How To Break RNA's "4-Minute Mile"
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
Every year at the beginning of December, I publish an annual outlook article with Life Science Leader magazine (also published here on Advancing RNA) to identify which RNA industry evolutions executives are most “gung-ho” about in the upcoming year. This year, I had four separate but equally invigorating interviews with four executives leading the RNA therapeutics charge, including Replicate Bioscience’s CEO & founder Nathaniel Wang; Combined Therapeutics’ CEO Romain Micol; Ethris’ CEO & co-founder Carsten Rudolph; and Orbital Therapeutics’ CSO Gilles Besin.
However, thanks to page constraints, only a small portion of my conversation with each expert can appear in the Life Science Leader magazine article. But as the saying goes: “Leave no stone good quote unturned unshared, and here at Advancing RNA, the phrase “page constraints” is not in our vocabulary. (To my boss’ chagrin.)
In this Q&A, I’ve captured some of these executives’ thoughts that didn’t make it into print. In particular, I’ve chosen each of these quotes because I see them in conversation with the following quote offered by Wang:
“I like to compare the progress of the RNA space to that of breaking the four-minute mile,” he explained. “Once you break it, a lot of people are going to be able to break it, and these modalities and the infrastructure to support them will explode as a result.”
Though Wang’s quote is in reference to manufacturing longer, more complex RNAs, I think we can all agree that breaking limits and reaching the “next level” of scientific and commercial advancement is essential for all currently nascent RNA modalities — linear, self-amplifying, and circular alike.
Below, each expert provides their take on some of the hot topics of discussion in the RNA therapeutics space. Whether they be homing in on platform development, much-needed scientific advancements, or commercialization considerations, each of these experts’ quotes speaks to the important “training efforts” we should be building into our “workout” regimens to condition our companies and our products to achieve (and surpass!) RNA’s own “four-minute mile(s).”
Anna Rose Welch: Since the beginning, we’ve called mRNA/RNA a “platform-able” technology. But this is a term/concept that has many different definitions depending on who you ask. How do you see this term taking shape in the context of the RNA therapeutics space today?
Gilles Besin: We typically think of the “platform” in two specific ways. There is a regulatory platform and there is a scientific platform. In the industry, each company has an RNA and a delivery method (e.g., LNP), and those two pieces make up the basis of your scientific platform. Likewise, in the industry, we often refer to the RNA platform as “plug and play,” in the sense that you can swap one sequence for another. However, this is a very simplistic way of looking at the term “platform”— and perhaps, it’s too simple for where we are today clinically considering that most of our in vivo data has been generated in mouse models. “Plug and play” may be applicable to certain animal studies today, but we need to be careful to not use the phrase “plug and play platform” as we are for in-human development. If we look at the “platform” through a regulatory lens, I liked how Peter Marks defined ‘platform,’ in which you have the same RNA ‘family,’ and you maintain a high percentage of the original sequence. This approach may make our research more complex, but in terms of safety, I think it's the best approach.
Nathaniel Wang: Broadly speaking, you can condense early RNA drug development and you can get into the clinic quicker because much of the manufacturing — even if you're altering each of the components — is relatively the same or only requires minor tweaks. But if you want to be able to build products for more challenging areas, whether it's oncology or immunology, I think you need to take time to build the actual drug development framework from the ground up. In other words, you need to approach each part of the drug product itself as modular: the insert is modular, the vector is modular, the delivery formulation is modular, the manufacturing is modular. If you can string all those modules together, then it becomes a platform that you can rapidly integrate and use for development. In the early days of the RNA space, people were trying to sell the notion that an RNA “platform” could work across all therapeutic areas. I certainly think that it eventually can be that way, but only if you start by doing the hard work of building the drug development infrastructure to accomplish this goal.
Carsten Rudolph: One of the big questions today is how we can arrive at a platform approach where, after the regulatory review and approval of a certain number of products, we may not have to carry out certain additional studies again for future products. This would be particularly valuable for companies developing multiple products that rely on the same delivery mechanism and are only switching out the mRNA drug substances. So, that's why I was excited to learn this year that regulators are starting to pay greater attention to the concept of the platform. The vaccines created the foundation for regulators’ thinking around how to regulate mRNA. But we are also beginning to see more companies — including Ethris — enter the clinic to explore mRNA in therapeutic indications beyond cancer vaccines. These clinical experiences using mRNA in therapeutic contexts will also play a key role in helping regulators evolve their thinking around how a platform approach can be applied to mRNA therapeutics, as opposed to just vaccines.
ARW: In what — if any — instances do you feel we, as an industry, have a solid basis for claiming an mRNA or mRNA-LNP platform?
Besin: I think we can say that the COVID mRNA vaccines are a “platform” today because we are changing only parts of the sequence every time a new variant arose. But if you have an RSV mRNA vaccine and a COVID mRNA vaccine, these would be two different platforms because they encode different proteins for different viruses.
Romain Micol: I’d argue that companies developing mRNA vaccines can claim that the mRNA-LNP formulation is “platform-able” today, because a vaccine is injected intramuscularly. However, if you want to use the same lipid platform to inject mRNA into your blood directly to treat cancer or another indication, it may not be appropriate to use the term ‘platform.’ Currently, we cannot say that any company has just one LNP formulation that can be applied successfully across all routes of injection, indications, or therapeutic applications. Not only will you need to change out the mRNA’s sequence to encode the right protein for each indication, but you may also need to change your LNP for better deliverability or efficacy in each therapeutic indication.
ARW: As we know, regulators are more carefully examining the term “platform” and what a regulatory designation for a platform might look like. What questions or opportunities do these discussions bring to the surface for the RNA therapeutics space?
Wang: There are several examples where we’ve seen technologies ‘platformed’ from a regulatory perspective, enabling regulatory agencies and industry applicants to rely on pre-existing knowledge. For example, being able to get a product into the clinic using peptides can be an abbreviated process because these are well-known products. Ultimately, the data packages that we as individual companies and as a broader industry submit help improve regulators’ understanding of technologies, like RNA, and how best to regulate them. But what we also know is that, when it comes to the FDA with novel technologies such as RNA, the guidance is evolving as our understanding, or knowledge, is improving. I think this is why we’re seeing the launch of more mRNA-specific consortiums and trade groups today, like Alliance for mRNA Medicines. As a growing industry sector, we need to unite our viewpoints around these big picture regulatory questions.
ARW: What other advancements — scientific or otherwise — will be the most game-changing for the RNA industry in the year(s) ahead?
Besin: I’m particularly interested in the work being done on the protein engineering front. We always aim to have the longest, most durable expression of our RNA cargo. But we don’t just need a durable RNA drug substance; we also need our products to express a durable protein. In turn, you could reduce dosing frequency and lessen likelihood of immunogenicity and reactogenicity. I’d also emphasize that less frequent dosing would be a great milestone for products to achieve in the RNA space. Not only would fewer injections be more patient-friendly, but arguably, we’d also be better able to control patients’ exposure to the costs of RNA medicines as well as expand access.
Wang: I think our immediate next step as an industry is to broaden the universe of accessible RNA molecules by increasing the amount of protein expressed, increasing the length of time that protein is expressed, and, specifically for vaccines, increasing a product’s immunogenicity to induce a longer-lived and more protective immune response. I think that's the part of the field that, if you asked almost every company, they would agree and say that these are areas in which we absolutely need to improve the technology. Fundamentally, everyone talks about the benefits of these improvements, but a large percentage of the field is currently only showing these improvements in animal models. Being able to show these technologies clinically can deliver the same impact at lower doses thanks to higher bioactivity is where we are going to get not stepwise changes but more quantum changes within the field.
Rudolph: It’s essential to keep our patients’ needs in mind from the start of development. To do this right, companies need to interact with KOLs, clinical networks, and patient registries from the beginning. The better you understand your patient population and their needs, the more capable you are of developing user-friendly formulations for your products and selecting the most meaningful clinical endpoints for each indication and patient population.
ARW: What attributes do you feel a “competitive” RNA therapeutics company should or must embody to ensure, first and foremost, that their products meet patients’ needs and can be competitive in the broader ATMP space?
Besin: Many companies have similar technology, but not everybody can just make a good therapy. Why? Because we need to have a solid understanding of each disease and targets. In the protein replacement therapeutics space, for example, we tend to think in black and white terms: If we encode for this missing protein, the disease will simply go away. There’s much more nuance required in understanding the biology of the underlying disease and demonstrating that you are encoding the right protein, that it is functioning as it should in vivo, and that the protein expression doesn’t catch the immune system’s attention. Those who will succeed with mRNA products won’t simply be taking the technology and testing it in a variety of diseases to see if works; they will be the experts in understanding the disease and how RNA technology is best equipped to address that disease.
Rudolph: Pharma companies need five things to successfully commercialize any drug — RNA or otherwise. They need the right target, the right tissue, the right patient, the right safety profile, and the right commercial market. I can’t take credit for this list; it was created by an AstraZeneca executive who wrote several papers on the topic of drug commercialization. But what I think is important to note is that this list has not changed in the past decade. Obviously, I think these scientific and commercial “must-haves” carry over into the mRNA space, but to make this list more RNA-specific, I would also add our products also need to have the “right stability profile.”
Micol: I see academia and private industry moving in the same direction, trying to improve the safety and efficacy of RNA products. There’s a great need to not only improve our products’ efficacy but also our biodistribution, which is not well controlled for mRNA-LNPs today. For example, in the cancer vaccine space, our goal is for our mRNA-LNP to generate an immune response that will then attack tumor cells. We need our mRNA product to target the site of injection and not end up in other organs like the liver, the kidney, or the heart. Luckily, I see the industry aligning around this challenge because I think we’ve all realized that companies that don’t meet — let alone beat — currently established safety and biodistribution thresholds will not be competitive.