Following the events of 2020 and 2021 in which mRNA vaccines burst onto the scene, RNA R&D professionals suddenly found themselves and the work they do catapulted into the spotlight. While they once toiled in near obscurity in resource-deprived labs, it’s now possible (albeit still slightly otherworldly) to attend conferences entirely devoted to the art of RNA process development and manufacturing.
In addition to celebrating the head-start of the mRNA vaccines sector, the RNA therapeutics sector also has grown increasingly kaleidoscopic over the past few years. Whether it be mRNA, self-amplifying RNA (saRNA), short-interfering RNA (siRNA), or circular RNA (circRNA), the appetite for scientific and manufacturing advancement across this nuanced therapeutic sector is unparalleled.
To figure out the most daunting challenges and greatest opportunities facing the therapeutics space in 2023, I sat down with four executives whose companies are leading the charge toward a future with commercialized mRNA and RNAi therapeutics. Here, Michelle Lynn Hall, AVP of genetic medicines for Eli Lilly; Thomas McCauley, CSO of Omega Therapeutics; Jacob Becraft, cofounder and CEO of Strand Therapeutics; and Christopher Anzalone, CEO of Arrowhead Pharmaceuticals, outline which industry challenges, strategic considerations, and opportunities should be top of mind as RNA therapeutics companies establish their to-do lists for 2023.
Where We Are & Where We Are Headed
To Omega’s McCauley, “The RNA therapeutics industry is still in its early stages. Not its infancy, per se, but despite its adolescence, there remains incredible untapped potential.”
For Lilly’s Hall, “mRNA vaccines were a wonderful proof-of-concept for the industry, but they are hardly the end of the potential for mRNA therapeutics.”
If we look toward the RNAi space, Arrowhead’s Anzalone argues, “There is no more powerful class of therapeutics that has ever been developed in the history of pharmaceuticals.”
Each of these impassioned statements reveals the extent of these experts’ — and the industry’s — excitement over the seemingly limitless possibilities of RNA therapeutics. But impassioned claims aside, these experts are under no illusion that we have barely even scratched the surface of all we can do to make these therapeutics more clinically and (eventually) commercially meaningful.
At its most basic level, we can break down the RNA therapeutics industry in terms of a therapeutic’s basic function. An RNA therapeutic (e.g., mRNA) either creates a specific protein in the body, or the therapeutic (e.g., siRNA) silences the production of a specific protein. If we were to break these two “basic” categories down even further, each “turning on” and “turning off” modality brings its own unique scientific and technical hurdles — not to mention, some are more established than others (i.e., mRNA vs. saRNA and/or circular RNA; siRNA vs. mRNA).
This variable level of market maturity was clearly demonstrated through the conversations I had with the three mRNA experts compared to that of Arrowhead’s Anzalone on the RNAi side. While the mRNA therapeutics space has yet to see any therapeutic approvals (outside of the vaccines), the siRNA therapeutic space saw its first approval in 2018 (Alnylam’s Onpattro). Since 2018, the FDA has approved an additional four siRNA products, bringing the industry to a total of five.
But beyond such blatant markers of scientific, clinical, and commercial success, Anzalone also noted that the industry is on the cusp of achieving a level of maturity that many other companies in the RNA therapeutics space (and advanced therapies space in general) have high on their bucket lists for the next few years.
“In the RNAi segment of the industry, we’re now transitioning from small orphan indications into large indications,” he said. “In the RNA therapeutics space, there are three stepwise measures of progress. The first is to deliver an RNA therapeutic to hepatocytes — the liver — to treat an orphan indication. We have accomplished this. Step two is to treat a larger indication, also by delivering to the liver, which Arrowhead is on the cusp of doing. Finally, step three would be to accomplish the largest challenge facing the entire RNA therapeutics space: addressing a disease — orphan or large population — that requires non-hepatic delivery.”
The RNAi space celebrated the approval of its first mass-market RNAi drug in the cardiovascular space when Novartis received approval for inclisiran in 2021. Arrowhead’s own cardiovascular candidates are all in or approaching Phase 3 studies, and Anzalone believes that RNA therapeutics have the potential to become a critical part of the heart disease armamentarium.
On the other hand, while the protein-producing (as opposed to silencing) side of the RNA therapeutics space may lack concrete definition, it is also luminous with possibility. As McCauley points out, the industry itself has “hit critical mass” in terms of company focus and investment. To be able to create a protein within a cell is a revolutionary concept, McCauley explained, not only because it enables the creation of a missing disease-causing protein, but it also enables us to achieve better therapeutics than what we currently have (e.g., vaccines). Such technology could also permit the creation of an entirely novel protein in vivo to regulate or tune gene expression. Big Pharma’s buy-in over the past few years is particularly encouraging to McCauley because it indicates a dramatic shift of the industry’s own assessment of mRNA therapeutics.
Pre-COVID, mRNA was considered an esoteric approach to solving a problem,” he explained. Now, people are no longer saying, ‘Will this work? How can we apply it? Is it stable on the bench and in the bloodstream?’ The success in the past few years has freed people’s imaginations to examine what else we can do with this technology. In fact, I’m sure we have not seen the last in terms of this technology’s applications.”
The past 10 years have been spent establishing “mRNA Generation 1.0” within which the vaccines demonstrated linear mRNA’s clinical safety, scalability, and reproducibility. Moving forward, “Generation 2.0” (or what McCauley calls “Gen 2.0 +”) will be examining the possibilities beyond protein creation for immunity or replacement for disease alleviation. Gen 2.0 + promises more nuanced regulation of the epigenome.
Hall believes RNA Gen 2.0 will be defined by the industry’s exploration and improvement of self-amplifying and circular RNA approaches, the latter of which she is most excited about. In particular, she sees circRNA as a pivotal tool for bringing in vivo gene editing — Hall’s personal Holy Grail for RNA technology — to future maturity.
“Depending on the patient and where the therapeutic is delivered, you may want a gene editor to be expressed for a long time,” she explained. While linear mRNA (the vaccine technology) expresses immediately and tapers off quickly, circRNA expresses and fades away much more gradually. In turn, more protein can be expressed by circRNA.
“By delivering a circRNA that encodes for a gene editing protein, I could ensure the editor is expressed long enough to do the work it needs to do,” she added. In addition to long-term expression, circRNA also boasts additional non-coding applications — for example, the absorption of micro RNAs to regulate downstream RNA and proteins — that make it an incredibly versatile API.
Delivery: One Scientific Challenge To Rule Them All
If there was one topic upon which all four experts are keenly focused, it’s delivery. Ensuring that an RNA therapeutic is successfully delivered to and/ or expressed within the target tissue will be critical to the future of the industry as a whole.
Arguably, the most “mature” delivery vehicle in the RNA space today is the lipid nanoparticle (LNP), thanks to decades of foundational research, analytical characterization, and our ability to rapidly and reproducibly scale LNPs. However, it’s also impossible to have a conversation about LNPs without confronting the caveat of its inherent gravitational pull to the liver — a factor that McCauley argues still shouldn’t be taken for granted.
While liver-targeting LNPs have been developed and are used in marketed products, safely targeting both hepatic and extra-hepatic tissues with high specificity and potency still requires significant care and expertise,” he noted. He also anticipates more to come from this delivery technology, considering we haven’t come close to exhausting the LNP compositions possible. “The physical and chemical space that is spanned by a typical four- or five-component LNP composition is immense,” he said. In fact, the compositions in existence today would “only paint a tiny corner of the entire LNP space.”
"The success [with mRNA] in the past few years has freed people’s imaginations to examine what else we can do with this technology. In fact, I’m sure we have not seen the last in terms of this technology’s applications.” — Thomas McCauley, CSO, Omega Therapeutics
Of course, we also can’t overlook that the LNP is only one of a variety of delivery methods today. I appreciated Anzalone’s use of the phrase “delivery strategy,” given that delivery in this space can — and does — extend beyond the vehicle- API combination. Rather than packaging the API into an LNP, exosome, or viral vector, for example, the API itself can be equipped with targeting ligands that guide the therapy to receptors on the necessary cell types.
It’s also important to remember that better potency and targeting depends equally on the strength and quality of the API. All four experts were in agreement that there remains a lot to be learned in the realms of RNA modifications, LNP/ API mixing, ligand-receptor pairing, etc., to promote more targeted delivery. In fact, to Becraft, mRNA delivery requires a much more nuanced conversation than we are currently having. So often, delivery to the intended organ/cell type is discussed as if the successful delivery itself is the only means of controlling mRNA expression.
“What if we said delivery wasn’t the only way to control mRNA expression?” Becraft asked. “While an mRNA will always express where it is delivered, there are different ways besides the location of delivery to control expression. Synthetic biology is one such tool to control mRNA specificity.”
As Becraft went on to explain, synthetic biology fits underneath the umbrella of systems biology — or the study of how the genes within the genome are expressed and regulated. In the world of mRNA therapeutics, taking a synthetic biology approach could mean engineering a synthetic version of a nucleic acid that boasts a new, more matrixed level of functionality. For example, you could design a gene to only be expressed in a specific cell type or types regardless of where it is delivered in the body. You could also program it to express only within a specific window of time. Such an approach enables the therapeutic to mimic the complexity of the genome itself in which multiple genes are expressed and diversely regulated in parallel. However, Becraft also considers synthetic biology as a means for the industry to ask different questions about common problems, such as delivery.
What Will A Mature RNA Industry Look Like, And What Can We Achieve In 2023?
I’m indebted to Hall for introducing me to the (FDA-coined) phrase “relentless incrementalism.” Whether we’re talking about delivery, process development, or regulatory guidance, progress in the RNA therapeutics space will always be made incrementally (and often in an iterative fashion).
When we think about maturity in the advanced therapeutics space, we often point toward the progress made in the monoclonal antibodies space. While it took decades of incremental improvements to get here, Becraft explains that innovation within the antibody space today resides primarily in target identification, as opposed to platform development. In other words, the mRNA therapeutics industry will be mature when we can identify, for example, what protein the mRNA must express, in which tissue it must be expressed, and in what ways we can ultimately control expression. However, right now, the industry is still challenged, not only to express mRNA in tissues outside of the liver, but also in building the necessary research and manufacturing infrastructure.
For example, Hall anticipates much “relentless incrementalism” ahead in the industry’s quest to achieve more meaningful use of machine learning to accelerate the RNA therapeutics discovery process. While building the appropriate data infrastructure is remarkably unglamorous work, she explained, it is a necessary investment from day one to ensure you can make the most of your data in the future.
“What if we said delivery wasn’t the only way to control mRNA expression? While an mRNA will always express where it is delivered, there are different ways besides the location of delivery to control expression." — Jake Becraft, CEO, Strand Therapeutics
One of the most important first steps to building this infrastructure is hiring and integrating data scientists and data engineers into your team from the start to ensure the data from each experiment is captured in the appropriate format and stored in a structured way. Such roles are critically important, first of all, to support the future of your organization’s drug discovery process. However, Hall also sees larger cultural implications in such an effort. Taking the time to painstakingly build that machine learning infrastructure — and the talent pool (e.g., data scientists and engineers) around it — is essential to nurturing greater cultural appreciation for how your data informs your organization’s scientific strategy.
Keeping quality and scalability in mind from the start is yet another great example of the “relentless incrementalism” facing the entire ATMP (advanced therapy medicinal products) space. Successfully making the leap from bench scale to a large patient population ultimately hinges upon a more “democratized” outsourcing industry. As McCauley explained — and Becraft reaffirmed — up to this point, biotechs working in the RNA space have had to shoulder the majority of R&D and process development for drug substance manufacturing. In fact, Becraft pointed to Moderna and Pfizer as two prominent case studies demonstrating the importance of some level of internal vertical integration.
“Up until very recently, the purveyors of the building blocks at the CDMO level for mRNA drug substance manufacturing and LNP formulation were dominated by a couple of small, boutique CDMOs,” McCauley added. In turn, “As a sponsor approaching a CDMO, you would need to bring your own process to get your mRNA made. It was not something that a typical CDMO could make for you.” That’s why, to McCauley, incremental progress toward broader and more democratized access to CDMO-supplied RNA drug substances and delivery solutions will be an important measure of maturity.
However, until we reach this point, Becraft cautions RNA therapeutics companies against thinking like a small molecule virtual company. “We’re unfortunately not yet at the point in the industry where we can come up with a good idea and outsource the rest of the development,” he added.
We often hear that the development cycle in the ATMP space overall has accelerated at a much quicker clip than the therapeutic classes that have come before. That these advanced therapies are also expected to “grow up” more quickly also can be clearly depicted in the FDA’s emphasis on comparability earlier in development, as well as biotechs’ efforts to build facilities and/or select secondary suppliers/outsourcing partners as early as Phase 1 clinical trials. While chemistry, manufacturing, and controls (CMC) and operational growing pains have been commonly felt in the wake of such acceleration, I appreciated McCauley’s emphasis on an easily overlooked but important bigger picture.
If we were to chart the traditional “plot points” in the life of a novel modality, we’d start with the discovery, followed by publication in the academic space. The biotechs — and the necessary funding — would come rushing in, followed by the eventual entrance of candidates into the clinic. However, as McCauley pointed out, a comparison of the time periods between discovery to clinical entry for antibodies, siRNA, and CRISPR technology all point to a much quicker arrival in the clinic for newer technologies. For example, between CRISPR’s discovery and development, McCauley estimates development was already well underway after only six years.
“The growth and maturation cycle for novel modalities — including RNA therapeutics — is getting shorter,” McCauley concluded. “Not only does this evolution suggest that the industry is on its way toward greater maturity, such acceleration also translates into a much more important point: Patients have greater opportunity to benefit from these advances more rapidly.”