according to Dr. Hovnanian.

“They showed that they were able to reduce JNK and keratin 14 messenger RNA (mRNA) and protein levels and IL-1ß mRNA levels when they used an IL-1ß antibody,” he says. “Upon treatment of patient keratinocytes with diacerein, they showed reduction of K14 and JNK mRNA levels. Importantly, they also demonstrated that treating these patients’ cells with an IL-1ß neutralizing antibody, or with diacerein, prevented keratin 14 aggregates from forming upon heat shock in culture. So, it was quite nice functional proof of an effect of blocking IL-1ß and diacerein on keratin 14 aggregation, indicating that these drugs were able to increase stability of the keratin network in [epidermolysis bullosa simplex] keratinocytes in culture.”

In the first successful pilot trial on the use of diacerein in five epidermolysis bullosa simplex patients, researchers found diacerein significantly reduced the number of blisters on treated skin by 66% to 78% within two weeks.²

The topical form of the drug has been shown to be safe, according to Hovnanian.

“It doesn’t enter the bloodstream so much. The levels are very low with topical application,” he says. “Previously it was used with oral delivery in children with osteoarthritis. It’s a repurposed drug. But it was not so effective and not well tolerated. It resulted in gastrointestinal pain. So by avoiding systemic delivery, you avoid the secondary effects.”

Disclosures: Drs. Hovnanian and Paller report no relevant disclosures.

References:

1 Wally V, Lettner T, Peking P, et al. The pathogenetic role of IL-1β in severe epidermolysis bullosa simplex. J Invest Dermatol. 2013;133(7):1901-3.

2 Wally V, Kitzmueller S, Lagler F, et al. Topical diacerein for epidermolysis bullosa: a randomized controlled pilot study. Orphanet J Rare Dis. 2013