Small molecule drug development for rare genodermatoses – evaluation of the current status in epidermolysis bullosa

Abstract

Background Hereditary epidermolysis bullosa (EB) comprises a heterogeneous group of rare genodermatoses, which are caused by mutations in genes involved in the maintenance of the structural and functional integrity of dermo-epidermal adhesion in various stratified epithelia. In severe variants, generalized skin disease, extracutaneous manifestations and multi-organ involvement cause considerable morbidity and mortality. Causal and early treatment by re-expression of a respective mutated gene is the major long-term goal in therapy development. However, characterization and targeted modulation of pathogenic molecular cascades in EB also holds great promise as a symptom-relieving approach to ameliorate phenotype, complications and quality of life. Small molecules are chemical structures of less than 900 Da that can diffuse across cell membranes and interfere with target biomolecules, thus influencing their function at different levels. They constitute the vast majority of active components of all approved drugs. Methods We performed PubMed and Google Scholar search for publications and screened FDA- and EMA-hosted clinical trial registries to identify studies using small molecule-based drugs for epidermolysis bullosa. Upon detailed analysis this resulted in the identification of a total of 84 studies. Results We identified 52 publications and 32 registered trials that investigate small molecules for their safety and efficacy as treatment for different aspects of epidermolysis bullosa. Further, a total of 38 different small molecules clinically used in EB were found. Most frequent outcome measures concerned wound healing, reduction in blister numbers, as well as reduction of itch and pain, predominantly for EBS and RDEB. Conclusion We provide a comprehensive summary of the current status of clinical small molecule development for EB and discuss prospects and limitations in orphan drug development for rare conditions like EB.

Clinical trial of ABCB5+ mesenchymal stem cells for recessive dystrophic epidermolysis bullosa

“…Over the past two decades, several treatment strategies for RDEB have been suggested and investigated (9)(10)(11)(12), yet cure or even effective symptom relief have not been achieved. Much research focuses on strategies targeting the genetic defect at the protein, mRNA or DNA level (12)(13)(14)(15).…”

Therapy Development for Epidermolysis Bullosa

“…In the context of EB several approaches addressing various complications have been reported, with the majority of primary outcomes measured being improvement of wound healing, reduction of blistering, and mitigation of itch. While some of the evaluated compounds have reached late stage clinical trials, first marketing approvals are still awaited [4][5][6][7]69].…”

“…While in some patients blisters heal without scarring, in patients suffering from more severe subtypes these degenerate into wounds and are accompanied by multiple comorbidities. Thus, preventing blistering or accelerating their resolution is a logical primary outcome measure for clinical trials due to its relevance to patients, at least in distinct patient cohorts [7]. Particularly in EBS, where patients only rarely develop wounds, reducing blister numbers will improve patients' QoL substantially.…”

“…learning to walk, or playing with other children. However, also for dystrophic and junctional EB clinical studies evaluating a treatment's impact on blister numbers have been published [7].…”

“…However, the increasing number of trials that are being conducted reflects significant progress in clinical research, including strategies to correct and/or modulate the aberrant molecules and mechanisms underlying this devastating disease. [4][5][6][7] The remarkable differences between EB-types and numerous subtypes, renders the development of therapies a complex challenge, as both inter-subtype and inter-individual differences require the development of more personalized treatments.…”