Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Amryt Pharmaceuticals DAC, 45 Mespil Road, Dublin 4, Ireland tel: 00 800 4447 4447 (toll free) tel: +44 1604 549 952 e-mail: medinfo@amrytpharma.com
Pharmacotherapeutic group: Preparations for treatment of wounds and ulcers, other cicatrizants
ATC code: D03AX13
Cell culture assays with human primary keratinocytes and fibroblasts and ex vivo studies with porcine skin show that the extract including the main component betulin modulate inflammatory mediators and are associated with activation of intracellular pathways known to be involved in keratinocyte differentiation and migration, wound healing and closure.
The precise mechanism of action of Filsuvez in wound healing is not known.
The efficacy and safety of Filsuvez in the treatment of partial thickness wounds associated with inherited EB were evaluated in a pivotal global Phase 3, randomised, double blind, controlled study in adults and children (Study BEB-13; EASE). Patients with DEB and JEB were randomised 1:1 to receive Filsuvez (n=109) or a blinded control gel (consisting of sunflower oil, refined; beeswax, yellow and carnauba wax) (n=114) and instructed to apply the investigational product at a thickness of approximately 1 mm to all their wounds at each dressing change (every 1 to 4 days) for 90 days. At randomisation, one wound was selected by the investigator as the target wound for the evaluation of the primary efficacy endpoint. The target wound was defined as a partial-thickness wound of 10-50 cm² in surface area and present for 21 days to 9 months prior to screening. The primary endpoint was the proportion of patients with first complete closure of the target wound by day 45 of the 90-day double blind phase (DBP) of the study. Following completion of the DBP, patients entered a 24-month open label phase (OLP) of the study during which all wounds were treated with Filsuvez.
Of the 223 patients randomised, the median age was 12 years (range: 6 months to 81 years), 70% were under 18 years of age and 8% of patients were below 4 years of age. 60% of patients randomised were male. Of these 223 patients, 195 had DEB of which 175 patients had recessive DEB (RDEB), 20 had dominant DEB (DDEB); in addition, there were 26 patients with JEB. In the DBP the majority of patients applied the study treatment to all wounds either daily or every 2 days (between 70% and 78%). Limited data are available for Black and Asian patients.
The results, including the primary endpoint, are presented in Table 2.
Table 2. Efficacy results (study BEB-13; 90-day double-blind phase, full analysis set):
| Efficacy parameter | Filsuvez n=109 | Control gel n=114 | p-value |
|---|---|---|---|
| Proportion of patients with first complete closure of target wound within 45 days | 41.3% | 28.9% | 0.013 |
| By EB subtype | |||
| RDEB (n=175) | 44.0% | 26.2% | 0.008 |
| DDEB (n=20) | 50.0% | 50.0% | 0.844 |
| JEB (n=26) | 18.2% | 26.7% | 0.522 |
| Proportion of patients with first complete closure of target wound within 90 days* | 50.5% | 43.9% | 0.296 |
* First key secondary endpoint
The median daily extent of exposure for all patients in DBP and OLP combined are presented in Table 3. The median duration of Filsuvez treatment for all patients in the DBP and OLP is 695 days with a maximum of 924 days.
Table 3. Mean daily and cumulative extent of exposure for DBP and OLP combined – all patients and by age category:
| All patients | 0 - <4 years | 4 - <12 years | 12 - <18 years | ≥18 years | |
|---|---|---|---|---|---|
| Median daily extent of exposure (grams per day) | 10 | 12 | 10 | 11 | 10 |
| Median cumulative extent of exposure (grams) | 1835 | 1218 | 2180 | 2446 | 1353 |
The European Medicines Agency has deferred the obligation to submit the results of studies with Filsuvez in one or more subsets of the paediatric population in the treatment of epidermolysis bullosa (see section 4.2 for information on paediatric use).
Systemic exposure to the main component betulin was assessed at baseline and periodically during BEB-13 using a dried blood spot bioanalytical method. Betulin venous blood concentrations were below quantitation limits (10 ng/mL) in the large majority of subjects. In a minority of subjects, measurable venous blood concentrations of betulin were observed, suggesting that there is minimal absorption of topically administered betulin. These venous blood concentrations, no greater than 207 ng/mL, were similar to those observed with ingestion of food sources containing betulin.
The plasma protein binding of betulin is >99.9%.
The in vitro metabolism of betulin was assessed in a suspension of human hepatocytes, where 99% were completely metabolised in five hours. The most abundant metabolite in vitro was formed through oxidation, methylation, and sulfation. Three other metabolites were formed by sulfation or glucuronidation. Non-CYP enzymatic pathways are expected to play the predominant role in the overall hepatic metabolism of betulin (75%), while the CYP mediated pathways (25%) are mainly driven by CYP3A4/5 isoenzyme.
Betulin showed a direct inhibition of CYP2C8 (test substrate amodiaquine) and CYP3A (test substrates testosterone and midazolam) with IC50 values of 0.60 µM (266 ng/mL), 0.17 µM (75 ng/mL) and 0.62 µM (275 ng/mL), respectively in human hepatocytes. In addition, betulin caused a very slight induction of CYP3A4 mRNA (2.7-fold). However given the negligible systemic exposure, no interaction with systemic treatments is expected.
No in vivo elimination studes have been performed.
Non clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction and development, and phototoxicity. After a 4-week topical treatment with Filsuvez gel, several reactions are observed at the site of administration in minipigs, including inflammatory effects, lympho-histiocytic inflammatory cell infiltration and epithelial hyperplasia. Following a 9-month dermal treatment in minipigs, epidermal hyperplasia, orthokeratotic hyperkeratosis, dermal lymphocytic and/or neutrophilic infiltration, and pustules in the stratum corneum were observed in some animals.
In vitro genotoxicity studies were negative. Further studies on genotoxicity or carcinogenicity have not been performed.
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