From The Editor | July 24, 2024

From "Up & Coming" To "Fully Formed": Maturing Our mRNA Outsourcing Partnerships

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

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A few months ago, I had the good fortune to find myself on stage discussing the future of the mRNA market at the World Vaccine Congress with Replicate Bioscience CDO Andy Geall, Orbital Therapeutics CSO Gille’s Besin, Beam Therapeutics CSO Gopi Shanker, and Hopewell Therapeutics CEO Kate Zhang. The entire world of mRNA R&D, manufacturing, and delivery was our oyster, and the plans for our discussion were ambitious. Though most of the WVC RNA-centric workshop was focused on advancements in vaccine development, our goal during this panel discussion was to explore the progress being made with linear, self-amplifying, and circular RNA in therapeutic indications.

As you can imagine, we delved into a variety of challenges we’re striving to overcome, whether it be getting multiple modalities/mechanisms of action into the clinic; sufficiently characterizing our complex drug products; or navigating the scientific and business-related challenges of running an RNA therapeutics company. But it also served as a great update about the current state of the industry, the biggest scientific and delivery challenges we face in moving from vaccines to therapeutics, and the outsourcing infrastructure that exists today to help us move forward.

In the first- of this three-part article series, these four execs share their perspectives on the world of partnering in the RNA therapeutics space, assessing first the current state of CDMO partnerships and how they anticipate this critical supportive infrastructure will grow in the years ahead.

The Current & Future Growth Of Our mRNA CDMO Infrastructure

We have the pandemic to thank for the growth of the CDMO infrastructure for mRNA development. The panel members at the WVC reinforced what I’ve been hearing in the space thus far: Our CDMO network remains flush with partner options and capacity for mRNA production, and there have certainly been advancements in CDMOs’ technical capabilities. As Replicate’s Geall explained, we’re welcoming the arrival of new bioreactors and production skids for downstream processing. Likewise, the more the space homes in on purification and strives to limit the production of double stranded RNA, the more diligently CDMO partners are establishing analytical tools to quantify and clarify what dsRNA means for the overall performance of our products.

However, as two previous conversations on Advancing RNA have revealed (here & here), while CDMO capacity for mRNA development may abound today, the maturity of capabilities remains a mixed bag across the board — especially for non-vaccine products and next-gen RNA modalities. As Geall and Beam’s Shanker emphasized during our panel, it behooves us to remain “scientific” in our choice of CDMO — especially seeing as we’re not working with a single modality and/or standardized process today. Not only do next-gen versions of RNA have different manufacturing processes, but we’re continuing to evaluate how changes to our processes impact our molecules’ structure and function. And to be clear, the “function” part of this equation remains fuzzy today in our predominantly preclinical industry. (Stay tuned for Part 3; translatability was a big topic of discussion with this panel!)

Given the fact we’re still an “up and coming” industry, Shanker emphasized that it’s up to us as biotechs to ensure we’re not turning a blind eye to or underestimating the assortment of challenges accompanying a new modality and a growing industry — be they shifting development timelines, quality issues and/or clarifying quality expectations, tech transfer difficulties, and/or employee/team turnover at the CDMO. It’s not just the CDMO industry’s responsibility to build our ecosystem and the necessary capabilities; the work mRNA/RNA biotechs are doing to select and manage these partnerships will ultimately dictate the future shape, know-how, and health of our CDMO landscape.

“As this field matures, as we create that ecosystem, we expand the options available on the table,” Shanker added. “We develop the technical know-how and skill sets within that ecosystem. The problems we’re facing today at this early stage will diminish or go away. But as of today, there are still some challenges. Selecting a partner takes a lot of due diligence and vetting — and we need to be doing that to build this ecosystem.”

I also appreciated Zhang’s reminder that growth in the CDMO space will come with greater regulatory maturity. “The strength and maturity of the CDMO field is ultimately defined by regulatory requirements,” she explained. “The supporting CDMO infrastructure is still young in this field because there have not been enough mature products that have gone through the entire regulatory process.”

Now it’s important to remember that, novel RNA modalities aside, compliance is compliance. Regardless of modality, the biopharma industry is built upon the foundations of Safety, Identity, Strength, Purity, and Quality (SISPQ) — and the RNA space is/will be no exception. But there are, of course, modality-specific CMC nuances around which we have yet to align with regulators considering the bulk of our mRNA-specific regulatory experience is limited to three linear mRNA vaccines, as well as two later-stage personalized cancer vaccines. The greater diversity of products in the clinic, the more informed we can be about the relationship between analytics/molecular structure and clinical function, all of which will inform our/our CDMOs’ long-term manufacturing and control strategies.

For example, as Zhang outlined, there remain several important questions we have yet to answer, particularly as we explore next-gen therapeutic use cases: “How do you look at excipients? How do you look at RNP clearance? How do you look at the half-life of your API and the half-life of the other components? The answers to these questions and our understanding of critical quality attributes will take shape when we have a greater number of products, not only in the clinic but being scrutinized by regulatory agencies.”

As she went on to explain, Zhang anticipates the work we’re doing in the gene editing space using linear and/or circular RNA has the power to “redefine” the regulatory requirements for RNA modalities. However, as we gain increasing clarity around the structure and function of our molecules and as our products get more biologically “complicated,” it’s important to reflect on the manufacturing “growing pains” other ATMP modalities encountered as more products entered the clinic. Whether it be starting matrixed potency assays early enough, demonstrating comparability of our clinical processes, or navigating increasingly clarifying quality expectations from regulators, it’s likely we’ll see greater attention lavished on our manufacturing processes. We may not be working with cells, but I appreciated Zhang’s reminder that we have our own challenges to navigate — the stability of our RNA being at the forefront. As I wrote in a previous “hot take” on mRNA scale-up, stability will be an increasingly challenging factor to navigate as we strive to optimize our manufacturing processes, move our drug substance swiftly between each unit of operation and/or manufacturing site(s), establish an analytical paradigm (particularly for personalized medicines), and navigate scale-up/scale-out.

Check out Part 2, in which we dig into some of the partnership dynamics taking shape in the mRNA/RNA delivery field!