Approximately one out of every 30,000-50,000 people is affected by epidermolysis bullosa simplex (EBS),1 the most common form of epidermolysis bullosa (EB). Patients with this rare skin disorder have a genetic defect that compromises the structural integrity of their skin, making it particularly fragile and prone to easy blistering. EBS can cause debilitating pain and symptoms that can range from occasional blisters that are localized to the hands and feet with minimal scarring to more extensive and severe blistering that can begin as early as birth and occur anywhere on the body.
There are currently no approved treatments available that target the disease mechanism of action for patients with EBS, many of whom are children. Current standard of care consists of pain management and bandaging and cleaning of open wounds to prevent infection.
Without an approved therapy available, some patients use topical products such as silver ointments or natural substances such as coconut oil or medical grade honey to help in pain and wound management and reduce the risk of infection.
However, most topical products are not supported by clinical evidence regarding their safety and efficacy for treatment of EBS.
There have been recent advances in research related to both palliative and potentially disease-modifying topical therapies that could lead to introduction of safer and more effective treatment options for many EBS patients around the world.
Some researchers are focused on developing topical therapies that can potentially alleviate the major symptoms of EBS such as the formation of skin blisters and lesions. Allantoin (also known as SD-101), a nitrogenous compound, is an FDA-designated breakthrough therapy in development for the daily treatment of wounds caused by all major types of EB. Allantoin is thought to reduce inflammation and stimulate the body’s natural mechanisms for removing damaged tissue and encouraging growth of replacement tissue, and may inhibit growth of bacteria.2
In a recent phase 2b randomized clinical trial, researchers studied 48 patients, ages six months to 44 years old, with three major types of EB including EBS. Topical SD-101 6% (SD-101 with 6% allantoin), SD-101 3% or placebo were applied to target lesions once a day for 90 days. Results showed 82% of patients treated with SD-101 6% cream had complete wound closure by two months, compared to 44% and 41% of patients treated with SD-101 3% and placebo, respectively. These results also show a significantly higher rate of wound closure in patients treated with SD-101 6% compared to SD-101 3% and placebo. SD-101 6% was also shown to be effective in patients with all three major types of EB: junctional, dystrophic, and simplex.3,4
An ongoing multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, designed based on the results of the phase 2b trial, included more than 160 patients one month and older with three major types of EB (simplex, recessive dystrophic and junctional [non-Herlitz]). Participants are randomized 1:1 with patients receiving either SD-101 6% or placebo applied over their entire body once daily for three months.5,6 The efficacy endpoints include time to wound closure within three months and proportion of patients with target wound closure at three months, as well as safety and improvement in itching, pain, and full-body wound and lesion coverage.
While results from this phase 3 trial are not expected until later this year, clinical data thus far suggest that SD-101 (allantoin) has multiple wound-healing effects, including anti-inflammatory and antimicrobial activity and tissue formation and differentiation, specifically in stimulating development of granulations and a tendency towards epithelialization (covering of cells over a wound).7
As research related to topical treatments for EBS continues, a topical therapy called keragelT® is currently approved and available for EB patients. keragelT is a keratin-based, low viscosity gel that can be used for daily wound management in patients with various forms of EB. It is designed for use on both intact skin and on open wounds to make the skin more robust and potentially less susceptible to skin breakdown and to accelerate healing. keragelT is available in several countries around the world and is used in some specialist EB centers and prescribed by many independent dermatologists in the U.S.8
For many patients, keragelT is used on skin blisters or lesions on parts of the body where a high degree of secondary protection is not needed, such as the face and neck. It can be subsequently used in combination with other (usually silicone-based) atraumatic dressings where secondary protection is needed. Over time, as blistering incidence reduces and the skin becomes more robust, fewer secondary dressings may be needed for many patients.8
The mechanism and use of keragelT in treatment of EB is supported by data from multiple clinical studies. A 2015 study published in the Journal of Wound Care found that patients treated with keratin gel reported faster healing and more resilient healed skin compared to standard of care. Consistent with other studies on keratin gel, patients also reported improvements in quality of life.9
A 2009 study, published in the Journal of the American Academy of Dermatology, evaluated a patient with EBS who applied keratin gel daily to one foot, using the other foot as an untreated control. Topical application resulted in decreased pain, improved wound healing, and a reduction in new blister formation in the treated versus untreated foot.10 Clinical data also show that, following treatment with keragelT, more than 75% of EBS patients with the Koebner sub-type respond very well and show significant improvement. In addition, about 60% of EBS patients with the generalized severe sub-type (also known as Dowling-Meara sub-type) have also reportedly responded well to treatment with keragelT gel.8
While other therapies are focused on wound healing, additional research is underway to advance topical therapies with the potential to target disease mechanism of action. Diacerein 1% ointment (CCP-020) blocks Interleukin 1 Beta (IL-1β), an inflammatory signaling pathway in EBS, which could stabilize epidermal tissue at the level of basal keratinocytes and support healing. In a phase 2 clinical trial involving 17 patients with EBS, treatment with diacerein 1% was associated with an average 60 percent reduction in blistering after four weeks. Three months after completion of drug treatment, only 12.5 percent of patients in the diacerein 1% treatment group returned to baseline blistering levels versus 67 percent of patients in the placebo group. Topical diacerein 1% was well tolerated with no treatment-related adverse events reported.11
There is a phase 2/3 clinical trial currently underway and enrolling patients to evaluate the safety and efficacy of diacerein 1% for the treatment of EBS. The randomized, double-blind, parallel group study known as the DELIVERS trial is being conducted at research sites in the U.S., Europe, Israel and Australia and will enroll about 80 participants who have a clinical and laboratory confirmed diagnosis of EBS. Researchers will compare the safety and efficacy of diacerein 1% to a control ointment when applied once-daily for eight weeks, measuring results using an EBS-specific Investigator Global Assessment (IGA) scale. Participants will report outcomes, including pruritus (itchy skin), pain, and mobility week-to-week using an electronic diary.12
With no treatment options that target disease mechanism of action and limited proven-effective topicals available, management of EBS remains a significant area of unmet need in healthcare. While more research is needed to better understand the underlying cause of EBS onset and progression, recent advances demonstrate the potential to bring patients safer and more convenient and effective treatment options in the years ahead.