Unravelling the regulatory riddle for exosome-based therapies

by Nermina Vejzagic

Exosomes are nanosized (30-150 nm) extracellular vesicles for which there is increasing awareness of their role in cell-to-cell communications. Exosomes are naturally produced by many cell types and function as a means to transfer proteins, lipids, DNA, microRNA, and mRNA to neighboring, or more distant cells [1-4], Figure 1. As such, exosomes have been identified to play an important in many different disease models, such as neurodegenerative disorders, cancer, and wound healing [4, 5]. Therefore, there is significant potential for exosomes to be exploited as new therapies, in many cases, via their anti-inflammatory activity [6].

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What needs to be considered in the development of an exosome-based therapeutic?

Use of exosomes as a therapy is still an emerging technology. Therefore, an “one size fits all” regulatory approach is unlikely to be appropriate and instead a case by case approach is needed for exosome-based products. There are hurdles still to overcome due to the complex nature of exosome-based therapeutics. Among them, determining the route of administration, optimal dose, the frequency of treatments, and time window for exosome administration to accomplish maximal efficacy without adverse effects are important factors.

Although there are several ongoing clinical trials based on exosome products [6], at present there are no specific regulatory guidelines for exosome therapies. However, safety standards for cell and tissue-based products may be of use as valuable roadmaps for the characterization of exosome-based therapeutics in nonclinical and clinical development [7]. Some key considerations in the development of exosomes as therapies are shown in Figure 2.

As for all pharmaceuticals, the chemistry, manufacturing, and control (CMC), nonclinical and clinical requirements are considered well in advance of phase I clinical trials, keeping in mind the end goal of having a cGMP compliant product for clinical use.

A comprehensive overview of specific topics especially relevant and challenging for exosomes is given in Figure 2. As a start, the manufacturing of exosome-based products requires a quality management system that takes into consideration both donor and recipient safety [1]. Due do the donor derived nature of exosomes, tight control measures have to be ensured to minimize the risk of transmission of communicable disease agents and to ensure patient safety [8]. Accordingly, when developing exosome-based therapeutics the choice and characterization of the source of exosomes for cGMP production is of highest relevance. At the same time, donor eligibility criteria need to be aligned with the applicable ethical and regulatory guidelines [9, 10]. As the product development proceeds, common challenges emerge in the transition from an R&D concept to regulatory compliant cGMP manufacturing, such as how to isolate and purify exosomes to a specific subpopulation of exosomes [3]. In this context, especially the characterization of exosome formulations, identification of exosome markers, and purity and quantity represent additional challenging but equally important aspects of quality control measure and process parameter definition [7].

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For nonclinical development, a particularly challenging hurdle is the selection of a representative animal model and should be identified and established well in advance of clinical studies investigating exosome-based therapeutics. As for all cell based therapeutics, this model has to allow the assessment of safety, toxicity, biodistribution, pharmacokinetics/pharmacodynamics profile, immunogenicity, and tumorigenicity [7] (see Figure 2). A risk-based approach, as laid out for advanced therapy medicinal products (ATMPs) by the EMA [11], should be considered where necessary. In parallel to nonclinical in vivo studies, in vitro biological characterization and the establishment of potency required for clinical development should be considered early [4, 7].

In conclusion, exosome-based therapeutics represent an emerging and highly promising new platform of potent biotherapeutics to treat a wide array of life-threatening conditions. However, due to the lack of specific regulatory guidance and with many potential obstacles for drug development, they remain a especially challenging product class. With many years of experience with innovative and emerging product classes, our team of regulatory experts in the field of CMC, nonclinical, and clinical development can support you in overcoming these hurdles and challenges and in bringing your exosome-based product to the clinic and market. Contact us to learn how we can guide you to boost your product to success.

References

1. Batrakova, E.V. and M.S. Kim, Development and regulation of exosome‐based therapy products. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 2016. 8(5): p. 744-757.

2. Samanta, S., et al., Exosomes: new molecular targets of diseases. Acta Pharmacologica Sinica, 2018. 39(4): p. 501-513.

3. Whitford, W. and P. Guterstam, Exosome manufacturing status. Future medicinal chemistry, 2019. 11(10): p. 1225-1236.

4. Willis, G.R., S. Kourembanas, and S.A. Mitsialis, Toward exosome-based therapeutics: isolation, heterogeneity, and fit-for-purpose potency. Frontiers in cardiovascular medicine, 2017. 4: p. 63.

5. Zhang, J., et al., Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. Journal of translational medicine, 2015. 13(1): p. 49.

6. Joo, H.S., et al., Current knowledge and future perspectives on mesenchymal stem cell-derived exosomes as a new therapeutic agent. International Journal of Molecular Sciences, 2020. 21(3): p. 727.

7. Lener, T., et al., Applying extracellular vesicles based therapeutics in clinical trials–an ISEV position paper. Journal of extracellular vesicles, 2015. 4(1): p. 30087.

8. Wiklander, O.P., et al., Advances in therapeutic applications of extracellular vesicles. Science translational medicine, 2019. 11(492): p. eaav8521.

9. Q5D, I., Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/Biological Products. 1997.

10. Q5A, I., Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. 1999.

11. EMA, Committee for Advanced Therapies (CAT), Guideline on the risk-based approach according to annex I, part IV of directive 2001/83/EC applied to advanced therapy medicinal products (EMA/CAT/CPWP/686637/2011). 2013.