From The Editor | December 11, 2023

Defining A Competitive Next-Gen RNA Therapeutic In 2024

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

In the broader advanced therapies space, going from zero to millions of patients in a short period of time is a commercial dynamic we have yet to encounter. Thanks to the myriad scientific and technical hurdles in making cell and gene therapies, we’ve had to start small and incrementally plan for greater access and larger patient populations much farther down the road.

Nathaniel Wang
When it comes to mRNA, on the other hand, we’re facing a drastically different challenge. Having kick-started mRNA’s commercial journey at a much larger scale, we’re now in the process of “scaling down” — both literally and figuratively — to better understand how we can use linear mRNA in more precise, therapeutic (i.e., non-prophylactic) ways. Of course, a large percentage of the RNA industry is striving to expand linear mRNA’s prophylactic vaccine potential. However, in parallel, the industry’s goals are also becoming much more focused on patient population, indication, and modality — a shift which necessitates a much deeper understanding of mRNA and RNA (e.g., self-amplifying and circular RNA) biology and quality. This foundational work will be essential for identifying the critical “attributes” that will be integral to a competitive RNA therapeutic.

Carsten Rudolph
To start singling-out where the opportunities exist to craft the next generation of RNA therapeutics, I sat down with four RNA executives: Nathaniel Wang, CEO & founder of Replicate Bioscience; Carsten Rudolph, CEO and cofounder of Ethris; Gilles Besin, CSO of Orbital Therapeutics; and Romain Micol, cofounder and CEO of Combined Therapeutics. Together, these four executives helped me piece together where we and our RNA therapeutics are today and which scientific advancements and mindsets will be essential to craft a “next generation” RNA therapeutic.

Gilles Besin
In 2021, the founders of BioNTech, Ugur Sahin and Ozlem Tureci, made a bold prediction in The Economist: “We believe that in 15 years, one-third of all newly approved drugs will be mRNA-based.”

This is the revolutionary quote Wang cited when we began our discussion by defining what a mature mRNA/ RNA therapeutics industry might look like. Though Wang acknowledged that 15 years is perhaps a bit too small a window in which to accomplish such meaningful market share, he, like many others, firmly believes we’re at the most “exciting” point in the industry. For instance, if we were to chart the growth of the RNA therapeutics industry using the famous “S-curve,” Wang believes we are currently positioned at the base of the S, poised to enter the exponential phase of industry growth.

Romain Micol
This exponential growth will be possible, in part thanks to the steady increase in capital in the biotech sector over the past 30 years since the rise of mABs. Such capital has been instrumental in constructing larger manufacturing ecosystems and bringing more tools to the market, all of which enables new therapeutic areas — like mRNA — to narrow the time frame between first and second market approvals. While it took eight years between the first and second antibody approvals, Wang anticipates that our financial landscape — despite its current precariousness for all biotechs — promises a much speedier path to market than was available in the earliest days of mABs.

But beyond investor confidence, Wang, Rudolph, Besin, and Micol are aligned in believing that a mature RNA space will in no way be limited to linear mRNA products. Rather, it will — and frankly, must — comprise multiple RNA technologies to be the most meaningful industry for patients.

“The field needs to expand the universe of molecules and MOAs [mechanisms of action] that are accessible with RNA technologies,” said Wang — an expansion Orbital’s Besin believes will only be possible if we continue moving forward propelled by the scientist’s evergreen desire to “overcome limits in new therapeutic ways.” For Besin, this means not only improving and optimizing linear mRNA based on lessons learned, but also exploring the development of innovative RNA modalities — like circular RNA — and alternatives to LNP [lipid nanoparticles] delivery.

The COVID vaccines were an essential first step for the industry and regulators to begin learning the ins-and- outs of first-generation mRNA-LNPs. But despite the indelible impact of the approval, launch, and use of the COVID vaccines, Rudolph sees our current moment in which additional therapeutic RNA candidates are approaching and entering the clinic as equally meaningful — if not more so — to the future of the space. Obviously, moving any new RNA therapeutic into the clinic will provide the much-needed clinical proofs of concept and data around where the greatest promise and/or the biggest gaps in RNA technology exist. However, both Rudolph and Micol are optimistic we’re on the cusp of receiving much needed confirmation that mRNA is not just a “one trick pony,” only capable of being used as a prophylactic vaccine.

We are still at the “the beginning of the mRNA cancer vaccine revolution,” Micol acknowledged, especially considering we don’t yet have data from completed Phase 3 or Phase 4 trials. But he sees mRNA’s push into personalized medicine as a particularly meaningful development for the oncology sector and patients as a whole.

“While immunotherapy has been successful in treating some cancers, it has been less effective in others due to its inability to personalize the treatment to each patient’s tumor type,” Micol explained. “mRNA is a very promising treatment given its speed of development and its ability to be customized to each patient’s biology.”

Not to mention, the ability to swiftly turn around a personalized vaccine and treat a patient within six weeks of diagnosis could also significantly alter a patient’s course of treatment — ideally even eliminating the need for chemotherapy.

Though the vaccines provided the integral proof-of-concept we needed to revitalize the mRNA and RNA space, Rudolph emphasized that prophylactic vaccines and therapeutic oncology vaccines cannot be the only bearers of momentum for the field.

“In the next year or so, it will be important to obtain clinical proofs of concept in indications beyond infectious diseases and oncology,” he explained. “I think clinical data in non-oncological therapeutic indications would really stimulate the field, help us learn more about RNA’s potential, and establish the data- centric foundation upon which a mature industry is built.”

As I’ve written in the past, our excitement about what the future may hold for RNA therapeutics often paints the picture that the space is more mature than it actually is. But greater transparency around the challenges the field is facing will be critical for us to define what our products ultimately need to be for patients.

“We’re seeing more transparency around the limitations we’re facing on the manufacturing side of the industry than we are on the biological side,” Wang explained, a fact that may seem strange given the shroud of secrecy that traditionally surrounds CMC (chemistry, manufacturing, and controls). While there are many benefits to and forms of transparency in the pharma industry, I particularly appreciated Wang’s perspective that greater acknowledgement of RNA’s limitations will be essential in helping us accomplish more successful second- and third-generation RNA products and companies.

From a product-specific level, this means stating one fact right off-the-bat: Despite the speed at which we moved and the importance of mRNA in getting us through the pandemic, “We are not at 100% efficacy for any RNA therapeutic product today — linear mRNA or otherwise,” Micol stated.

To achieve the most beneficial safety and efficacy profile for our products, each expert pointed to the specific advancements that will piece together their ideal of the most competitive and therapeutically valuable mRNA or RNA product.

On the therapeutic cancer vaccine side of the industry, Micol said we still have much to learn about the durability and safety of multidose mRNA products, particularly in older patient populations — some of which we can glean from previously released data in the prophylactic vaccine spaces for COVID and flu. Of course, as Besin added, durability is not limited to the expression of the therapeutic protein. We must also consider the durability of an RNA molecule in vivo to ensure it produces enough of the necessary protein to function. Achieving the perfect balance of RNA and protein expression longevity will be imperative to reduce dosing frequency and bolster the long-term efficacy of our vaccines and therapeutics.

We can’t talk about RNA therapeutics without calling attention to the elephant in the room named, “Delivery.” Like Micol, who homed in on the importance of improving our products’ biodistribution profiles, Rudolph reaffirmed that the better control we’re able to assert over the delivery of our therapeutics, the safer and more efficacious they become. But so often our discussion of delivery focuses solely on the barriers to cell-specific, ex-hepatic delivery. Though Rudolph reiterated the enormity of this challenge, he also broadened the scope of the delivery discussion to include how we can broaden access to mRNA-lipid nanopartical (LNP) drug products to the broader population. This is not only limited to improving their thermostability profiles and reducing their reliance on the cold chain but also to improving their mechanical stability, as well.

“Mechanical stability remains an unspoken challenge,” Rudolph explained. “The COVID vaccine labels specify the drug product must not be shaken because this can cause aggregation. In turn, we believe developing stabilization technologies for the LNP will be a critical improvement, making it easier for distributors and end users to handle the drug, both in shipping and stocking and in administration. How easily a doctor or patient can administer a drug is an often overlooked but a critical measure of a therapy’s maturity.”

Establishing a pipeline of RNA therapeutics that improves upon many of these first-generation limitations also requires a certain corporate mindset. As we’ve learned in the months and years following the pandemic, only a small handful of mRNA COVID vaccines could be commercially sustainable, especially given the large fluctuations in demand. These case studies emphasize how essential it is for a company to carve its own niche within the RNA space.

Besin added, “It’s essential to differentiate at this point in the RNA industry to avoid becoming a ‘me-too’ company.”

For Besin and Orbital, this means blending optimization (e.g., of linear mRNA) and innovation (e.g., novel RNA modalities) under one roof. Investing in a mix of “older” and nascent RNA technologies enables a young company to carve out its own identity and — as Wang described it, “to have a quality story” — in an increasingly populous space in which “me too” products can proliferate.

But given the rapid evolution in RNA scientific advancements and the fact that talent remains at a premium, each company must also have a certain amount of humility as it fine-tunes its strategy and internal platform.

“You have to be open-minded and acknowledge that, while you may have one of the good platforms in the market, you’re not necessarily the star with the be-all end-all of platforms,” Besin said. In fact, he sees a company’s ability to play to its strengths and partner around its weaknesses as a competitive differentiator when attracting substantial investments.

“Investors appreciate when a company can acknowledge it doesn’t have all the answers in-house and needs additional resources to explore external technologies in partnership with other innovator companies,” Besin added. “We will only have a mature RNA industry when everyone is able to work together.”