Therapeutics


approval of an RNAi therapeutic for hATTR in adults. As of July 2018, 69 companies are actively developing mRNA, antisense RNA, RNAi or RNA aptamer therapeutics (Graph 1) with 315 ongoing clinical trials (Graph 2). Table 1 highlights the major RNA drugs in five or more clinical trials and their current highest development


stage.


Furthermore, the forecast global sales for RNA- based therapeutics is expected to exceed US$10 bil- lion by 2024 (based on an analysis carried out using the GlobalData Plc database (Graph 3). The market has recently witnessed several strate-


gic collaborations and partnerships between big Pharma and Biotech companies, which leverage proprietary technology platforms. For example, Moderna (Cambridge, USA) has established a number of strategic partnerships to advance mRNA medicines. In April 2018, Arbutus Biopharma Corporation, which has proprietary LNP and ligand-conjugate delivery technologies, and Roivant Sciences entered into an agreement to launch Genevant Sciences (Burnaby, Canada) – a jointly-owned company aiming to develop and commercialise a range of RNA therapeutics target- ing genetic disorders with limited or no treatment options available. Genevant plans to develop prod- ucts both in-house and in industrial partnerships across RNAi, mRNA and gene editing modalities with the goal of delivering between five and 10 RNA programmes to the clinic by 2020. Recently (in August 2018), BioNTech AG entered into a multi-year research and development collaboration with Pfizer to jointly develop mRNA-based influenza vaccines. These new and exciting strate- gic collaborations and partnerships will potentially lead to ground-breaking developments in the RNA-based therapeutics field.


Outlook RNA-based therapeutics offer opportunities for Biotech and Pharma companies to go beyond their existing repertoire of small-molecule and antibody portfolios. However, the development of RNA- based therapeutics is challenging since RNA is inherently unstable and prone to degradation, is immunogenic and rapidly cleared and requires safe and effective delivery. The use of RNA modifica- tions to enhance stability and improved synthetic delivery carriers, such as nanoparticle systems, have helped overcome some of these development hurdles. However, delivery across the lipid bilayer remains a significant challenge and approaches to enhance endosomal escape of RNA drugs are required. To date, four RNA-based drugs – Macugen, Exondys 51, Spinraza and Onpattro –


Drug Discovery World Fall 2018


have successfully made it through to market and several other RNA agents are currently in clinical programmes. In addition, new screening tools are making it easier to identify disease-associated RNA sequences to target. To date, drug discovery efforts have primarily focused on mRNAs, silencing gene expression using antisense RNAs and siRNAs, or developing RNA aptamers that bind to specific molecular targets. Emerging technologies and modalities, including CRISPR-Cas9 genome edit- ing and small-molecule modulators of RNA or RNA-modifying enzymes, offer further opportuni- ties to target mRNA for drug discovery. Future advances in RNA therapeutic design and delivery technologies will help exploit the full commercial potential of RNA-based therapeutics.


Acknowledgements We would like to thank Ajay Karandikar at GlobalData Plc for help with database searches, Peter Turnbull for assistance with Figure 1 graph- ics, and Drs Annette Bak and Sara Richardson at AstraZeneca (Gothenburg, Sweden) and Dr Neil Jones at CRUK-TDL (London, UK) for critically reviewing this article and for providing construc- tive feedback.


DDW


Continued from page 21


12 Zhao, Y and Huang, L. Lipid nanoparticles for gene delivery. Adv Genet. 2014; 88: 13-36. 13 Zhou, J and Rossi, J. Aptamers as targeted therapeutics: current potential and challenges. Nat Rev Drug Discov. 2017; 16(3):181-202. 14 Chakradhar, S. Bringing RNA into the fold: Small molecules find new targets in RNA to combat disease. Nat Med. 2017; 23(5): 532-534.


Dr Xiaoqiu Wu is associate principal scientist at AstraZeneca (Gothenburg, Sweden)


in the


Pharmaceutical Sciences iMed Biotech Unit where she is involved in developing methods for new modalities including mRNA formulation and anal- ysis. Xiaoqiu obtained a PhD in Medical Biochemistry from the Karolinska Institutet, Sweden, and postdoctoral research at the Structural Genomics Consortium at Oxford University. Subsequently, she worked at several Biotech companies in Sweden including IMED AB, Etvax and Alligator Bioscience AB.


Dr Andrew P. Turnbull is senior principal scientist at CRUK Therapeutic Discovery Laboratories (CRUK-TDL) where he established protein crys- tallography. Previously, he was team leader in the X-ray crystallography group at the Structural Genomics Consortium at Oxford University and, prior to that, worked at the Protein Structure Factory in Berlin in the high-throughput crystal structure analysis unit located at the BESSY syn- chrotron source. Andrew obtained a PhD in Biochemistry from the University of Sheffield.


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