mRNA & RNA Therapeutics In 2023: Where Do We Go From Here?

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

One of my favorite times of year is late fall as we begin to prepare for the holiday — also known in the editorial world as the start of “outlook” article season.

This year’s “outlook season” has been particularly exciting for me, as I’ve spent the past few months networking and traveling to learn and write more about the nuances of the burgeoning mRNA/RNA therapeutics space. To figure out what the future holds for companies in this sector of the ATMP space, I sat down with four executives to discuss their wildest hopes, dreams, and expectations: Michelle Lynn Hall, AVP of genetic medicines, Eli Lilly; Jacob Becraft, cofounder & CEO, Strand Therapeutics; Thomas McCauley, CSO, Omega Therapeutics; and Christopher Anzalone, CEO of Arrowhead Pharmaceuticals.

A majority of their predictions and insights can be explored in this feature in the January issue of Life Science Leader magazine. However, thanks to the space limitations of a print publication (and my unconquerable love of writing long articles), there were insights from each conversation that didn’t fit into the final Life Science Leader feature.

In the Q&A below, you can find the valuable thoughts they shared that didn’t make it to print. As you’ll note, there is no shortage of work facing the RNA therapeutics industry in the year(s) ahead. But there’s also a lot for which we can hope.

Welch: What did the pandemic confirm or teach us about mRNA that we (perhaps) didn’t know before?

McCauley: The successful development of the vaccines proved we can use computational tools and rapidly design and make these molecules at scale. mRNA is programmable, meaning it’s much more amenable to design using computational tools — including different types of artificial intelligence — which can make development much more efficient than what was historically possible with small molecules and proteins.

Hall: A lot of the foundational work has been done; for example, we learned more about mRNA API synthesis and how to make mRNA cleanly. We also learned more about the structure and function of LNPs and how to scale-up and store LNP-mRNA drug products. These were incredibly meaningful accomplishments for the future of the industry.

Welch: As we segue from vaccines to mRNA therapeutics, what challenges do you anticipate will take center stage?

Becraft: I think one of the biggest problems the mRNA therapeutics industry is facing today is herd mentality. We’re seeing a lot of effort and capital applied to solving the same problems using the same scientific and technological approaches. The danger with this is that, should these well-funded approaches not work, the willingness to invest across the RNA sector could become significantly less, in turn harming other companies working with mRNA technology but using different approaches. 

McCauley: The challenge for the industry at large is achieving greater durability of mRNA therapeutics. mRNA is notoriously unstable in vivo — even with chemical modification. Short-term expression can be favorable when treating indications that don’t require long-term drug exposure to achieve the clinical benefit. However, in many rare, monogenic diseases where the bulk of ATMP investments are today, you need the therapeutic to remain long-term in the body to attain full clinical effect. This is why one of the most exciting — albeit not new — technologies today is circular RNA (circRNA), thanks to its stability and longer-term, potentially broadly applicable expression profile. There are still technical complexities that will serve as a barrier to entry, much like we saw with linear mRNA in the beginning. But the industry’s progress with circRNA is worth watching as we move forward.

Welch: What is the current “state of the union” in the arguably more mature, non-coding RNAi space?

Anzalone: The beauty of the RNA interference (RNAi) space is that we know the RNAi machinery works; it has been a clinical success in thousands of patients to date. Similarly, we are not reliant on any other innovation or ancillary technology to see the clinical benefit of RNAi. Thanks to the human genome project, we can genotype people much more affordably now, giving us insights into where mutations occur in certain genes. In turn, RNAi has become more predictable therapeutically. We can know the sequence of the gene we want to silence, and, with the help of bioinformatics, we can be hyper-specific and only silence that one gene. This translates into fewer off-target effects and much more consistent activity than you’d see with small molecule drugs.

Welch: What are some of the biggest barriers you see standing in the way of bringing RNA/mRNA therapeutics to broader patient populations?

Hall: mRNA vaccines rely on local administration. But as we consider the future indications and applications for mRNA — for example gene editing — we will be relying on systemic (IV) administration. Tuning mRNA and the nanocarrier to have cellular and tissue specific expression will be central steps toward more effective delivery. But we also need to consider how current administration methods may be limiting to broader uses of mRNA technology. The current state of the art for systemic delivery is pre-treating a patient with corticosteroids and having them undergo an infusion at their healthcare provider’s office. This is an adequate place to start for earlier generations of mRNA therapeutics in smaller indications. But long-term, it will not be palatable for a mainstream therapeutic.

Anzalone: From a manufacturing standpoint, we need greater capacity to be able to manufacture RNAi therapeutics at scale and to supply large patient populations. The world has never had to manufacture nucleotides in such a huge quantity. As these therapies enter mass-market indications like cholesterol and heart disease, we need to ramp up the supply-chain and manufacturing capacity. We don’t necessarily need “new” ways of scaling-up to serve these large markets, per se; this will just require more time and greater investment.

Becraft: In the upcoming year, I’d like to see us transition beyond using mRNA technology in vaccines, bringing the technology into additional indications. I would also like to see companies in our field releasing and publishing more rigorous scientific data. A lot of new therapeutic RNA technologies — our candidates at Strand included — need to take the next step forward and transition into the clinic. We have announced plans to advance our first candidate in a clinical trial in oncology next year. As an industry, we ultimately need to figure out how to make mRNA more effective and utilizable beyond vaccines.

Welch: How should we define “next-generation” mRNA/RNA?

Hall: If we are looking at the vaccine space, reducing the immunogenicity of the delivery vehicle will be an incredibly important innovation to bolster public adoption. We’ve made a lot of progress, but we still have a long way to go. On the therapeutic side, I would like to see us move from vaccines into more immune-oncology indications. That’s probably too ambitious an ask for 2023, but I am excited to see more developments with mRNA in immuno-oncology. In particular, I’d like to see the industry better tune the specificity of the nanocarrier to target adaptive immune cells as opposed to innate immune cells. It’s difficult to transfect adaptive immune cells but doing so can really boost the potency of an immune-oncology therapy.

Anzalone: The challenge with RNA therapeutics has and will always be designing a molecule that arrives where you need it to go and in the appropriate quantity. When we talk about targeted medicine, the more that you can focus the delivery to a certain cell type, the better off you are in terms of off-target effects and potency. In turn, you may also find that less material needs to be delivered, which can translate not only to better safety/side-effect profiles, but also to a lower cost of goods sold (COGS). We at Arrowhead and other companies within the RNAi space are all striving to refine our manufacturing paradigms to create purer products. Not only can we substantially increase the purity of the end-product, but I also anticipate this will help us substantially reduce COGS over the next five to six years.

Welch: What initiatives are you watching with interest or that are currently unavailable that could help the next generation of RNA therapeutics advance?

Hall: At Lilly, we did a holistic sweep of the software packages that were available to store data in the hopes we could purchase one off-the-shelf to support our machine learning initiatives. However, this data infrastructure does not yet exist in the genetic nanomedicine space. There is well-established data warehousing infrastructure for small molecules, and the infrastructure for protein-based biologics continues to mature. Now, I would love to see the commercial software space develop tools for genetic medicines and nanomedicines. 

I’d also be remiss if I didn’t mention my excitement about the technologies being developed for high-throughput in vivo screening. In the nanomedicine space, there is a striking lack of correlation between in vitro and in vivo results, meaning we typically need to run everything in vivo. So, the ability to make a wide variety of APIs and nanoparticles, package the API, and formulate, characterize, and test these candidates in vivo in a high-throughput manner will enable future machine learning models and accelerate the discovery process.

Welch: How do you consider the term “platform” in this space? Is mRNA truly a platform technology, and what doors could this open for companies/the industry once it becomes a true, more mature platform?

McCauley: At this stage, I believe that mRNA truly is a platform technology. In the vaccine space where there’s a significant public health aspect, the platform approach would be tremendously valuable in helping us rapidly and annually develop new vaccines. Though we don’t necessarily like to use the term “plug & play,” this level of flexibility was and remains a central component of mRNA’s promise. Once you can design and manufacture one sequence, you could make many others. Overall, a platform approach would allow companies to think not only about developing a portfolio, but how a portfolio can be encompassed within a single product.

Welch: What hard conversations, questions, or concepts do we as individual companies need to be considering in 2023 to advance the industry?

Becraft: Companies need to be asking themselves: Do we understand every aspect of our molecule? Do we understand how it is produced and how that process is optimized and analyzed? How is our dose calculated? How is our sequence selected? We are in such a new space that companies cannot be relying entirely on a CDMO partner to answer those questions for them. Bringing forward next-generation therapeutics demands ownership, which requires companies to ask hard questions about how unique their scientific approach is within the broader space.

Anzalone: The next great leap forward for all RNA therapeutics is addressing diseases that do not involve delivery to the liver. Delivery efficiency will be key for future generations. This requires the industry to ask and answer two separate questions: ‘How do we get into the necessary cell type?’ and ‘How do we make our payload hyper potent?’ This second question is essential to address because we may only get a very small amount of the therapeutic into these hard-to-reach cell types. To see optimal therapeutic effect, we will need to deliver the most potent molecule we can.

McCauley: On the R&D side, the focus should be on defining your therapeutic product profile (TPP). Companies need to identify what they want to achieve in terms of specificity, durability of effect, and safety profile. On the manufacturing side, companies will need to decide if and at what point/phase they may want to be in the commercial manufacturing business. It’s about striking the right balance between devoting company resources to the complex biology of R&D and manufacturing/scale-up from the beginning — especially as the company progresses farther into development and the market outlook may shift. The importance of getting a firm handle on process development and manufacturing early in development should not be underestimated, especially since robust external capabilities are not a sure thing or a commodity in this currently unstandardized space.