Blog | November 13, 2023

Peter Marks: An Early Preview of mRNA, Gene Therapy Platforms

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

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A few months ago, I attended the next-generation mRNA Therapeutics Summit. As I joked in an editorial of takeaways following the conference, the excitement over the different “flavors” of RNA and their potential was palpable — so much so, I felt a bit like Alice in an mRNA Wonderland.

But cool science aside, I was most excited by the fact that we were going to get to hear from the FDA’s Peter Marks. Though he has become a “household” name in the ATMP space over the past few years, I had not yet heard him focus his attention, expectations, and predictions on the burgeoning mRNA space beyond the scope of the pandemic. Of course, as was to be expected, half of his presentation was focused on our learnings from the pandemic and the overarching clinical and access limitations with mRNA we need to overcome. What I wasn’t expecting, however, was for him to pivot his discussion to a regularly used term that both glimmers with prestige but that has yet to be “well characterized,” if you will: the fabled “platform.”

Though Marks emphasized that this concept/designation at the regulatory level is still somewhat of a “we’ll-know-it-when-we-see-it” phenomenon, his remarks this summer — as well as a few additional discussions that have occurred throughout 2023 — add a bit more clarity to our understanding of what a gene therapy platform can be. Not only will it have implications for the technical and regulatory choices we make in the future, but such a regulatory designation (once it exists) has the real potential to help the ATMP space solve the glaring affordability and access challenges facing our mRNA and AAV gene therapies.

Oh, Where (And What) Art Thou, Efficiency?

In the gene therapy manufacturing world, “the platform” arguably remains an aspirational concept — at least for most of us. It will, at least someday, be synonymous with “efficiency” and “reproducibility.” But as we’re painfully aware today, our gene therapies (broadly speaking) are not affordable, nor are they accessible for COGS- and logistics/cold-chain-related reasons. Ergo, it makes sense we are currently striving to arrive at a streamlined — and reproducible — set of upstream/downstream & formulation unit operations, not only to improve development efficiency and reliability, but also to reduce our COGS.

In parallel to our discussions of manufacturing platforms and their eventual efficiencies, we also regularly emphasize the importance of “streamlining” the regulatory paradigm for our therapies. Like Goldilocks and the three bears, we’re trying to define what amount of information is “just right” to thoroughly demonstrate and document our process and product knowledge to regulators. In this light, “the platform” has implications beyond just streamlining our manufacturing and COGS; it also becomes a tool with which we can potentially carry certain data across “highly similar” products in our pipelines.

We’ve been referring to mRNA as a “platform technology” — or at least a highly platform-able technology — for several years now given our ability to quickly swap out the gene of interest. But it wasn’t until I heard Peter Marks broach this concept as it relates to AAV gene therapies at another conference in March that I started to see our fragmented discussions on this topic across the ATMP space coming together in a more concrete way.

“Gene therapy vectors give us an opportunity to do something we generally can’t do for a lot of other molecules,” he explained. “With vectors, in particular, there is a portion of the molecule —the vector backbone — which could be the same between several different products. It’s possible we could get to a place where, if we can characterize the manufacturing of our first and second [highly similar/backbone-sharing] products well, and the same manufacturing process is used for both molecules, we could potentially say we have a platform with which you could make certain modifications to future products without having to redo all the toxicology or CMC data. We could just focus in on the critical issues for each product.”

In our comparability-laden world, “linking” products together under a regulatory “platform designation” would be one way to bolster regulatory efficiency. As he went on to explain, biologics manufacturing processes often get “frozen in time” following approval because it’s challenging to update that process and file an sBLA documenting any changes.

However, “If you had ten linked products and you were to change something in the reference or the original product, it could cascade down and help keep manufacturing more up to date across multiple products,” he added.

Despite the fact it’s always interesting to hear how the FDA is thinking about our therapies, I dare say if Marks had stopped his discussion after describing these aspirational concepts, it would’ve been slightly too theoretical to be noteworthy. But luckily, he didn’t stop there. In case you missed the (not well-publicized) memo, a 4,000-page bill signed last December included a platform technologies provision under the Food & Drug Omnibus Reform Act of 2022/FDORA, which granted the FDA the ability to explore and designate platform technologies in the future. (For those interested, the article I linked to above specifies the still-broad legal criteria of what a platform must entail. Scroll down to the section on specific drug and biologic reforms.) In other words, we’re facing a future in which the “platform” will become a more concrete regulatory concept. 

How The FDA Is Approaching “The Platform” In The mRNA Space Today

To say that this platform designation is in its “earliest days” would be an understatement. In fact, during his presentation at the mRNA Therapeutics Summit in July, Marks admitted this designation remains more of a “we’ll know it when we see it” concept than one he can clearly put into words or guidance — at least not when pressed on the spot at a conference. But as I’ve emphasized before, two FDA-approved mRNA vaccine products does not translate into a mature industry, by any stretch, and we can see the lack of broader mRNA experience reflected in how the agency is approaching mRNA as a platform technology today.

As you can imagine, at this point, there are only specific — and, yes, limited — instances in which the agency is comfortable with product-specific modifications as it relates to mRNA vaccines. For example, “We know that, for the current vaccines, we’re comfortable with the strain changes, a couple amino acids, a few dozen base pairs,” he shared. But the agency is still likely to consider vaccines that engage a different part of the immune system, for example, “radically different.”

To be fair, comfort is based on experience — and Marks was the first to admit that we still “don’t know how far we can go.” It may be as short — or as long — as five years before the FDA considers mRNA vaccines a broader platform that will permit “more swapping” without asking for additional toxicity data or large-scale clinical trial data. Likewise, though we may be excited by the prospect of relying upon cross-target (e.g., COVID & RSV) platform data (i.e., biodistribution and clearance), Marks continued to emphasize we’re still trying to unpack what characteristics and/or side effects may be inherent in all mRNA vaccine products, and which are sequence-dependent. Though reactogenicity may be a common trait to all vaccines — mRNA and traditional vaccines alike — the jury remains out on whether side effects we encountered during the pandemic (i.e., myocarditis) are specific to the COVID viral pathogen or will be a risk across other mRNA vaccines. (How such a platform designation would be applied to mRNA therapeutics, on the other hand, was not discussed during this presentation, but should still tell us something about the nascence of both mRNA technology and its relation to the platform designation conceptually.)

Just as our therapies have a risk vs. benefit profile, every new industry must also weigh the risks and benefits of embracing too much efficiency too fast. As the AAV field knows all too well, a tragedy early on in a new therapeutic class can have detrimental effects on the growth trajectory of a nascent industry.

“We’re going to lean in — don’t get me wrong,” Marks said. “We will lean in. But we want to be careful that we do this in a measured way.”

I’ll acknowledge it’s easy to be cynical when it comes to the world of regulatory CMC —especially when we hear words like “measured.” Afterall, what we believe is “measured” may not exactly be what the agency defines as “measured. Aligning around what such terms even mean and where we as industry and regulators can efficiently meet in the middle will be one of the bigger challenges ahead.

But it bears emphasizing that a measured approach — though speed is of the essence for our patients — stands to benefit not just patient safety and the uninhibited growth of the mRNA space; it’s also essential to ensure that this platform designation in practice will be as revolutionary as it promises to be. The FDA may be the gatekeeper to the commercial market, but as we know, it is not within the FDA’s purview to weigh the overall costs of a therapy or dictate the specific manufacturing materials, technologies, or processes with which we choose to make them (all of which informs COGS).

That’s why, in my eyes, this forthcoming platform designation will serve as more than just a mechanism with which we can streamline manufacturing and expedite the regulatory review. It’s also a real, concrete way the FDA can do its part in promoting more long-term and equitable commercial opportunities for our ATMPs. If that’s not worth taking the time to “get right,” I don’t know what else is.