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20 Pharmaceutical Technology ® The Real Message Behind Commercial mRNA Products April eBook 2023 PharmTech.com Development Indeed, in spite of being considered a "winner"" in RNA therapeutics space, Alnylam is a textbook exam- ple of how challenging development of RNA drugs can be (4). Formed in 2002, Alnylam spent more than $2 billion in its pursuit of an approved drug. The road to successful approval of the first RNAi therapeutic Onpattro in 2018 was not only rocky but very costly. Onpattro treats polyneuropathy in patients with he- reditary transthyretin amyloidosis and its list price for an annual course is $450,000. Due to these challenges in efficient drug delivery, stability, and cost, RNA therapies were a bit on the backburner in Big Pharma's pipeline. However, the COVID-19 pandemic brought the RNA approach back into the spotlight. In 2021, the market for RNA therapeutics was valued at more than $5 billion with projection to expand to more than $20 billion by 2030 (5). Analysts attribute this im- pressive growth to newly rising interest in RNA thera- peutics after the pandemic, as well as development of new technologies. What: leading innovators The RNA therapeutics market has a growing number of companies that bring remarkable innovation to this space. The following companies can be considered as leading stars and innovators in this field. Af ter the success of mRNA vaccines to prevent COVID-19 infection, Moderna and BioNTech became household names. During the pandemic, Moderna's revenues multiplied almost exponentially from ap- proximately $60 million in 2019 to almost $18 billion in 2022 (6). Currently, Moderna has 48 programs in de- velopment. In addition, its board has approved a sig- nificant increase to R&D investments, with a budget for 2023 of around $4.5 billion (7). Alnylam is a long-time player in the RNAi space. T h is compa ny ha s severa l com mercia l produc t s including ONPAT TRO (patisiran), GIVLA ARI (giv- osiran), OXLUMO (lumasiran), AMVUTTRA (vutri- siran) and Leqvio (inclisiran), which is being devel- oped with Alnylam's partner, Novartis (8). Ionis Pharmaceuticals, founded more than 30 years ago, is focused on antisense therapy development. As of today, the company has three commercially ap- proved medicines: Spinraza (Nusinersen), Tegsedi (Inotersen), and Waylivra (Volanesorsen), and more drugs are in development (9). In 2021, AstraZeneca and Ionis signed a deal to commercialize eplontersen, a liver-targeted antisense therapy for the treatment of transthyretin amyloidosis (10). Overall, Big Pharma companies, such as AstraZeneca and Novartis, tend to collaborate with innovative RNA companies or acquire biotech with newly developed tech- nology for further development into clinic. For example, in December 2022, Eli Lilly and Company expanded its RNA editing collaboration with ProQr using its Axiomer RNA editing platform to target disorders of the liver and nervous system (11). When: new arrivals Although leading companies continue to do innova- tive research, small biotech ventures also bring break- through methodologies. New trends include transfer RNA (tRNA), circular RNA, and self-replicating RNA. Alltrna and Shape Therapeutics are both working on tRNA molecules that can correct for errors in the genetic code that would otherwise impair protein production. Laronde and Orna Therapeutics are working on therapeutics based on circular RNA. This type of mol- ecule can be found naturally in cells and is considered much more stable than mRNA. Unlike mRNA, they don't produce proteins. Laronde's and Orna's techno- logical platforms are to synthesize circular RNAs with specific genetic codes (12). Repl icate Biosciences i s foc used on sel f-repl i- cating RNA that can be a vector for vaccines and immunotherapies (13). There are also companies that offer a new approach to RNA-based drug manufacturing. Nutcracker Thera- peutics develops ACORN: a microfluidic platform that functions as a computer-controlled RNA manufactur- ing system that starts with a nucleic acid sequence of interest and produces optimized nanoparticle-en- capsulated RNA therapeutics on specific, single-use biochips (14). The advantage is that all steps are per- formed in an automated, fully isolated microf luidic path, enabling efficient manufacturing of high-qual- ity products within smaller footprint facilities with reduced operating costs compared to conventional bioreactor manufacturing. All these exciting novel trends open new venues for R&D. Why: pluses and minuses Overall, RNA-based therapeutics are popular because they exhibit a wide variety of advantages such as target- ing undruggable targets, fast production, application in rare diseases. However, RNA drug development is also facing several well-known challenges such as drug de- livery, stability of the molecules, and even simple logis- tics of shipping and storage of these drugs. The COVID-19 pandemic as well as government initia- tives for large-scale sequencing projects helped to drive RNA-based drug development. Indeed, many companies including mRNA vaccines manufacturers addressed de- livery problems with specific chemical modifications. Moderna and BioNTech modified their mRNA mole- cule using lipid nanoparticle (LNP) approach, while companies like Arrowhead, Silence Therapeutics, and Dicerna are utilizing GalNAc–siRNA conjugates for the treatment of hepatitis B, hereditary haemochromatosis, and primary hyperoxaluria (15).