By Anna Rose Welch, Editorial & Community Director, Advancing RNA
It’s not every day you read the following phrase in an interview with a CEO: “Don’t get me wrong, I think circular RNA is the shit; but there are an incredible number of challenges that people have completely glossed over.”
When I stumbled upon this article in Nature featuring the previous quote from Jacob Becraft, CEO of Strand Therapeutics, I knew it was high time we sat down for another conversation. Becraft and I originally sat down in fall 2022 to discuss his thoughts on where the RNA therapeutics industry was headed for my 2023 RNA Industry Outlook in Life Science Leader magazine and the Cell & Gene Collaborative blog. During that conversation, we tackled everything from the financing landscape, the industry’s delivery challenges, and what we mean when we say the word “platform” in the mRNA space.
Over the past year following the publication of that article, I’ve grown increasingly fascinated by the mRNA industry’s “quest for identity” within the ATMP and broader biologics space. In fact, as I argued in a recent article, I anticipate the industry will face some unique regulatory and “public relations” challenges as we rely on mRNA as a vaccination and a therapeutic tool. However, as Becraft and I went on to discuss, it’s not just the public we need to educate about the possibilities and limitations of mRNA therapeutics. Members of the biopharmaceutical industry at large and the investors supporting emerging and established RNA therapeutics companies could also use a post-pandemic “refresher” about mRNA’s potential use cases beyond vaccines and the (often under-emphasized) truths of what it will take to successfully achieve these use cases.
mRNA: A Well-Rounded, But Misunderstood “Darling”
As we’re all well aware, the cell and gene therapy industry is not a homologous industry. In keeping with its diverse CGT “parents,” the RNA sector is equally diverse, boasting linear, self-amplifying, and circular RNA modalities, all of which we’re exploring in a variety of therapeutic contexts. Vaccines and protein replacement may be the most prominently explored therapies in pipelines today, but we’re also delving into personalized cancer vaccines, ex- and in vivo cell therapies, and in vivo gene editors. Though each of these RNA modalities have the IVT manufacturing process in common, each potential therapeutic use case comes with its own molecule design, process development, analytical, purification, delivery, scale-up/out, and consumer-facing supply-chain considerations. This complexity and the regulatory and operational challenges this may pose for companies working across modalities/therapeutic contexts is rarely discussed and, frankly, is often oversimplified in the industry today.
“I think people — whether it be the general public or members of this industry — get misconceptions about what we’re doing when we say we’re working on mRNA programs,” Becraft explained. “For example, when I talk about Strand’s oncology mRNA programs, many assume we’re working on cancer vaccines. When I say we’re working on mRNA therapeutics for solid tumors, it’s not unusual to hear the following phrase in response: ‘But it’s mRNA.’ This isn’t unique to the general public; there are still parts of the broader industry that have this preconceived notion that mRNA equals vaccines, and vaccines equal mRNA.”
Like many others, Becraft believes mRNA has a lot of untapped therapeutic potential, the possibilities of which have not yet become a widely recognized part of the RNA story. The proliferation of infectious disease vaccine development and therapeutics targeting the liver may be essential proofs of concept for the broader growth of the industry. However, as Becraft also argued, the “proof-of-concept” mindset can be limiting for an industry with such ambitious therapeutic goals. Though there will be broader regulatory, manufacturing, and clinical learnings from our earliest experiences with mRNA therapies — most of which have been infectious disease vaccines or liver-targeting therapeutics — it remains to be seen if and how succinctly these learnings will scientifically translate into advancing a broader array of more targeted therapeutics. In turn, this begs the (perhaps loaded) question of whether we are at risk of building our complex industry and modality on the foundation of an overly simplistic story?
Don’t get me wrong: simplicity is warranted in certain situations — education of the general public being one of them. But when it comes to tackling rare diseases and expanding RNA’s therapeutic relevance, simple solutions will only carry us and our molecules so far. And, as Becraft pointed out, it wasn’t unusual to see companies emerging with single-pronged approaches to solving some of linear mRNA’s clinical limitations — particularly in the early years of the mRNA investment rush.
“I think a lot of folks were under the assumption that a single scientific advancement would be the answer to linear mRNA’s limitations,” Becraft said.
But unlike Nike with its catchy phrase “just do it!” there’s no “just changing linear mRNA to circular RNA” to overcome mRNA’s durability challenges, nor can we “just conjugate the lipid nanoparticle to another molecule” to solve mRNA’s delivery limitations.
“This is a complicated space, and none of these singular approaches are going to be solutions in a vacuum,” Becraft said.
A Difficult Balance: Confidence & Humility — And How We’ll Achieve It
Any new industry comes onto the scene boasting revolutionary promises of what its novel therapeutics can be and potentially do for patients. As the industry continues to grow and the realities (positive and negative) of our science reveal themselves, the industry enters a much more humbled and, frankly, thoughtful phase of development. We saw this in the cell and gene therapy space, and I saw it in the biosimilar space prior. The RNA space is no exception.
As my conversation with Becraft continued, it became clear that we’re somewhere in between the brazen and more humble stages of growth in the RNA therapeutics space. There are many benefits to a cell-free manufacturing process we can celebrate, and we’re taking full advantage of these efficiencies by exploring, for example, in vivo production of cell-based therapies (e.g., CAR-T therapies or antibodies). However, for Becraft, the beauty and promise of the RNA therapeutics space lies in its complexity — not its simplicity.
For the past few years, the mRNA story has been that we could plug and play any sequence into an mRNA backbone and create any drug we wanted. “But that’s not even how RNA works within our body,” Becraft added. “It’s not like we have one mRNA transcript for every gene; there are all sorts of different regulatory elements underpinning a fully functioning gene.”
In reality, there are multiple scientific and technical advancements that need to come together to make a functioning RNA therapeutic. As is usually the case, we can rarely attribute the most revolutionary developments within an R&D program to a single action or change. Nor are these game-changing best practices or operational frameworks the glitziest topics of discussion. In turn it behooves (but also challenges) small biotechs to make the case for investments in areas for which the value may not be immediately understood or appreciated.
In fact, as Becraft emphasized, spending significant amounts of money to “build things that don’t go into value creating events” is one of the most important things a young biotech can do for itself. For example, he explained that Strand formed a small modality engineering team to explore various RNA modalities and provide data around their durability and how they might function in different therapeutic contexts.
“This data is very well received and enables us as a company and our pipeline to stand out,” Becraft said. However, “This team is only able to produce this data because of the tools and infrastructure that were collectively built by divisions that don’t get recognized externally.”
Obviously, prioritizing infrastructure building is not unique to RNA companies; but as we’re still at the very beginning of expanding RNA’s story, I see Becraft’s example having significant implications for the future of the RNA industry.
A few weeks ago, I published an outlook article entitled, “How to Break RNA’s 4-Minute Mile.” As we pin down our processes, file INDs, and enter the clinic, we hope to see our products establish new quality, safety, and/or clinical thresholds across which every RNA company henceforth must meet (or exceed) to remain therapeutically relevant. It’s only with more data that our industry — biotechs, regulators, and investors alike — will be able to confidently ascertain where each therapy falls within these industry-wide thresholds. Our therapies don’t — or at least shouldn’t — exist in a vacuum, and it’s up to us to teach each other what makes this space “tick.” For Becraft and Strand, this has meant sharing data with potential partners — some of whom may have their own R&D arms — and/or investment partners.
“I’ve been really impressed by some of the partners we’ve been talking to over the past year, Becraft concluded. “They can look at something — for example, our manufacturing data from a GMP run — and understand now what data is ‘average’ compared to what is currently the ‘best.” This provides each company or potential partner a greater sense of what quality means and looks like today, as well as fosters greater appreciation for what all it will take — beyond money and talent — to move the industry from good to great.”