From "Barbieland" To ATW 2024: Evolving Beyond "Stereotypical" Advanced Therapies

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

Barbie had been on my watchlist since it hit theatres last summer. But it wasn’t until I finally boarded my connection to Miami to attend Phacilitate’s Advanced Therapies Week (ATW) that I found myself in the appropriate “hot pink” mindset to give it a try. Little did I know how much this movie would go on to influence my takeaways from the conference.

For those of you who haven’t seen the movie, it profiles “Stereotypical Barbie” on her journey from Barbieland to the real world and then back to Barbieland — the cumulative experiences of which trigger an existential crisis. By the end of the movie, she finds that her past as “Stereotypical Barbie” no longer seems to fit who she is and who she wants to be. As she explains quite beautifully towards the end of the movie: “I want to be a part of the people that make meaning, not the thing that’s made. I want to do the imagining; I don’t want to be the idea.”

It may seem strange to equate the ATMP space with the plight of “Stereotypical” Barbie. In fact, even I bristle at the thought there is any such thing as a “stereotypical” ATMP. After all, they are still too novel, too scientifically and technologically diverse, and too revolutionary for patient populations to be something we’ve dangerously oversimplified already. But like it or not, I’d argue in the past year (or few years), there have been some big oversimplifications that have emerged to color the space and peoples’ perceptions of its worth — their high price tags, access limitations, and logistical/scalability concerns being just a few. And don’t even get me started on mRNA’s unique reputation problems. 

What I was met with this year at ATW was an industry that knows its worth, but which is facing similar issues as Barbie around what its long-term identity can be and how it can transcend beyond being just a promising idea. In which areas should we standardize, and in which areas should we not? How much should we be striving to break “out of the [Barbie] box,” if you will, to successfully reach patients, and when should we just follow the leaders?

Last year, I walked away with a list of “Hot Takes” from ATW, all of which are still relevant today. But this time around, I’ve come up with a few snippets of “identity-chiseling” wisdom for the ATMP space. Though I’ve targeted a number of these takeaways specifically toward the (even more) nascent RNA therapeutics field, these concepts are applicable to any ATMP, regardless of modality.

Follow The Leaders — Or, Maybe, Don’t?

Last year, I argued that we are not built to be a standardized industry. After the conversation I listened to on the role of automation in cell therapy manufacturing kicking off the conference, I stand by that argument. The biological complexity of an ATMP product — and the fact that biology doesn’t always behave the way we want/need it to — leaves us all straddling the line between standardization and customization/innovation in establishing our manufacturing platforms. This is a difficult discussion to have in our current environment which is riddled with concerns about affordability, accessibility, reproducibility, and scalability of some of our products. In fact, in keeping with the notion of “dangerous stereotypes” impacting the ATMP industry today, such discussions could make us (or less informed industry observers) assume that “standardization” equates to arriving at one “silver bullet” solution. Likewise, in our complicated industry in which an ATMP product launch is a momentous occasion, it can be easy to assume that the market leaders not only have all the answers but that the path they paved to market is the only one we can take.

But as one ATW speaker reminded us, despite our desire for operational and technical simplicity, our manufacturing processes remain as diverse as our products and our patients’ diseases/biology. As he nicely put it, “We can innovate our way out of our manufacturing problems. But I don’t think that there is a solution; there are always solutions.”

On the one hand, the diverse ATMP space offers multiple “solutions” to these different challenges (auto vs. allo, ex vivo vs. in vivo, nonviral vs. viral). But on the manufacturing front, I appreciated one speaker’s encouragement to the industry to continue embracing the “intellectual inertia” to move beyond the examples market leaders have established thus far.

“It’s a safe haven to say that a process isn’t broken because Company X did it this way, got their BLA approved, and are successful,” he explained. “But broken is a relative term. If your goal is to improve clinical benefit for patients, you can’t be averse to taking novel approaches. Yes, trailblazers can get burned, but we need to keep innovating — albeit carefully and prudently — at some level. We can’t keep doing the same thing, even if it’s ‘kinda-sorta’ working.”

Obviously, we can safely apply this advice to the personalized manufacturing world where scalability and out-bound supply chains demand novel approaches and, yes, more standardization — namely on the logistics/clinical administration side of things. There also remains much room to grow in terms of producing more effective therapies, particularly in the solid tumor space, within which there’s currently little consistency in efficacy across products. But I also appreciated this advice for the RNA therapeutics space in particular which is striving to expand its worth and reputation beyond the double-edged sword of its success as a vaccine during the pandemic. This brings me to my next point —

Beyond “One & Done:” Consider Different Perspectives On Treatment Risk

One of the goals I set for myself as I boarded the plane for Miami was to see if I could start to apply some words to RNA’s unique value proposition within the broader ATMP space. We’ve heard (and continue to beat) the same drum many times: We’re not working with cells, so automatically we get to boast about manufacturing simplicity, turn-around-time, and cost of goods reduction (maybe). But I’ll admit, even I’ve been challenged to think about how our (most likely) chronically dosed RNA products will play within the current realm of advanced therapies — especially seeing as the ATMP industry was built upon the therapeutic promise of “one-and-done.”

Now, to be fair, the broader ATMP space is pursuing a variety of nonviral and in vivo approaches beyond RNA in the hopes of improving clinical efficacy and to enable redosing when necessary. In fact, there were a handful of presentations at ATW outlining the work being done with nonviral transfection, in vivo (lentiviral)-based cell therapies, and nanoparticle-based delivery of all kinds of cargo. But it wasn’t until listening to a presentation by an expert from Moderna that something clicked into place.

As I’ve written before, we’re still trying to determine if our RNA therapeutic (non-infectious disease) products will be “leading actors” or “supporting actors” — or, in keeping with this article’s theme, if they’ll be Barbie or one of Barbie’s sidekicks. It was in this latter “sidekick” category that the expert at Moderna sees mRNA’s greatest value proposition today — and as he went on to emphasize, this is not something to be ashamed of in this industry of one-and-done leading actors. In fact, he sees this being “the right time for mRNA” given some of the high-profile limitations facing current viral vector-based gene therapies (i.e., immunogenicity, redosing and oncogenicity concerns).

If there was one thing about the RNA modality that was confirmed (or reaffirmed) by attending ATW, it was that mRNA — at the very least — will be a necessary therapeutic alternative or sidekick to our traditional viral vector-based CGTs. In addition to discussions about mRNA’s use as a non-viral transfection method, a redosable cell therapy, a CAR-T booster, and an in vivo gene editing tool, I also began to see RNA therapeutics as an important means to expand access to patients. After all, though many of our one-and-done therapies may be miraculous for patient populations, they will not be for everyone. For example, some patients are already barred from receiving AAV gene therapies given immunogenicity to AAV capsids. But I also appreciated one speaker’s reminder that each patient will have their own appetites for risk in selecting therapies. I dare say you’d be hard-pressed to find a patient population — particularly in the rare disease realm — that would scoff at having multiple treatment options, be they viral vector-based or non-viral; “one-and-done” or chronic.

In fact, as one FDA representative shared, a wider availability of products for patients could ultimately help us as an industry continue to move the quality and efficacy needle forward for ATMPs in the long run.

“I’m hoping we find ourselves in a situation where there are so many treatments out there for rare disease that we’ll be in a position to step back and ask, ‘How do we make these treatments even better?’” they said.  

Is That “Kenough?” Embrace Method Diversity In Analytical Development

For those of you who did watch Barbie, you’ll know one of the biggest plot points of the movie was for the Barbies to unite and dismantle the patriarchy that “the Ken’s” erected while Stereotypical Barbie was stuck in the real-world. Despite my delight to see Barbieland return to its utopic matriarchy by the end of the film, it goes without saying that — in our real, therapeutics-developing world — a diversity of perspectives is necessary and something for which we’re always striving. Just as we wouldn’t wish to live in a strict patriarchal or matriarchal society, we wouldn’t expect a limited number of methods (“perspectives”) to be sufficient in helping us understand our molecules — especially when some of our products comprise multiple drug substances.

For a great example of this complexity, look no farther than Intellia's mRNA-based in vivo gene editing product. As one speaker shared, the company's lead gene editing candidate comprises two RNA products (a guide RNA and an mRNA encoding CAS-9), and an LNP comprising a novel lipid/excipient. In other words, this one single product comprises four module threes within one BLA filing. In the case of this one example, that’s 15-20 analytical methods for release per platform (i.e., platforms = sgRNA, mRNA, and LNP).

We don’t call our products advanced therapies for nothing.

To be fair, we’re no stranger to the importance of extensive analytical characterization (not just release assays) for developing our processes and working with regulators. We’re also more than aware of how much talent and money it takes to sufficiently characterize our products and processes. Given our ongoing financial climate, companies will no doubt continue to find themselves challenged to balance the costs of running multiple “for information only” characterization assays and releasing their product — especially as analytical characterization needs intensify through clinical development. (As one speaker offered, when in doubt, take samples for characterization later.)

But in addition to deepening our investment in analytical development as our products move later into the clinic, it’s also important to keep sensitivity and reproducibility of each method top of mind. For example, Intellia discovered that running an identical lot of gRNA through two separate chromatography methods — one well optimized, one less optimized — resulted in different purity readouts for the same substance (i.e., 88 percent for method 1 vs. 62 percent for method 2). In turn, by not overlooking Method A’s lower resolution and taking its higher purity read-out at face value, the company was able to go back to the process development team to improve gRNA quality and lower the risk of seeing undesirable clinical impacts in patients. 

The ultimate hope, as well, is that greater investment in the analytical paradigm will pay off in the future by enabling a company to platform their analytics as much as possible.

As one speaker shared, “Not only do we hope to leverage our manufacturing process for future highly similar products, but we also hope to leverage the analytical tools that we used to characterize the product, as well,” the speaker added. “The regulatory bodies’ feedback will inform the extent to which we need to characterize our products moving forward.”

Teamwork (With Regulators & Patients) Makes The World Go Round

Stereotypical Barbie couldn’t dismantle the patriarchy in Barbieland by herself. We also can’t be expected to bring our products to market without the help of regulators and our patient populations.

One of my biggest takeaways from the past year was how collaboration-forward the FDA has been. Throughout 2023, the FDA launched a number of initiatives, including the Collaboration on Gene Therapies Global (CoGEnT Global) Pilot Program, the Emerging Technology Program, and the Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program — to name just a few. But in addition to these efforts to accelerate development timelines and improve agency-industry communication, I was also struck by the lesser-proclaimed efforts the agency is implementing to improve cross-industry communication and — even more importantly — patient education.

For example, as the FDA’s Celia Witten explained, the Rare Disease Endpoint Advancement Pilot Program was launched to improve endpoint identification and provide more opportunities for industry-agency communication. But if you look even further into the details, education is a core tenant of this program.

“To enroll in this program, the sponsor has to agree to disclose certain information about their development program or their endpoints,” Witten added. “It’s a voluntary program, so it’s not a requirement that companies participate. But if a sponsor does want to participate, we urge them to look at the required disclosures because education of the FDA and the public at large is one of the main goals of this program.”

Likewise, Witten also called out its “widely attended” #RegenMedEd initiative: an educational workshop and webinar series for patients, caregivers, and patient advocacy organizations. Previous session topics include patient experiences in clinical trials and patient advocacy efforts in product development.

On the one hand, we can celebrate that this initiative is in place to address the unique challenges patients may face when striving to access ATMPs in the future (i.e., travel constraints; insurance networks & reimbursement; physician education, etc.) But given the mRNA industry’s unique reputation challenges, I was also excited by the potential role this program could play in future FDA mRNA education campaigns. If everything goes as we hope and RNA plays a meaningful therapeutic role in the rare disease space alongside traditional CGTs, it will behoove the FDA (and industry) to use its current tools/programs like #RegenMedEd — and perhaps some new initiatives — to expand the public’s knowledge about the role of mRNA in rare diseases. (Shout out to the newly launched Alliance for mRNA Medicines…an initiative for which to advocate in the future.)