Safety and tolerability of losartan to treat recessive dystrophic epidermolysis bullosa in children (REFLECT): an open-label, single-arm, phase 1/2 trial

Background Recessive dystrophic epidermolysis bullosa (RDEB) is a skin fragility disorder characterised by life-long mechanically induced skin blistering, fibrosis-driven pseudosyndactyly, and multi-organ involvement. Preclinical studies have suggested mitigated progression by angiotensin II type I receptor blockade through losartan. We aimed to determine the safety and tolerability of systemic losartan treatment among children with RDEB, and to obtain initial data on its clinical benefit. Methods We conducted an open-label, single-arm, phase 1/2 trial at the Medical Center-University of Freiburg, Germany. Children with molecularly-confirmed RDEB, aged 2-16 years (starting from the 25th month of life) were eligible. Key exclusion criteria comprised anaemia with haemoglobin <8 g/dl; hypotension (defined as age-related systolic blood pressure under the 5th percentile); cardiologic contraindications, requirement for any medications that are likely to cause interactions with losartan; renal artery stenosis or renal insufficiency with creatinine clearance <30 ml/min; severe liver failure; severe, untreated electrolyte disturbances; history of cancer or chronic viral infections; hypersensitivity to losartan or any of the excipients and known or persistent abuse of medication, drugs, or alcohol. Treatment duration with losartan comprised 10 months, encompassing 16 weeks up-dosing of losartan, 24 weeks full dose losartan (final target dose of 1.4 mg/kg), and 4 weeks losartan tapering, followed by 12 weeks follow-up without losartan. The primary endpoint was occurrence of a serious safety concern, defined as one of the following side effects of losartan: clinically relevant severe hypotension, immediate hypersensitivity reactions to the drug or clinical relevant severe hypo- and hyperkalaemia. EB-specific scores (the EBDASI activity and damage score, Birmingham Epidermolysis Bullosa Severity Score (BEBS)) and other clinical outcome parameters were evaluated at five clinical visits as secondary outcomes: pain (Wong-Baker FACES Scale for pain), quality of life (Quality Of Life in EB [QOLEB] questionnaire and Children's Dermatology Life Quality Index [CDLQI]), itch (Itch Assessment Scale for the Paediatric Burn Patients), dysphagia (Mayo Dysphagia Questionnaire-day 30 [MDQ-30]), pseudosyndactyly progression (our own morphometric scoring instrument), and hand function (Score of Colville and Terrill). All analyses (safety and efficacy) were performed in the safety population, defined as participants who received at least one dose of trial medication with losartan. This trial is registered with EudraCT, 2015-003670-32. Findings Between Jul 28, 2017, and Feb 12, 2021, 29 children were enrolled. Of those 27 received the full treatment. Losartan was well tolerated, no treatment-related severe complications leading to a serious safety concern occurred. The patients revealed improvement in the RDEB clinical scores, namely a mean reduction at week 40 of -7.36 points (95%-CI: -16.13 to 1.41) in the EBDASI activity score and -10.50 points (95%-CI: -20.81 to -0.19) in the EBDASI damage score, while the Children's Dermatology Life Quality Index rose by 2.64 points (95%-CI: -4.55 to -0.90). Similar to the EBDASI score, the BEBS showed a mean reduction of -3 points, 95%-CI: -0.21 to -5,79, P = 0.036). In the Wong-Baker FACES Scale for Pain an improvement of at least one level was identified for 9 of 28 patients between baseline and at month 9 (95%-CI: 15.9%-52.4%; P = 0.57). Regarding the Quality of Life in EB Score, five of 28 patients showed an improvement in the total scale of at least one level at month 9 (95%-CI: 6.1%-36.9%; P = 0.71). With the Itch assessment scale for the paediatric burn patients an improvement of at least one level could be observed in 12 of 28 patients (95%-CI: 24.5%-62.8%; P = 0.24). The MDQ-30 showed no relevant difference at 9 months after treatment start, as compared to baseline. We observed improvement of finger span with our own morphometric scoring instrument of pseudosyndactyly progression, revealing an increase of the maximal distance between thumb and index finger at month 9 by 6.92 mm, 95%-CI [3.48, 10.37] P = 0.0009. With the Hand function assessment score of Colville and Terrill, an improvement of at least one level was documented for 3 of 28 patients, i.e., 10.7% (95%-CI: 2.3%-28.2%; P = 0.63). Interpretation Our results suggest that losartan was well tolerated by children with RDEB, and provide preliminary evidence that it may reduce disease burden. Further research with larger sample sizes and longer durations is needed to establish the treatment's long-term efficacy and safety.