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The COVID-19 pandemic helped to showcase RNA molecules and their therapeutic potential. There were also lessons learned in terms of drug delivery, manufacturing, logistics, and storage.
RNA-based therapeutics have been in development for decades. The RNA drug development trend was on the rise in early 2000s; however, its popularity went down due to unique challenges. The COVID-19 pandemic helped to bring a spotlight on RNA molecules and their therapeutic potential.There were also lessons learned in terms of drug delivery, manufacturing, logistics and storage. This is the silver lining of the pandemic, where necessity and emergency need for vaccine and therapy highlighted potential solutions. Hopefully, it also opens the door for novel RNA therapeutics.
Historically, RNA research began from discovery of nucleic acids by Watson and Crick and later studies on messenger RNA (mRNA) molecule in the 1960s. However, it took decades for RNA biology to “explode” in the 1990s and early 2000s leading to discovery of variety of novel RNA molecules for therapy: antisense oligonucleotides, small interfering RNAs, aptamers, and more (1). RNA drug development, however, proved to be a challenging pathway for commercialization. Currently, only a dozen of RNA-based medicine are approved and available in the market.
The first RNA drug on the market was fomivirsen (Vitravene). It is an antisense antiviral that was used for treatment of cytomegalovirus retinitis (CMV) in immunocompromised patients. It was approved by FDA in 1998; however, by 2006 Novartis withdrew it from the European Union and the United States markets due to lower cases of CMV and consequently no further need for such medication (2).
It took another decade for another antisense drug, Kynamro, to be approved in 2013. Overall, in addition to antisense platform, small interfering RNAs and mRNA drugs were approved in the past five to seven years (3). This is not surprising because RNA research is known to be challenging and costly.
Indeed, in spite of being considered a “winner”” in RNA therapeutics space, Alnylam company is a textbook example 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 hereditary 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 impressive growth to newly rising interest in RNA therapeutics after the pandemic, as well as development of new technologies.
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.
After 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 approximately $60 million in 2019 to almost $18 billion in 2022 (6). Currently, Moderna has 48 programs in development. In addition, its board has approved a significant 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. This company has several commercial products including ONPATTRO (patisiran), GIVLAARI (givosiran), OXLUMO (lumasiran), AMVUTTRA (vutrisiran) and Leqvio (inclisiran), which is being developed 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 approved 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 technology 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).
Although leading companies continue to do innovative research, small biotech ventures also bring breakthrough 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 molecule 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 technological platforms are to synthesize circular RNAs with specific genetic codes (12).
Replicate Biosciences is focused on self-replicating 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 Therapeutics develops ACORN: a microfluidic platform that functions as a computer-controlled RNA manufacturing system that starts with a nucleic acid sequence of interest and produces optimized nanoparticle-encapsulated RNA therapeutics on specific, single-use biochips (14). The advantage is that all steps are performed in an automated, fully isolated microfluidic path, enabling efficient manufacturing of high-quality 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.
Overall, RNA-based therapeutics are popular because they exhibit a wide variety of advantages such as targeting undruggable targets, fast production, application in rare diseases. However, RNA drug development is also facing several well-known challenges such as drug delivery, stability of the molecules, and even simple logistics of shipping and storage of these drugs.
The COVID-19 pandemic as well as government initiatives for large-scale sequencing projects helped to drive RNA-based drug development. Indeed, many companies including mRNA vaccines manufacturers addressed delivery problems with specific chemical modifications. Moderna and BioNTech modified their mRNA molecule 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).
Moreover, when mRNA vaccines were finally approved, pharma manufacturers faced challenges of storage and transportation of RNA-based vaccine that require -80 ºC temperature (16).
Despite all the challenges, RNA-based therapeutics were proven to hold enormous potential to cure many diseases.
It is quite remarkable that the discovery of mRNA in 1960s led to a whole new world of RNA molecules. RNA research holds untapped potential for drug development especially for unmet needs, such as rare diseases.
However, R&D in the RNA space also highlights challenges and limitations of almost every drug development process: stability issues, drug delivery aspects, cost, logistics etc. Approval of new RNA therapeutics in the past couple of years proved true value of this platform.
The pandemic definitely highlighted the importance of novel science especially in the times of emergency needs. It also brought to attention the quality of research and showed that new therapies can have positive and negative sides.
More importantly, it forced the public to learn and appreciate what science and research can do for us as society and that future investment in research and biotech are necessary to forward and improve our lives and health.
Marina Necdina is a business development manager, former pharma analyst, and research scientist.
Editor's note: This article was updated on April 11, 2023 to include missing text.