Abstract

EV Therapeutics - Challenges of Clinical Translation

Eva Rohde, Head of Department for Transfusion Medicine, Director of GMP Laboratory, Paracelsus Medical University Salzburg

Extracellular vesicles (EV) have emerged as promising biological therapeutics representing the first truly new biologic drug modality since about three decades. Challenges in manufacturing of EVs with reproducible identity and potency are major hurdles to widespread application of EVs, especially for therapeutic purposes. A central topic of many discussions is how we, as experts in EV research, develop practical biopharmaceutical standards that can help to accelerate clinical testing of EV-Tx. An example for the clinical translation to treat inner ear traumatic injury is provided. EVs derived from the secretome of human mesenchymal stromal cells (MSC) contain numerous factors that are known to exert anti-inflammatory effects. MSC-EVs may serve as promising cell-based therapeutics for the inner ear to attenuate inflammation-based side effects from cochlear implantation which represents an unmet clinical need. In this individual treatment performed on a ‘named patient basis’, we intraoperatively applied allogeneic umbilical cord-derived MSC-EVs produced according to good manufacturing practice. A 55-year-old patient suffering from Menière’s disease was treated with intracochlear delivery of EVs- prior to the insertion of a cochlear implant. This first-in-human use of UC-MSC-EVs demonstrates the feasibility of this novel adjuvant therapeutic approach. The safety and efficacy of intracochlear EV-application to attenuate side effects of cochlea implants are planned in future controlled clinical trials. Most importantly, in early (pre)clinical research, the paradigm of “the process is the product” is valid for complex biological products such as cells or EVs. There will be no “one-size-fits-all” solution to technical and regulatory issues in (large-scale) EV production. The manufacturing, the intended therapeutic use and the claimed mechanism of action of a candidate EV-Tx will determine the requirements to be met. Benchmarking of candidate EV-Tx with complex approved biopharmaceutics is a focused approach to define individual roadmaps to be followed for each therapeutic concept.