From The Editor | May 20, 2024

Multidisciplinary mRNA: What Can We Learn From Other CGTs?

ARW Edit Headshot 2

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

Helping Hand-GettyImages-1314188794

Last year, prior to launching Advancing RNA, I debuted a series of creative videos to explore the parallels between mRNA development and the world that exists outside of pharma. One of these videos, “Michelangelo Meets mRNA,” united the past, present, and future of mRNA with that of the (often forgotten!) history and creation of Michelangelo’s famous sculpture David.

But as I prepared my keynote address for BioPhorum’s annual ATMP conference this spring — which began with this “mRNA-meets-Art-History” Lesson — I realized that this metaphor has evolved since I first came up with it.

As we all know, the sculpture of David — despite some of its early “development pitfalls” — went on to be hailed as the epitome of Renaissance sculpture. However, based on mRNA’s current diversity of therapeutic approaches, it would seem we’re not going to have one shining example — or a “David-esque” example — of an RNA therapeutic. Rather, if Michelangelo were still alive today (hello, multiverse) and putting together a sculpture (or sculptures) that would become the “ideal representation” of an mRNA therapeutic, I’d argue that he would not be creating the singularly iconic David. I’d like to believe that Michelangelo’s creation would be (at least conceptually) like…

Hello, mRNA Barbie.

Yeah, that’s right. I said it.

There are several reasons why I think the Barbie brand is a great metaphor for the current mRNA/RNA therapeutics space — starting with the fact that the Barbie slogan, “She’s everything!” applies very nicely to mRNA’s broad applicability across therapies. (In fact, I think we should steal this slogan for our industry’s own purposes.) The overall diversity of the Barbie brand serves as a fantastic role model for us as we move from the COVID vaccines — our own “Malibu Barbie” — to mRNA/RNA candidates of all “shapes,” “sizes” and therapeutic “talents.” In fact, we’re in the early days of “fleshing out” what mRNA vaccine & therapeutic “role models” will look like in terms of quality, stability, durability, immunogenicity, and deliverability.

The question then becomes:

How can our industry become more like Barbie?

(i.e., “What steps must we take to identify and hone our products’ “talents”?)  

Overall, there are four high-level best practices/mindsets I proposed during my BioPhorum presentation that I believe will be crucial for us to bring some talented RNA therapeutic role models to the forefront. But there was one best practice that I think is worth emphasizing more than the others: We have to embrace being multidisciplinary.

We evolve based on our experiences and the “prior knowledge” these give us. The same goes for our therapeutics, regardless of modality, as we strive to bring them and their future generations to the market. Though every new sector of the pharma industry emphasizes the importance of cross functional communication and cross-industry communication, siloing ourselves off by modality is easier than we’d probably like to admit. But I’d argue that curiosity about and awareness of what has come before us in the ATMP space is particularly important for those of us in the RNA therapeutics space today, given how well-rounded mRNA is shaping up to be.   

Despite their different manufacturing processes, our viral vector-based therapeutic counterparts have learned a lot about how to get into the clinic while navigating a “clarifying” regulatory paradigm and occasionally stubbing their toes in the process.

Below, I’ve included a few areas where I see some crossover between the RNA space and the viral vector CGT space which, at first glance, may seem irrelevant. But if you look carefully, they do offer experiential learnings or opportunities to standardize. Afterall, an important part of chiseling out an efficient RNA sector is to determine where we must create our own wheels and where we can and ultimately must rely on the work/learnings that have come before. 

Lessons From Outside The mRNA Universe: Where Should We Look?

  • Regulatory Milestones

To be clear, the regulatory space is always tricky. Not only do we face the challenge of product-specific nuances, but there’s also a whole history of behind-the-scenes regulatory interactions and risk vs. benefit considerations underlying each BLA’s approval. But there were a few great advisory committee meetings for non-RNA products that showcase how the FDA may approach the concepts we typically only discuss at a high level and/or theoretically.  

Take for example, the Sarepta adcom meeting for its AAV gene therapy in DMD. As I shared in a two-part article, this regulatory “drama” was a case study of how (cautiously) the agency may address a product encoding an “engineered” (not an endogenous) protein, as well as the seemingly tenuous relationship between (protein) expression and clinical function.

Likewise, the Sarepta adcom was our first public example of a clinical comparability exercise, thanks to a change in manufacturing partner/platform and a resulting shift in AAV packaging efficiency. On the one hand, this was a great reminder of the pitfalls that can befall any of us in analytical method transfers. But just as important, as we start to discuss packaging efficiency (or the lack thereof) in mRNA-LNP mixing/formulation, previous conversations about full-empty capsids in the AAV space set the stage for the amount of analytical understanding and process control we will likely need to demonstrate to the agency to justify our mRNA-LNP ratios.  

[For a few recent mRNA-specific regulatory publications/resources, I’d encourage you to check out this Nucleic Acids Insights’ article on current regulatory gaps; my recent Advancing RNA LIVE! Event panel discussion on current/future regulatory outlook; and this article breaking down how mRNA fits (or maybe doesn’t fit?) into the EU GTMP classification.

  • Personalized Medicine Advances/Challenges

Though making mRNA may be more efficient compared to cell-based therapies and viral vector development, we haven’t strayed entirely from playing in the autologous/ex vivo world. Overall, it behooves those of us on the RNA cell therapy, ex vivo gene editing, and personalized cancer vaccine fronts (all of which require some element of patient-specific material collection and administration) to stay in touch with the efforts made by Standards Coordinating Body to standardize patient material collection and labeling in the CGT space, as well as their efforts to unify administration platforms and protocols. Differentiation is important, but the cell therapy space has taught us that we should be pursuing differentiation in terms of clinical and patient access benefits, not in terms of administration tools/tech/procedures. Our sites of care will thank us.

I’d also argue the non-RNA-based cell therapy space with its scalability challenges can/should keep the mRNA space grounded. It’s taken cell therapies quite a few years to achieve turn-around times of 14-30 days. But based on some of the estimates I’ve heard for mRNA cancer vaccines (i.e., “somewhere” between 30 days to nine weeks), it’s clear we’re still facing our own turn-around-time constraints and considerations, despite our cell-free process. Manufacturing efficiency of mRNA is only one piece of this equation; ensuring our analytics can “keep up” and working with regulators on antigen prediction for cancer vaccines are poised to be big hurdles facing those of us on the personalized RNA front.

  • Risk vs. Benefit

Predominantly, we discuss this (rather loaded) equation in terms of regulatory decisions (a great example being the Bluebird Bio gene therapy adcoms a few years ago.) But beyond a therapy’s all-important clinical impact in the disease state and against standards of care, there are several other angles from which we will need to evaluate our mRNA therapeutics. We are always advised to “keep the end in mind” as it relates to CMC. But the competitive dynamics of the overall CGT and biologics space are also an essential piece of this discussion.

For example, some of our mRNA/RNA therapeutics will end up playing alongside other predominantly “one and done” ATMP products. Now, to be clear, not every approved CGT has been curative. But given the high cost and complexity of developing all advanced therapies (mRNA included), “one and done” is certainly an alluring prospect. Meanwhile, in the RNA space, current estimations suggest we can anticipate a dose frequency of 4-6 doses per year for an mRNA cancer vaccine and 8-12 doses per year of a protein replacement therapy. (For reference, a protein replacement therapeutic will require protein expression levels anywhere from 50-600x that of the COVID-19 vaccines.) It goes without saying these expected dosing regimens put pressure on us to lower our overall COGS. Our products will need to demonstrate a staggeringly significant clinical benefit to demand both high costs and routine dosing.

I am starting to hear it said with increasing frequency: One and done is not always a strength. As I explained in this previous (and coincidentally also Barbie-themed article), mRNA’s ability to be redosed poses a number of benefits, particularly from an access standpoint. Afterall, not all patients are eligible to receive a viral vector-based therapeutic in the first place, thanks to pre-existing immunogenicity concerns. Likewise, as we all know well, durability in the ATMP space is treatment- and indication-dependent and, in most cases, remains an “open” question. We’re already starting to see companies exploring alternative methods to be able to re-dose CGTs when necessary.  

As such, there’s a lot more work the RNA industry can do to communicate the benefits of chronic therapies in the ATMP space in general, as well as the role such products can play alongside our viral vector-based brethren. Not only are patients familiar with and accepting of chronic treatment regimens thanks to antibodies, but our reimbursement model already supports such regimens — an incredibly important benefit we should not sell short.