FormalPara Key Summary Points

Oleogel-S10 gel has been approved in the EU and UK for use in dystrophic epidermolysis bullosa (DEB) and junctional epidermolysis bullosa (JEB) for the treatment of partial thickness wounds on the basis of results from the EASE phase 3 study.

A retrospective case series of 13 patients with DEB in Colombia was conducted to explore real-world clinical outcomes of Oleogel-S10.

Oleogel-S10 demonstrated a reduction in wound burden using two separate measurements, body surface area percentage (BSAP; reduced from 27.3% at baseline to 10.4% at 24 months) and the skin component of EB disease and activity and scoring index (EBDASI; mean reduction in activity score of − 16.2 at 24 months and mean reduction in damage score of − 15.42 at 18 months).

There was a reduction in the proportion of patients requiring more frequent dressing changes over 24 months (daily or every other day), 53.8% of patients reported an increase in self-esteem, and 53.8% similarly reported improvements in sleep.

In this case series, Oleogel-S10 treatment was well tolerated and resulted in clinical meaningful reductions in wound burden for patients with EB in addition to reductions in wound dressings, and improvements in patient-reported outcomes.

Introduction

Epidermolysis bullosa (EB) is a rare heterogeneous group of genetic disorders involving fragility of the epithelium characterised by blistering and erosions of epithelial surfaces in response to mild trauma or friction [1]. In severe cases, lifelong skin blistering and partial thickness wounds result in itching, pain, scarring, disfigurement, loss of function and immobility, as well as a high risk of infections and aggressive squamous cell carcinoma. EB also has extracutaneous manifestations such as oesophageal strictures, anaemia, and malnutrition [2, 3]. Patients face a significant negative impact on quality of life due to chronic symptoms, low self-esteem, depression, and social isolation among a range of other factors [4].

Currently, there is no cure for EB. Management is mainly based on supportive care, including wound care, control of infection, and prevention or early treatment of complications [5]. Although information regarding prognostic factors in EB is scarce, progression has been related to disease severity at diagnosis and response to treatment [6].

Recently, Oleogel-S10, a topical sterile gel containing 10% birch triterpenes (betulin, lupeol, erythrodiol, betulinic acid, and oleanolic acid) formulated with sunflower oil [7], has demonstrated efficacy in the treatment of EB [8]. Oleogel-S10 acts at various stages of the wound-healing process, including modulation of inflammatory mediators, keratinocyte migration, and stimulation of keratinocyte differentiation [9]. The globally conducted randomised, phase III, double-blind, vehicle-controlled study (EASE), which included 223 patients with dystrophic and junctional EB, showed a statistically higher proportion of target wound closures in Oleogel-S10-treated patients vs control gel (P = 0.013) [10]. The clinical significance of this accelerated wound healing was demonstrated by several of the secondary endpoints including reductions in wound burden, frequency of dressing changes (one fewer dressing change every 2 weeks), procedural pain, and a lower incidence of target wound infection [10]. These findings supported the approval by the European Commission in June 2022 for the use of Oleogel-S10 in treating wounds in patients with EB.

There is currently no published real-world data regarding the effectiveness of Oleogel-S10 in patients with EB. Herein, we describe the outcomes of 13 patients with EB treated with Oleogel-S10 in clinical practice in Colombia.

Methods

We conducted an observational retrospective study by reviewing the medical records of patients diagnosed with dystrophic EB treated with Oleogel-S10 through an early access programme in different regions of Colombia. An Oleogel-S10 layer of approximately 1 mm thickness was applied to all EB partial thickness wounds and covered with a non-adhesive wound dressing. Alternatively, Oleogel-S10 was applied to the wound dressing so it was in direct contact with the wound. This procedure was repeated during all dressing changes with a frequency defined by the treating dermatologist.

A standard form was used to collect personal and clinical data. The patient’s medical history, clinical symptoms, outcome measures, and the patients’ and physicians’ perspectives were recorded. The body surface area percentage (BSAP) affected and the number of open wounds on the patient’s body were measured at baseline, 6, 12, 18, and 24 months. Total body wound burden was assessed over the same time frames using the skin component of the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI), which has separate scores for activity and damage [11, 12].

Adverse events and general safety events/signals were monitored. Assessments were carried out per routine clinical management every 6 months over 2 years.

A descriptive analysis was performed. Qualitative variables were described as absolute and relative frequencies, while quantitative variables were expressed through measures of central tendency. Reported data were analysed using the SPSS statistical program, version 25.0.

As a retrospective study of routine patient care, this study was not subject to institutional review board approval. The study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. All the patients or their representatives provided written consent for their clinical data and photos to be published in the current study.

Results

Baseline Patients’ Characteristics

A total of 13 patients diagnosed with EB were included in the analysis. The demographic and clinical characteristics are listed in Table 1. Most subjects were female (69.2%), and the mean age was 19 years (ranging from 3 to 53). All patients suffered from generalised dystrophic EB. Diagnosis was achieved with genetic testing in five patients, by immunofluorescence or electron microscopy in a further five patients, three had clinical diagnoses only, and six patients reported a family history of EB. Besides the typical blistering and erosions secondary to the skin fragility, some patients had milia, nail dystrophy, anonychia, and mitten deformity of hands or feet. Eleven patients had extracutaneous manifestations such as oesophageal stricture, chronic anaemia, mucosal involvement, and IgA nephropathy, among others. All patients reported family and social relationship dysfunction, and some experienced poor self-esteem, anxiety, and depression.

Table 1 Baseline demographic and clinical characteristics
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Prior to treatment with Oleogel-S10, all patients had been treated according to the Wounds International Consensus [5] including lancing of blisters, maintenance debridement, atraumatic dressing (Vaseline-impregnated gauze, soft silicone foam), and topical medications (such as steroid ointments, antibiotics, and over-the-counter emollient medications). All patients were in receipt of emollients, antipruritic treatment, and pain control.

More than one-third of the patients (38.5% n = 5/13) had more than 30% of their bodies covered by wounds. All patients had a skin involvement with partial thickness wounds of more than 10% of the patients’ total BSA (ranging from 11% to 47%), with a mean of 27.3% (± 11.4%). The mean BSA affected was 353 cm2 (± 325 cm2), and the mean number of wounds was 34.4 (± 27.0). The mean EBDASI skin activity and damage scores at baseline were 28.3 (± 11.5) and 31.6 (± 17.0) respectively.

Effectiveness of Oleogel-S10 in Healing EB Partial Thickness Wounds

Patients were followed for up to 24 months. All patients demonstrated some preliminary wound closure, epithelialization, and a significant reduction in skin involvement within the first month of Oleogel-S10 treatment. Sustained improvement in BSAP affected was observed over time with Oleogel-S10 use (Fig. 1, Table 2). At baseline, 6, 12, 18, and 24 months, the mean percentage of BSA affected was 27.3%, 19.6%, 13.2%, 10.2%, and 10.4%, respectively. A reduction in EBDASI skin activity and damage index was also recorded (Fig. 2a, b). At 24 months EBDASI activity score was reduced by − 16.2. At 18 months EBDASI damage score was reduced by − 15.42. A trend of reduced frequency in dressing changes was observed over time, with the proportion of patients who required daily changes or changes every other day decreasing over 24 months (Fig. 3). Examples of wound images from patients treated with Oleogel-S10 are shown in Fig. 4.

Fig. 1
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Mean BSAP over 24 months with Oleogel-S10

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Table 2 Change in percentage of affected BSA during Oleogel-S10 treatment (disaggregated data per patient)
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Fig. 2
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a Mean change in EBDASI skin activity score from baseline (score 28.25) during Oleogel-S10 treatment. b Mean change in EBDASI skin damage score from baseline (score 31.60) during Oleogel-S10 treatment

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Fig. 3
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Frequency of dressing changes during Oleogel-S10 treatment

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Fig. 4
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Wound images from patients treated with Oleogel-S10. Case 1: 13-year-old patient with dominant dystrophic EB (DDEB) at baseline (a), and after 1 month (b), and 9 months (c) of Oleogel-S10 treatment. Case 2: 15-year-old patient with recessive dystrophic EB (RDEB) at baseline (a), and after 1 month (b) of Oleogel-S10 treatment. Case 3: 12-year-old patient with recessive dystrophic EB (RDEB) at baseline (a), and after 4 months (b) of Oleogel-S10 treatment. Case 4: 20-year-old patient with recessive dystrophic EB (RDEB) at baseline (a), and after 20 days (b) of Oleogel-S10 treatment

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Tolerability and Safety

Increased itching, local pain, and erythema and worsening wounds related to the use of conventional dressings (adherent gauzes) occurred in two patients. These adverse events were resolved with the use of non-adherent dressings, and discontinuation of Oleogel-S10 was not required. Deaths occurred during treatment interruption in two patients due to severe anaemia, dehydration, and sepsis; these deaths were deemed not related to Oleogel-S10 by the treating physicians.

Practical Use of Oleogel-S10

All patients used Oleogel-S10 in line with recommended application practices. Oleogel-S10 was applied either to the wound or the dressing to a thickness of at least 1 mm and was not rubbed in. In two patients, a white residue was note on wounds and was not considered the result of a build-up of gel that occurred when wounds were not cleansed thoroughly prior to reapplication of Oleogel-S10. The residue was successfully removed by bathing in warm water and patients were instructed to cleanse wounds thoroughly to remove residue before reapplying Oleogel-S10.

Physicians’ Perspectives

Treating dermatologists observed faster closure of wounds with Oleogel-S10 than with conventional care and stated they were satisfied with the Oleogel-S10 results. Although treatments were repeatedly interrupted because of issues of medication access, results were considered positive in those patients treated.

Patients’ and Caregivers’ Perspectives

Oleogel-S10 was well tolerated by all patients, especially in texture and odour, and was easily introduced into the normal wound dressing routine by both patients and caregivers. Patients and their caregivers reported an improvement in mood and self-esteem (53.8%) and an increase in sleep time (53.8%) following treatment with Oleogel-S10. An improvement in movement and the ability to wear clothes according to their preferences, climate, and routines was reported by 38.0% of patients. Fewer dressing changes allowed more free time and availability for socialising. Family relationships improved (53.8%), as well as social activities, returning to academic activities, or going back to work (61.5%). Overall, patients were adherent and reported satisfaction with the treatment with subjective improvements in productivity, self-esteem, and social interaction.

Discussion

EB is a rare, chronic condition that significantly impacts patients’ quality of life, affecting productivity, family, and social relationships. Impaired wound healing is seen as the driver for systemic disease, predisposing patients to serious and potentially fatal complications, and deformities [13]. Therefore, therapies such as Oleogel-S10 that target wound healing could help address these severe and debilitating disease manifestations. Indeed, in a recent survey carried out by Bruckner and colleagues, 71% of patients and 81% of carers rated accelerating wound healing/closure as a top priority for future treatment options [14]. The study reported here presents our experience treating patients with EB with Oleogel-S10, a non-commercialised topical treatment in Colombia.

Our results showed a persistent response to Oleogel-S10 treatment with a decline in BSAP over 24 months in all patients (more than 50% reduction in BSAP from baseline). These results are consistent with those previously reported in the EASE study where an approximate 50% reduction in BSAP with 24 months of Oleogel-S10 treatment was demonstrated [15]. This is encouraging given the nature of EB, a chronic genetic disorder in which the fragile skin of patients repeatedly leads to the development of new wounds and is particularly relevant in this setting considering the known barriers to therapy access and treatment interruption in our patients.

The EBDASI skin activity score reduced over the study period of 24 months by − 16.5 and the EBDASI skin damage score by − 15.42 over 18 months. These values exceed the clinically important threshold of a reduction of 9 points (as previously reported on the basis of total activity and damage across all sections of the EBDASI scoring system) [11].

Patients with EB and their caregivers outlined that ‘decreasing time for dressing change’ was one of the most important factors for future approved prescription therapies [14]. Dressing changes are typically daily, painful, time consuming, and result in psychological distress for both patients and caregivers [16]. In our study, the proportion of patients undertaking daily or every other day dressing changes reduced over 24 months of Oleogel-S10 treatment whilst those conducting less burdensome dressing changes twice a week increased over the same time. These data are consistent with that from the double-blind phase of the EASE study where a reduced requirement for daily dressing changes was observed for patients using Oleogel-S10 (reductions in dressing change requirements equated to one fewer dressing change every 2 weeks [p = 0.001]) [10].

In this case series, Oleogel-S10 was observed to provide benefit in terms of reduction in wound burden from baseline where standard of care treatment was primarily focussed on dressing changes. The data align with that observed in the EASE study, the largest phase 3 to be conducted in EB which consisted of double-blind phase (90 days) and the long-term 2-year data [10, 15]. Whilst no control data from patients in our centre are available, the data reported here replicates the positive findings reported from EASE regarding Oleogel-S10 treatment accelerating wound healing thereby positively impacting on BSAP and EBDASI scores. In this case series, we observed that patients treated with Oleogel-S10 over the course of 24 months experienced reductions in wound burden and reported improvements in important aspects of their lives. This is contrary to natural history data published by Bageta et al. [17] in a severe subtype of EB which demonstrated that overall disease severity worsens over time.

Consistent with that seen in the EASE study, Oleogel-S10 was well tolerated with an acceptable safety profile. We observed whitish-coloured residue over wounds in two patients which was associated with excessive use or build-up of Oleogel-S10 over time. These findings highlight the importance of cleansing wounds thoroughly and removing any previous application prior to reapplying Oleogel-S10. Indeed, bathing and regular cleaning of wounds also helps reduce infection and promotes healing and therefore plays a central role in wound management in EB [5, 18].

Altruism has been noted in a previous study to be high among people with EB with a high willingness to participate in clinical studies, particularly those with severe forms of EB [19]. However, our personal experience is contrary to this with patients with severe forms of EB often less likely to be accepting of new therapies. Therefore positive patient perspectives of Oleogel-S10 in this case series are encouraging. In our study patients with EB outlined that using Oleogel-S10, a topical gel, was easy and convenient to apply within the patients’ own wound dressing routine.

Patients severely affected by EB, particularly children and their caregivers, experience a significant deterioration in their quality of life [20]. In these data we found subjective improvements in mood, self-esteem, sleep time, movement, and the ability to wear clothes as well as family relationships in our patients treated with Oleogel-S10. Evaluating patient-reported outcomes in future studies with validated tools would be useful [21].

To our knowledge, this is the first observational study that demonstrated the effectiveness of Oleogel-S10 in a clinical practice setting. Our results demonstrated sustained improvement in wound burden, reduced dressing change frequency together with an improvement in key aspects of patients’ lives. Further real-world evidence studies will be important to determine the long-term impact of Oleogel-S10 in EB.