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Clinical data: Epidermolysis Bullosa

The following summarises the key clinical data supporting AP101 (Oleogel-S10.) Links are also available to the scientific publications on PubMed of these data below under Publications. If you would like further information, please contact Medical Information Enquiries.

The Phase II Study BEB-10 in Epidermolysis Bullosa is a Phase II study in 10 patients with dystrophic EB to assess the efficacy and safety of AP101 (Oleogel-S10) and was conducted at the University Medical Centre Freiburg, Germany. The primary efficacy endpoint of the study was healing of wounds (re-epithelialisation) to either Day 14 in ‘recent wounds’ or Day 28 in ‘chronic wounds’; with the half of the wound treated with AP101 (Oleogel-S10) and non‑adhesive wound dressing compared to the other half of the wound covered with non‑adhesive wound dressing only (intra‑individual comparison).

The efficacy was studied in 12 wounds in 10 patients. AP101 (Oleogel-S10) plus non-adhesive wound dressing significantly accelerated the re-epithelialisation in eight of eight decided cases (p=0.0078, binomial test), no case was scored in favour of dressing only and four cases were undecided (i.e. it could not be decided which wound or wound half showed faster re-epithelisation). In terms of safety there were no adverse events which showed a clear or probable causal relationship to therapy. Taken together AP101 (Oleogel-S10) showed a significant effect on wound healing in patients with EB including wounds with healing delays and chronic wounds.

Case studies in EB

AP101 (Oleogel-S10) has been used for the treatment of chronic wounds in a case series of four patients with different subtypes of EB. Of those, a 57-year‑old male with DEB presented with a chronic wound on the scrotal area present for three months. Within six days of treatment, the wound size decreased from 9.48 cm2 to 0.65 cm2. In a three‑year old girl with JEB, the size of a chronic abdominal wound decreased within 2 days of treatment from 13.63 cm2 to 9.58 cm2. A four‑year old boy with EBS had chronic wounds on the upper back and lower abdomen that completely healed within three months of treatment with AP101 (Oleogel-S10).

Partial thickness wound studies

Comprehensive clinical data are also available for the treatment of adult patients with partial thickness wounds, and resulted in final marketing authorisation of AP101 (Oleogel-S10) in the European Union under the trade name Episalvan®.

AP101 (Oleogel-S10) was found to accelerate wound healing in partial thickness wounds: in split-thickness skin graft donor site wounds the 17-day healing period with standard treatment was reduced by one to two days, in Grade 2a burn wounds the nine-day healing period with standard treatment was reduced by one day. Although the effect size may appear to be small, AP101 (Oleogel-S10) was developed for severe partial thickness wounds and the risk of healing delays and complications is directly correlated with time to wound closure. At the same time, AP101 (Oleogel-S10) had a good safety profile and was well tolerated.

Please see our section on publications for access to abstracts of the data or contact medical information department for more details on these studies.

Data in split-thickness skin graft donor sites

AP101 (Oleogel-S10) was studied in a Phase II study in 24 patients with split-thickness skin graft (STSG) donor site wounds. In this study, AP101 (Oleogel-S10) was found to be superior to wound dressing only in 83% of patients (Metelmann, Brandner et al. 2015).

Subsequently, three Phase III studies (BSH-12, BSG-12 and BBW-11) were conducted to assess the efficacy and safety of AP101 (Oleogel-S10) in the treatment of partial thickness wounds of the skin. Two studies, studies BSH-12 and BSG-12 investigated STSG donor site wounds, and one study, BBW-11, investigated Grade 2a burn wounds.

BSH-12 and BSG-12 were blindly evaluated, randomised, controlled, Phase III studies that investigated the intra individual difference in time to wound closure in STSG donor sites of 219 adult patients. Donor site wounds were divided into two equal halves and were randomised 1:1 to AP101 (Oleogel-S10) plus non-adhesive wound dressing or to the same non-adhesive wound dressing only, as standard of care (SOC) control. Wounds were treated until complete closure of both wound halves, for a maximum of 28 days. Wound dressings were changed every three to four days. Wound halves treated with AP101 (Oleogel-S10) healed faster than the wound halves treated with standard of care (mean 1.1 days, p<0.0001). Wounds treated with AP101 (Oleogel-S10) closed faster than without it (15.3 vs. 16.5 days; mean intra-individual difference= -1.1 days; p<0.0001).

Grade 2a burn wounds

BBW-11 was an open, blindly evaluated, prospective, intra-patient controlled, randomised, Phase III study that investigated the efficacy and tolerability of AP101 (Oleogel-S10) in accelerating the healing of Grade 2a burn wounds in adult patients. The target wound was divided into two halves of similar size; one half was treated with AP101 (Oleogel-S10) and covered with fatty gauze dressing, the other half was treated with Octenilin® Wound Gel and was also covered with fatty gauze dressing, as SOC control.

Overall, 61 adult patients were enrolled into the study. Earlier healing was demonstrated for the wound halves that had been treated with AP101 (Oleogel-S10) compared to those treated with SOC control. Wound halves treated with AP101 (Oleogel-S10) healed faster than the wound halves treated with standard of care (mean differences -1.0 day in favour of AP101 (Oleogel-S10)).

Phase III Long-term Outcome BSH-12, BSG-12, and BBW-11

In follow-up visits at three months and 12 months after the surgery or of burn injury the treated wound halves were found to be equal in the majority of patients with regard to pigmentation, redness, texture and hair growth of the regenerated epidermis. For a subset of patients blinded photo-evaluation indicated better results for AP101 (Oleogel-S10) treated wound halves compared to standard of care in pigmentation, redness, and texture of the former wound areas.

Phase III Pooled Safety Analyses

For safety analysis, safety data of the three studies were pooled and included 280 patients and 253 (90.4%) patients completed the study. A total of 27 (9.6%) patients prematurely discontinued treatment, and for 10 (3.6%) of these patients, the primary reason for premature discontinuation was an adverse effect (AE). Treatment-related AEs were reported by 25 patients (9%), including pain of skin (2.9%), pruritus (1.4%), and a few patients with other AEs, e.g. wound complication and post procedural complications. Application-site AEs were reported for the AP101 (Oleogel-S10) treatment site for four patients (1.4%), for the control for 15 patients (5.4%), and for both treatment halves (meaning that the location of the AE could not be further differentiated) for 36 patients (12.9%).

Publications

This is a list of the key publications in Epidermolysis Bullosa and AP101 (Oleogel-S10). Included are links to the papers on PubMed. If you would like further information, please contact Medical Information on medinfo@amrytpharma.com.

Author Title
Boeira V L S Y, Souza E S, Rocha B O et al. (2013). Inherited epidermolysis bullosa: clinical and therapeutic aspects
Bruckner-Tuderman L and Has C. (2012). Molecular heterogeneity of blistering disorders: the paradigm of epidermolysis bullosa
Denyer J, Pillay E, Clapham J. (2017). Best practice guidelines for skin and wound care in epidermolysis bullosa
El Hachem M G, Zambruno E, Bourdon-Lanoy A et al. (2014). Multicentre consensus recommendations for skin care in inherited epidermolysis bullosa
Fine, J. D. (2010) Inherited epidermolysis bullosa
Fine J D. (2016). Epidemiology of Inherited Epidermolysis Bullosa Based on Incidence and Prevalence Estimates From the National Epidermolysis Bullosa Registry.
Fine J D, Bruckner-Tuderman L, Eady R A et al. (2014). Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification
Pope E, Lara-Corrales I, Mellerio J et al. (2012). A consensus approach to wound care in epidermolysis bullosa
Schwieger-Briel A, Chakkittakandiyil A, Lara-Corrales I et al. (2015). Instrument for scoring clinical outcome of research for epidermolysis bullosa: a consensus-generated clinical research tool
Uitto J, McGrath J A, Rodeck U et al. (2010). Progress in epidermolysis bullosa research: toward treatment and cure

Publications on Single Thickness Skin Grafts

Author Title
Barret J P, Podmelle F, Lipovy B et al. (2017). Accelerated re-epithelialization of partial-thickness skin wounds by a topical betulin gel: Results of a randomized phase III clinical trials program
Metelmann H R, Brandner J M, Schumann H et al. (2015). Accelerated reepithelialisation by triterpenes: proof of concept in the healing of surgical skin lesions
Schwieger-Briel A, Kiritsi D, Schempp C et al. (2017). Betulin-Based Oleogel to Improve Wound Healing in Dystrophic Epidermolysis Bullosa: A Prospective Controlled Proof-of-Concept Study
Ebeling S, Naumann K, Pollok S et al. (2014). From a Traditional Medicinal Plant to a Rational Drug: Understanding the Clinically Proven Wound Healing Efficacy of Birch Bark Extract
Woelfle U, Laszczyk M N, Kraus M et al. (2010). Triterpenes promote keratinocyte differentiation in vitro, ex vivo and in vivo: a role for the transient receptor potential canonical (subtype) 6
Wardecki T P, Werner M, Thomas M F et al. (2016). Influence of Birch Bark Triterpenes on Keratinocytes and Fibroblasts from Diabetic and Nondiabetic Donors
Laszczyk M, Jäger S, Simon-Haarhaus B et al. Physical, Chemical and Pharmacological Characterization of a New Oleogel-Forming Triterpene Extract from the Outer Bark of Birch (Betulae Cortex)
Galgon, T., W. Wohlrab and B. Drager (2005) Betulinic acid induces apoptosis in skin cancer cells and differentiation in normal human keratinocytes