By Anna Rose Welch, Director, Cell & Gene Collaborative
Subscribe to my blog ARW on CGT here!
Over the past ten years at Life Science Connect, I’ve had the unique opportunity to launch editorial communities in three different biopharma sectors. My journey started first in the fledgling (U.S.) biosimilar space. I then moved into the cell & gene therapy space, which more and more regularly includes the mRNA modalities. Of course, mAbs, cell therapies, gene therapies, and mRNA products have their own development and commercial distinctions. However, as I’ve observed with each market transition I’ve undergone, every new therapeutic industry shares the same intoxicating dream: that, thanks to [insert modality here], our medicine development and regulatory paradigms will never quite be the same again.
Of course, there is some truth to this promise across the ATMP space. The science underpinning our ATMPs, our focus on underserved or unserved patient populations, and the ongoing regulatory evolutions — including the pandemic’s mRNA renaissance — all speak to the game-changing transformations the pharma industry has undergone. Likewise, having just returned from the Hanson Wade mRNA Therapeutics Summit, I can attest to our excitement over the seemingly endless promise of mRNA and its many different “flavors” (e.g., saRNA & circRNA). There are brilliant minds at work in the mRNA space, and during the conference, I truly felt like a 30-something-year-old Alice in an mRNA Wonderland. But as we also know, Alice’s story doesn’t end with her staying in wonderland.
We can apply many of the lessons from the Alice in Wonderland story to the mRNA space in the long-term, including the importance of embracing the unexpected, being ceaselessly curious, and celebrating
everyone’s each modality’s differences. But in keeping with some of my recent articles on the importance of growing up in the CGT space (here, here, & here), I also see Alice’s return from wonderland as symbolic of her awakening into adulthood. And the mRNA sector will eventually find itself here, just as every biotherapeutic sector before it has.
If there was one overarching takeaway I garnered from the mRNA Therapeutics Summit, it’s that we have a lot of work ahead of us to carve out what a competitive mRNA product and platform even is. This is an exciting place to be, and I have no doubt we will celebrate some significant triumphs in the future. But there are three critical realities (or perhaps difficult truths) I was reminded of during the mRNA Therapeutics Summit worth reiterating to keep us grounded through all our uninhibited dreaming.
- mRNA is not a commodity drug substance (a.k.a. it’s not “easy”)
I know some of you are saying no s%^$, ARW. But having traveled to five mRNA conferences in the past year and hosting my own panel discussions/private interviews, I think this bears repeating because we often talk about our development and understanding of mRNA (both the DS & DP) in a been-there-done-that manner. The incredible mRNA vaccine launches and mRNA’s cell free development process are no doubt big contributors to this mindset.
But I’d like to return to my favorite quote from the entire mRNA therapeutics conference: “There are many wrong ways to make mRNA. In fact, there are more wrong ways than right ways to make mRNA.” As this speaker went on to explain at depth, they’ve seen some very “interesting” plans for mRNA production throughout their tenure at a CDMO.
It’s a truth universally acknowledged that our upstream process dictates how heavy of a lift our downstream process. This is true for any biologic therapy — and though it’s technically a “cell-free” process, mRNA is no exception. We don’t have to look much farther than the currently diverse mRNA purification process to realize that such “creativity” downstream is reflective of unwanted upstream “creativity.” And remember, our current discussions are predominantly focused on linear mRNA, whereas our therapeutic desires are getting more complicated. We are also exploring the longer, more complex self-amplifying RNA (saRNA); circRNA; multicistronic mRNA (i.e., same RNA expressing multiple proteins); and multiplexed mRNA products (i.e., multiple mRNAs encoding different proteins).
As one speaker nicely laid out, there are nine (yes, 9) big reasons why mRNA has yet to become a commodity/wide-spread modality. In addition to the different “flavors” of mRNA, we are grappling with process development “creativity;” plasmid DNA and guide RNA sourcing/quality challenges; nonreproducible scientific literature; an unclear understanding of process-related impurities; and a lack of formulation know-how and capabilities. Following several other presentations throughout the two-day summit, I’d also add that we have a fuzzy if not poor understanding of our raw material quality/CQAs and an even murkier understanding of what fit-for-purpose means in the mRNA development paradigm.
We also cannot forget that we’re missing the corner pieces to our puzzle: RNA-centric regulatory guidance. The COVID pandemic provided us with two great case studies on what is possible in terms of regulatory flexibility and turn-around time in an emergency — the key word here, of course, being emergency. But two vaccine products do not an established therapeutics/vaccine industry make. Nor should we necessarily assume that the regulatory burdens of proof should or will be the same across mRNA modalities, use cases, and companies — especially in the upcoming years. Right now, we are an industry working within our own individual corporate “wonderlands.” As such, there has been little opportunity to gain insight into where our internal quality metrics fit into the big picture of the rest of the industry. Such knowledge will be essential for the mRNA space to become an established industry.
- The “Academy” is still out on whether our mRNA therapeutic products will be nominated as “the best actors” or the “best supporting actors”
One of the most intriguing non-CMC challenges we have facing us is figuring out what exactly an mRNA therapeutic is. There are a lot of ways to think about this question. But I find it particularly intriguing to think about our products’ eventual commercial identities (i.e., what mRNA can bring/offer within the overall biologics’ landscape). As it stands right now, we have little clarity around whether the bulk of our mRNA therapies will be, A., patients’ only therapeutic answer, and, in turn, a singular standard of care; B., a side-kick to another therapy in a combination; C. a long-term maintenance drug; or D., a “placeholder” drug that’s used until a patient reaches a specific milestone (i.e., age), at which point they transition to another therapy or surgical procedure.
Of course, the answers to these questions will likely be modality- and indication-dependent. But as several experts during the opening plenary discussions emphasized, one of the biggest challenges facing us as an industry is to arrive at a better understanding of mRNA’s unique value proposition within each indication. We are not trying to be a “biobetter,” offering marginally better clinical improvement over a therapeutic for a higher price. Nor is there any sense in replacing what other non-RNA modalities can and already are doing for patients.
I’d also argue determining the value proposition of our therapies is as much a regulatory as it is a commercial question. We already know that an mRNA therapeutic (not a prophylactic vaccine) is considered an ATMP by the EMA and a biological product/gene therapy by the FDA. But I was also struck by the FDA’s response to a question around why the mRNA vaccine and gene therapy classifications exist separately, especially given the similarities that currently (and I’d also emphasize seemingly) exist between both types of therapies from a CMC standpoint. Besides the fact it would be a PR nightmare to classify mRNA vaccines as gene therapies, the FDA’s Peter Marks also reemphasized the different clinical effects each type of therapy must achieve. While a vaccine is characterized by transient expression, a gene therapy must have durable clinical expression.
Seeing as we are currently grappling with clinical durability concerns for mRNA products in general, you’ll probably understand why Mark’s answer gave me pause — especially as we weigh what an mRNA therapeutic is and can mean for patients and their doctors in the long run. It’s still very early days for most of our products, and I’m a firm believer that durability improvements will be realized incrementally. But if our products’ identities from a regulatory standpoint hinges upon their clinical durability, we may have our work cut out for us as we attempt to position our products as competitive, innovative biologic therapies to patients, physicians and payers in our journey toward the market.
- Our definitions of “platform” are most likely different from the regulators’ definitions
Please note: This is a rich topic that deserves (and will receive) more ink from me in the upcoming weeks/months/years. But for the sake of brevity in this already long takeaway article, the regulatory discussions at this conference started adding much-needed meat to the bones of how we as an industry — including the regulators — are defining platform technologies.
For starters, U.S. legislation does recognize platform technologies, particularly within Sec. 506 [advanced platform technologies] of the U.S. Food & Drug Omnibus Reform Act. There is also FDA draft guidance forthcoming on platform technology. Likewise, the European Commission is establishing a regulatory framework to enable the industry’s reliance on platform technology. So far, its biggest steps have been to expand the master file concept to legally allow companies to leverage prior knowledge with a platform technology.
However, despite the prominence of the term “platform” in our discussions, we are still trying to find a concise way of defining what a platform means in the context of mRNA.
In the broader industry, we regularly hear the term “platform” used in relation to manufacturing technology. In fact, Marks himself acknowledged that a manufacturing technology could certainly be a platform if we can demonstrate that it fits within some yet-TBD “guiderails.” In the CMC space, we’ve traditionally talked about “platforms” within the context of “platform processes,” or sets of unit operations from USP to DSP through to drug product that ultimately result in a reproducible and high-quality product. (Broadly speaking, we ATMP-ers are still working toward this goal across all the modalities.)
Finally, in the mRNA space, we commonly refer to mRNA as a platform technology because we can rapidly swap out the gene of interest and continue on our merry way to a new product. (The ever-present need for optimization tends to be left out of this short-and-sweet definition.)
But what emerged throughout the discussion at the mRNA Therapeutics Summit was a much less tangible idea of what a “platform” or a platform approach could be for our industry. Rather than tying it to manufacturing technologies or processes and operations, industry members and regulators were keen to interpret platform in terms of how we can use our prior knowledge/data and apply it across multiple products.
It would seem regulators and industry are aligned around the importance of using prior preclinical, clinical and/or manufacturing knowledge to reduce the amount of data we need to generate for a new mRNA vaccine or gene therapy product. As one EMA regulator nicely summarized, the COVID-19 pandemic was a great example of how we could rely on nonclinical data from previous versions of the mRNA vaccines to accelerate the launch of newer versions. But as this regulator also continued, the discussion gets tricky, especially as companies make changes to their manufacturing processes or as minor but not-yet-well-understood differences come to exist within one platform.
Ultimately, as these regulatory discussions demonstrated, the biggest conversations — and perhaps debates — will be around how we define our platforms’ boundaries and in which situations we fall out of bounds of those platforms. It’s only when we have a clear understanding of these boundaries that we can determine which forms of prior knowledge can carry us forward and which forms cannot. (And, yes, this may ultimately be a product-by-product discussion, which arguably will add to the complexity of defining an mRNA platform, in particular.)