Epidermolysis Bullosa (EB) is a group of genetically determined diseases of the skin. The disease is characterized by the blistering of the skin, either spontaneously or after minor physical trauma. Not only it affects the skin but the connective tissue inside the body as well. EB causes blisters, disfigurement, bleeding, and constant pain. Due to their extremely fragile skin, those with EB are sometimes referred to as "butterfly children."  For many, it is lethal. According to current estimates, 1/50,000 live births are affected by this disease [1].

EB is classified into four major types according to the depth at which blisters form on the skin. Each of these types is caused by defects in different proteins and has a distinctive clinical course. Alongside EB simplex (EBS, blisters in the basal keratinocyte layer), there is junctional EB (JEB, blisters along the basement membrane and blisters below the basement membrane), Kindler syndrome (KS, blisters at multiple levels), and Recessive Dystrophic Epidermolysis Bullosa (RDEB). The latter is caused by mutations in the COL7A1 gene, which encodes collagen VII. Lack of collagen VII causes reduced skin elasticity, skin blistering, severe fibrosis, and even cancer [2].

At the moment, there is no cure for EB. Many children with EB have complex needs. They require a team of medical specialists working together for their care. Treatment revolves around controlling the symptoms of the disease, taking care of the affected skin and reducing the risk of developing complications, such as infection and malnutrition. Available medicines for EB support wound healing. Some complications of EB must be treated with surgery. It is being investigated whether there is a cure, or at least a more effective treatment for EB [3].

Losartan was developed in the 1980’s by DuPont as the first angiotensin II receptor antagonist [5]. Further drug development led to the marketing authorization of losartan tablets (trade name Cozaar®, Organon) for treatment of hypertension in adults and later also in children 6 years and older. It is also used for diabetic kidney disease, heart failure, and left ventricular hypertrophy [6].

Losartan is a medicine of a well-studied safety profile in hypertension patients, both adults and children. In a clinical trial that included 3700 hypertensive adult participants, the incidence of adverse reactions was comparable to placebo. Dizziness was the only adverse reaction that had higher incidence in the losartan group than in the placebo group (2.4% versus 1.3%) [9]. In another trial that included hypertensive children 6 to 16 years old, it was found that losartan was well tolerated in hypertensive children as well. Only fourteen patients out of 175 experienced drug-related adverse reactions - most commonly an upper respiratory infections and headaches [10]. Additionally, a clinical trial that included 99 hypertensive children treated with losartan aged 6 months to 6 years was performed. Treatment with losartan was well tolerated also in that population, and the incidence of drug-related adverse reaction was similar to that observed in the previous study [11].

In 2015, researchers in Freiburg published that losartan reduced fibrotic scarring and prevented fusion of digits in a mouse disease model of dystrophic EB [7]. In a first clinical trial, the DEBRA-funded REFLECT phase II trial investigated the safety of losartan for patients with RDEB [4]. However, more evidence is needed whether losartan is indeed suitable for the treatment of EB and the prevention of fibrotic scarring. Furthermore, losartan is only available as tablets which are poorly suited for treatment of EB [8]. Our objective is to develop a pediatric, easy-to-swallow formulation of losartan. With this new losartan formulation, we aim to create the medical evidence whether Losartan is safe and efficacious for the treatment of EB. In case of positive results, our end goal is to achieve regulatory approval of losartan as new medicine for treatment of EB.

Drug development requires a huge effort, even with an ‘easy’ development path as in the present drug repurposing example, assessing the established active substance losartan for the new indication EB. Outside of large pharmaceutical companies, drug development requires close collaboration by a multidisciplinary team and a large collaborative network. The core for such a network has been formed with the Medical Center – University of Freiburg (clinical expertise), Midas Pharma (drug formulation and manufacturing expertise) and 3R Pharma Consulting (regulatory expertise). A dedicated company has been established for repurposing of losartan for EB, Crowd Pharma Losartan GmbH & Co. KG.

There are several institutions committed to discovering new therapeutic pathways and helping people affected by EB.

DEBRA was established by Phyllis Hilton as a support group for her daughter Debra who had EB. Today it is an international medical research charity dedicated to fighting epidermolysis bullosa, which has groups in over 40 countries (including the United States, the United Kingdom, Ireland and Australia). In addition to funding pioneering research in order to find effective treatments, the foundation helps to improve the quality of life for those living with EB by providing care and support.

The EB Research Partnership (EBRP) was founded in 2010 by two members of Pearl Jam, in partnership with a group of parents who are dedicated to funding research into treating and curing EB. Through their scientific advisory board, the company identifies the most promising research projects, vetting them and granting them funding in exchange for taking a financial interest in the university or business.

Cure EB (formerly Sohana Research Fund) was founded in 2011, by the parents of a child with EB. The aim of this project is to accelerate research, translate results into treatments and take them to patients.

University of Freiburg's Medical Center provides world-class medical treatment of rare skin diseases including EB. Clinical care and scientific research are closely intertwined as part of the Center's concept. It focuses on developing new diagnostic procedures and treatments, and it utilizes the latest findings in clinical and biomedical research. Children and adults with rare diseases have access to specialised, multi-professional, and coordinated care at the Center through the collaboration of eleven clinics and institutes of various disciplines.

1 Has, C., et al. “Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.” British Journal of Dermatology,ttps vol. 183, no. 4, 1 Oct. 2020, pp. 614–627, https://doi.org/10.1111/bjd.18921. Accessed 13 Mar. 2024

2 Nyström, Alexander, et al. “Dystrophic Epidermolysis Bullosa: Secondary Disease Mechanisms and Disease Modifiers.” Frontiers in Genetics, vol. 12, 28 Sept. 2021, www.frontiersin.org/articles/10.3389/fgene.2021.737272, 10.3389/fgene.2021.737272. Accessed 25 Nov. 2021

3 NHS Choices. “Treatment - Epidermolysis Bullosa.” NHS, 2019, www.nhs.uk/conditions/epidermolysis-bullosa/treatment/. Accessed 8 Dec. 2021

4 Freeman, Sara. “Losartan Showing Promise in Pediatric Epidermolysis Bullosa Trial.” Www.mdedge.com, 4 Feb. 2020, www.mdedge.com/dermatology/article/216653/wounds/losartan-showing-promise-pediatric-epidermolysis-bullosa-trial. Accessed 8 Dec. 2021

5 Timmermans, P. B., et al. “Discovery of Losartan, the First Angiotensin II Receptor Antagonist.” Journal of Human Hypertension, vol. 9 Suppl 5, 1 Nov. 1995, pp. S3-18, www.pubmed.ncbi.nlm.nih.gov/8583479/. Accessed 28 Nov. 2021

6 Mulla, Sana, and Waqas J. Siddiqui. “Losartan.” PubMed, StatPearls Publishing, 2020, www.ncbi.nlm.nih.gov/books/NBK526065/. Accessed 28 Nov. 2021

7 Nyström, Alexander, et al. “Losartan Ameliorates Dystrophic Epidermolysis Bullosa and Uncovers New Disease Mechanisms.” EMBO Molecular Medicine, vol. 7, no. 9, 20 July 2015, pp. 1211–1228, www.ncbi.nlm.nih.gov/pmc/articles/PMC4568953/, 10.15252/emmm.201505061. Accessed 8 Dec. 2021.

8 Freeman, Sara. “Losartan Showing Promise in Pediatric Epidermolysis Bullosa Trial.” Www.mdedge.com, 4 Feb. 2020, www.mdedge.com/dermatology/article/216653/wounds/losartan-showing-promise-pediatric-epidermolysis-bullosa-trial. Accessed 8 Dec. 2021

9 Goldberg, A., and C. Sweet. “Efficacy and Safety of Losartan.” The Canadian Journal of Cardiology, vol. 11 Suppl F, 1 Aug. 1995, pp. 27F32F, www.pubmed.ncbi.nlm.nih.gov/7664215/. Accessed 8 Dec. 2021

10 SHAHINFAR, S, et al. “A Double-Blind, Dose-Response Study of Losartan in Hypertensive Children.” American Journal of Hypertension, vol. 18, no. 2, Feb. 2005, pp. 183–190, academic.oup.com/ajh/article/18/2/183/121717, 10.1016/j.amjhyper.2004.09.009. Accessed 8 Dec. 2021

11 Webb, Nicholas J.A., et al. “A Randomized, Open-Label, Dose-Response Study of Losartan in Hypertensive Children.” Clinical Journal of the American Society of Nephrology : CJASN, vol. 9, no. 8, 7 Aug. 2014, pp. 1441–1448, www.ncbi.nlm.nih.gov/pmc/articles/PMC4123403/, 10.2215/CJN.11111113. Accessed 8 Dec. 2021.