From The Editor | June 20, 2024

A "Hot Take" on Personalized mRNA Medicines

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

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“Toto, I’ve a feeling we’re not in Kansas anymore.”

As I sat down to plot out my second “Hot Takes” article based on a BioPhorum ATMP member event this past spring, I couldn’t get this famous Wizard of Oz quote out of my head.

There are a lot of reasons why this statement beautifully applies to the advanced therapies space, regardless of modality. In the mRNA space alone, we can look at the light-speed approval of the mRNA COVID vaccines and the synthetic IVT manufacturing process as two clear signs we haven’t been in Kansas for a little while now. However, as I argued in a previous article, there’s an element of danger in assuming that, just because we’re working with a relatively novel modality and manufacturing paradigm, we are, by default, not in familiar territory anymore. This is particularly true in the arena of personalized medicine.

mRNA’s small-scale and cell-free production are often-touted benefits in the personalized medicines sphere — especially when considering the manufacturing, scalability, and commercialization challenges we’ve struggled with in the autologous cell therapy/gene therapy space. But as I reviewed my notes from the BioPhorum ATMP member event, I found myself coming face to face with a difficult truth: When it comes to personalized mRNA production, maybe we actually still are “in Kansas.”

Hot Take #2: New Modality/Promises… Same Old Problems

Having spent a few years in the CGT CMC space prior to taking over Advancing RNA, I became well acquainted with the challenges facing the autologous/ex vivo cell & gene therapy spaces — be they logistics-, cold chain-, manufacturing-, and/or quality-related. (And please, don’t forget the challenges so nicely laid out in this article about U.S. healthcare infrastructure limitations.)

As ATMP developers, we’ve been striving to overcome these challenges for years. But I’d argue it wasn’t until the approval of the world’s first ex-vivo CRISPR gene therapy that we became even more aware of how concerned the commercial market is about the feasibility of the autologous treatment model. There were a variety of concerns raised in the slew of surprisingly non-celebratory headlines about Casgevy’s approval, including the product’s pricing, potential side effects (i.e., patient infertility), and patient access concerns. But of all the articles published at the time, it was this one from Endpoints News that has stayed top-of-mind for me: “Excitement over sickle cell now shifts to long slog of delivering treatments, in pivotal year for bluebird gene therapy.”

As I emphasized in my previous article, mRNA offers us the opportunity to improve personalized therapy manufacturing timeframes, as well as to explore non-viral transduction approaches and to transform the ex vivo into the in vivo for cell therapies in the future. But until the in vivo becomes a clinically tested reality and our mRNA manufacturing timelines for personalized medicines improve, our cell-free manufacturing process hasn’t freed us from the trials and tribulations of global scale-out that the CGT space has been grappling with for years.

Perhaps the most notable hurdle we need to overcome initially is improving our turn-around time. (Yes, even “quick to produce” mRNA has a ways to go in terms of speed to patient…) Consider, for example, BioNTech and Genentech’s nine-week turn-around-time for their pancreatic cancer vaccine. (For reference, CAR-Ts are between 21-30 days, with Kite recently achieving a 14 to 16-day vein-to-vein time.) Of course, we’re still much younger than the cell therapy space, and Kite’s Yescarta certainly didn’t come to market with a two-week turn-around-time. But even as we decrease our turn-around times, our ability to (eventually) produce personalized mRNA products quickly has the potential to be a double-edged sword for us given the complexity (and time!) of scaling analytical development for personalized approaches.

For example, consider the indications we’re currently targeting with cancer vaccines; there are upwards of 450,000 new patients diagnosed per year with melanoma and 500,000 new patients diagnosed with pancreatic cancer per year. As one expert during the BioPhorum event outlined, tackling 2-3 percent of the pancreatic cancer population with a personalized cancer vaccine equates to roughly 10,000 patients per year or 10,000 unique RNAs — each of which requires their own analytics and release. And, since we’re talking about analytical development, we can take this a bit further; 10,000 patients actually translates into 20,000 batches for analytical folks, seeing as they have to account for both the drug substance and the drug product. I dare say I don’t need to explain why analytical scalability is a huge concern keeping mRNA experts up at night.

But our attention also needs to expand beyond the operational. Though COGS remains an evergreen concern across the entire CGT space, improving our COGS will be an important challenge we shouldn’t underestimate on the road to personalized mRNA medicines. This was solidified by some comments comparing cell culture development and mRNA development. As one expert with a background in cell culture explained, though we don’t have to deal with the variability of cell culture/patients’ cells, the current percentage of batch and time losses in mRNA production, as well as generally lower yields, all contribute to a “relatively shocking” COGS today.

This is why I will always emphasize the importance of keeping our eyes trained on the work that’s been done (and is being done) in the non-RNA autologous CGT worlds. I’m a firm believer that we in the RNA field can learn a lot from the experiences of the broader autologous CGT space. Likewise, there’s existing infrastructure and forums of ongoing conversation within which we shouldn’t be skittish about participating.

Yes, each modality will have its own intricacies, and each technology will have its strengths and weaknesses. But we need to start seeing the scalability and commercial challenges of the autologous/personalized medicines field as what they are: modality agnostic. They won’t be solved single-handedly by mRNA or cell-based products; they will be solved by the entire personalized medicines field in concert.


Continue on to the next installment featuring not one but TWO hot takes on mRNA delivery.