Considerations for clinical translation of extracellular vesicles as new class of therapeutics

by Alexey Bersenev on January 15, 2016 · 0 comments

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Extracellular vesicles (EV), which include microvesicles and exosomes, are gaining popularity as experimental therapeutics. At least 3 companies (ReNeuron, Capricor and Aegle Therapeutics) are pursuing right now therapeutic use of EV in regenerative medicine indications. However, analogously to cell therapies, many challenges should be addressed with clinical translation of EV as new class of therapeutics. It is not clear what regulatory pathway should be applied to EV, what manufacturing standards and quality controls should be used. Recently, the International Society for Extracellular Vesicles (ISEV) released a position paper, where outlined what regulatory, clinical and manufacturing requirements must be considered by developers of EV-based therapies. This paper is a real gem! Everyone, who ever thought of translation of EV into therapies must read it! My quick summary below.

The most advanced area of EV application is oncology. Dendritic cell-derived and tumor-derived exosomes are used as vaccines in Phase 1/2 trials. Another promising areas are immunotherapy of non-malignant diseases and regenerative medicine. Mesenchymal stromal cell-derived exosomes are getting to the first clinical trials.

Unmodified EVs from MSCs, endothelial progenitors, Tregs, DCs, and NSCs, as well as of many other cell types, hold promising therapeutic potential in regenerative medicine and immune therapy. As in many of the described studies, human EVs proved effective in different animal models, and the therapeutic capability of at least some EV entities seem to be conserved across species.

There is a consensus on regulation of EV as biologic (medicinal product). Unlike many cellular therapeutic products, European EMA considers EV as “not an advanced therapy medicinal product (ATMP)”. However EV, derived from gene-modified cells are categorized as gene therapy (ATMP). In US, EV-based products are regulated as biologic by FDA’s CBER. It is still unclear if any specific guidance will be required and developed for EV as separate class of biological therapeutic products. It is also not clear if EV-based products, derived from autologous and allogeneic donor should be regulated differently. Essential part of EV-based therapeutics classification and regulation is their mechanisms of action (MOA):

Searching for the MoA of EV-based therapeutics is essential and will proceed as an iterative process during clinical translation. The dissection between “active substances” and “excipients” (“claim of action”) is important for the characterization and definition of appropriate strategies to control the quality of EV-based therapeutics. Phase I clinical trials may be permitted, if safety and quality standards are adequately met and a plausible hypothesized MoA is provided.

Since, EV-based products are regulated as biologics, clinical trials are required for demonstration of safety and efficacy:

… although uncertainties about the MoA, the nature of the targets and the relevance of animal models exist, a number of arguments support the assumption that EV-based therapeutics derived from human tissues and cells do not per se fall under the high-risk definition of investigational new drugs.

EV could be manufactured as byproduct of cell therapeutic production (this strategy is especially attractive for cell-based regenerative medicine companies) or as separate product. In any case, there are multiple methods for EV isolation without any consensus on standardization. GMP standards are applicable to EV-based products manufacturing. The paper gives a set of recommendations for developers on different aspects of EV-based product manufacturing. For example, special attention should be paid to donor material (cells, fluids, tissues), contaminants of the final product (serum, reagents), isolation technique and storage.

Currently, no standardized procedure is available for the isolation as well as for the storage of EVs. The impact of the EV matrix and applied technologies, reagents and storage containers as well as of storage times must be investigated for each intended of EV-based product. Tailor-made protocols need to be developed.

One of the biggest challenges in EV manufacturing field is product characterization and potency. The composition of EV could be variable with presence of multiple types of vesicles in the final product. There are no standards on quantification of EV number in the product. Analogously to cell therapy products, multiple MOA could be identify in single EV-based biologic.

Gold standards for EV quantification, and molecular and physical EV characterization are still lacking. Qualified in vitro potency assays are required to predict the intended therapeutic potential of EV fractions aimed to be used as EV-based therapeutics.

I’d encourage you to read one more great review on EV manufacturing for therapies:

If the cell manufacturing industry adopts EV production and spearheads efforts toward standardization by establishing scalable processes and informing scientifically appropriate parameters, the entire field — from basic scientists to regulators and crucially to patients — could benefit.

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